Professional Documents
Culture Documents
Material appearing in this workbook is adapted from matter originally published in the following chapters:
Coyle EA. Infectious diseases. In: Bainbridge JL, Barbour SY, Coyle EA et al. Updates in Therapeutics: The Ambulatory Care Pharmacy
Preparatory Review Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(2):43-82.
Dopp AL. Policy, practice, and regulatory issues. In: Dugan J, El-Ibiary S, Foote EF, et al. Updates in Therapeutics: The Pharmacotherapy
Preparatory Review and Recertification Course, 2012 ed. Lenexa, KS: American College of Clinical Pharmacy, 2012:275-94.
Foote EF. Nephrology. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review and
Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):449-80.
Harris IM. Ambulatory care. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory
Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2012(1):231-280.
Hemstreet BA. Gastrointestinal disorders. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy
Preparatory Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2012(1):69-144.
Irons BK. Endocrine and metabolic disorders. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy
Preparatory Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):229-68.
Mueller BA. Nephrology. In: Bainbridge JL, Barbour SY, Coyle EA et al. Updates in Therapeutics: The Ambulatory Care Pharmacy
Preparatory Review Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):43-70.
Page RL. Cardiology III. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review
and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(2):269-306.
Rodgers JE. Cardiology I. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review
and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(2):203-34.
Smith CL. Infectious diseases. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory
Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):365-406.
Sowinski KM. Biostatistics: a refresher. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy
Preparatory Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(1):143-62.
Sowinski KM. Clinical trials: fundamentals of design and interpretation. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in
Therapeutics: The Pharmacotherapy Preparatory Review and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy,
2011(1):163-86.
Wiggins BS. Cardiology II. In: Dugan, Jl, El-Ibirary, S., Foote, E.F., et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Review
and Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2011(2):235-68.
Copyright 2013 by American College of Clinical Pharmacy. No part of this publication may be reproduced, stored in a retrieval system,
or transmitted, in any for or by any means, electronic or mechanical, including photocopy, without prior written permission of the American
College of Clinical Pharmacy.
Nephrology .............................................................................................................................. 1
Endocrinology ......................................................................................................................29
Biostatistics ...........................................................................................................................56
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Program Goals
The Pharmacotherapy Review Program for Advanced Clinical Pharmacy Practice is designed to help
pharmacists who are preparing for the Board of Pharmacy Specialties certification examination in the
pharmacotherapy specialty as well as those seeking a general review and refresher on
pharmacotherapeutics and clinical skills.
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Faculty
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Program Agenda
March 20, 2013
Introduction and Welcome 9:00 a.m.9:30 a.m.
Nephrology 9:30 a.m.10:30 a.m.
Dr. Lau
Break 10:30 a.m.10:45 a.m.
Nephrology (cont.) 10:45 a.m.12:15 p.m.
Dr. Lau
Lunch 12:15 p.m.1:45 p.m.
How to Prepare for the Certification Examination 1:45 p.m.2:15 p.m.
Faculty Panel
Endocrinology 2:15 p.m. 3:15 p.m.
Dr. Stacy
Break 3:15 p.m.3:30 p.m.
Endocrinology (cont.) 3:30 p.m.5:30 p.m.
Dr. Stacy
March 21, 2013
Biostatistics and Clinical Trials 9:00 a.m.10:30 a.m.
Dr. DeYoung
Break 10:30 a.m.10:45 a.m.
Biostatistics and Clinical Trials 10:45 a.m.11:45 a.m.
Dr. DeYoung
Policy, Practice and Regulatory Issues 11:45 a.m. 12:15 p.m.
Dr. Lau
Lunch 12:15 p.m.1:45 p.m.
Infectious Diseases in the Ambulatory Care Setting 1:45 p.m.3:15 p.m.
Dr. DeYoung
Break 3:15 p.m.3:30 p.m.
Infectious Diseases in the Acute Care Setting 3:30 p.m.5:00 p.m.
Dr. Hemstreet
March 22, 2013
Gastroenterology 9:00 a.m.11:00 a.m.
Dr. Hemstreet
Lunch 11:00 a.m.1:00 p.m.
Cardiology 1:00 p.m.3:00 p.m.
Dr. Stacy
Break 3:00 p.m.3:15 p.m.
Cardiology (cont.) 3:15 p.m.4:15 p.m.
Dr. Stacy
Pulmonary Diseases 4:15 p.m.5:15 p.m.
Dr. Hemstreet
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NEPHROLOGY
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Learning Objectives:
1. Categorize acute kidney injury (AKI) as prerenal, intrinsic, or postrenal on the basis of patient his- tory,
physical examination, and laboratory values.
2. List risk factors for AKI and formulate strategies to decrease risk of AKI in specific patient populations.
3. Formulate a therapeutic plan to manage AKI.
4. Identify medications and medication classes associated with acute and chronic kidney damage.
5. Discuss factors that determine the efficiency of dialysis of drugs.
6. Identify the stage of chronic kidney disease (CKD) on the basis of patient history, physical exami- nation,
and laboratory values.
7. List risk factors for the progression of CKD and formulate strategies to slow the progression of CKD.
8. Describe the common complications of CKD.
9. Develop a care plan to manage the common complications observed in patients with CKD (e.g., anemia,
secondary hyperthyroidism).
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ACEI = angiotensin-converting enzyme inhibitor; AIN = acute interstitial nephritis; ATN = acute tubular necrosis; BPH = benign
prostatic hypertrophy; BUN = blood urea nitrogen; CHF = congestive heart failure; FENa = fractional excretion of sodium; GFR
= glomerular filtration rate; NSAID = nonsteroidal anti-inflammatory drug; SCr = serum creatinine; RBC = red blood cell
(count); W BC = white blood cell (count).
D. Prevention of AKI
1. Avoid nephrotoxic drugs when possible.
2. Ensure adequate hydration.
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3. Patient education
4. Drug therapies to decrease incidence of contrast-induced nephropathySee Drug
Nephrotoxicity section.
A. Introduction: Drugs are responsible for kidney damage through many mechanisms. Evaluate potential
drug-induced nephropathy on the basis of the period ingested, patient risk factors, and the propensity
of the suspected agent to cause kidney damage.
1. Risk factors
a. History of CKD
b. Increased age
2. Epidemiology
a. 7% of all drug toxicities
b. 18%27% of AKI in hospitals
c. 1%5% of NSAID users in community
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ii. Subject to all the standards for medication management in a health system
g. Nephrogenic systemic fibrosis also known as nephrogenic fibrosing dermopathy
i. Rare. Associated with gadolinium-based agents used in high doses for magnetic
resonance angiogram
ii. Occurs in patients with moderate CKD to ESRD given contrast. Systemic acidosis seems
to be a risk factor. Magnevist, Omniscan, and OptiMARK considered inappropriate for
use in patients with AKI or CKD
iii. Onset 218 days after exposure
iv. Presents as burning, itching, swelling/hardening/tightening of skin, skin patches, spots on
eyes, joint stiffness, and muscle weakness
v. Can cause organ damage. Deaths have occurred.
vi. In 2010, the U.S. Food and Drug Administration (FDA) required an added warning
to prescribing information.
4. Cisplatin and carboplatin nephrotoxicity
a. Incidence: 6%13% with appropriate dosing and administration
b. Pathogenesis Complex. Direct tubular toxin
c. Presentation
i. SCr peaks 1012 days after starting therapy but may continue to rise with subsequent
cycles of therapy.
ii. Renal Mg wasting is common (may be severe with central nervous system symptoms)
and may be accompanied by hypokalemia and hypocalcemia.
iii. May result in irreversible kidney damage
d. Risk factors for toxicity: Many courses of cisplatin, patient age, dehydration, concurrent
nephrotoxins, kidney irradiation, alcohol abuse
e. Prevention
i. Avoid concurrent use of nephrotoxins.
ii. Use smallest dose possible, and decrease frequency of administration.
iii. Aggressive intravenous hydration: 14 L within 24 hours of high-dose cisplatin or
carboplatin
iv. Amifostine: Cisplatin-chelating agent. Should be considered in patients at risk of
nephrotoxicity
5. Amphotericin B nephrotoxicity
a. Incidence
i. Increases as cumulative dose increases
ii. Approaches 80% with cumulative doses of 4 g or more
b. Pathogenesis
i. Direct proximal and distal tubular toxicity
ii. Arterial vasoconstriction
c. Presentation
i. Manifests after 23 g
ii. Loss of tubular function leads to electrolyte wasting (especially K+, Na+, and Mg2+)
and distal tubular acidosis.
iii. Patients may require substantial K+ and Mg2+ replacement.
iv. SCr increases and GFR decreases because of a decrease in kidney bloodflow from
vasoconstriction caused by amphotericin.
d. Risk factors for toxicity: Existing kidney dysfunction, high average daily doses, diuretic use,
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i.
Use therapies other than NSAIDs when appropriate (e.g., acetaminophen for
osteoarthritis).
ii. Sulindac is a potent NSAID that may affect prostaglandin synthesis in the kidney to a
lesser extent than other NSAIDs.
iii. Question the utility of COX-2specific inhibitors. They have not been found to prevent
kidney dysfunction, and they increase cardiovascular complications.
f. If NSAID-induced AKI is suspected, discontinue drug and give supportive care.
Recovery is usually rapid.
4. Cyclosporine and tacrolimus
a. Incidence
i. The 5-year risk of developing CKD after transplantation of a nonrenal organ ranges from
7% to 21%.
ii. The occurrence of kidney failure in the transplant patient population has a 4-fold
increased risk of death.
b. Pathogenesis
i. Results from a dose-related hemodynamic mechanism
ii. Causes vasoconstriction of afferent arterioles through possible increased activity of
various vasoconstrictors (thromboxane A2, endothelin, sympathetic nervous system) or
decreased activity of vasodilators (nitric oxide, prostacyclin)
iii. Increased vasoconstriction from angiotensin II may also contribute.
iv. Effects usually resolve with dose reduction.
c. Presentation
i. Can occur within days of starting therapy
ii. SCr rises and GFR decreases.
iii. Patients often have hypertension, hyperkalemia, and hypomagnesemia.
iv. A biopsy is often needed for kidney transplant patients to distinguish this from acute
allograft rejection.
d. Risk factors for toxicity: Increased age, high initial cyclosporine dose, kidney graft rejection,
hypotension, infection, and concomitant nephrotoxins
e. Prevention
i. Monitor serum cyclosporine and tacrolimus concentrations closely.
ii. Use lower doses in combination with other nonnephrotoxic immunosuppressants.
iii. Calcium channel blockers may help antagonize the vasoconstrictor effects of cyclosporine
by dilating afferent arterioles.
D. Tubulointerstitial Disease
1. Involves the renal tubules and the surrounding interstitium
2. Onset can be acute or chronic.
a. Acute onset generally involves interstitial inflammatory cell infiltrates, rapid loss of kidney
function, and systemic symptoms (i.e., fever and rash).
b. Chronic onset shows interstitial fibrosis, slow decline in kidney function, and no systemic
symptoms.
3. Acute allergic interstitial nephritis
a. Cause of up to 3% of all cases of AKI. Results from an allergic hypersensitivity reaction that
affects the interstitium of the kidney
b. Many medications and medication classes can cause this type of kidney failure. The most
commonly implicated are the -lactams and the NSAIDs (although the presentations are
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different).
i. Penicillins: Classic presentation of acute allergic interstitial nephritis. Signs/symptoms
occur about 12 weeks after therapy initiation and include fever, maculopapular rash,
eosinophilia, pyuria, hematuria, and proteinuria. Eosinophiluria may also be present.
ii. NSAIDs: Onset much more delayed, typically begins about 6 months into therapy.
Usually occurs in elderly patients on chronic NSAID therapy. Patients usually do not have
systemic symptoms.
c. Kidney biopsy may be needed to confirm diagnosis.
d. Treatment includes discontinuing the offending agent and possibly initiating steroid therapy.
4. Chronic interstitial nephritis
a. Often progressive and irreversible
b. Lithium
i. Toxicity results from a dose-related decrease in response to an antidiuretic hormone.
ii. AKI from lithium usually occurs during acute lithium intoxication.
Patients become dehydrated secondary to nephrogenic diabetes insipidus. There is also
direct damage to the proximal and distal tubules.
iii. Risks include elevated serum concentrations and repeated episodes of AKI from
lithium toxicity.
iv. Prevention is accomplished by maintaining the lowest serum lithium concentrations
possible, avoiding dehydration, and monitoring kidney function closely.
c. Cyclosporine: Presents later in therapy (about 612 months) than hemodynamically mediated
toxicity
5. Papillary necrosis
a. Form of chronic interstitial nephritis affecting the papillae, causing necrosis of the collecting
ducts
b. Results from the long-term use of analgesics
i. Classic example was with products that contained phenacetin.
ii. Occurs more often with combination products
iii. Products containing caffeine may also pose an increased risk.
c. Evolves slowly as time progresses
d. Affects women more often than men
e. Difficult to diagnose, and much controversy remains regarding risk, prevention, and cause
E. Obstructive Nephropathy
1. Results from obstruction of the flow of urine after glomerular filtration
2. Renal tubular obstruction
a. Caused by intratubular precipitation of tissue degradation products or precipitation of drugs or
their metabolites
i. Tissue degradation products
(a) Uric acid intratubular precipitation after tumor lysis after chemotherapy
(b) Drug-induced rhabdomyolysis leading to intratubular precipitation of myoglobin
(c) Results in rapid decline in kidney function, with resultant oliguric or anuric kidney
failure
ii. Drug precipitation: Sulfonamides, methotrexate, acyclovir, ascorbic acid; can be
diagnosed by observing needlelike crystals in leukocytes found on urinalysis
b. Prevention includes pretreatment hydration, maintenance of high urinary volume, and
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F. Glomerular Disease
1. Proteinuria is the hallmark sign of glomerular disease and may occur with or without a decrease in
GFR.
2. A few distinct drugs can cause glomerular disease.
a. NSAIDs: Associated with acute allergic interstitial nephritis
b. Heroin: Can be caused by direct toxicity, toxicity from additives, or infection from injection.
End-stage renal disease develops in most cases.
c. Parenteral gold: Results from immune complex formation along glomerular capillary loops
A. Background
1. Prevalence: Difficult to assess, according to NHANES (19992004); 16.8% of adults (20 years or
older) have CKD. There were 382,343 prevalent dialysis patients in 2008 (up 3.6% from 2007)
and 165,639 prevalent transplant patients. Incidence rate is relatively flat, so growth in population
of ESRD is mainly because of the longer life span of these patients.
2. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) Advisory
Board recommends a definition of CKD and staging guidelines.
a. Definition
i. Kidney damage for more than 3 months, as defined by structural or functional
abnormality of the kidney, with or without decreased GFR, manifested by either
pathologic abnormalities or markers of kidney damage, including abnormalities in the
composition of blood or urine or abnormalities in imaging tests
ii. GFR less than 60 mL/minute/1.73m2 for 3 months, with or without kidney damage
b. Stages of CKD
i. Stage 1 kidney damage with normal or increased GFR (90 mL/minute/1.73m2 or more)
ii. Stage 2 kidney damage with mild decrease in GFR (6089 mL/minute/1.73m2)
iii. Stage 3 moderate decrease in GFR (3059 mL/minute/1.73m2)
iv. Stage 4 severe decrease in GFR (1529 mL/minute/1.73m2)
v. Stage 5 kidney failure (less than 15 mL/minute/1.73m2 or on dialysis
B. Etiology
1. Diabetes (40% of new ESRD cases in the United States)
2. Hypertension (25% of new cases)
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3. Glomerulonephritis (10%)
4. OthersUrinary tract disease, polycystic kidney disease, lupus, analgesic nephropathy, unknown
C. Risk Factors
1. Susceptibility (associated with an increased risk, but not proved to cause CKD): Advanced age,
reduced kidney mass, low birth weight, racial/ethnic minority, family history, low income or
education, systemic inflammation, and dyslipidemia. Mostly not modifiable
2. Initiation (directly cause CKD): Diabetes, hypertension, autoimmune disease, polycystic kidney
diseases, and drug toxicity. Modifiable by drug therapy
3. Progression (result in faster decline in kidney function): Hyperglycemia, elevated BP, proteinuria,
and smoking
D. Albuminuria/Proteinuria
1. Marker of kidney damage, progression factor, and cardiovascular risk factor. Can be classified as
follows
a. Normal: Albumin excretion less than 30 mg/24 hours
b. Microalbuminuria: 30300 mg/24 hours
c. Macroalbuminuria: (overt proteinuria) more than 300 mg/24 hours. Nephrotic range
proteinuria: More than 3 g/24 hours
2. Assessment for proteinuriaUsually assessed by measurement of urinary albumin-to-creatinine
ratio. Spot urine: Untimed sample is adequate for adults and children (screening test).
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than 60 mL/minute/1.73m2
7. For children, Schwartz and Counahan-Barratt formulas
F. Diabetic Nephropathy
1. Pathogenesis
a. Hypertension (systemic and intraglomerular)
b. Glycosylation of glomerular proteins
c. Genetic links
2. Diagnosis
a. Long history of diabetes
b. Proteinuria
c. Retinopathy (suggests microvascular disease)
3. Monitoring
a. Type IBegin annual monitoring for microalbuminuria 5 years after diagnosis.
b. Type IIBegin annual monitoring for proteinuria immediately (do not know how long they
have had diabetes mellitus).
4. Management/slowing progression
a. Aggressive BP management
i. In patients with diabetes and CKD, target BP is less than 130/80 mm Hg.
ii. ACEIs and ARBs are preferred and should be used with any degree of proteinuria, even if
the patient is not hypertensive. Use moderate to high doses with proteinuria. Hold ACE/
ARB if K is greater than 5.6 or there is a rise in SCr greater than 30% after initiation.
iii. Most patients will require diuretic in combination. (Thiazide with stages 13 and loop in
stages 45.) If BP is greater than 160/100 mm Hg, start with two-drug regimen.
iv. Calcium channel blockers (nondihydropyridine) are second line to ACEIs/ARBs. Data are
emerging for combined therapy.
v. Dietary sodium less than 2.4 g/day. Modify DASH to limit K.
b. Intensive blood glucose control. Glycosylated hemoglobin less than 7%. Less aggressive with
more advanced CKD
c. Protein restrictionThere are insufficient data in diabetes, but 0.8 g/kg day might slightly
reduce progression and decrease risk of ESRD. Patients should avoid high-protein diets.
G. Nondiabetic Nephropathy
1. Manage hypertension. If proteinuric and hypertensive, use ACE and ARB. Often need to add (or
start with) combination. Diuretic is usual second drug.
2. Minimize protein in diet. Controversial. May slow progression on the basis of MDRD study but
may also impair nutrition. Very low-protein diet may increase mortality.
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E. Peritoneal Dialysis
1. Peritoneal dialysis membrane is 12 m2 (approximates the body surface area) and consists of the
vascular wall, the interstitium, the mesothelium, and the adjacent fluid films. From 1.5 to 3 L of
peritoneal dialysate fluid may be instilled in the peritoneum (fill), allowed to dwell for a specified
time, and then drained.
2. Solutes and fluid diffuse across the peritoneal membrane.
3. Peritoneal dialysis is usually not used to treat AKI in adults.
4. Peritonitis
a. Infection of the peritoneal cavity. Patient technique and population variables influence the
infection rate. Elderly patients or those with diabetes have a higher infection rate. Peritonitis
is a major cause of failure of peritoneal dialysis.
b. Treatment
i. Most common gram-positive organisms include Staphylococcus epidermis, S. aureus,
and streptococci. Most common gram-negative organisms include Escherichia coli and
Pseudomonas aeruginosa.
ii. Empiric treatment should cover gram-positive and gram-negative bacteria. Adjust as
needed.
5. Types of peritoneal dialysis
a. Continuous ambulatory peritoneal dialysis. Classic. Requires mechanical process, which
requires many manual changes throughout the day. Can be interruptive to daytime routine
b. Automated peritoneal dialysis. Many variants exist, but continuous cycling peritoneal dialysis
is the most common. Patient undergoes many exchanges during sleep by a cycling machine.
May have one or two dwells during day. Minimizes potential contamination. Lowest
incidence of peritonitis
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V. COMPLICATIONS OF CKD
A. Anemia
1. Several factors are responsible for anemia in CKD: Decreased erythropoietin production (most
important), shorter life span of red blood cells (RBCs), blood loss during dialysis, iron deficiency,
anemia of chronic disease, and renal osteodystrophy
2. Prevalence: 26% of patients with a GFR greater than 60 mL/minute have anemia versus 75%
of patients with a GFR less than 15 mL/minute.
3. Signs and symptoms. Symptoms of anemia of CKD are similar to anemia associated with other
causes.
4. TreatmentTreatment of anemia in CKD can decrease morbidity/mortality, reduce left
ventricular hypertrophy, increase exercise tolerance, and increase quality of life. Recent studies
have suggested that treatment to high hemoglobin concentrations (greater than 13 g/dL) increases
cardiovascular events. Most recently, TREAT (Trial to Reduce Cardiovascular Events with
Aranesp Therapy) failed to show a benefit in outcomes but was associated with increased stroke
(N Engl J Med 2009;361).
a. Anemia workupInitiate evaluation when CrCl is less than 60 mL/minute or hemoglobin is
less than 10 g/dL.
i. Hemoglobin/hematocrit
ii. Mean corpuscular volume
iii. Reticulocyte count
iv. Iron studies
(a) Transferrin saturation (total iron/total iron-binding capacity)Assesses available iron
(b) FerritinMeasures stored iron
v. Stool guaiac
b. Erythropoiesis-stimulating agents (ESAs). Note: ESAs are now under the FDAs Risk
Evaluation and Mitigation Strategy program.
i. Epoetin-
(a) Same molecular structure as human erythropoietin (recombinant DNA technology)
(b) Binds to and activates erythropoietin receptor
(c) Administered subcutaneously or intravenously
ii. Darbepoetin-
(a) Molecular structure of human erythropoietin has been modified from 3 N-linked
carbohydrate chains to 5 N-linked carbohydrate chains; increased duration of activity.
The advantage is less-frequent dosing.
(b) Binds to and activates erythropoietin receptor
(c) May be administered subcutaneously or intravenously. Initial dose 0.45 mcg/kg/week;
typically 40 mcg
c. Goal hemoglobin. Because of concern about high hemoglobin concentrations, the 2007 update
to the KDOQI guidelines suggests a goal of 1112 g/dL and the avoidance of a hemoglobin
concentration greater than 13 g/dL. Since June 2011, the FDA-approved product prescribing
information has recommended using the lowest dose sufficient to reduce the need for red
blood cell transfusions. The product label further states that in controlled trials with CKD
patients, patients experienced greater risks for death, serious adverse cardiovascular reactions,
and stroke when administered ESAs to target a hgb level of > 11 g/dL. More recently, the
KDIGO guidelines recommend that for CKD ND (non-dialysis) patients, ESA therapy not be
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initiated with Hb concentration 10 g/dL. With Hb Concentration <10 g/dL, decision to start
ESA should be individualized based on the rate of Hb concentration, prior response to iron
therapy, risk of needing a transfusion, the risks related to ESA therapy and the presence of
symptoms attributable to anemia. For CKD 5D (dialysis) patients, ESA therapy should be
started when the Hb is between 9 and 10 g/dL. Individualization of therapy is reasonable for
improvement of quality of life in some patients with Hb >10 g/dL.
d. ESA dose adjustment is based on hemoglobin response.
i. Adjustment parameters are the same for epoetin- and darbepoetin-.
ii. Dosage adjustments upward should not be made more often than every 4 weeks. In
general, dose adjustments are made in 25% intervals.
e. ESA monitoring
i. Hemoglobin concentrations initially every 12 weeks and then every 24 weeks when
stable
ii. Monitor BP because it may rise (treat as necessary).
iii. Iron stores
(a) Ferritin: HD target is 200500, and peritoneal dialysis/CKD target is 100500.
(b) Transferrin saturation target is greater than 20% (upper limit of 50% removed
from recent guidelines).
f. Common causes of inadequate response to ESA therapy:
i. Iron deficiency is the most common cause of erythropoietin resistance. Increased use of
intravenous iron products has reduced this problem, however.
ii. Infection and inflammation
iii. Other causes include chronic blood loss, renal bone disease, aluminum toxicity, folate or
vitamin B12 deficiency, malignancies, malnutrition, hemolysis, and vitamin C deficiency.
g. Iron therapy
i. Most patients with CKD who are receiving erythropoietic therapy require parenteral iron
therapy to meet needs (increased requirements, decreased oral absorption).
ii. For CKD patients not on iron or ESA therapy, KDIGO guidelines recommend a trial of
IV iron (or in CKD ND patients, alternatively, a 1-3 month trial of oral iron therapy) if an
increase of Hb without starting ESA is desired and when the TSAT is 30% and ferritin is
500 ng/mL.(guideline 2.1.2)
iii. For CKD patients on ESA therapy, KDIGO guidelines recommend a trial of IV iron (or in
CKD ND patients, alternatively, a 1-3 month trial of oral iron therapy) if an increase of
Hb or reduction in ESA dose is desired and when the TSAT is 30% and ferritin is 500
ng/mL. (guideline 2.1.3)
iv. Follow transferrin saturation and ferritin as noted during erythropoietic therapy.
v. Four commercial iron preparations are approved in the United States (Table 2).
vi. IV iron therapy is more effective in CKD 5 patients (both HD and PD). Oral iron
therefore not recommended for these patients. For CKD ND patients, the advantage of IV
over oral therapy is rather small. The route of iron administration can therefore be IV or
oral.
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CKD = chronic kidney disease; HD = hemodialysis; IV = intravenous; IV P = IV push; IV PB = IV piggyback; N/A = not
applicable; NSS = normal saline solution; TSAT = transferrin saturation.
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4. Treatment
a. Therapy goalsTable 3
Table 3. KDOQI Guidelines for Calcium, Phosphorus, Ca x PO4 Product, and PTH in CKD Stages 35
CKD Stage 3 CKD Stage 4 CKD Stage 5
Calcium (mg/dL) a
Normal Normal 8.49.5
Phosphorus (mg/dL) 2.74.6 2.74.6 3.55.5
Ca PO4 product < 55 < 55 < 55
PTH (pg/mL) 3570 70110 150300
a
Use corrected calcium = serum calcium + (0.8 [4.0 patient albumin]).
CKD = chronic kidney disease; KDOQI = Kidney Disease Outcomes Quality Initiative; PO4 = phosphate; PTH = parathyroid
hormone.
b. Nondrug therapy
i. Dietary phosphorus restriction 8001200 mg/day in stage 3 CKD or higher
ii. Dialysis removes various amounts of phosphorus depending on treatment modalities but,
by itself, is insufficient to maintain phosphorus balances in most patients.
iii. Parathyroidectomy. Reserved for patients with unresponsive hyperparathyroidism
c. Drug therapy
i. Phosphate binders: Take with meals to bind phosphorus in the gut; products from
different groups may be used together for additive effect.
(a) Aluminum-containing phosphate binders (aluminum hydroxide, aluminum carbonate,
and sucralfate). Effectively lowers phosphorus concentrations. In general, avoid. Not
used as often because of aluminum toxicity (adynamic bone disease, encephalopathy,
and erythropoietin resistance)
(b) Calcium-containing phosphate binders (calcium carbonate and calcium acetate)
(1) Widely used phosphate binder. Calcium binders are initial binder of choice
for stage 3 and 4 CKD. Calcium (or nonionic binders) is considered initial binder
of choice in stage 5 CKD. Carbonate salt is relatively inexpensive.
(2) Carbonate is also used to treat hypocalcemia, which sometimes occurs in patients
with CKD, and can decrease metabolic acidosis.
(3) Calcium acetate: 667-mg capsule contains 167 mg of elemental calcium.
Better binder than carbonate, so less calcium given
(4) Use may be limited by development of hypercalcemia.
(5) Total elemental calcium is 2000 mg/day (1500-mg binder; 500-mg diet).
(c) Sevelamer: A nonabsorbable phosphate binder
(1) Effectively binds phosphorus
(2) As with calcium, considered primary therapy in CKD stage 5. In particular,
consider if calcium x phosphorus product is greater than 55 mg2/dL2 or if
calcium intake exceeds recommended dose with calcium-containing binders.
(3) Decreases low-density lipoprotein cholesterol and increases high-density
lipoprotein cholesterol
(4) Hypocalcemia may occur if sevelamer is sole phosphate binder. Metabolic
acidosis may worsen with sevelamer HCl.
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antidepressants, thioridazine).
(g) Cinacalcet is primarily metabolized by CYP3A, so drugs that are potent inhibitors of
CYP3A (ketoconazole) may increase cinacalcet concentrations up to 2-fold
B. GFR is the most important aspect of kidney function with respect to adjustment of drug dosing, and it
cannot be measured easily by direct measures.
C. Creatinine
1. Creatinine is a product of creatine metabolism from the muscle.
2. Production is dependent on muscle mass.
3. Creatinine is freely filtered and not reabsorbed.
a. A small quantity of creatinine is secreted (about 10%) in healthy adults.
b. Secretion is maintained even at lower GFRs; consequently, creatinine secretion
accounts for a larger percentage of creatinine in urine at lower GFRs (which leads to an
overestimation of GFR).
4. Several factors affect creatinine.
a. Age Less muscle tissue as we age; hence, less creatinine produced. A little old lady with
an SCr of 0.2 mg/dL does NOT have great renal function; rather, she has little muscle mass.
b. Body mass Controversy is related to this aspect. Increased muscularity means more
creatinine, but fat does not produce creatinine.
i. Obese individuals often have a little more muscle to haul around their extra fat.
ii. Nonetheless, most CrCl estimates use IBW (see Cockcroft-Gault below).
iii. Special equations have been developed for special populations (e.g., obese individuals,
paraplegics, children [because of their differing muscle masses]).
c. Sex Men typically have more muscle mass than do women.
d. Diets high in meats Creatinine from ingested muscle can appear in the urine.
e. Drugs affecting creatinine secretion (e.g., cimetidine, trimethoprim, probenecid) will raise SCr
values, resulting in falsely low estimates of CrCl when only SCr is used in the calculation.
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c. CKD-EPI equation (Ann Intern Med 2009;150:60412) The CKD-EPI equation, expressed as
a single equation, is:
GFR = 141 min(SCr/,1) max(SCr/,1)-1.209 0.993Age 1.018 [if female] 1.159 [if
African American]
where SCr is serum creatinine (mg/dL), is 0.7 for females and 0.9 for males, is 0.329 for
females and 0.411 for males, min indicates the minimum of SCr/ or 1, and max indicates
the maximum of SCr/ or 1.
For men:
For women:
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*k = is dependent on
CrCl = (k* Ht (cm)) Infant (low birth weight less than 1 year), k = 0.33
SCr (mg/dL) Infant (term less than 1 year), k = 0.45
Child or adolescent girl, k = 0.55
Adolescent boy, k = 0.70
2. Most drug doses have been designed using the Cockcroft-Gault equation, even though this method
is likely less accurate than the MDRD equation, creating confusion regarding which method to
use clinically (Dowling TC, et al. Evaluation of renal drug dosing: prescribing information and
clinical pharmacist approaches. Pharmacotherapy 2010;30:77686).
A. Dosages of many drugs will require adjustment to prevent toxicity in patients with CKD; adjustment
strategies will vary, depending on whether the patient is receiving RRT and, if so, the type of RRT.
The National Kidney Disease Education Program of the National Institutes of Health/National
Institute of Diabetes and Digestive and Kidney Diseases suggests that either eGFR or eCrCl be used
for drug dosing. If using eGFR in very large or small patients, the eGFR should be multiplied by the
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C. Pharmacodynamic Changes Can Also Occur (e.g., patients with CKD can be more sensitive to
benzodiazepines).
D. General Recommendations:
1. Patient history and clinical data
2. Estimate CrCl ( Jeliffe or Brater in AKI; Cockcroft-Gault or MDRD study equations in stable
kidney function).
3. Identify medications that require modification (Table 4).
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E. Drug Dosing in HD
1. Dosing changes in HD patients may be necessary because of accumulation caused by kidney
failure AND/OR because the procedure may remove the drug from the circulation.
2. Drug-related factors affecting drug removal during dialysis:
a. Molecular weightWith high-flux membranes, larger molecules (such as vancomycin)
can be removed.
b. Water solubleNon-soluble drugs not likely removed
c. Protein bindingBecause albumin cannot pass through membranes, protein-bound drugs
cannot either.
d. Volume of distributionDrugs with a small Vd (less than 1 L/kg) available in central
circulation for removal. Drugs with large Vd cannot be removed (digoxin and tricyclic
antidepressants), even if the protein binding is very low.
3. Procedure-related factors affecting drug removal
a. Type of dialyzerHigh flux widely used now
b. Bloodflow rate. Increased rates will increase delivery and maintain gradient across membrane.
c. Duration of dialysis session
d. Dialysate flow rate. High rates of flow will increase removal by maintaining the gradient
across membranes
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REFERENCES
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ENDOCRINOLOGY
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Learning Objectives:
1. Differentiate between the diagnostic and classification criteria for various metabolic and endocrine
disorders including type 1 and 2 diabetes mellitus, disorders of the thyroid gland, and syndrome of
inappropriate antidiuretic hormone secretion.
2. Compare and contrast the various therapeutic agents used in treating endocrine and metabolic disor-
ders.
3. Select appropriate treatment and monitoring options for a given patient presenting with one of the
above disorders.
4. Recommend appropriate therapeutic management for secondary complications from diabetes or thy-
roid disorders.
I. DIABETES MELLITUS
A. Consensus Recommendations
1. American Diabetes Association. Updated yearly in the January supplement of Diabetes Care
(www.diabetes.org)
2. American College of Endocrinology/American Association of Clinical Endocrinologists
(ACE/AACE)
3. Canadian Diabetes Association
4. Various European groups
5. For the remainder of this section, unless otherwise noted, we will follow the American
Diabetes Association recommendations.
B. Classification
1. Type 1 diabetes mellitus (DM)
a. Attributable to cellular-mediated -cell destruction leading to insulin deficiency (insulin
required for survival)
b. Accounts for 5%10% of DM
c. Formerly known as insulin-dependent diabetes, juvenile-onset diabetes
d. Prevalence in the United States: 0.12%, 340,000 in the United States
e. Usually presents in childhood or early adulthood but can present in any stage of life
f. Usually symptomatic with a rapid onset in childhood but can be slower in older adults
2. Type 2 DM
a. Result of insulin resistance with subsequent defect in insulin secretion
b. Accounts for 90%95% of DM
c. Formerly known as noninsulin-dependent diabetes, adult-onset diabetes
d. Prevalence in the United States: 7.8%, 23.6 million (and growing!)
e. Often relatively asymptomatic with a slow onset. Cause for improved screening (below)
and assessment for complications at diagnosis
f. Disturbing trends in type 2 DM in children and adolescents attributable to increase in
obesity
3. MODY (maturity-onset diabetes of the young)
a. Result of genetic disorder leading to impaired secretion of insulin with little or no
impairment in insulin action
b. Onset usually before age 25 and may mimic either type 1 or 2 DM
4. Gestational diabetes
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C. Screening for DM
1. Type 1 DM
a. Symptomatic patients
b. Asymptomatic patients at higher risk
i. History of transient hyperglycemia or relatives with type 1 DM
ii. Measure islet autoantibodies to assess for risk of type 1 DM.
2. Type 2 DM
a. Age 45 or older, repeat every 3 years if normal
b. Younger age if body mass index (BMI) of 25 kg/m2 or greater and one of the following
risk factors:
i. History of cardiovascular disease
ii. Impaired glucose tolerance or impaired fasting glucose
iii. History of PCOS (polycystic ovary syndrome)
iv. High-density lipoprotein cholesterol (HDL-C) less than 35 mg/dL and/or
triglycerides (TG) greater than 250 mg/dL
v. Hypertension
vi. Women with a diagnosis of gestational diabetes or women who delivered a baby
weighing more than 4.1 kg (9 lb)
vii. High-risk ethnicity: African American, Latino, Native American, Asian American,
Pacific Islander
viii. First-degree relative with DM
ix. Physical inactivity
3. Gestational DM
a. Screen at 2428 weeks of gestation using a 75-g oral glucose tolerance test (OGTT).
b. If gestational DM is the diagnosis, screen for diabetes 612 weeks after delivery.
D. DM Diagnosis
1. Type 1 and 2 DM diagnosis
a. Glycemic parameters in nonpregnant patients
i. Fasting plasma glucose (FPG)
(a) Easy and preferred method
(b) 126 mg/dL or greater
ii. Random plasma glucose
(a) 200 mg/dL or greater with symptoms of hyperglycemia
(b) Common hyperglycemia symptoms include polyuria, polydipsia, and
unexplained weight loss
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c. Peak postprandial glucose (12 hours after a meal) less than 180 mg/dL
5. Nonglycemic therapy goals
a. Blood pressure less than 130/80 mm Hg (updated 2011 American Diabetes Association
guidelines suggest higher or lower systolic blood pressure goals are appropriate in some
patients but do not specifically define who these patients are)
b. Lipids
i. Low-density lipoprotein cholesterol (LDL-C) less than 100 mg/dL; less than 70 mg/
dL an option in those with existing cardiovascular disease
ii. TG less than 150 mg/dL
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d. Adverse effects
i. Common: Hypoglycemia, weight gain
ii. Less common: Rash, headache, nausea, vomiting, photosensitivity
e. Contraindications/precautions
i. Hypersensitivity to sulfonamides
ii. Patients with hypoglycemic unawareness
iii. Poor renal function (glipizide may be a better option than glyburide or glimepiride in
elderly patients or in those with renal impairment because drug or active metabolites
are not renally eliminated)
f. Efficacy
i. 1%2% A1c reduction
ii. Note: For this and all medications used to treat hyperglycemia, the absolute decrease
in A1c is larger for higher baseline A1c values and smaller for lower A1c values.
2. Metformin (biguanide)
a. Mechanism of action: Reduces hepatic gluconeogenesis. Also has favorable effects on
insulin sensitivity and intestinal absorption of glucose
b. Dosing
i. Initial: 500 mg once or twice daily (once daily with extended-release formulations)
ii. Maximal daily dose: 2550 mg (more commonly 2000 mg/day)
iii. Can increase at weekly intervals as necessary
iv. Small initial dosage and slow titration secondary to gastrointestinal (GI) disturbances
c. Adverse effects
i. Common: Nausea, vomiting, diarrhea, epigastric pain
ii. Less common: Decrease in vitamin B12 levels, lactic acidosis (rare)
iii. Signs or symptoms of lactic acidosis include acidosis, nausea, vomiting, increased re-
spiratory rate, abdominal pain, shock, and tachycardia.
d. Contraindications/precautions
i. Renal impairment: Serum creatinine 1.5 mg/dL or greater in men and 1.4 mg/dL or
greater in women or reduced creatinine clearance (CrCl) (CrCl cutoff is not well es-
tablished, but it may be as low as 30 mL/minute). Renal insufficiency increases risk
of lactic acidosis.
ii. Age 80 years or older
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iii.
High risk of cardiovascular event or hypoxic state
iv.
Hepatic impairment
v.
Congestive heart failure (especially if prone to exacerbations)
vi.
Interrupt therapy if undergoing procedures using iodinated contrast dye because of its
nephrotoxicity. Reinitiate after 48 hours and achievement of normal serum creatinine
concentrations.
e. Efficacy
i. 1%2% A1c reduction
ii. Some benefit in TG reduction and weight loss
iii. Considered first-line therapy unless contraindicated on the basis of adverse effect
profile, reduction in A1c, cost, and limited data on reduction of cardiovascular events
in overweight patients
3. Meglitinides
a. Mechanism of action: Very similar to that of sulfonylureas in increasing insulin secretion
from the pancreas but with a more rapid onset and shorter duration of activity
b. Glucose-dependent activity
c. Two currently available: Repaglinide and nateglinide
d. Dosing
i. Repaglinide
(a) Initial: 0.51 mg 15 minutes before meals
(b) Maximal daily dose: 16 mg
ii. Nateglinide
(a) 120 mg before meals
(b) 60 mg if A1c near goal
iii. Repaglinide can be increased in weekly intervals if needed.
e. Adverse effects: Hypoglycemia (though less than with sulfonylureas), weight gain, upper
respiratory infection
f. Contraindications/precautions
i. Hypersensitivity
ii. Caution in concomitant use of repaglinide and gemfibrozilcan lead to greatly
increased repaglinide levels
g. Efficacy
i. 0.5%1.5% A1c reduction (repaglinide shown to reduce A1c more than nateglinide)
ii. Most effective on postprandial glucose excursions
4. Thiazolidinediones (often called TZDs or glitazones)
a. Mechanism of action
i. Peroxisome proliferator-activated receptor agonist
ii. Increases expression of genes responsible for glucose metabolism, resulting in
improved insulin sensitivity
b. Two agents available: Pioglitazone and rosiglitazone
i. In September 2010, the U.S. Food and Drug Administration initiated restricted access
to rosiglitazone secondary to continued concerns about its cardiovascular safety.
ii. When fully implemented, rosiglitazone will be restricted to patients unable to obtain
glycemic control with other agents and in situations in which pioglitazone is not used
for medical reasons.
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c. Dosing
i. Pioglitazone
(a) Initial: 15 mg once daily
(b) Maximal daily dose: 45 mg
ii. Rosiglitazone
(a) Initial: 12 mg once daily
(b) Maximal daily dose: 8 mg
iii. Dose titration is slower with these agents, and the maximal effect of a dose change
may not be observed for 812 weeks.
d. Adverse effects
i. Weight gain
ii. Fluid retention (particularly peripheral edema), worse with insulin use (manufacturer
of rosiglitazone states that it should no longer be used with insulin). Edema less
responsive to diuretic therapy
iii. Risk of bone fractures
iv. Increased risk of heart failure
(a) Both have a black box warning.
(b) More than 2-fold higher relative risk, though absolute risk is quite small
v. Controversial increase in myocardial infarction and cardiovascular death with
rosiglitazone
e. Contraindications/precautions
i. Hepatic impairment
ii. Class III/IV heart failure iii. Existing fluid retention
f. Efficacy
i. 0.5%1.4% A1c reduction
ii. Both increase HDL-C, but pioglitazone has better effects on reducing LDL-C and TG
compared with rosiglitazone.
5. -Glucosidase inhibitors
a. Mechanism of action: Slows the absorption of glucose from the intestine into the
bloodstream by slowing the breakdown of large carbohydrates into smaller absorbable
sugars
b. Two agents available: Acarbose and miglitol
c. Dosing (both agents dosed similarly)
i. Initial: 25 mg 3 times/day at each meal
ii. Maximal daily dose: 300 mg
iii. Slow titration, increasing as tolerated every 48 weeks to minimize GI adverse
effects
d. Adverse effects
i. Flatulence, diarrhea, abdominal pain
ii. Increased liver enzymes observed with high doses of acarbose
e. Contraindications/precautions: Inflammatory bowel disease, colonic ulcerations,
intestinal obstruction
f. Efficacy
i. 0.5%0.8% reduction in A1c
ii. Targets postprandial glucose excursions
iii. May not be as effective in patients using low-carbohydrate diets
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I. Incretin Analogs
1. GLP-1 analog
a. Mechanism of action: Synthetic analog of human GLP-1 that binds to GLP-1 receptors,
resulting in glucose-dependent insulin secretion, reduction in glucagon secretion, and
reduced gastric emptying; promotes satiety
b. Two agents available (exenatide and liraglutide)
c. Dosing
i. Exenatide
(a) Initial: 5 mcg subcutaneously twice daily administered no more than 60 minutes
before morning and evening meals
(b) Maximal daily dose: 20 mcg/day
(c) Dose titration from 5 to 10 mcg twice daily after 1 month if tolerated
ii. Liraglutide
(a) 0.6 mg subcutaneously once daily for 1 week (regardless of mealtime)
(b) Dose titration from 0.6 to 1.2 mg/day if tolerated
(c) Maximal daily dose: 1.8 mg/day
iii. Both agents available in prefilled, multidose syringes
d. Adverse effects
i. Nausea, vomiting, diarrhea very common
ii. Hypoglycemia common with concurrent sulfonylurea (consider reduction in
sulfonylurea dose if adding exenatide)
iii. Postmarketing reports of pancreatitis, acute renal failure, or impairment
e. Contraindications/precautions
i. Impaired renal function, CrCl less than 30 mL/minute
ii. History of severe GI tract disorder
iii. History of pancreatitis
iv. For liraglutide: Contraindicated in patients with a personal or family history of
medullary thyroid carcinoma (adverse effect found in rodent studies but not in
humans)
f. Efficacy
i. A 0.5%1.1% reduction in A1c
ii. Effects on postprandial hyperglycemia better than fasting glucose concentrations
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J. Insulin
1. Categorized on the basis of therapy duration after injection
a. Short acting: Regular human insulin
b. Rapid acting: Insulin aspart, lispro, and glulisine
c. Intermediate acting: Neutral protamine Hagedorn (NPH)
d. Long acting: Insulin glargine and detemir; cannot be mixed with other insulins
2. Combination products (NPH/either regular or rapid-acting insulin): 70/30, 75/25
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a
Table 2. Insulin Characteristics
Injection Time
Before Meal Peak Duration
Category Drug Name Clarity Onset (minutes) (hours) (hours)
Short acting Regular Clear 3060 30 23 46
minutes
Rapid acting Aspart/lispro/glu Clear 520 minutes 15 13 35
lisine
Intermediate NPH Cloudy 12 hours N/A 48 1020
acting
Long acting Detemir Clear 24 hours N/A 68 624
Glargine 12 hours peakless ~24
a
Note: The above times are dependent on the source of data and intersubject variability.
N/A = not applicable; NPH = neutral protamine Hagedorn.
3. Glycemic target
a. Regular and short-acting insulins target postprandial glucose concentrations.
b. Intermediate- and long-acting insulins target fasting glucose concentrations.
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ii. Typically, patients will begin to estimate bolus requirements on the basis of the
amount of carbohydrates to be ingested.
h. Advantages over NPH plus regular approach: More physiologic, less hypoglycemia, more
flexible to patient mealtimes
i. Disadvantages: Cost and increased frequency of daily injections
Note: The same process of basal/bolus insulin therapy can apply to a patient with
type 2 DM who is receiving intensive insulin therapy with or without oral DM
medications.
5. Correctional insulin needs
a. Occasionally, a need to correct for hyperglycemic excursions despite optimal basal/bolus
therapy
b. 1800 Rule: 1800/TDI = No. of mg/dL of glucose 1 unit of rapid-acting insulin will
lower
i. For example: If TDI is 60 units, 1800/60 = 30, suggesting 1 unit of rapid-acting
insulin will reduce blood glucose concentrations by 30 mg/dL.
ii. Some advocate the 1500 Rule when using regular human insulin.
c. More patient-specific than traditional sliding-scale insulin
6. Continuous subcutaneous insulin infusion (insulin pump)
a. Device allows very patient-specific hourly basal dosing and bolus insulin dosing.
b. Uses rapid-acting insulins
c. Requires considerable patient education and carbohydrate counting
7. Assessing therapy and dosage adjustment
a. Know the goals for fasting and postprandial glucose concentrations.
b. Identify when patient is at goal and not at goal (hypo- or hyperglycemia). Look for
consistent trends rather than isolated events.
c. Identify which insulin affects problematic glucose concentrations.
d. Adjust insulin dose or patient behavior accordingly.
e. The same process for treating type 2 DM applies (see below).
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a. Step 1: As above
b. Step 2: Either a or b below
i. Add pioglitazone.
(a) If inadequate control, add sulfonylurea
(b) If inadequate control with metformin-pioglitazone-sulfonylurea, change to
metformin-basal insulin combination
ii. Add exenatide. If inadequate control, change to metformin-pioglitazone-sulfonylurea
combination or change to metformin-basal insulin combination
c. Step 3: As above
4. Initial insulin therapy: Use insulin early with any of the following baseline characteristics:
a. A1c greater than 10%
b. Random glucose greater than 300 mg/dL or fasting glucose greater than 250 mg/dL
c. Hyperglycemic symptoms
d. Presence of urine ketones
5. Changing from oral DM medications to insulin-only management (e.g., because of adverse
effects, contraindications, lack of efficacy of oral medications)
a. Can follow NPH/regular insulin or basal/bolus approach similar to that in type 1 DM as
previously described
b. The TDI requirements in type 2 DM are usually higher than those in type 1 DM.
6. Changing from NPH to long-acting insulin (either insulin glargine or detemir)
a. If adequate glycemic control already obtained, initiate insulin glargine at 80% of total
daily NPH dose
b. Detemir may be initiated on a unit-to-unit basis, and it may require higher daily insulin
dosages after conversion; however, this is determined by glycemic response.
A. Hypoglycemia
1. Degree of intervention depends on glucose concentrations and presence of symptoms.
2. Symptoms are very patient-specific.
3. Definition: Plasma glucose less than 70 mg/dL with or without symptoms
4. Mild to moderate hypoglycemia
a. Oral ingestion of 1520 g of glucose or equivalent
b. Repeat glucose concentration in 15 minutes and, if still less than 70 mg/dL, repeat.
5. Severe hypoglycemia (altered consciousness, requires assistance from others)
a. Glucagon 1 mg intramuscularly
b. Intravenous dextrose if patient does not respond to glucagon
B. Diabetic Ketoacidosis
1. More common in type 1 DM but can occur in type 2 DM
2. Usually occurs because of a precipitating factor that considerably stresses the body, resulting
in increased counterregulatory hormones
a. Inappropriate (including nonadherence) or inadequate insulin therapy and infection are
the two most common causes.
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C. Nephropathy
1. Screen annually with random spot collection of urine albumin-to-creatinine ratio starting at
diagnosis in type 2 DM and after 5 or more years in type 1 DM.
a. Normal: Less than 30 mg/g (or micrograms per milligram)
b. Microalbuminuria: 30299 mg/g
c. Macroalbuminuria: 300 mg/g or greater
2. Estimate CrCl yearly as well.
3. With type 1 DM, hypertension, and any degree of nephropathy: Angiotensin-converting
enzyme (ACE) inhibitor therapy
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4. With type 2 DM, hypertension, and microalbuminuria: ACE inhibitor or angiotensin receptor
blocker (ARB) therapy
5. With type 2 DM, hypertension, macroalbuminuria, and serum creatinine greater than 1.5
mg/dL: ARB therapy
6. The above differences in choice of drug class reflect what is documented in the literature.
7. ACE inhibitors and ARBs are often used regardless of whether the patient has hypertension.
8. Dietary protein restriction as renal function declines
D. Retinopathy
1. Screen annually with dilated and comprehensive eye examinations starting at diagnosis in
type 2 DM and after 5 or more years in type 1 DM.
2. Frequency can be reduced to every 23 years after one or more normal examinations.
3. No specific pharmacotherapy recommended except to adequately control glucose
concentrations
E. DM Neuropathies
1. Can have nerve damage in any area of the body
2. Screen for distal polyneuropathy using monofilament once yearly.
a. Screen after 5 years of type 1 DM and at diagnosis with type 2 DM.
b. Diminished sensitivity is a significant risk factor for diabetes-related foot ulcer and
increases the need for frequent visual inspection by patients if it exists.
3. Treatment of neuropathies is for symptomatic improvement and does not prevent progression.
4. Symptoms are patient-specific but may include numbness, burning, and a tingling sensation.
5. Neuropathic pain
a. Tricyclic antidepressants (amitriptyline, desipramine)
i. Effective but limited because of anticholinergic effects (some recommend using
secondary amine tricyclic antidepressants (e.g., desipramine, nortriptyline) because
they may have a lower anticholinergic effect than tertiary amines (e.g., amitriptyline,
imipramine)
ii. Daily dose is less than doses used for depression.
b. Anticonvulsants (gabapentin, lamotrigine, pregabalin)
i. Comparative data of gabapentin and pregabalin against tricyclic antidepressants show
similar efficacy with fewer adverse effects. Adverse effect profile is still significant
(fatigue, dizziness, etc.).
ii. Pregabalin is the only anticonvulsant approved for use in DM neuropathic pain.
c. Selective serotonin reuptake inhibitor/selective serotonin and norepinephrine reuptake
inhibitor (duloxetine, paroxetine, citalopram)
i. Duloxetine is the only approved agent in this category.
ii. No comparative data with other agents
d. Tramadol/acetaminophen
e. As effective as gabapentin, different adverse effect profile
6. Gastroparesis
a. Autonomic neuropathy causes considerable nausea/vomiting after meals because of
delayed gastric emptying.
b. Nonpharmacologic strategies
i. More frequent but smaller meals
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F. Cardiovascular Disease
1. Most common cause of morbidity and mortality as well as health care expenditures in DM
2. Proper DM management should always focus on cardiovascular disease risk reduction
3. Stress and continually assess the blood pressure and lipid goals previously described.
4. Blood pressure management
a. Given lower goal than for essential hypertension, often requires more antihypertensive
medications
b. Hypertensive regimen should include an ACE inhibitor or ARB.
5. Lipid management
a. Assess fasting lipid profile annually.
b. Statin therapy recommended regardless of baseline lipid levels for:
i. Established cardiovascular disease
ii. No history of cardiovascular event but older than 40 years with at least one
cardiovascular risk factor other than DM
c. A 30%40% reduction in LDL-C can be an alternative goal in those who do not attain an
LDL-C less than 100 mg/dL.
d. TG goal: Less than 150 mg/dL
e. HDL-C goal: Greater than 40 mg/dL for men, greater than 50 mg/dL for women
6. Antiplatelet therapy
a. Low-dose aspirin (75162 mg/day)
i. With existing cardiovascular disease
ii. For primary prevention, if 10-year risk is greater than 10% (includes most men older
than 50 and women older than 60 who have at least one cardiovascular risk factor)
b. Clopidogrel for those intolerant of aspirin therapy
G. Preventive Immunizations
1. Annual influenza vaccine
2. Pneumococcal polysaccharide vaccine
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A. Classification
1. Hyperthyroid disorders (thyrotoxicosis)
a. Toxic diffuse goiter (Graves disease): Most common hyperthyroid disorder
i. Autoimmune disorder
ii. Thyroid-stimulating antibodies directed at thyrotropin receptors mimic thyroid-stim-
ulating hormone (TSH) and stimulate triiodothyronine/thyroxine (T3/T4) production.
b. Pituitary adenomas: Excessive TSH secretion that does not respond to normal T3
feedback
c. Toxic adenoma: Hot nodule in thyroid, autonomous of pituitary and TSH
d. Toxic multinodular goiter (Plummer disease): Autonomous follicles, if large enough,
cause excessive thyroid hormone secretion.
e. Painful subacute thyroiditis: Self-limiting thyroiditis caused by viral invasion of the
thyroid parenchyma, resulting in release of stored hormone
f. Drug induced (e.g., excessive thyroid hormone use, amiodarone)
2. Hypothyroid disorders
a. Hashimoto disease: Most common hypothyroid disorder
i. Autoimmune-induced thyroid injury resulting in decreased thyroid secretion
ii. Disproportionately affects women more than men
b. Surgery or radioiodine induced (iatrogenic)
c. Iodine deficiency or excessive intake
d. Secondary causes
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B. Diagnosis
1. Hyperthyroid disorders
a. Elevated total T4 and free T4 serum concentrations
b. Suppressed TSH concentrations (except in TSH-secreting adenomas)
c. If examination and history do not provide exact etiology, radioactive iodine uptake may
be employed.
i. Radioactive iodine uptake is elevated if thyroid gland actively and excessively
secretes T4 and/or T3: Graves disease, TSH-secreting adenoma, toxic adenoma,
multinodular goiter
ii. Radioactive iodine uptake is suppressed in disorders caused by thyroiditis or
hormone ingestion.
d. Can also assess thyroid-stimulating antibodies, thyroglobulin, thyroid biopsy, etc.
2. Hypothyroid disorders
a. Decreased total T4 and free T4 serum concentrations
b. Elevated TSH concentrations (normal or low if secondary cause etiology)
c. Thyroid antibodies: Antithyroid peroxidase and antithyroglobulin autoantibodies
C. Clinical Presentation
1. Hyperthyroid disorders
a. Weight loss/increased appetite
b. Lid lag
c. Heat intolerance
d. Goiter
e. Fine hair
f. Heart palpitations/tachycardia
g. Nervousness, anxiety, insomnia
h. Menstrual disturbances (lighter or more infrequent menstruation, amenorrhea)
i. Sweating or warm, moist skin
j. Exophthalmos, pretibial myxedema in Graves disease
2. Hypothyroid disorders
a. Cold intolerance
b. Dry skin
c. Fatigue, lethargy, weakness
d. Weight gain
e. Bradycardia
f. Slow reflexes
g. Coarse skin and hair
h. Periorbital swelling
i. Menstrual disturbances (more frequent or longer menstruation, painful menstruation,
menorrhagia)
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E. Pharmacotherapy
1. Hyperthyroidism
a. Treatment of choice for Graves disease, toxic nodule, multinodular goiter: Radioactive
iodine ablative therapy and surgical resection for adenomas based on patient preferences
or comorbidities. Ablative therapy often results in hypothyroidism.
b. Pharmacotherapy usually reserved for the following:
i. Awaiting ablative therapy or surgical resection
(a) Depletes stored hormone
(b) Minimizes risk of posttreatment hyperthyroidism because of thyroiditis
ii. Not an ablative or surgical candidate
iii. When ablative therapy or surgical resection fails to normalize thyroid function
c. Thioureas (i.e., propylthiouracil [PTU], methimazole)
i. Mechanism of action: Inhibits iodination and synthesis of thyroid hormones; PTU
may block T4-to-T3 conversion in the periphery as well
ii. Dosing
(a) Propylthiouracil
(1) Initial: 100 mg by mouth 3 times/day
(2) Maximal: 400 mg 3 times/day
(b) Methimazole
(1) Initial: 510 mg by mouth 3 times/day
(2) Maximal: 40 mg 3 times/day
(c) Either drug can be given once daily if tolerated (disparity between
pharmacokinetics and pharmacodynamics).
(d) Monthly dose titrations as needed (on the basis of symptoms/TSH)
iii. Adverse effects
(a) Hepatotoxicity issue with PTU (black box warning)
(b) Transient leucopenia (white blood cell count less than 4000 cells/m3)
(c) Rash
(d) Arthralgias, lupuslike symptoms
(e) Fever
(f ) Granulocytosis early in therapy
iv. Efficacy
(a) Slow onset in reducing symptoms (weeks). Maximal effect may take 46 months.
(b) Neither drug appears superior to the other in efficacy.
(c) On a milligram-to-milligram basis, methimazole is 10 times more potent than
PTU.
(d) Remission rates low: 40%50%
d. -Blockers (primarily propranolol, sometimes nadolol)
i. Mechanism of action: Block many hyperthyroidism manifestations mediated by
-adrenergic receptors. Also may block T4-to-T3 conversion
ii. Dosing
(a) Initial: 2040 mg by mouth 3 or 4 times/day
(b) Maximal: 240480 mg/day
iii. Adverse effects
iv. Efficacy
(a) Primarily used for symptomatic relief (e.g., palpitations, tachycardia, tremor,
anxiety)
(b) Poor remission rates: 20%35%
(c) Primary role is treatment of thyroiditis and during thyroid storm.
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ii. Dosing
(a) Initial: 25 mcg/day
(b) Average maintenance dose: 2575 mcg/day
iii. Adverse effects: May be higher incidence of cardiac adverse effects than
levothyroxine
iv. Efficacy: If properly dosed, efficacy should be similar to levothyroxine. Has shorter
halflife than levothyroxine
c. Liotrix
i. Mechanism of action: Synthetic T4/T3 in 4:1 ratio. Mimics bodys natural ratio
ii. Seldom used. No actual need because T4 is easily converted to T3
d. Desiccated thyroid (Thyroid USP)
i. Mechanism of action: Hog-, beef-, or sheep-derived levothyroxine, liothyronine in
specific ratios to thyroglobulin
ii. Used less secondary to potential risk of hypersensitivity reactions
iii. Dosed in grains: 1 grain of Armour Thyroid equals 100 mcg of levothyroxine.
F. Subclinical Hypothyroidism
1. Definition: Elevated TSH (above upper limit of reference range) with normal T4. Often the
result of early Hashimoto disease
2. Risk?
a. TSH greater than 7.0 mIU/L in the elderly associated with increased risk of heart failure
b. TSH greater than 10 mIU/L associated with increased risk of coronary heart disease
3. Treatment of subclinical hypothyroidism is controversial because benefits in identified
patients are inconclusive.
4. Whom to treat
a. Patients with symptoms
b. TSH greater than 10 mIU/L
c. TSH between 5 and 10 mIU/L and goiter or antithyroid peroxidase antibodies present
5. If untreated, screen regularly for the development of overt hypothyroidism (decreased free T4
concentrations).
G. Thyroid Storm
1. Severe and life-threatening decompensated thyrotoxicosis. Mortality rate may be as high as
20%.
2. Precipitating cause (trauma, infection, antithyroid agent withdrawal, severe thyroiditis, posta-
blative therapy)
3. Presentation: Fever, tachycardia, vomiting, dehydration, coma, tachypnea, delirium
4. Pharmacotherapy
a. PTU: 300400 mg 3 times/day
b. Iodide therapy after PTU initiation (dosed as previously described)
c. -Blocker therapy: Esmolol commonly used (can use other agents [e.g., propranolol])
d. Antipyretic therapy: Acetaminophen (avoid nonsteroidal anti-inflammatory drugs
[NSAIDs] because of displacement of protein-bound thyroid hormones)
e. Corticosteroid therapy: Prednisone 25100 mg/day in divided doses (or equivalent doses
of dexamethasone, hydrocortisone, etc.)
H. Myxedema Coma
1. Severe and life-threatening decompensated hypothyroidism; mortality rate 30%60%
2. Precipitating causes: Trauma, infections, heart failure, medications
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3. Presentation: Coma is not required and is uncommon despite terminology, altered mental
state (very common), diastolic hypertension, hypothermia, hypoventilation
4. Pharmacotherapy
a. Intravenous thyroid hormone replacement
i. T4: 100- to 500-mcg loading dose, followed by 75100 mcg/day, until patient can
tolerate oral therapy. Lower initial dose in frailer patients or in patients with estab-
lished cardiovascular disease
ii. Some advocate the use of T3 over T4 given that T3 is more biologically active and
T4-to-T3 conversion may be suppressed in myxedema coma. Cost and availability
limit intravenous T3 use.
b. Antibiotic therapy: Given common cause, some advocate empiric therapy with broad-
spectrum antibiotics.
c. Corticosteroid therapy
i. Hydrocortisone 100 mg every 8 hours (or equivalent steroid)
ii. Can be discontinued if random cortisol concentration not found to be depressed
Figure 2. Normal total body sodium content and small increases in extracellular fluid volume.
Na = sodium.
B. Mechanism: Increased release of antidiuretic hormone (ADH) from the posterior pituitary or in-
creased responsiveness of the collecting duct to ADH
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2. Rate of administration
3. Use of diuretics in the treatment of SIADH
a. Mechanism of action of diuretics
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REFERENCES
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BIOSTATISTICS
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Learning Objectives:
I. INTRODUCTION TO STATISTICS
B. Useful Tools for Quantifying Clinical and Laboratory Data in a Meaningful Way
C. Assists in Determining Whether and by How Much a Treatment or Procedure Affects a Group
of Patients
F. Several papers have investigated the various types of statistical tests used in the biomedical literature.
The data from one paper are illustrated below.
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1. Statistical content of original articles in The New England Journal of Medicine, 20042005
% of Articles % of Articles
Containing Containing Methods
Statistical Procedure Methods Statistical Procedure
No statistics/descriptive 13 Adjustment and standardization 1
statistics Multiway tables 13
t-tests 26 Power analyses 39
Contingency tables 53 Cost-benefit analysis <1
Nonparametric tests 27 Sensitivity analysis 6
Epidemiologic statistics 35 Repeated-measures analysis 12
Pearson correlation 3 Missing-data methods 8
Simple linear regression 6 Non-inferiority trials 4
Analysis of variance 16 Receiver-operating 2
Transformation 10 characteristics 2
Nonparametric correlation 5 Resampling 2
Survival methods 61 Principal component and cluster
Multiple regression 51 analyses 4
Multiple comparisons 23 Other methods
2. Statistical content of original articles from six major medical journals from January to March
2005 (n=239 articles). Papers published in American Journal of Medicine, Annals of Internal
Medicine, BMJ, JAMA, Lancet, and The New England Journal of Medicine. Table modified from
JAMA 2007;298:101022.
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A. Definition: Data: A variable whose observed values may be considered outcomes of an experiment
and whose values cannot be anticipated with certainty before the experiment is conducted
C. Discrete Variables
1. Can only take a limited number of values within a given range
2. Nominal: Classified into groups in an unordered manner, with no indication of relative sever-
ity (e.g., sex, mortality, disease state)
3. Ordinal: Ranked in a specific order but with no consistent level of magnitude of difference
between ranks (e.g., NYHA [New York Heart Association] functional class describes the
functional status of patients with heart failure, and subjects are classified in increasing order
of disability: I, II, III, IV )
4. COMMON ERROR: Measure of central tendency: In most cases, means and SDs should not
be reported with ordinal data. What is a common incorrect use of means and SDs to show
ordinal data?
A. Descriptive Statistics: Used to summarize and describe data that are collected or generated in
research studies. This is done both visually and numerically.
1. Visual methods of describing data
a. Frequency distribution
b. Histogram
c. Scatterplot
2. Numeric methods of describing data: Measures of central tendency
a. Mean (i.e., average)
i. Sum of all values divided by the total number of values
ii. Should generally be used only for continuous and normally distributed data
iii. Very sensitive to outliers and tend toward the tail, which has the outliers
iv. Most commonly used and most well-understood measure of central tendency
v. Geometric mean
b. Median
i. Midpoint of the values when placed in order from highest to lowest. Half of the ob-
servations are above and below.
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B. Inferential Statistics
1. Conclusions or generalizations made about a population (large group) from a study of a
sample of that population
2. Choosing and evaluating statistical methods depend, in part, on the type of data used.
3. An educated statement about an unknown population is commonly referred to in statistics as
an inference.
4. Statistical inference can be made by estimation or hypothesis testing.
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A. Discrete Distributions
1. Binomial distribution
2. Poisson distribution
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V. CONFIDENCE INTERVALS
B. CIs can also be used for any sample estimate. Estimates derived from categorical data such as risk, risk
differences, and risk ratios are often presented with the CI and will be discussed later.
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6. The results of the hypothesis testing will indicate whether enough evidence exists for H0 to be
rejected.
a. If H0 is rejected = statistically significant difference between groups (unlikely attributable to
chance)
b. If H0 is not rejected = no statistically significant difference between groups (any apparent
differences may be attributable to chance). Note that we are not concluding that the treat-
ments are equal.
B. To determine what is sufficient evidence to reject H0: Set the a priori significance level () and generate
the decision rule.
1. Developed after the research question has been stated in hypothesis form
2. Used to determine the level of acceptable error caused by a false positive (also known as level of
significance)
a. Convention: A priori is usually 0.05.
b. Critical value is calculated, capturing how extreme the sample data must be to reject H0.
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iii. Parametric tests assume that the data being investigated have variances that are
homogeneous between the groups investigated. This is often referred to as
homoscedasticity.
b. Nonparametric tests are used when data are not normally distributed or do not meet other
criteria for parametric tests (e.g., discrete data).
C. Parametric Tests
1. Student t-test: Several different types
a. One-sample test: Compares the mean of the study sample with the population mean
b. Two-sample, independent samples, or unpaired test: Compares the means of two independent
samples
i. This is an independent samples test.
Group 1 Group 2
Group 1
Measurement 1 Measurement 2
d. Common error: Use of multiple t-tests with more than two groups
2. Analysis of variance (ANOVA): A more generalized version of the t-test that can apply to more than
two groups
a. One-way ANOVA: Compares the means of three or more groups in a study. Also known as a
single-factor ANOVA. This is an independent samples test.
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Related Measurements
Group 1 Measurement 1 Measurement 2 Measurement 3
d. Many more complex factorial ANOVAs can be used.
e. Several comparison procedures are used to determine which groups actually differ
from each other. Post hoc tests: Tukey HSD (Honestly Significantly Different),
Bonferroni, Scheff, Newman-Keuls
3. Analysis of covariance: Provides a method to explain the influence of a categorical variable
(independent variable) on a continuous variable (dependent variable) while statistically con-
trolling for other variables (confounding)
4. Pearson correlation (discussed later)
5. Simple regression (discussed later)
D. Nonparametric Tests
1. These tests may also be used for ordinal data and continuous data that do not meet the
assumptions of the t-test or ANOVA.
2. Tests for independent samples
a. Wilcoxon rank sum and Mann-Whitney U-test, compares two independent samples
(related to a t-test)
b. Kruskal-Wallis one-way ANOVA by ranks
i. Compares three or more independent groups (related to a one-way ANOVA)
ii. Post hoc testing
3. Tests for related or paired samples
a. Sign test and Wilcoxon signed rank test: Compares two matched or paired samples
(related to a paired t-test)
b. Friedman ANOVA by ranks: Compares three or more matched/paired groups
E. Nominal Data
1. Chi-square (2) test: Compares expected and observed proportions between two or more
groups
a. Test of independence
b. Test of goodness of fit
2. Fisher exact test: Specialized version of chi-square test for small groups (cells) containing
fewer than five observations
3. McNemar: Paired samples
4. Mantel-Haenszel: Controls for the influence of confounders
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2 Samples 2 Samples > 2 Samples > 2 Samples
Type of Variable (independent) (related) (independent) (related)
Nominal 2 or Fisher exact test McNemar test 2 Cochran Q
Ordinal Wilcoxon rank sum Wilcoxon signed Kruskal-Wallis Friedman ANOVA
Mann-Whitney U-test rank (MCP)
Sign test
Continuous Equal variance t-test Paired t-test 1-way ANOVA Repeated-measures
No factors Unequal variance (MCP) ANOVA
t-test
1 factor ANCOVA 2-way repeated- 2-way ANOVA 2-way repeated-
measures ANOVA (MCP) measures ANOVA
ANCOVA = analysis of covariance; ANOVA = analysis of variance; MCP = multiple comparison procedures.
F. Correlation and Regression (see section IX)
VIII. DECISION ERRORS
A. Summary of Decision Errors
Underlying Truth or Reality
Test result H0 Is True (no difference) H0 Is False (difference)
Accept H0 (no difference) No error (correct decision) Type II error (beta error)
Reject H0 (difference) Type I error (alpha error) No error (correct decision)
B. Type I Error: The probability of making this error is defined as the significance level .
1. Convention is to set to 0.05, effectively meaning that, 1 in 20 times, a type I error will occur
when the H0 is rejected. So, 5.0% of the time, a researcher will conclude there is a statistically
significant difference when actually, one does not exist.
2. The calculated chance that a type I error has occurred is called the p-value.
3. The p-value tells us the likelihood of obtaining a given (or a more extreme) test result if the
H0 is true. When the level is set a priori, H0 is rejected when p is less than . In other words,
the p-value tells us the probability of being wrong when we conclude that a true difference
exists (false positive).
4. A lower p-value does not mean the result is more important or more meaningful, but only
that it is statistically significant and not likely attributable to chance.
C. Type II Error: The probability of making this error is termed .
1. Concluding that no difference exists when one truly does (not rejecting H0 when it should
be rejected)
2. It has become a convention to set to between 0.20 and 0.10.
D. Power (1 )
1. The probability of making a correct decision when H0 is false, the ability to detect differences
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1 0 +1
perfect negative linear no linear relationship perfect positive linear
relationship relationship
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D. Spearman Rank Correlation: Nonparametric test that quantifies the strength of an association
between two variables and does not assume a normal distribution of continuous data. Can be used
for ordinal data or nonnormally distributed continuous data
E. Regression
1. A statistical technique related to correlation. There are many different types; for simple linear
regression: one continuous outcome (dependent) variable and one continuous independent
(causative) variable
2. Two main purposes of regression: (1) development of prediction model and (2) accuracy of
prediction
3. Prediction model: Making predictions of the dependent variable from the independent
variable; Y = mx+ b (dependent variable = slope independent variable + intercept)
4. Accuracy of prediction: How well the independent variable predicts the dependent variable.
Regression analysis determines the extent of variability in the dependent variable that can be
explained by the independent variable.
a. Coefficient of determination (r2) measured describing this relationship. Values of r2 can
range from 0 to 1.
b. An r2 of 0.80 could be interpreted as saying that 80% of the variability in Y is explained
by the variability in X.
c. This does not provide a mechanistic understanding of the relationship between X and Y,
but rather, a description of how clearly such a model (linear or otherwise) describes the
relationship between the two variables.
d. Like the interpretation of r, the interpretation of r2 is dependent on the scientific arena
(e.g., clinical research, basic research, social science research) to which it is applied.
5. For simple linear regression, two statistical tests can be employed.
a. To test the hypothesis that the y-intercept differs from zero
b. To test the hypothesis that the slope of the line is different from zero
6. Regression is useful in constructing predictive models. The literature is full of examples of
predictions. The process involves developing a formula for a regression line that best fits the
ob- served data.
7. Like correlation, there are many different types of regression analysis.
a. Simple linear regression: One continuous independent (response) variable, one
continuous or categorical dependent (explanatory) variable
b. Multiple linear regression: One continuous response variable and two or more continuous
or categorical response variables
c. Simple logistic regression: One categorical response variable and one continuous or
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X. SURVIVAL ANALYSIS
A. Studies the Time Between Entry in a Study and Some Event (e.g., death, myocardial infarction)
B. Censoring makes survival methods unique, takes into account that some subjects leave the study
for reasons other than the event (e.g., lost to follow-up, end of study period)
C. Considers that all subjects do not enter the study at the same time
D. Standard methods of statistical analysis such as t-tests and linear or logistic regression cannot be
applied to survival data because of censoring.
F. Log-rank test Compares the survival distributions between (two or more) groups
1. This test precludes an analysis of the effects of several variables or the magnitude of
difference between groups or the CI (see below for Cox proportional hazards model).
2. H0: No difference in survival between the two populations
3. Log-rank test uses several assumptions:
a. Random sampling and subjects chosen independently
b. Consistent criteria for entry or end point
c. Baseline survival rate does not change as time progresses.
d. Censored subjects have the same average survival time as uncensored subjects.
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REFERENCES
1. Strassels SA. Biostatistics. In: Dunsworth 11. Gaddis ML, Gaddis GM. Introduction
TS, Richardson MM, Chant C, et al, eds. to biostatistics. Part 4, statistical infer-
Pharmacotherapy Self-Assessment Program, 6th ence techniques in hypothesis testing. Ann
ed. Kansas City, MO: ACCP, Emerg Med 1990;19:8205.
2007. 12. Gaddis ML, Gaddis GM. Introduction to
2. DeYoung GR. Understanding biostatistics: an biostatistics. Part 5, statistical inference
approach for the clinician. In: Zarowitz B, techniques for hypothesis testing with
Shumock G, Dunsworth T, et al, eds. nonparametric data. Ann Emerg Med
Pharmacotherapy Self-Assessment Pro- gram, 1990;19:10549.
5th ed. Kansas City, MO: ACCP, 13. Gaddis ML, Gaddis GM. Introduction to
2005. biostatistics. Part 6, correlation and regression.
3. Harper ML. Biostatistics for the clinician. Ann Emerg Med 1990;19:14628.
In: Zarowitz B, Shumock G, Dunsworth 14. Kusuoka H, Hoffman JIE. Advice on statistical
T, et al, eds. Pharmacotherapy Self-Assessment analysis for circulation research. Circ Res
Program, 4th ed. Kansas City, MO: ACCP, 2002. 2002;91:66271.
4. Hayney MS, Meek PD. Essential clinical 15. Larson MG. Descriptive statistics and
concepts of biostatistics. In: Carter BL, Lake graphical displays. Circulation
KD, Raebel MA, et al, eds. Pharmacotherapy 2006;114:7681.
Self-Assessment Program, 3rd ed. Kansas City,
16. Sullivan LM. Estimation from samples.
MO: ACCP, 1999.
Circulation 2006;114:4459.
5. Rector TS, Hatton RC. Statistical concepts and
17. Davis RB, Mukamal KJ. Hypothesis testing:
methods used to evaluate pharmacotherapy. In:
means. Circulation 2006;114:107882.
Zarowitz B, Shumock G, Dunsworth T, et al, eds.
Pharmacotherapy Self-Assessment Program, 2nd 18. Larson MG. Analysis of variance. Circulation
ed. Kansas City, MO: ACCP, 1997. 2008;117:11521.
6. Overholser BR, Sowinski KM. Biostatistics 19. Crawford SL. Correlation and regression.
primer: part 1. Nutr Clin Pract Circulation 2006;114:20838.
2007;22:62935. 20. Rao SR, Schoenfeld DA. Survival methods.
7. Overholser BR, Sowinski KM. Biostatistics Circulation 2007;115:10913.
primer: part 2. Nutr Clin Pract 21. Tsuyuki RT, Garg S. Interpreting data in
2008;23:7684. cardiovascular disease clinical trials: a bio-
8. Gaddis ML, Gaddis GM. Introduction to statistical toolbox. In: Richardson MM, Chant C,
biostatistics. Part 1, basic concepts. Ann Emerg Cheng JWM, et al, eds. Pharmacotherapy Self-
Med 1990;19:869. Assessment Program, 7th ed. Kansas City, MO:
ACCP, 2010.
9. Gaddis ML, Gaddis GM. Introduction to
biostatistics. Part 2, descriptive statistics. Ann 22. Windish DM, Huot SJ, Green ML. Medicine
Emerg Med 1990;19:30915. residents understanding of the biostatistics and
results in the medical literature. JAMA
10. Gaddis ML, Gaddis GM. Introduction to
2007;298:101022.
biostatistics. Part 3, sensitivity, specificity,
predictive value, and hypothesis testing. Ann 23. Jones SR, Carley S, Harrison M. An intro-
Emerg Med 1990;19:5917. duction to power and sample size estimation.
Emerg Med J 2003;20:4538.
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Learning Objectives:
1. Define, compare, and contrast the concepts of internal and external validity, bias, and confounding in
clinical study design.
2. Identify potential sources of bias in clinical trials; select strategies to eliminate or control for bias.
3. Outline the hierarchy of evidence generated by various study designs.
4. Compare and contrast the advantages and disadvantages of various study designs (e.g., prospective;
retrospective; case-control; cohort; cross-sectional; randomized controlled clinical trials; systematic
review; meta-analysis).
5. Select from various biostatistical tests to appropriately compare groups or their assessments from
various study designs and use their findings/output to interpret results.
6. Define and evaluate odds, odds ratio, risk /incidence rate, risk ratio/relative risks, and other risk
estimates. Compute and evaluate number needed to treat and number needed to harm.
I. INTRODUCTION
Interpret biomedical literature with respect to study design and methodology, statistical analysis,
and significance of reported data and conclusions
Knowledge of: Biostatistical methods, clinical and statistical significance, research hypothesis
generation, research design and methodology, and protocol and proposal development
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Experimental/
Descriptive Obser vational Studies
Inter ventional
Ideas, Cross-
opinions, and Case Report Case Series Case-control Cohort sectional RDBCT
reviews
Systemic Reviews and Meta-analysis
Figure 1.
RDBCT = randomized double-blind, placebo-controlled clinical trial.
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A. Document and Describe Experiences, Novel Treatments, and Unusual Events. Allows hypothesis
generation that can be tested with other study designs. Note that the title does not state study.
1. Possible adverse drug reactions in one or more patients: QT-interval prolongation associated
with fluoroquinolone antibiotics
2. Case report: One patient
3. Case series: More than one patient with a similar experience or many case reports combined
into a descriptive review
4. Reports should provide sufficient detail to allow readers to recognize same/similar cases at
their center/practice.
5. Is IRB (institutional review board) approval required?
B. Advantages: Hypotheses are formed, which is may be the first step in describing an important
clinical problem. Easy to perform and inexpensive
Disadvantages: Does not provide explanation other than conjecture and does not establish
causality or association
B. Case-Control Study: Study Exposure in Those With and Without the Outcome of Interest
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C. Cohort Study
1. Determine the association between exposures/factors and disease/condition development.
Allows an estimation of the risk of outcome (and the RR between the exposure groups).
Study outcome of interest in those with and without the exposure of interest. Classic
examples:
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a. Example: Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and
secondary prevention of coronary events in the nurses health study. A prospective,
observational study. Ann Intern Med 2001;135:18.
b. Advantages: Better able to control for confounding factors, easier to plan for data
collection
c. Disadvantages: More expensive and time-intensive, loss of subject follow-up, difficult
to study rare diseases/conditions at a reasonable cost
5. Measure of association: Relative risk or risk ratio: The risk of an event or development of
a condition relative to exposure; the risk of developing a condition when exposed
compared with someone who has not been exposed
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A. Incidence
1. Measure of the instantaneous rate of developing a disease so that it reflects the rate of disease
development
2. Divide the number of individuals who develop a disease by the total amount of time these
individuals were at risk of developing a disease (measured in persons/year).
B. Prevalence: Measure of the number of individuals who have a condition or disease at any given
time
RR OR Interpretation
<1 <1 Negative association
Risk is lower in the exposed group
=1 =1 No association
Risk between the two groups is the same
>1 >1 Positive association
Risk is greater in the exposed group
OR = odds ratio; RR = relative risk /risk ratio.
b. Magnitude of risk
RR OR Interpretation
0.75 0.75 25% reduction in the risk /odds
1.0 1.0 No difference in the risk /odds
1.5 1.5 50% increase in the risk /odds
3.0 3.0 3-fold (or 300%) increase in the risk /odds
OR = odds ratio; RR = relative risk /risk ratio.
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D. Causation
1. REMEMBER: In general, we do not prove or show causality with observation studies, but
there is some general guidance to consider when evaluating them. It is important to
recognize that in many situations, the conduct of studies to establish causality is not possible
or practical.
2. Questions used to evaluate causality
a. Was statistical significance observed?
b. What was the strength of the association, as measured by the OR or the RR?
c. Were dose-response relationships evaluated?
d. Was there a temporal relationship between exposure and disease/outcome?
e. Have the results been consistently shown?
f. Is there biologic plausibility to the association?
g. Is there any experimental (animal, in vitro, etc.) evidence?
A. Characteristics
1. Experimental or interventional, investigator makes intervention and evaluates cause and
effect. Examine etiology, cause, efficacy, etc., using comparative groups.
2. Some information should exist to suggest that the intervention employed will likely be
beneficial.
3. Design allows assessment of causality.
4. Minimizes bias through randomization and/or stratification
5. May use parallel or crossover design
a. Crossover provides practical and statistical efficiency.
b. Crossover is not appropriate for certain types of treatment questions. Effect of treatment
on a disease that worsens quickly over time or worsens during the study period
6. Examples:
a. Clinical trial: Comparison of two drugs, comparison of two behavioral modifications, etc.
b. Educational intervention: Online course versus lecture class format
c. Health care intervention: Pharmacist-based health care team versus nonpharmacist-
based health care team
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c. Were subjects analyzed in the groups to which they were randomized? Was intention-to-
treat, per-protocol, or actual treatment analysis used?
d. How was blinding conducted (subject, investigator, etc.), if applicable?
e. Were the inclusion and exclusion criteria appropriate, or were they too restrictive or
inclusive? Were the groups similar at the start of the trial?
f. Was the sample size sufficient, and was a power calculation included?
g. Were the groups handled the same way, aside from the intervention(s)?
h. Were the statistical tests appropriate and understandable?
i. Were surrogate markers or true outcomes assessed? Were a priori subgroup
analyses performed?
2. What were the results?
a. How large was the treatment effect?
b. How precise was the effect (were the CIs)?
c. Did the authors properly interpret the results?
3. Can I apply the results of this study to my patient population? Will they help me care for my
patients?
a. Can the results of this study be applied to general practice?
b. Was a representative population studied? Can I apply this to my setting?
c. Do the patients I care for fill the enrollment criteria for this study?
d. Do the patients I care for fill the subgroup criteria evaluated?
e. Do the expected benefits outweigh the expected and/or unanticipated risks?
A. Subgroup Analysis
1. Important part of controlled clinical trials (if set a priori)
2. Many times, they are overused and over-interpreted, leading to unnecessary research,
misinterpretation of results, and/or suboptimal patient care.
3. Qualitative versus quantitative interactions or differences
a. Quantitative: Studied treatment is superior for both subgroups (ex. male and female).
b. Qualitative: Studied treatment is superior in only ONE of the subgroups (ex. male or
female). These types of differences should be viewed with caution.
4. Many potential pitfalls in identifying and interpreting:
a. Failure to account for several comparisons or to adjust p-values
b. Problems with sample size (power), classification, and lack of assessment of interaction
B. Composite End Points: Often, the Impression Is that This Practice Is Not a Good Practice.
1. The primary end point is one of the most important decisions to make in the design of a
clinical study.
2. A composite end point combines several end points:
a. For example, cardiovascular death, nonfatal myocardial infarction (MI), and cardiac
arrest with resuscitation
b. Usually combines measures of morbidity and mortality
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A. Study design
1. Was the studied sample representative of the population or the individual to whom the
results were being applied?
2. Were the inclusion/exclusion criteria appropriate, or were they overly restrictive or inclusive?
3. Sufficient sample size, power, etc.? Was a power analysis included?
4. Is a study objective and/or hypothesis provided?
5. Was the study blinded and to whom? (subject, investigator, study personnel, or all?)
6. Was a run-in phase employed? If so, why? Did it affect the interpretation of the trial?
7. What type of randomization method was performed? Did the randomization process produce
equal baseline characteristics between all groups?
B. Outcomes/Assessments
1. Are the primary and/or secondary outcomes identified, are they reasonable, and do they
apply to clinical practice?
2. Is a composite outcome employed, and are all the individual components identified and
clearly stated in the methods and results?
3. Are surrogate markers employed instead of (or in addition to) clinically relevant
outcomes?
C. Analysis
1. What analysis technique was used: intention-to-treat, actual treatment, or per-protocol?
2. Are the statistical tests appropriate?
D. Interpretation: Is the authors interpretation appropriate and within the confines of the study
design?
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E. Extrapolation
1. Are you applying the results to similar patients in a similar setting?
2. Are there possible additional adverse effects that are not measured in this study?
A. Intention-to-Treat Analysis
1. Compares outcomes on the basis of initial group assignment or as randomized. The
allocation to groups was how they were intended to be treated, even though they may not
have taken the medication for the full duration of the study or they dropped out, etc.
2. Determines effect of treatment under usual conditions of use. Analogous to routine clinical
practice in which a patient receives a prescription but may not adhere to the drug
3. Gives a conservative estimate of differences in treatments; may underestimate treatment benefits
4. Most common approach to assessing clinical trial results
B. Per-Protocol Analysis
1. Subjects who do not adhere to allocated treatment are not included in the final analysis; only
those who completed the trial and adhered to the protocol (based on some predetermined
definition [e.g., 80% adherence])
2. Provides additional information about treatment effectiveness and provides more generous
estimates of differences between treatments
3. Subject to several issues because of factors such as lower sample size and definitions
of adherence. Results are more difficult to interpret.
C. As-Treated Analysis
1. Subjects are analyzed by the actual intervention received. If subjects were in the active
treatment group but did not take active treatment, the data would be analyzed as if they were
in the placebo group.
2. This analysis essentially ignores the randomization process for those who did not adhere to
the study design.
X. SYSTEMATIC REVIEW/META-ANALYSIS
A. Introduction
1. Dramatic increase in the number of this type of papers
2. First meta-analysis probably published in 1904: Assessment of typhoid vaccine effectiveness
B. Systematic Review
1. Summary that uses explicit methods to perform a comprehensive literature search, critically
appraise it, and synthesize the world literature on a specific topic. Instead of the subjects being
human subjects, the individual studies are the study subjects (i.e., the subjects are studies).
2. Differs from a standard literature review: The study results are more
comprehensively synthesized and reviewed.
3. As with a controlled clinical trial (or other studies), the key is a well-documented and
described systematic review.
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4. Some systematic reviews will attempt to statistically combine results from many studies.
5. Differs from other reviews, which combine evaluation with opinions
C. Meta-analysis
1. Systematic review that uses mathematical/statistical techniques to summarize the results of
the evaluated studies
2. These techniques may improve on:
a. Calculation of effect size
b. Increase statistical power
c. Interpretation of disparate results
d. Reduce bias
e. Answers to questions that may not be addressable with additional study
3. Forest plots
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A. Cost-minimization Analysis
1. Outcome: Equal, only cost is addressed
2. Determines the lowest cost alternative
B. Cost-benefit Analysis
1. Outcome: Monetary; is a treatment worth the cost?
2. Determines the greatest net benefit alternative
C. Cost-effectiveness Analysis
1. Clinical units
2. Determines the most cost-effective alternative
D. Cost-utility Analysis
1. Utility
2. Determines the greatest benefit alternative
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C. Positive Predictive Value: Proportion of Patients with a Positive Test Who Are Given a Correct
Diagnosis
D. Negative Predictive Value: Proportion of Patients with a Negative Test Who Are Given a Correct
Diagnosis
E. Example: Relationship Between Test and Correct Diagnosis Identified by Pathology (data from: J
Nucl Med 1972;13:90815)
Pathology
Test Abnormal Normal Total
Abnormal (positive test) 231 32 263
Normal (negative test) 27 54 81
Total 258 86 344
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REFERENCES
1. Strassels SA, Wilson JP. Pharmacoepidemi- 8. Mann CJ. Observational research methods.
ology. In: Dunsworth TS, Richardson MM, Chant Research design II: cohort, cross sectional and
C, et al, eds. Pharmacotherapy Self- Assessment case-control studies. Emerg Med J
Program, 6th ed. Lenexa, KS: ACCP, 2007. 2003;20:5460.
2. Shermock KM. Secondary data analysis/ 9. Dasgupta A, Lawson K A, Wilson JP. Eval-
observational research. In: Dunsworth TS, uating equivalence and noninferiority trials. Am
Richardson MM, Chant C, et al, eds. Phar- J Health Syst Pharm 2010;67:133743.
macotherapy Self-Assessment Program, 5th ed.
10. Lesaffre E. Superiority, equivalence and non-
Kansas City, MO: ACCP, 2005.
inferiority trials. Bull NY U Hosp Jt Dis
3. Smith GH, Mays DA. Clinical study design and 2008;66:1504.
literature evaluation. In: Zarowitz B, Shumock G,
11. Lagakos SW. The challenge of subgroup
Dunsworth T, et al, eds. Phar- macotherapy Self-
Assessment Program, 4th ed. Kansas City, MO: analyses reporting without distorting. N Engl
ACCP, 2002. J Med 2006;354:16679.
4. Quilliam BJ, Barbour MM. Evaluating drug- 12. Tomlinson G, Detsky AS. Composite end-
induced cardiovascular disease: a points in randomized trials: there is no free
pharmacoepidemiologic perspective. In: lunch. JAMA 2010;303:2678.
Richardson MM, Chant C, Cheng JWM, 13. Neely JG, Magit AE, Rich JT, et al. A practical
et al, eds. Pharmacotherapy Self-Assessment guide to understanding systematic reviews and
Program, 7th ed. Lenexa, KS: ACCP, 2010. meta-analysis. Otolaryngol Head Neck Surg
2010;142:614.
5. Tsuyuki RT, Garg S. Interpreting data in 14. DiPietro NA. Methods in epidemiology:
cardiovascular disease clinical trials: a bio- observational study designs. Pharmacother- apy
statistical toolbox. In: Richardson MM, Chant 2010;30:97384.
C, Cheng JWM, et al, eds. Pharma- cotherapy 15. Koretz RL. Methods of meta-analysis: an
Self-Assessment Program, 7th ed. Lenexa, KS: analysis. Curr Opin Clin Nutr Metab Care
ACCP, 2010. 2002;5:46774.
6. Windish DM, Huot SJ, Green ML. Medi- cine 16. Altman DG, Bland JM. Diagnostic tests 1:
residents understanding of the biosta- tistics and sensitivity and specificity. BMJ
results in the medical literature. JAMA 1994;308:1552.
2007;298:101022.
17. Altman DG, Bland JM. Diagnostic tests 2:
7. Clancy MJ. Overview of research designs. predictive values. BMJ 1994;309:102.
Emerg Med J 2002;19:5469.
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POLICY, PRACTICE AND
REGULATORY ISSUES
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Policy, Practice and Regulatory Issues
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Learning Objectives:
1. Explain the prescription drug approval process of the U.S. Food and Drug Administration.
2. Identify implications for clinical research while adhering to institutional review board requirements.
3. List the purpose and function of an investigational drug service.
4. Describe national efforts aimed at improving and ensuring health care quality in the United States,
including the Joint Commission, National Committee for Quality Assurance, National Quality Forum, and
Agency for Healthcare Research and Quality.
5. Interpret legislative activity and regulatory opportunities for pharmacists.
OVERVIEW
The purpose of this review of policy, practice, and regulatory issues is to highlight areas of importance for
clinical pharmacists as they pertain to patient care outcomes and clinical research activity. Specifically, the
rules and regulations set forth by several agencies within the U.S. Department of Health and Human Services
will be outlined.
I. THE U.S. FOOD AND DRUG ADMINISTRATION AND THE PRESCRIPTION DRUG
APPROVAL PROCESS
A. Basics
1. The U.S. Food and Drug Administration (FDA) is the agency within the U.S. Department of
Health and Human Services (DHHS) responsible for the safety of most foods (human and animal)
and cosmetics, and it regulates both the safety and effectiveness of human drugs, biologics (e.g.,
vaccines, blood and blood components), medical devices, and animal drugs.
2. Most federal laws giving the FDA this authority are provisions in and amendments to the Federal
Food, Drug, and Cosmetic Act (FD&C Act), and they are organized in the Code of Federal
Regulations (CFR) Title 21. The FDA is funded through discretionary spending every fall in
Congresss Appropriations bill written by the Senate and House Appropriations Committees, but
the Senate Health, Education, Labor, and Pensions and the House Energy and Commerce
Committees have jurisdiction over its reauthorization.
3. It is organized by two offices, one research center, and six product centers:
a. Office of the Commissioner conducts overall agency coordination; the FDAs top official, the
Commissioner, requires Senate confirmation.
b. Office of Regulatory Affairs, the largest office, regulates all inspection and enforcement
activities.
c. National Center for Toxicological Research supports the six product centers with scientific
technology, training, and technical expertise.
d. Center for Drug Evaluation and Research (CDER) regulates prescription and
nonprescription drugs.
e. Center for Biologics Evaluation and Research regulates vaccines, blood, and gene therapy.
f. Center for Devices and Radiological Health regulates medical devices.
g. Center for Food Safety and Applied Nutrition regulates most foods, food additives, infant
formulas, dietary supplements, and cosmetics.
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B. Definitions
1. The Abbreviated New Drug Application (ANDA) contains data that, when submitted to the FDAs
CDER, Office of Generic Drugs, allows the review and ultimate approval of a generic drug
product.
2. An authorized generic drug is a listed drug that is marketed, sold, or distributed directly or
indirectly to retail class of trade with labeling, packaging (other than repackaging as the listed
drug in blister packs, unit doses, or similar packaging for use in institutions), product code, labeler
code, trade name, or trademark that differs from that of the listed drug.
3. A biologics license application (BLA) is a submission that contains specific information on the
manufacturing processes, chemistry, pharmacology, clinical pharmacology, and medical effects of
a biologic product (monoclonal antibodies, enzymes, immunomodulators, growth factors, and
cytokines) seeking approval to market in the United States.
4. A clinical trial is a research study of humans conducted to answer specific questions about
vaccines, new therapies, or new ways of using known treatments. Clinical trials required by the
FDA seek to determine whether new drugs or treatments are both safe and effective.
5. An Investigational New Drug (IND) application is used for a new drug, a new indication, or off-
label use that will be used in a clinical investigations preclinical development in order for that
new drug to be distributed across state lines before undergoing full FDA review.
6. A New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that
the FDA approve a new pharmaceutical for sale and marketing in the United States.
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c. Authorized the FDA to regulate advertising of prescription drugs and establish good
manufacturing practices
7. The Orphan Drug Act of 1983 established grants, federal assistance for research, and tax
incentives to develop drugs targeted for a patient population of less than 200,000.
8. The Food and Drug Administration Act of 1988 officially established the FDA as an agency in
DHHS.
9. Prescription Drug User Fee Act (PDUFA) of 1992
a. Requires drug, biologics, and medical device (MDUFA) manufacturers to pay fees for product
applications, supplements, and other services
b. Reauthorized every 5 years (1997, 2002, 2007)
10. The Dietary Supplement Health and Education Act of 1994 allows nutritional supplements and
vitamins to be regulated.
11. FDA Modernization Act of 1997
a. Streamline clinical research on drugs and devices
b. Exclusivity provisions for pediatric drugs
c. Authorizes the creation of a databank (ClinicalTrials.gov) to provide easy access to
information on federally and privately supported clinical trials for a wide range of diseases
and conditions
i. Provides abstracts of clinical study protocols that investigators are required to submit
(a) Summary and purpose of study
(b) Recruiting status
(c) Criteria for patient participation
(d) Location for trial and specific contact information
(e) Research study design
(f) Phase of trial
(g) Disease or condition and drug or therapy under study
ii. More than 115,000 clinical trials have been listed in over 170 countries.
12. Food and Drug Administration Amendments Act of 2007 (FDAAA)
a. Vehicle for reauthorizing PDUFA
b. Statutory authority to require Risk Evaluation Mitigation Strategies (REMS)
13. The Family Smoking Prevention and Tobacco Control Act of 2009 gave the FDA authority to
regulate tobacco products.
14. The Patient Protection and Affordable Care Act of 2010 established a regulatory approval
pathway for biosimilars or follow-on biologics.
15. The Reducing Prescription Drug Shortages Executive Order was signed by President Barack
Obama on October 31, 2011. It requires the FDA to:
a. Broaden reporting of manufacturing discontinuances that may lead to shortages of drugs that
are life supporting or life sustaining or that prevent debilitating disease;
b. Expedite regulatory review to avoid or mitigate existing or potential drug shortages. Reviews
may include new drug suppliers, manufacturing sites, and manufacturing changes; and
c. Communicate to the Department of Justice any evidence of or behaviors by market
participants that have contributed to stockpiling or exorbitant prices.
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a
NDA = New Drug Approval.
b
The safety update report is usually submitted 120 days after the NDA submission.
E. Generic Drugs
1. Around 69% of all drugs dispensed are generic.
2. A generic drug product is one that is identical (bioequivalent) to an innovator drug product in
dosage form, strength, route of administration, quality, performance characteristics, and intended
use. The Drug Price Competition and Patent Term Restoration Act of 1984, also known as the
Hatch-Waxman Act, defined bioequivalence statutorily as a means to approve a generic drug.
3. Once an ANDA is submitted to and approved by CDERs Office of Generic Drugs, the applicant
can manufacture and market the generic drug as a safe, effective, and low-cost option to the
public.
4. All approved products are listed in the FDAs Approved Drug Products with Therapeutic
Equivalence Evaluations (Orange Book).
5. ANDAs generally do not require preclinical or clinical data, but rather, they must demonstrate bio-
equivalence.
6. Pharmaceutical equivalents
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7. Therapeutic equivalents can be substituted with the expectation that the substituted product will
produce the same clinical effect and safety profile as the prescribed product.
a. Criteria
i. Pharmaceutical equivalent
ii. Therapeutic equivalence codes rated A by the FDA
b. Assigns therapeutic equivalence code on the basis of data submitted in an ANDA to
demonstrate bioequivalence
i. ANDA contains adequate scientific evidence establishing through in vivo and/or in vitro
stud- ies of bioequivalence of the product to the reference listed drug.
ii. Products deemed by the FDA not therapeutically equivalent are B rated.
8. An authorized generic is a prescription drug produced by the brand pharmaceutical company and
marketed at generic prices during and after the 180-day exclusivity period that is identical to the
brand alternative both in active and inactive ingredients.
9. At-risk launch of a generic occurs when a generic drug manufacturer challenges the validity of the
existing patent of a brand drug.
10. Follow-on biologics or biosimilars are drugs or vaccines that have been produced in living cells.
a. Biosimilars are approved new versions of an innovator biopharmaceutical product after patent
expiration; this is a fairly controversial area between the government, industry, and patient
advocacy organizations.
b. Legislation has created a statutory pathway for the FDA to approve these products after 12
years of data exclusivity for the manufacturer of a new biologic product.
F. Medical Devices
1. An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other
similar or related article, including a component part, or accessory that is:
a. Recognized in the official National Formulary, or the United States Pharmacopoeia, or any
supplement to them
b. Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation,
treatment, or prevention of disease, in humans or other animals
c. Intended to affect the structure or any function of the body of humans or other animals that
does not achieve any of its primary intended purposes through chemical action within or on
the body
of human beings or other animals and that is not dependent on being metabolized for the
achieve- ment of any of its primary intended purposes
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Box 3. Risk Evaluation and Mitigation Strategies Requirements of Elements to Ensure Safe Use
Elements to Ensure Safe Use may include one of the following:
Health care providers who prescribe the drug have particular training or experience or are specially certified
Pharmacies, practitioners, or health care settings that dispense the drug are specially certified
Drug dispensed only in certain health care settings
Drug dispensed to patients with evidence of safe-use conditions, such as laboratory test results
Each patient using the drug is subject to monitoring
Each patient using the drug is enrolled in a registry
The FDA does not have the authority to impose penalties on pharmacies and pharmacists not in
3.
com- pliance with REMS requirements, but there may be legal implications such as misbranding
violations or civil liability issues.
H. MedWatch Through the FDA Is a Voluntary Safety Information and Adverse Event Reporting
Program.
I. Critical Path Initiative
1. Created in response to a significant decline in NDAs, BLAs, and medical device applications
because of the widening gap between basic science discovery and the challenging, inefficient, and
costly development of medical product development
2. Prioritizes the most pressing development problems and identifies areas that provide the greatest
opportunities for rapid improvement and public health benefit through three dimensions:
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Assessing safety Show that the product is Preclinical: Show that product is safe enough for human testing
adequately safe for each Eliminate products with safety problems early
stage of development Clinical: Show that the product is safe enough for commercial
distribution
Demonstrating Show that the product Preclinical: Select appropriate design (devices) or candidate
medical utility benefits people (drugs) with high probability of effectiveness
Clinical: Show effectiveness in people
II. INSTITUTIONAL REVIEW BOARD (IRB) IMPLICATIONS FOR CLINICAL PRACTICE AND
RESEARCH
A. Basics
1. Every institution that conducts or supports biomedical or behavioral research involving human
participants must, by federal regulation, have an IRB that initially approves and periodically
reviews research protocols to protect the rights of human participants.
2. Governed by DHHS Office for Human Research Protections (OHRP) regulations at Title 45 CFR
Part 46; requires the IRB or ethics committee to protect the rights, safety, and well-being of all
study subjects. Specifically, Subpart A constitutes the Federal Policy (Common Rule) for the
Protection of Human Subjects.
3. IRB approval is required for interventional and observational studies, and applications must be
reviewed annually.
B. Definitions
1. The Health Insurance Portability and Accountability Act (HIPAA) of 1996 provides protection for
the privacy of certain individually identifiable health data, referred to as protected health
information (PHI).
2. Human subject means a living individual about whom an investigator conducting research obtains
1) data through intervention or interaction with the individual or 2) identifiable private
information.
3. Informed consent is the process of learning the key facts about a clinical trial before deciding
whether to participate.
4. An informed consent document describes the rights of the study participants and includes details
about
the study including purpose, duration, required procedures, risks, benefits, and key contacts.
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C. The IRB is composed of at least five members with varying backgrounds to promote complete and
adequate review of research activities while adhering to institutional commitments and regulations,
applicable law, and standards of professional conduct and practice.
1. The committee must be sufficiently qualified through the experience, expertise, and diversity of its
members, including race, gender, cultural background, and sensitivity to issues such as community
attitudes, to promote respect for its advice and counsel.
2. At least one member whose primary concerns are in scientific areas
3. At least one member whose primary concerns are in nonscientific areas
4. At least one member who is not affiliated with the institution and who is not an immediate family
member of a person affiliated with the institution
F. The HIPAA Privacy Rule Supplements and Expands the Common Rule Regulation of Human
Subjects Research.
1. Protections for the confidentiality of PHI used in clinical practice, research, and the operation of
health care facilities
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G. Typical Documents Submitted to the IRB for an Initial Review. Examples of these documents can be
found at NIHs National Institute on Aging Clinical Study Investigators Toolbox.
Box 4. Documents That May Need to Be Submitted to an IRB for Initial Review
Cover sheet
Conflict of interest assessment
Application
Formal protocol
Informed consent forms
HIPAA authorization forms
Recruitment materials
Surveys, questionnaires, other instruments
Federal grant, if applicable
Documentation of IRB approval from another institution
Data and safety monitoring plan
Additional supportive documents as requested by IRB
HIPAA = Health Insurance Portability and Accountability Act; IRB = institutional review board.
H. Informed Consent
1. Basic elements
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a. A statement that the study involves research, an explanation of the purposes of the research,
the expected duration of the subjects participation, a description of the procedures to be
followed, and the identification of any procedures that are experimental
b. A description of any reasonably foreseeable risks or discomforts to the subject
c. A description of any benefits to the subject or to others that may reasonably be expected from
the research
d. A disclosure of appropriate alternative procedures or courses of treatment that might be
advantageous to the subject
e. A statement describing the extent to which confidentiality of records identifying the subject
will be maintained
f. For research involving more than minimal risk, an explanation regarding whether there is any
compensation and an explanation regarding whether any medical treatments are available if
injury occurs and, if so, what they consist of, or where further information may be obtained
g. An explanation of whom to contact for answers to pertinent questions about the research and
research subjects rights and of whom to contact in the event of a research-related injury to the
subject
h. A statement that participation is voluntary, refusal to participate will involve no penalty or
loss of benefits to which the subject is otherwise entitled, and the subject may discontinue
participation at any time without penalty or loss of benefits to which the subject is otherwise
entitled
2. Waiver will be considered if
a. Research involves no more than minimal risk to subjects;
b. The waiver or alteration will not adversely affect the rights and welfare of subjects;
c. The research could not practicably be carried out without the waiver or alteration; and
d. Where appropriate, the subjects will be provided with additional pertinent information after
participation.
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NAME OF INSTITUTION
And
Principal Investigator: Include name of PI (PI contact telephone number) (PI contact e-mail)
INVITATION
You are invited to participate in this research study about: Provide brief description of research in terms under-
standable to a layperson.
You are invited to take part because you: Describe why the person is being asked to participate as a research
subject in the study. Give an approximation of the number of individuals who will participate in the study.
Your participation in this research study is voluntary. If you decide not to participate, the health care provided
to you by the insert institution name will not be affected in any way.
We will also collect the following information about you for this research study:
1. From you: List the demographic information that you will collect from the subject (i.e., birth date, home
address, phone number, e-mail address). List the health information that you will collect from the subject
(i.e. diet, exercise habits, use of tobacco, use of alcohol).
2. From your medical records, health records (such as x-rays), and/or billing records: List the information
from the subjects medical or other health or billing records that will be used for this research.
3. From medical tests or other procedures performed for this study: List the medical tests or other procedures
that will be performed for this study and the information generated by each (e.g., white blood cell count
from blood test).
List any benefits to the subject in a way that is not coercive, enticing, or self-serving. This section should in-
clude a statement that there may be no benefit to the subject.
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Describe, in terms understandable to a layperson, any risks to research participants. This could include health
risks and/or psychosocial risks including breach of confidentiality resulting in legal issues, and insurability and
employability problems. Example: The main risk of taking part in this study is that your study information could
become known to someone who is not involved in performing or monitoring this study.
Sample statement: The information collected from you during this study and from your medical records will be
used by the researchers and research staff of at this institution for this study. It may also be shared with others
outside of this institution.
Describe how research data will be kept confidential by the investigator. Specify the measures that will be
implemented by your research group to safeguard the PHI from unauthorized use or disclosure. For paper forms
of PHI, your plan should address, at least, the following: Locking up your research files while they are
unsupervised, shredding excess copies of paper documents, protections for codes that link patients to their data.
For electronic forms of PHI, plan should address, at least, the following: Workstation locks that secure a users
computer from unauthorized access when not in use, defining the electronic location where PHI will be stored
and the technical security measures in place to protect the data while it is stored there, authentication
requirements to access the PHI, including whether authentication occurs at the network, device, folder or file
level, audit trails to record accesses or changes to data, and transmission protocols that assure data cannot be
intercepted while in transit If PHI is to be disclosed outside your institution, describe the plans of any research
collaborators to protect the PHI you will share with them.
List others inside and outside the institution of record who may need to use PHI in the course of the research
protocol (i.e. Institutional regulatory and research oversight boards and offices, Accounting and billing perso nel)
Certificate of Confidentiality
Sample statement: To help us protect your privacy, we have obtained a Certificate of Confidentiality from the
National Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information that
may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative,
legislative, or other proceedings. The researchers will use the Certificate to resist any demands for information
that would identify you, except as explained below.
The Certificate cannot be used to resist a demand for information from personnel of the United States
Government that is used for auditing or evaluation of Federally funded projects or for information that must be
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA).
You should understand that a Certificate of Confidentiality does not prevent you or a member of your family from
voluntarily releasing information about yourself or your involvement in this research. If an insurer, employer, or
other person obtains your written consent to receive research information, then the researchers may not use the
Certificate to withhold that information.
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, without your
consent, information that would identify you as a participant in the research project in certain circumstances.
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Your permission is voluntary. You do not have to sign this form and you may refuse to do so. If you refuse to sign
this form, however, you cannot take part in this research study.
You may completely withdraw from the study at any time. You also may choose to cease participation or skip any
questions that you do not feel comfortable answering.
By signing this form you are giving permission for your health information to be used by and shared with the
individuals, companies, or institutions described in this form. Unless you withdraw your permission in writing to
stop the use of your health information, there is no end date for its use for this research study. You may withdraw
your permission at any time by writing to the person whose name is listed below:
Beginning on the date you withdraw your permission, no new information about you will be used. Any
information that was shared before you withdrew your permission will continue to be used. If you withdraw your
permission, you can no longer actively take part in this research study.
Please take as much time as you need to think over whether or not you wish to participate. If you have any
questions about this study at any time, contact the Principal Investigator: Include name of PI and contact
telephone number.
If you are not satisfied with response of research team, have more questions, or want to talk with someone about
your rights as a research participant, contact: Insert institutions patient relations representative (or title specific
to the institution) and provide telephone number
I have read this consent and authorization form describing the research study procedures, risks, and benefits, what
health information will be used, and how my health information will be used. I have had a chance to ask questions
about the research study, including the use of my health information, and I have received answers to my questions.
I agree to participate in this research study, and permit the researcher to use my health information as described
above.
Include date of version and leave room for IRB stamp of approval according to institutions specifications
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A. Basics
1. The American Society of Health-System Pharmacists Policy on Institutional Review Boards and
Investigational Use of Drugs (0711) strongly supports pharmacists management of the control
and distribution of drug products used in clinical research.
2. The purpose of an IDS is to procure, manage, prepare, dispense, and dispose of investigational
drugs according to protocol and in compliance with the state and federal requirements that govern
investigational drug activities.
B. Definitions Drugs, as defined by the FD&C Act, are (A) articles intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease, and (B) articles (other than food) intended to
affect the structure or any function of the body of man or other animals [FD&C Act, sec. 201(g)(1)].
An investigational drug is a chemical or biologic substance that has been tested in a laboratory and
been approved by the FDA to be tested in human subjects. An investigational (also referred to as
experimental) drug may be:
1. A new chemical or compound that has not been approved by the FDA for general use or
2. An approved drug undergoing further investigation for an approved or unapproved indication,
dose, dosage form, administration schedule, or under an IND application in a controlled,
randomized, or blinded clinical trial
C. In addition to the regulations outlined by the Office of Human Research Protection (Common Rule)
and the FDA to conduct research in accordance with the principles of good clinical practice and
human subjects protection, there are federal and state requirements of an IDS:
1. The Joint Commission Standards require policies for the use of investigational drugs that
specifically
address their storage, dispensing, labeling, and distribution.
2. The Environmental Protection Agency and Occupational Safety and Health Administration
regulate the disposal of investigational drugs.
3. The American Society of Health-System Pharmacists provides practice standards.
4. The local IRB
5. State-specific laws may vary.
D. A Study-Specific Notebook Is Maintained Where Study Drugs Are Stored. It contains the following
files and contents:
Drug information Investigators brochure, drug data sheet, package inserts (if commercially available)
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Correspondence Correspondence
Drug accountability records Data accountability record for each drug/dosage form/package size/strength
IRB = institutional review board.
E. In addition to managing the activities outlined under the purpose of an IDS, an investigational drug
pharmacists duties may include
1. Participating in IRB as a voting member
2. Maintaining a working relationship with the IRB, Pharmacy and Therapeutics Committee,
principal investigators, and the pharmacy department
3. Reviewing new and existing investigational drug study protocols
4. Meeting with investigators, study monitors, and other study personnel responsible for coordinating
the logistics of a clinical trial
5. Receiving, organizing, and maintaining the contents of study notebooks
6. Providing randomization, blinding, or control functions of a clinical trial
7. Conducting the training of IDS staff and personnel regarding investigational protocols and study
drug procedures
A. The programs outlined in this section are not federal regulatory programs, but they play an important
role in the pharmacists ability to provide patient-centered, safe, and effective care.
B. The Joint Commission is a not-for-profit, independent organization that sets standards for accrediting
health care facilities through its mission to continuously improve health care for the public, in
collaboration with other stakeholders, by evaluating health care organizations and inspiring them to
excel in providing safe and effective care of the highest quality and value.
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1. Basics
a. Accredits and certifies more than 19,000 health care organizations in the United States
b. Standards address an organizations performance in functional areas of patient rights, patient
treatment, medication safety, and infection control. Hospitals provide data from a selection of
57 inpatient measures.
2. Definitions
a. National Patient Safety Goals were established to help accredited organizations address
specific areas of concern in patient safety in the areas of ambulatory health care, behavioral
health care, critical access hospital, home care, hospital, laboratory, long-term care,
Medicare/Medicaid long- term care, and office-based surgery.
b. ORYX is a Joint Commission performance measurement and improvement initiative
implemented to integrate outcomes with accountability measures in the areas of acute
myocardial infarction, heart failure, pneumonia, surgical care improvement project, childrens
asthma care, perinatal, hospital outpatient measures, venous thromboembolism, hospital-based
inpatient psychiatric ser- vices, and stroke in its accreditation process.
i. Common standardized measures between the Joint Commission and the CMS are called
National Hospital Quality Measures.
ii. Accountability measures and processes that result in the greatest improvement in patient
out- comes have been identified by the Joint Commission. These measures and processes
must be of sound scientific evidence, have close proximity between process and outcome,
accurately measure the process, and minimize adverse effects without inducing
unintended consequenc- es. Measures are updated frequently. Examples of current
inpatient measures are listed below. (a) Acute myocardial infarction
(1) Aspirin at arrival
(2) Aspirin at discharge
(3) Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB) at discharge
(4) -Blocker at discharge
(5) Fibrinolytic therapy within 30 minutes
(6) Primary PCI (percutaneous coronary intervention) balloon within 90 minutes
(7) Smoking cessation advice/counseling
(b) Heart failure care requiring an ACE inhibitor or ARB at discharge
(c) Pneumonia care
(1) Pneumococcal vaccination
(2) Blood culture in emergency department
(3) Antibiotics for immunocompetent patients
(4) Influenza vaccination
(d) Surgical care (Surgical Care Improvement Project [SCIP]) (1) Antibiotics within 1
hour before the first surgical cut (2) Appropriate prophylactic antibiotics
(3) Discontinuing antibiotics within 24 hours
(4) Cardiac patients with controlled 6 a.m. postoperative blood glucose
(5) Patients with appropriate hair removal
(6) -Blocker patients who received -blocker perioperatively
(7) Prescribing venous thromboembolism prophylaxis
(8) Receiving venous thromboembolism prophylaxis
(e) Childrens asthma care
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D. NQF is a nonprofit organization that aims to improve quality through a three-part mission: setting
national priorities and goals for performance improvement; endorsing national consensus standards for
measuring and publicly reporting on performance; and promoting the attainment of national goals
through education and outreach programs. Basics:
1. Membership includes stakeholders from consumer organizations, public and private purchasers,
physic cians, nurses, accrediting and certifying bodies, supporting industries, and health care
research and quality improvement organizations.
2. Through the passing of the Medicare Improvements for Patients and Providers Act of 2008,
DHHS entered into a contract with NQF to establish a portfolio of quality and efficiency measures
for use in reporting on and improving health care quality for the federal government to determine
a return on investment on health care spending.
a. Formulation of a national strategy and priorities for health care performance measurement in
order to review and synthesize evidence related to 20 high-priority conditions identified by
CMS that account for more than 95% of their costs
b. Implementation of a consensus process for endorsement of health care quality measures
c. Maintenance of consensus-endorsed measures
d. Promotion of electronic health records (EHRs)
e. Focused measurement of the development, harmonization, and endorsement efforts to fill
critical gaps in performance measurements
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F. The PQA
1. Basics
a. The mission of PQA is to improve the quality of medication use across health care settings
through a collaborative process in which key stakeholders agree on a strategy for measuring
and reporting performance information related to medications.
b. Developed performance measures including proportion of days covered, gap in medication
therapy, diabetes medication dosing, suboptimal treatment of hypertension in patients with
diabetes, use of high-risk medications in the elderly, drug-drug interactions, and medication
therapy for individuals with asthma.
2. Demonstration projects have been funded across the country.
A. The American Recovery and Reinvestment Act (ARRA) of 2009 provided a vehicle for passing
the Health Information Technology for Economic and Clinical Health (HITECH) Act, which
authorized DHHS to create programs to improve health care quality, safety, and efficiency through
the promotion of HIT, including EHRs.
1. Created the Office of the National Coordinator to coordinate nationwide implementation efforts
2. The Standards and Certification Criteria Final Rule is the initial approach to adopting standards,
implementing specifications, and providing certification criteria to enhance the interoperability,
functionality, utility, and security of HIT and to support its meaningful use.
3. The Incentive Program for Electronic Health Records was issued by CMS to provide a financial
incentive to eligible professionals, eligible and critical access hospitals, and Medicare Advantage
Organizations that are meaningful users of EHRs.
a. ARRA 2009 specified three main components for Meaningful Use:
i. Use of certified EHRs in a meaningful manner (i.e., e-Prescribing)
ii. Use of certified EHR technology for electronic exchange of health information to improve
quality of health care
iii. Use of certified EHR technology to submit clinical quality and other measures
b. Incentive payments began in fiscal year 2011 and will gradually decrease until fiscal year
2015, when penalties are put into effect.
B. The Patient Protection and Affordable Care Act of 2010 contains several provisions, ranging from
protecting consumers to improving health care quality and lowering costs to increasing access to care.
As the law translates into regulation, unique opportunities exist for pharmacists to become engaged.
1. Funding opportunities will be available for pharmacists to demonstrate their contributions as
providers of medication therapy management.
2. The patient-centered medical home model emphasizes primary care as a central role in managing
the chronic conditions of patients using a team-based care approach.
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3. ACOs are a set of providers associated with a defined population of patients accountable for the
quality and cost of care delivered to that population.
4. Independence at Home Demonstration Program promotes the interdisciplinary collaboration of
clinicians to provide home-based medical care for Medicare beneficiaries.
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REFERENCES
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Infectious Diseases in the Ambulatory Care Setting
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Learning Objectives:
1. Be able to design appropriate pharmacologic and nonpharmacologic treatment regimens for various patient
populations with urinary tract infections, prostatitis, community-acquired pneumonia, influenza, upper
respiratory tract infections, skin and soft tissue infections, and sexually transmitted diseases.
2. Recognize and recommend appropriate immunizations to meet the requirements of CDC (Centers for
Disease Control and Prevention) recommendations for routinely recommended immunizations for infants
and children.
3. Identify risk factors and clinical circumstances in which antimicrobial resistance is a risk, and be able to
appropriately design antimicrobial regimens to treat resistant infections and prevent future development.
4. Be able to apply patient and clinical factors to design antimicrobial regimens that are appropriate and cost-
effective for the patient.
I. COMMUNITY-ACQUIRED PNEUMONIA
B. CAP Description
1. CAP is a lower respiratory tract infection in patients who are not hospitalized or who have not
been in a health care nonambulatory setting, with infiltrates on chest radiographs or consistent
with auscultatory findings.
2. Risk factors
a. Age older than 65 years
b. Asthma
c. Chronic obstructive pulmonary disease
d. Diabetes
e. Smokers
f. Congestive heart failure
g. Chronic renal failure
h. Immunocompromised/HIV (human immunodeficiency virus)
i. Recent antibiotic therapy
j. Alcohol abuse
3. Pathogenesis: Organisms gain entry to lower respiratory tract through:
a. Inhalation of aerosolized particles
b. Entrance to the lung through the bloodstream from an extrapulmonary infection site
c. Aspiration of oropharyngeal contents
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C. Etiology
1. Streptococcus pneumoniaeAbout 75% of CAP cases
2. Haemophilus influenzae
3. Mycoplasma pneumoniae
a. About 20% of CAP cases
b. Atypical pneumonia pathogen
4. Chlamydia pneumoniae
a. Atypical pneumonia pathogen
b. 5%15% of CAP cases
5. Legionella pneumophila
a. 2%15% of CAP cases
b. Atypical pneumonia pathogen
6. Respiratory viruses: Influenza A and B, adenovirus, respiratory syncytial virus, and parainfluenza
7. Less common: Methicillin-resistant Staphylococcus aureus (MRSA) and community-acquired
MRSA (CA-MRSA), Pseudomonas, Acinetobacter
a. Mainly in the elderly or in patients with severe comorbidities such as alcoholism and diabetes
b. Patients who have been recently hospitalized or in nursing homes; in these instances, it is
referred to as health careassociated pneumonia
D. Diagnosis
1. Signs and symptoms
a. CAP diagnosis is primarily based on clinical signs and symptoms, with the most common
symptoms being fever (temperature greater than 38C/100.4F) and cough with or without
sputum.
b. Symptoms may be nonspecific in older patients.
c. Other symptoms
i. Dyspnea
ii. Pleuritic chest pain
iii. Wheezing
iv. Myalgia, sweats, rigors
2. Diagnostic and laboratory tests
a. Physical examination
i. Rales, rhonchi, inspiratory crackles
ii. Dullness to percussion
iii. Increased tactile fremitus, egophony
b. Positive chest radiograph: False negatives can be seen in severe dehydration, early pneumonia,
neutropenia
c. Microbiologic testing
i. Not routinely done in outpatient practice
(a) The Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS)
2007 guidelines recommend testing if the result is likely to change individual
treatment.
(b) May be indicated if previous antibiotic therapy has failed
ii. Sputum Gram stain usually reveals many polymorphonuclear cells, with the predominance
of a bacterial pathogen.
iii. Blood and sputum cultures are more likely to be performed in severe cases
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E. Treatment
1. Therapy goals: Eradicate infecting organism, prevent complications, and prevent resistance.
2. The IDSA/ATS guidelines suggest treatment protocols because they have been shown to decrease
mortality.
3. Initial treatment will be empiric and should target the most likely organisms. Ability to cover both
typical bacterial pathogens (S. pneumoniae, H. influenzae) and atypical pathogens (M.
pneumoniae, C. pneumoniae, and Legionella)
a. -Lactams do not cover atypical pathogens.
b. Macrolides and fluoroquinolones cover both typical and atypical pathogens.
c. Doxycycline covers both typical and atypical pathogens, but it may not adequately cover more
resistant pathogens such as penicillin-resistant S. pneumoniae.
4. Antimicrobials should have the ability to reach adequate concentrations within the respiratory
secretions.
5. Risk factors and where patient is to be treated (outpatient or inpatient) should be considered in
therapy decisions.
6. Treatment duration should be for 710 days unless otherwise noted (i.e., azithromycin package
dosing of 5 days).
7. Outpatient treatment based on IDSA/ATS guidelines
a. Previously healthy and no antimicrobials in past 3 months
i. Macrolide (azithromycin, clarithromycin)
ii. Doxycycline
b. Presence of comorbidities such as diabetes; alcoholism; immunosuppression; asplenia; chronic
heart, lung, or liver disease; use of antimicrobial in past 3 months (be sure to choose an
antimicrobial from a class that differs from that previously administered)
i. Respiratory fluoroquinolone (levofloxacin 750 mg, moxifloxacin, gemifloxacin)
ii. -Lactam(high-dose amoxicillin 1 g three times/day; amoxicillin/clavulanate 2 g two
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F. Resistance
1. Resistance patterns vary geographically, and empiric antibiotic selections should consider local
susceptibility patterns.
2. Drug-resistant S. pneumoniae
a. Penicillin
i. Current breakpoints for nonmeningeal infections set in 2008 by the Clinical and
Laboratory Standards Institute (CLSI)
(a) Susceptibility of 2 mg/L or less
(b) Intermediate 4 mg/L
(c) Resistant 8 mg/L or greater
ii. Although MICs have risen during the past 20 years for penicillin, data suggest the
clinically relevant level of resistance is greater than 4 mg/L.
b. Macrolides and fluoroquinolones i. Continue to rise
ii. Resistance is associated with more clinical failures.
c. Multidrug resistant
i. In the late 1990s, there was an increase in -lactam plus macrolide-resistant S.
pneumoniae.
ii. A 2008 study found less than 5% multidrug resistance in Europe; the decreased number
probably reflects changes in CLSI susceptibility breakpoints for penicillin.
3. Risk factors for resistance
a. Age younger than 2 years or older than 65 years
b. Previous -lactam, macrolide, or fluoroquinolone exposure
c. Alcoholism
d. Medical comorbidities
e. Immunosuppression
f. Exposure to children in a day care setting
II. INFLUENZA
A. Overview
1. Influenza caused by RNA viruses, predominantly influenza A or B
2. Each year, 5%20% of the population is infected.
3. Very large impact on outpatient health services
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4. Influenza season is defined as when influenza viruses are circulating in the community, anywhere
from about September to April in the Northern Hemisphere; usually most predominant in winter
months (December to March)
5. Associated with high morbidity and mortality rates in the United States each year
a. Average of 36,000 deaths
b. Greater than 200,000 hospitalizations
6. Most infections are self-limited and resolve without complications.
7. Severe disease can lead to hospitalization and even death, especially in high-risk patients.
a. Elderly
b. Very young
c. Comorbid medical conditions
8. Vaccination is the best method for prevention, and it should be administered to all who are at risk.
B. Diagnosis
1. Signs and symptoms
a. Sudden onset of fever and cough is the most predictive (sensitivity greater than 70%).
b. Headache
c. Myalgias
d. Tiredness, weakness, exhaustion
e. Chest discomfort
f. Symptoms often seen, but they are not as specific, and they may be more consistent than those
for the common cold
i. Stuffy nose
ii. Sneezing iii. Sore throat
g. Diarrhea
i. Up to 28% seen in infants and young children
ii. Not as commonly seen in adults
h. Presentation can vary by age, comorbidities, immune status
2. Diagnostic specimens
a. Diagnosis is often made by clinical presentation only.
b. Nasopharyngeal aspirates and swabs preferably taken within 5 days of illness onset; if taken
after more than 5 days, false-negative tests may result because of decreased viral shedding
c. Tests available for influenza
i. Reverse transcriptase-polymerase chain reaction (RT-PCR)
(a) Most sensitive and specific
(b) Will differentiate influenza type (i.e., H1N1, H5N1)
ii. Commercial rapid influenza tests
(a) Results in 1030 minutes
(b) Less sensitive than RT-PCR
(c) Performance depends on patient age, illness duration, and sample type.
(d) A follow-up with RT-PCR may be needed.
iii. Immunofluorescence
(a) Antigen detection
(b) Performance depends greatly on laboratory expertise.
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C. Pathophysiology
1. Type A
a. Grouped by variations in hemagglutinin and neuraminidase (i.e., H1N1, H5N1, H1N2)
b. Can see epidemics every 13 years; for example, the H1N1 epidemic of 20092010
2. Type B
a. Carries one form of hemagglutinin and one form of neuraminidase
b. Can see epidemics less often than in type A, every 5 years
D. Treatment
1. Recommended for adults and children with the following:
a. Patients having highly suspected or laboratory-confirmed influenza who are within 48 hours of
symptom onset
b. Patients with high risk of complications
c. Patients who require hospitalization
d. Patients with persistent moderate to severe symptoms more than 48 hours after initial onset
2. Current recommendations and susceptibilities should always be checked when initiating therapy
because antiviral susceptibility can vary from year to year, depending on the years predominant
pathogen. Information is available on the Centers for Disease Control and Preventions (CDC)
influenza Web site (www.cdc.gov/flu).
3. Adamantanes: Amantadine (Symmetrel) and rimantadine (Flumadine)
a. Work by inhibiting viral uncoating and release of viral nucleic acid by inhibiting M2 protein
b. Work only against influenza A virus
c. Therapy is preferably initiated within 48 hours of symptom onset.
d. Adverse effects
i. Central nervous system
ii. Peripheral edema
iii. Orthostatic hypotension
e. Rimantadine tends to have a more favorable adverse effect profile and is preferred in the 2009
influenza IDSA guidelines.
f. Dose
i. 100 mg orally two times/day for 37 days
ii. Adjust in renal disease.
iii. Should decrease to 100 mg/day in elderly
4. Oseltamivir (Tamiflu)
a. Works by inhibiting neuraminidase, thereby decreasing viral shedding
b. Effective against influenza A and B
c. Therapy preferably initiated within 48 hours of symptom onset
d. Dose
i. 75 mg orally two times/day for 5 days
ii. If creatinine clearance less than 30 mL/minute, decrease dose to 75 mg/day
e. Tolerated relatively well, but can be associated with nausea and vomiting
5. Zanamivir (Relenza)
a. Works by inhibiting neuraminidase, thereby decreasing viral shedding
b. Effective against influenza A and B
c. Therapy preferably initiated within 48 hours of symptom onset
d. Associated with bronchospasm (50%) if not used with 2-agonist
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E. Prevention
1. Vaccination is the best means of prevention.
2. For patients older than 1 year who are unable to be vaccinated (severely immunocompromised,
lack or shortage of vaccine), chemoprophylaxis is an option.
a. The CDCs influenza Web site (www.cdc.gov/flu) will give the most up-to-date
recommendations based on current influenza susceptibilities and outbreaks.
b. Oseltamivir, zanamivir, and rimantadine are the only recommended agents.
c. Duration
i. If vaccination is given, chemoprophylaxis should be fine to discontinue at 2 weeks
enough time to allow peak immune response.
ii. If vaccination is unable to be given, patients at high risk of complications from
chemoprophylaxis should be continued as long as influenza viruses are circulating in the
community.
A. Introduction
1. Upper respiratory tract infections are responsible for most antibiotics prescribed in ambulatory
practice.
2. Most infections are caused by viral pathogens and are self-limiting; this can lead to a great deal of
unnecessary antibiotic use.
3. Studies have shown that antibiotic exposure for upper respiratory infections can lead to the
development of resistance to that antibiotic.
a. Effect is greatest in the month immediately after exposure.
b. Resistance risk can persist for up to 12 months.
(Guideline: IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Adults and Children.
CID, March 21, 2012.)
B. Acute Sinusitis
1. Inflammation and/or infection of the paranasal and nasal mucosa
2. Viral respiratory infections usually precede sinusitis.
3. Primarily viral in origin, but differentiation between viral and bacterial causes can be difficult
a. Viral infections tend to resolve after 710 days.
b. Persistence or worsening of sinusitis may indicate bacterial infection.
4. Other things that can present like sinusitis
a. Allergies
b. Trauma
c. Environmental exposures
d. Anatomic abnormalities
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Table 1.
C. Pharyngitis
1. Acute inflammation of the oropharynx or nasopharynx
2. Viruses cause most cases (rhinovirus, coronavirus, influenza, parainfluenza, Epstein-Barr).
3. Group A Streptococcus (S. pyogenes) is the most common bacterial etiology in 15%30% of all
cases.
a. Predominantly seen in children 515 years old
b. Parents of school-aged children
4. Spread by direct contact with droplets of infected saliva or nasal secretions
(Guideline: Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012
Update by the Infectious Diseases Society of America. CID, September 9, 2012.)
D. Clinical Presentation
1. Difficult to differentiate viral from bacterial etiology
2. Signs and symptoms
a. Acute onset of sore throat
b. Pain with swallowing
c. Fever
d. Erythema and inflammation of tonsils and pharynx with or without exudates
e. Tender and swollen lymph nodes
3. Diagnosis
a. Need to determine whether viral or group A Streptococcus infection; definitive diagnosis cannot
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A. Introduction
1. Skin and soft tissue infections (SSTIs) involve any of the skin layers.
a. Epidermis
b. Dermis
c. Fascia
d. Muscle
2. Categorized as complicated or uncomplicated; complicated infections:
a. Involve deeper structures (fascia, muscle)
b. Require significant surgical intervention
c. Occur in immunocompromised patients
3. SSTIs are among the most common infections seen in the community setting.
4. Obtaining a detailed patient history is imperative to aid in diagnosis.
a. Immune status information
b. Geographic locale
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c. Travel history
d. Recent trauma or surgery
e. Previous or current antimicrobial therapy
f. Hobbies
g. Animal exposure or bites
5. Issues with SSTIs
a. Diagnosis
b. Severity of infection
c. Pathogen and antibiotic resistance patterns; CA-MRSA
i. Although MRSA is traditionally considered a nosocomial infection, in recent years, it has
been isolated from patients without typical risk factors such as prior hospitalization or
exposure to a long-term care facility.
ii. CA-MRSA differs genetically and in susceptibility from nosocomial MRSA.
(a) Strains often carry genes for toxins such as Panton-Valentine leukocidin, responsible for
tissue necrosis and virulence.
(b) Usually susceptible to agents such as clindamycin, doxycycline, and
trimethoprim/sulfamethoxazole
(c) Health care providers need to be aware of geographic patterns and outbreaks of CA-
MRSA when assessing patients for SSTIs.
B. General Etiology
1. Gram-positive organisms, many from the skin surface
a. S. aureus
b. S. pyogenes (-hemolytic Streptococcus)
c. Coagulase-negative Staphylococcus (CNS)
d. Corynebacterium spp. (diphtheroids)
2. Gram-negative organisms are not as common in community-acquired infections, but incidence
increases with nosocomial exposure.
a. Pseudomonas aeruginosa
b. Escherichia coli
c. Acinetobacter
3. Yeast (Candida spp.)
4. Likely etiology may vary on the basis of SSTI type.
C. Impetigo
1. Superficial skin infection with discrete purulent lesions
2. Primarily seen in children 25 years of age, but can be seen in older children and adults
3. Most common in hot, humid climates
4. Readily spread with close contact, especially in schools and day care centers
5. Most common organisms
a. S. pyogenes
b. S. aureus
6. Commonly infected sites are exposed areas of the body.
a. Face
b. Extremities
7. Signs and symptoms
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a. Lesions can be bullous or nonbullous; they initially appear as superficial vesicles and rapidly
enlarge to bullae or pus-filled blisters that readily rupture to produce characteristic golden-yellow
crusts.
b. Systemic signs of infection are minimal.
c. Regional lymph nodes may be enlarged.
8. Diagnosis
a. Cultures of vesicles or bullae should preferably be from crusted lesions and non-open draining
pustules. Open pustules may be colonized with skin flora.
b. A complete blood cell count may show leukocytosis.
9. Treatment
a. May be self-limiting, but antimicrobial treatment is preferred to prevent new lesions, alleviate
symptoms, and prevent complications
b. Oral antimicrobialsConsider erythromycin resistance.
c. Mupirocin ointment three times/day can be used in patients with a limited number of lesions or
involvement of a small surface area.
d. Antimicrobial treatment should be for 710 days.
Table 2.
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E. Cellulitis
1. An acute, diffuse, quickly spread skin infection that initially affects the epidermis and dermis and can
spread readily to the deeper tissues
2. Ability to spread through the lymphatic tissue to the bloodstream
3. Etiology
a. Most common pathogens
i. S. aureus (MSSA, MRSA, and CA-MRSA)
ii. S. pyogenes
b. Other pathogens
i. Gram-negative bacilli
ii. Anaerobes
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F. Erysipelas
1. Infection of the upper dermis and superficial lymphatics
a. Clinically, looks very similar to cellulitis
b. Differs from cellulitis, which affects the deeper dermis and subcutaneous fat
2. More common among infants, young children, and older adults
3. EtiologyAlmost always -hemolytic Streptococcus (S. pyogenes)
4. Signs and symptoms
a. Very bright red lesion with edema and possible lymphatic streaking
b. Unlike cellulitis, the erysipelas lesion is raised with clearly demarcated margins.
c. Patients usually have fever or flulike symptoms.
5. DiagnosisMay be able to culture by aspirating from the edge of the lesion
6. Treatment
a. Treatment is for 710 days.
b. Penicillin is the treatment of choice because of the exquisite susceptibility of S. pyogenes to
penicillin (intramuscularly or orally).
i. Adult
(a) Oral: Penicillin VK 250500 mg orally every 6 hours
(b) Intramuscular: Procaine penicillin G 600,000 units intramuscularly every 12 hours
ii. Pediatric less than 30 kg Oral: Penicillin VK 2550 mg/kg orally in three or four divided
doses
c. Clindamycin or erythromycin can be used for penicillin-allergic patients. Practitioners must be
aware of the resistance of S. pyogenes to macrolides.
d. Antimicrobial treatment should be for 710 days.
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times/day
g. Treatment is usually 710 days, but it may go up to 2 weeks or longer depending on the response
to the infection.
V. COLLATERAL DAMAGE
A. Overuse or inappropriate use of antimicrobial therapy can lead to the selection of drug-resistant
organisms or unwanted colonization or infection with Clostridium difficile diarrhea or multidrug-resistant
organisms.
1. Broad-spectrum antibiotics and resistance
a. Broad-spectrum antimicrobials are convenient for a one-size-fits-all approach to the treatment
of infections, especially if the agent has good efficacy and convenient dosing.
b. Several studies have shown a parallel increase in resistance with increased use of
fluoroquinolones and third-generation cephalosporins.
i. Third-generation cephalosporin-associated resistance
(a) Vancomycin-resistant enterococci
(b) Extended-spectrum -lactamaseproducing E. coli and Klebsiella spp.
ii. Fluoroquinolone use and increased resistance
(a) MRSA
(b) Fluoroquinolone-resistant gram-negative bacilli such as E. coli and P. aeruginosa
iii. Fluoroquinolones are the most prescribed antimicrobials for adults in ambulatory care
settings and emergency departments.
(a) A study in a single institution showed that 50% of levofloxacin prescribing for CAP in
an emergency department was inappropriate on the basis of practice guidelines.
(b) Fluoroquinolone-resistant E. coli has been seen in populations of cancer patients with
previous exposure to levofloxacin.
2. C. difficile diarrhea
a. Mild to severe diarrhea caused by overgrowth in the large bowel of the anaerobic gram-positive
spore-forming toxin A and Bproducing bacillus
b. Risk factors
i. Broad-spectrum antimicrobial therapy
ii. Prolonged antimicrobial therapy
iii. Age older than 65 years
iv. Comorbidities
v. Inflammatory bowel disease
vi. Malignancy
c. Treatment
i. If possible, remove the offending agent.
ii. Metronidazole 500 mg intravenously or orally three times/day for 10 days
iii. Vancomycin 250 mg ORALLY four times/day for 10 days
B. Antimicrobial Stewardship
1. Key to combating and preventing antimicrobial resistance
2. Emphasis of most stewardship programs. Examples come from institutional practices; however,
antimicrobials are mainly prescribed in outpatient settings.
3. Appropriate antimicrobial prescribing is imperative.
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a. Avoid the prescribing/use of antibiotics when they are not warranted (viral infections).
b. Avoid the prolonged use of antimicrobials.
c. Use practice guidelines and/or protocols when feasible.
d. Educating practitioners on the risks of antimicrobial resistance and appropriate antimicrobial
prescribing
To review this information, please see the Appendix for the CDC Recommended Immunization Schedule(s) or go to
www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-11x17-fold-pr.pdf.
Table 3.
Drug Dose/Length Cost
Total
Unit Cost Treatment Manufacturer
($) ($)
Community-Acquired Pneumonia
Azithromycin 500 mg once, 250 mg/day 4 7.78 46.70 Teva
days
Clarithromycin 500 mg two times/day 7 days 4.52 63.28 Ranbaxy
Doxycycline 100 mg two times/day 7 days 0.58 8.12 Teva
Levofloxacin 750 mg/day 7 days 30.23 211.61 Ortho-McNeil
Moxifloxacin 400 mg/day 7 days 16.35 114.45 Schering
Amoxicillin 1 g three times/day 7 days 0.37 (500- 15.54 Teva
mg capsule)
Amoxicillin/clavulanate 2 g/125 mg two times/day 7 days 4.14 115.92 Glaxo
(1-g tablet)
Influenza
Rimantadine 100 mg two times/day 7 days 1.83 25.62 Caraco
Oseltamivir 75 mg two times/day 5 days 9.76 97.60 Roche
Zanamivir 2 inhalations (5 mg/inhalation) two 70.80 70.80 Glaxo
times/day 5 days (Diskhaler)
Upper Respiratory Tract Infections
Amoxicillin 500 mg three times/day 10 days 0.37 11.1022.20 Teva
1 g three times/day 10 days
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REFERENCES
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APPENDIX
FIGURE
These 1. Recommended
recommendations must beimmunization schedule
read with the footnotes that for persons
follow. aged
For those who0fall
through 18start
behind or years
late,2013 (for those
provide catch-up who fall
vaccination at behind oropportunity
the earliest start late, as
see the
catch-up
indicated by schedule [Figure
the green bars 2]) 1. To determine minimum intervals between doses, see the catch-up schedule (Figure 2). School entry and adolescent vaccine age
in Figure
These are
groups recommendations
in bold. must be read with the footnotes that follow. For those who fall behind or start late, provide catch-up vaccination at the earliest
opportunity as indicated by the green bars in Figure 1. To determine minimum intervals between doses, see the catch-up schedule (Figure 2). School entry and
adolescent vaccine age groups are in bold.
1 2 4 6 9 12 15 18 19-23 2-3 4-6 7-10 11-12 13-15 16-18
Vaccines Birth mo mos mos mos mos mos mos mos mos yrs yrs yrs yrs yrs yrs
Pneumococcal
polysaccharide6b,c (PPSV23)
1st 2nd
Varicella10 (VAR) dose dose
2 dose series
Hepatitis A11 (HepA) see footnote 11
Human papillomavirus12
(3 dose
(HPV2: females only; HPV4: series)
males and females)
Meningococcal13 (Hib-MenCY
1st
6 wks; MCV4-D9 mos; see footnote 13 booster
dose
MCV4-CRM 2 yrs.)
Range of recommended Range of recommended Range of recommended Range of recommended Not routinely
ages for all children ages for catch-up ages for certain high-risk ages during which catch- recommended
immunization groups up is encouraged and for
certain high-risk groups
This schedule includes recommendations in effect as of January 1, 2013. Any dose not administered at the recommended age should be administered at a subsequent visit,
when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Vaccination providers
should consult the relevant Advisory Committee on Immunization Practices (ACIP) statement for detailed recommendations, available online at http://www.cdc.gov/
vaccines/pubs/acip-list.htm. Clinically significant adverse events that follow vaccination should be reported to the Vaccine Adverse Event Reporting System (VAERS) online
(http://www.vaers.hhs.gov) or by telephone (800-822-7967). Suspected cases of vaccine-preventable diseases should be reported to the state or local health department.
Additional information, including precautions and contraindications for vaccination, is available from CDC online (http://www.cdc.gov/vaccines) or by telephone
(800-CDC-INFO [800-232-4636]).
This schedule is approved by the Advisory Committee on Immunization Practices (http://www.cdc.gov/vaccines/acip/index.html), the American Academy of Pediatrics (http://
www.aap.org), the American Academy of Family Physicians (http://www.aafp.org), and the American College of Obstetricians and Gynecologists (http://www.acog.org).
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FIGURE 2. Catch-up immunization schedule for persons aged 4 months through 18 years who start late or who are more than 1 month behind
United States, 2013
Thefigure
The figurebelow
belowprovides
provides catch-up
catch-up schedules
schedules andand minimum
minimum intervals
intervals between
between doses doses for children
for children whose vaccinations
whose vaccinations have beenhave beenAdelayed.
delayed. A vaccine
vaccine series does series
not needdoes
to
notrestarted,
be need to regardless
be restarted, regardless
of the time thatofhas
the time that
elapsed has elapsed
between between
doses. Use doses.
the section Use the section
appropriate appropriate
for the childs for the
age. Always childs
use age.inAlways
this table use this
conjunction table
with in conjunc-
Figure 1 and the
tion with Figure 1 and
footnotes that follow. the footnotes that follow.
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VACCINE AGE GROUP 19-21 years 22-26 years 27-49 years 50-59 years 60-64 years 65 years
Tetanus, diphtheria, pertussis (Td/Tdap) 3,* Substitute 1-time dose of Tdap for Td booster; then boost with Td every 10 yrs
Zoster 6 1 dose
FIGURE 2. Recommended vaccinations indicated for adults based on medical and other indications1
Immuno- HIV infection Asplenia (including
compromising CD4+ T lymphocyte Heart disease, elective splenectomy
conditions count 4,6,7,10,14,15
Men who chronic and persistent Kidney failure,
(excluding human have sex lung disease, complement Chronic end-stage renal
immunodeficiency < 200 200 with men chronic component liver disease, receipt Healthcare
VACCINE INDICATION Pregnancy virus [HIV])4,6,7,10,15
cells/L cells/L (MSM) alcoholism deficiencies) 10,14
disease of hemodialysis Diabetes personnel
Influenza 2,* 1 dose IIV annually 1 dose IIV or LAIV
annually 1 dose IIV annually 1 dose IIV or LAIV
annually
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Learning Objectives:
1. Describe the appropriate treatment of patients with pneumonia, urinary tract infections (UTIs),
infective endocarditis, Clostridium difficile infection, and sepsis in the acute care setting.
2. Identify appropriate preventive therapy for pneumonia, UTIs, infective endocarditis, and C. difficile
infection in the acute care setting.
I. PNEUMONIA
A. Introduction
1. Pneumonia is the most common cause of death attributable to infectious diseases (very high
rates in the elderly) and the seventh most common cause of death in the United States.
2. Hospital-acquired pneumonia is the second most common nosocomial infection (0.6%1.1%
of all hospitalized patients)There is an increased incidence of patients both in the intensive
care unit recovering from thoracic or upper abdominal surgery and in the elderly.
3. Mortality rates
a. Community-acquired pneumonia without hospitalization: Less than 1%
b. Community-acquired pneumonia with hospitalization: About 14%
c. Nosocomial: About 33%50%
B. Community-Acquired Pneumonia
1. Definition: Acute infection of the pulmonary parenchyma, accompanied by the presence of an
acute infiltrate consistent with pneumonia on chest radiograph or auscultatory findings.
Patients must also NOT have any of the following characteristics: hospitalization 2 days or
more in the past 90 days; residence in a long-term care facility; receipt of intravenous
antibiotic therapy, chemotherapy, or wound care in the past 30 days; or attendance at a
hospital or hemodialysis clinic.
2. Symptoms of community-acquired pneumonia are listed below (must have any two). Elderly
patients often have fewer and less severe findings (mental status changes are common).
a. Fever or hypothermia
b. Rigors
c. Sweats
d. New cough with or without sputum (90%)
e. Chest discomfort (50%)
f. Onset of dyspnea (66%)
g. Fatigue, myalgias, abdominal pain, anorexia, and headache
3. Predictors of a complicated course of community-acquired pneumonia are listed below.
Hospitalization should be based on severity-of-illness scores (e.g., CURB-65, PSI
[pneumonia severity index]).
a. Age older than 65 years
b. Comorbid illness (diabetes mellitus, congestive heart failure, lung disease, renal failure,
liver disease)
c. High temperature: More than 38C (101F)
d. Bacteremia
e. Altered mental status
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C. Hospital-Acquired Pneumonia
1. Hospital-acquired pneumoniaPneumonia that occurs 48 hours or more after admission and
is not incubating at the time of admission
2. Ventilator-associated pneumoniaPneumonia that arises more than 4872 hours after
endotracheal intubation
3. Health careassociated pneumoniaPneumonia developing in a patient who was hospitalized
in an acute care hospital for 2 or more days within 90 days of the infection; resided in a
nursing home or long-term care facility; received intravenous antibiotic therapy,
chemotherapy, or wound care within the last 30 days of the current infection; or attended a
hospital or hemodialysis clinic. Risk factors for hospital-acquired pneumonia:
a. Intubation and mechanical ventilation
b. Supine patient position
c. Enteral feeding
d. Oropharyngeal colonization
e. Stress bleeding prophylaxis
f. Blood transfusion
g. Hyperglycemia
h. Immunosuppression/corticosteroids
i. Surgical procedures: Thoracoabdominal, upper abdominal, thoracic
j. Immobilization
k. Nasogastric tubes
l. Prior antibiotic therapy
m. Admission to the intensive care unit
n. Elderly
o. Underlying chronic lung disease
D. Microbiology
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E. Therapy
1. Community-acquired pneumonia (duration, at least 5 days)
a. Empiric treatment of nonhospitalized patients
i. Previously healthy and no antibiotic therapy in the past 3 months
(a) Macrolide (macrolide: clarithromycin or azithromycin if Haemophilus influenzae
is suspected)
(b) Doxycycline
ii. Comorbidities (chronic obstructive pulmonary disease, diabetes mellitus, chronic
renal or liver failure, congestive heart failure, malignancy, asplenia, or
immunosuppression) OR recent antibiotic therapy (within the past 3 months)
(a) Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
(b) Macrolide (or doxycycline) with high-dose amoxicillin (1 g 3 times/day) or
amoxicillin/clavulanate (2 g 2 times/day) or a cephalosporin (ceftriaxone,
cefuroxime, or cefpodoxime)
b. Empiric treatment of hospitalized patients with moderately severe pneumonia
i. Respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750 mg])
ii. Ampicillin, ceftriaxone, or cefotaxime (ertapenem in select patients) plus a macrolide
(or doxycycline)
c. Empiric treatment of hospitalized patients with severe pneumonia requiring intensive care
unit treatment: Ampicillin/sulbactam, ceftriaxone, or cefotaxime plus either a respiratory
fluoroquinolone or azithromycin (may need to add other antibiotics if Pseudomonas
aeruginosa or methicillin-resistant S. aureus [MRSA] is suspected)
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d. Treatment durationAt least 5 days, with 4872 hours afebrile and no more than one
sign of clinical instability (elevated temperature, heart rate, or respiratory rate; decreased
systolic blood pressure; or arterial oxygen saturation) before therapy discontinuation
2. Hospital-acquired pneumonia
a. Early onset (less than 5 days) and no risk factors for multidrug-resistant (MDR)*
organisms. Common organisms include Streptococcus pneumoniae, H. influenzae,
methicillin-sensitive S. aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter
spp., and Proteus spp.
i. Third-generation cephalosporin (cefotaxime or ceftriaxone)
ii. Fluoroquinolone (levofloxacin, moxifloxacin, ciprofloxacin)
iii. Ampicillin/sulbactam
iv. Ertapenem
b. Late onset (5 days or longer) or risk factors for MDR organisms. Common organisms
include those previously listed for early onset plus P. aeruginosa, K. pneumoniae
(extended-spectrum -lactamase positive), Acinetobacter spp., MRSA, and Legionella
pneumophila.
i. Ceftazidime or cefepime plus aminoglycoside or fluoroquinolone (cipro-, levo-)
ii. Imipenem, meropenem, or doripenem plus aminoglycoside or fluoroquinolone
(ciprofloxacin, levofloxacin)
iii. Piperacillin/tazobactam plus aminoglycoside or fluoroquinolone (ciprofloxacin,
levofloxacin)
iv. Vancomycin or linezolid should be used only if MRSA risk factors (e.g., history of
MRSA infection/colonization, recent hospitalization or antibiotic use, presence of
invasive health care devices) are present or there is a high incidence locally (greater
than 10%15%).
c. Treatment durationEfforts should be made to decrease therapy duration to as short as 7
or 8 days (14 days for pneumonia secondary to P. aeruginosa).
i. Antibiotic therapy within the past 90 days
ii. Hospitalization for 5 days or more
iii. High resistance in community or hospital unit
iv. Risk factors for health careassociated pneumonia
v. Immunosuppressive disease and/or therapy
F. Influenza
1. Characteristics of influenza infection
a. Epidemic with significant mortality
b. Epidemics begin abruptly and peak in 23 weeks; resolve in 56 weeks
c. Occurs almost exclusively in the winter months (December to April)
d. Average overall attack rates of 10%20%
e. Mortality greatest in those older than 65 years (especially with heart and lung disease):
More than 80% of deaths caused by influenza are from this age group (20,000 deaths per
year in the United States)
2. Is it a cold or the flu?
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3. Pathophysiology
a. Type A
i. Influenza further grouped by variations in hemagglutinin and neuraminidase (e.g.,
H1N1, H1N2)
ii. Changes through antigenic drift or shift
(a) Annual, gradual change caused by mutations, substitutions, and deletions, in
response to the development of human antibodies
(b) Less common dramatic change leading to pandemics
iii. Causes epidemics every 13 years
b. Type B
i. Type B influenza carries one form of hemagglutinin and one form of neuraminidase,
both of which are less likely to mutate than the hemagglutinin and neuraminidase of
type A influenza.
ii. Changes through antigenic drift (minor mutations from year to year); when enough
drifts occur, an epidemic is likely
iii. Causes epidemics every 5 years
4. Prevention
a. Amantadine, rimantadine
i. Prevents about 50% of infections and 70%90% of illnesses (similar to the influenza
vaccine)
ii. Dose/recommendations: short term (57 weeks or the duration of the epidemic);
prophylaxis during a presumed outbreak of influenza A in patients who cannot
receive vaccine (or 2 weeks only if the vaccine is given at the same time)
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G. Pneumonia Immunizations
1. Pneumococcal vaccine
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i.
Pneumococcal vaccine contains 23 purified capsular polysaccharide antigens of S.
pneumoniae.
ii. The 23 capsular types account for 85%90% of invasive S. pneumoniae infection.
iii. All six serotypes that commonly cause drug-resistant S. pneumoniae infection are in
the vaccine.
iv. Antibody levels remain elevated for at least 5 years.
b. Recommendations (Table 3)
2. Influenza vaccine
a. Characteristics
i. Each years vaccine contains two strains of type A and one strain of type B
Selected by worldwide surveillance and antigenic characterization
ii. Prevents illness in 70%90% of healthy people younger than 65 years
iii. Prevents illness in 53%, hospitalization in 50%, and death in 68% of the elderly
iv. Administer yearly in September or October.
b. Recommendations
i. Everyone older than 6 months should receive the vaccine annually.
ii. Patients with HIV (human immunodeficiency virus)
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(a) No risk to the patient and should be given to anyone receiving antiretrovirals
(b) Studies show a decreased antibody response (less than 60% have adequate
response).
(c) Intranasal live-attenuated vaccine (FluMist)
(1) Indicated for people 249 years of age without underlying illnesses (including
health care workers)
(2) Use of inactivated vaccine is preferred for vaccinating household members,
health care workers, and others who have close contact with
immunosuppressed people.
A. Introduction
1. Most common bacterial infection in humans: 7 million office visits per year; 1 million
hospitalizations
2. Many women (15%20%) will have a urinary tract infection (UTI) during their lifetime.
3. From age 1 to 50, UTIs predominantly occur in women; after age 50, men are affected
because of prostate problems.
B. Microbiology
C. Predisposing Factors
1. Age
2. Female sex
3. Diabetes mellitus
4. Pregnancy
5. Immunosuppression
6. Urinary tract instrumentation
7. Urinary tract obstruction
8. Renal disease; renal transplantation
9. Neurologic dysfunction
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D. Clinical Presentation
1. Lower UTICystitis (elderly patients may have only nonspecific symptoms, such as mental
status changes, abdominal pain, and decreased eating or drinking)
a. Dysuria
b. Frequent urination
c. Urgency
d. Occasionally, gross hematuria
e. Occasionally, foul-smelling urine
2. Upper UTIPyelonephritis (elderly patients may have only nonspecific symptoms, such as
mental status changes, abdominal pain, and decreased eating or drinking)
a. Frequency, dysuria, hematuria
b. Suprapubic pain
c. Costovertebral angle tendernessFlank pain d. Fever, chills
e. Increased white blood cell (count) (WBC)
f. Nausea, vomiting
3. Factors associated with or used to define complicated UTI
a. Male sex
b. Hospital acquired
c. Pregnancy
d. Anatomic abnormality of the urinary tract
e. Childhood UTIs
f. Recent antimicrobial use
g. Diabetes mellitus
h. Indwelling urinary catheter
i. Recent urinary tract instrumentation
j. Immunosuppression
4. Recurrent cystitis
a. Relapse: Infection with the same organism within 14 days of discontinuing antibiotics for
the preceding UTI
b. Reinfection: Infection with a completely different organismMost common cause of
recurrent cystitis
E. Diagnosis: Urinalysis (blood cultures will be positive in 20% of patients with upper UTIs)
1. Pyuria (WBC greater than 510 x 103 cells/mm3)
2. Bacteriuria (greater than 102 CFU [colony-forming units]/mL is diagnostic)
3. Red blood cells
4. Cloudiness
5. Nitrite positive
6. Leukocyte esterase positive
7. Casts (if pyelonephritis)
F. Therapy
1. Uncomplicated cystitis
a. Three-day treatment regimen (vs. 510 days: equal in symptomatic but not in
bacteriologic cure)
i. Trimethoprim/sulfamethoxazole (TMP/SMZ)
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ii. TMP
iii. Fluoroquinolone
b. Alternatives
i. Nitrofurantoin (7-day course)
ii. Fosfomycin (single dose)
c. Single-dose therapy
i. Improved adherence; fewer adverse effects; cheaper
ii. Reduced cure rates compared with a 3- or 7-day regimen
iii. Inappropriate for patients with occult upper tract involvement
iv. First-line antibiotics as listed earlier
2. Pregnancy (pregnant women should be screened for bacteriuria and treated, even if
asymptomatic)
a. Seven-day treatment regimen
i. Amoxicillin
ii. Nitrofurantoin
iii. Cephalexin
iv. TMP/SMZ
b. Antibiotics to avoid
i. Fluoroquinolones
ii. Tetracyclines
iii. Aminoglycosides
iv. TMP/SMZ (often used but avoidance recommended, especially during the late third
trimester)
3. Recurrent cystitis
a. Relapse
i. Assess for pharmacologic reason for treatment failure.
ii. Longer treatment (for 26 weeks, depending on length of initial course)
b. Reinfection (reassess need for continuous prophylactic antibiotics every 612 months)
i. If patient has two or fewer UTIs in 1 year, use patient-initiated therapy for
symptomatic episodes (3-day treatment regimens).
ii. If patient has three or more UTIs in 1 year and they are temporally related to sexual
activity, use post-intercourse prophylaxis with TMP/SMZ single strength, cephalexin
250 mg, or nitrofurantoin 50100 mg.
iii. If patient has three or more UTIs in 1 year that are unrelated to sexual activity, use
daily or three times/week prophylaxis with trimethoprim 100 mg, TMP/SMZ single
strength, cephalexin 250 mg, norfloxacin 200 mg, or nitrofurantoin 50100 mg.
4. Uncomplicated pyelonephritis
a. Outpatient therapy (if patient is not immunocompromised or does not have nausea and
vomiting)
i. TMP/SMZ
ii. Fluoroquinolone
b. Therapy duration: 514 days (5 days with levofloxacin, 14 days with TMP/SMZ)
5. Complicated UTIs
a. Inpatient therapy
i. Fluoroquinolone
ii. Aminoglycoside
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III. ENDOCARDITIS
A. Introduction
1. Infection of the heart valves or other endocardial tissue
2. Platelet-fibrin complex becomes infected with microorganismsVegetation
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3. Main risk factors include mitral valve prolapse, prosthetic valves, and intravenous drug
abuse.
4. Three or four cases per 100,000 population per year
B. Presentation/Clinical Findings
1. Signs and symptoms
a. Fever: Low grade and remittent
b. Cutaneous manifestations (50% of patients): Petechiae (including conjunctival), Janeway
lesions, splinter hemorrhage
c. Cardiac murmur (90% of patients)
d. Arthralgias, myalgias, low back pain, arthritis
e. Fatigue, anorexia, weight loss, night sweats
2. Laboratory findings
a. Anemia: Normochromic, normocytic
b. Leukocytosis
c. Elevated erythrocyte sedimentation rate and C-reactive protein d. Positive blood culture
in 78%95% of patients
3. Complications
a. Congestive heart failure: 38%60% of patients
b. Emboli: 22%43% of patients
c. Mycotic aneurysm: 5%10% of patients
C. Microbiology
1. Three to five blood cultures of at least 10 mL each should be drawn during the first 2448
hours.
2. Empiric therapy should be initiated only in acutely ill patients. In these patients, three blood
samples should be drawn during a 15- to 20-minute period before initiating antibiotics.
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D. Treatment
Vancomycin 4 6
Staphylococcus Oxacillin or nafcillin 6 6b
methicillin sensitive - Gentamicin for 35 days
- Plus rifampin in prosthetic valves
Cefazolin 6 6b
- Gentamicin for 35 days
- Plus rifampin in prosthetic valves
Vancomycin (only if severe PCN allergy) 6 6b
- Plus rifampin in prosthetic valves
Staphylococcus Vancomycin 6 6b
methicillin resistant - Plus rifampin in prosthetic valves
Enterococcus Penicillin G or ampicillin + gentamicin or 46 6
streptomycin
Vancomycin + gentamicin or streptomycin 6 6
Enterococcus Ampicillin/sulbactam or vancomycin + 6 6
penicillin resistant gentamicin
Enterococcus faecium Linezolid 8 8
penicillin, aminoglycoside,
and vancomycin resistant Quinupristin/dalfopristin 8 8
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E. Prophylaxis
Allergic to penicillin and Clindamycin Adults: 600 mg; children: 20 mg/kg IV within 30 minutes
unable to take oral before procedure
medications
Cefazolin or Adults: 1 g IM/IV; children: 50 mg/kg IM/IV within 30 minutes
ceftriaxone before procedure
IM = intramuscularly; IV = intravenously.
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A. Introduction
1. C. difficile is transmitted by the fecal-oral route.
2. Overgrowth in the GI tract occurs after antibiotic therapy.
3. Risk factors: Hospital stays, medical comorbidities, extremes of age, immunodeficiency
states, advancing age, use of broad-spectrum antibiotics for extended periods
4. Production of endotoxins A and B causes pathogenesis.
5. Symptoms: Watery diarrhea, abdominal pain, leukocytosis, GI tract complications
6. New strain (BI/NAP1) produces more enterotoxin, produces binary toxin, has increased
sporulation capacity, and is resistant to fluoroquinolones. Increased risk of metronidazole
failure, morbidity, and mortality
B. Therapy
1. Determining severity of infection (based on IDSA [Infectious Diseases Society of America]
guidelines)
a. Initial episode, mild or moderate = WBC 15,000/mm3 or lower and a serum creatinine
level of less than 1.5 times the premorbid level
b. Initial episode, severe = WBC 15,000/mm3 or higher or a serum creatinine level of 1.5
times or greater than the premorbid level
c. Initial episode, severe complicated = hypotension or shock, ileus, megacolon
2. Initial episode mild-moderate: Metronidazole 500 mg orally or intravenously three times/day
for 1014 days
3. Initial episode, severe: Vancomycin 125 mg orally four times/day for 1014 days
4. Initial episode, severe complicated: Vancomycin 500 mg four times/day by mouth or
nasogastric tube plus metronidazole 500 mg intravenously three times/day
5. First recurrence: Treat the same as for initial episode.
6. Second recurrence: Vancomycin in a tapered and/or pulsed regimen
7. Fidaxomicin (Dificid) 200-mg tablet orally twice daily for 10 days
a. FDA (U.S. Food and Drug Administration) label approved for patients 18 years or older
b. Not systemically absorbed, few adverse effects (nausea, vomiting, abdominal pain)
c. Activity fairly specific for Clostridium, fewer effects on normal gut flora
d. Significantly reduced incidence of recurrent infections compared with vancomycin
e. Very expensive
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REFERENCES
Pneumonia Endocarditis
1. Mandell LA, Wunderink RG, Anzueto A, et al. 1. Wilson W, Taubert KA, Gewitz M, et al.
Infectious Diseases Society of Prevention of infective endocarditis. Guidelines
America/American Thoracic Society consensus from the American Heart Association.
guidelines on the management of community- Circulation 2007;115:1656-8.
acquired pneumonia in adults. Clin Infect Dis 2. Baddour L, Wilson WR, Bayer AS, et al.
2007;44(suppl 2):S27-S72. Infective endocarditis: diagnosis, antimicrobial
2. American Thoracic Society; Infectious Diseases therapy, and management of complications. A
Society of America. Guidelines for the statement for healthcare professionals from the
management of adults with hospital-acquired, Committee on Rheumatic Fever, Endocarditis,
ventilator-associated, and healthcare-associated and Kawasaki Disease, Council on
pneumonia. Am J Respir Crit Care Med Cardiovascular Disease in the Young, and the
2005;171:388-416. Councils on Clinical Cardiology, Stroke, and
Cardiovascular Surgery and Anesthesia,
Urinary Tract Infections American Heart Association. Circulation
1. Warren JW, Abrutyn E, Hebel JR, et al. 2005;111:e394-e433.
Guidelines for antimicrobial treatment of
uncomplicated acute bacterial cystitis and acute Gastrointestinal Infections
pyelonephritis in women. Clin Infect Dis 1. Clinical practice guidelines for Clostridium
1999;29:745-58. difficile infection in adults: 2010 update by the
2. Treatment of urinary tract infections in Society for Healthcare Epidemiology of America
nonpregnant women. ACOG Practice Bulletin (SHEA) and the Infectious Diseases Society of
91. American College of Obstetricians and America (IDSA). Infect Control Hosp Epidemiol
Gynecologists. Obstet Gynecol 2008;111:785- 2010;31:431-55.
94.
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Learning Objectives:
1. Review and apply national guideline treatment strategies to the following gastrointestinal (GI) disor-
ders: gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), viral hepatitis, chronic
liver disease, and prevention of stress-related mucosal disease (SRMD).
2. Recommend appropriate pharmacologic and nonpharmacologic interventions for the management of
GERD.
3. Differentiate between clinical signs, symptoms, risk factors, and treatment of both Helicobacter pylo-
ri and nonsteroidal anti-inflammatory drugassociated PUD.
4. Discuss the role of pharmacologic intervention inprevention of SRMD.
5. identify the common manifestations of chronic liver disease and their treatment.
6. Review the treatment and prevention of both acute and chronic viral hepatitis.
7. Recognize pertinent information for educating patients and prescribers regarding the appropriate use
of pharmacologic agents for various GI disorders.
8. Recommend appropriate pharmacologic and nonpharmacologic interventions for diarrhea and consti-
pation.
9. Understand commonly encountered statistical tests and concepts using GI disorders as examples.
A. Definition
1. A condition which develops when reflux of stomach contents causes troublesome symptoms
and/or complications. This newer definition is based on the Montreal classification (Am J
Gastroenterol 2006;101:190020) and is used as the basis for the recent American
Gastroenterological Association (AGA) guidelines (Gastroenterology 2008;135:138391).
a. Strength of guideline evidence is rated grade A, B, C, D, or insufficient, and quality is
rated good, fair, or poor.
b. Nonerosive reflux disease is not included as a classification in these new guidelines.
2. Definition subdivides GERD into the following categories:
a. Esophageal syndromes
i. Symptomatic syndromes
(a) Typical reflux syndrome
(b) Reflux chest pain syndrome (presents similarly to cardiac chest pain)
ii. Syndromes with esophageal injury
(a) Reflux esophagitis
(b) Reflux stricture
(c) Barrett esophagus
(d) Adenocarcinoma
b. Extraesophageal syndromes
i. Established association
(a) Reflux cough
(b) Reflux laryngitis
(c) Reflux asthma
(d) Reflux dental erosions
ii. Proposed association
(a) Sinusitis
(b) Pulmonary fibrosis
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(c) Pharyngitis
(d) Recurrent otitis media
3. Symptoms
a. Patients ultimately decide how troublesome symptoms are on the basis of their
interference with normal daily activities or well-being.
b. Typical symptoms: Heartburn (pyrosis), regurgitation, acidic taste in the mouth
c. Extraesophageal symptoms (formerly referred to as atypical): Chronic cough, asthma-like
symptoms, recurrent sore throat, laryngitis/hoarseness, dental enamel loss, and
noncardiac chest pain; sinusitis/pneumonia/bronchitis/otitis media are less common
atypical symptoms
d. Alarm symptoms: Dysphagia (troublesome dysphagia is the preferred term in the new
guidelines), odynophagia, bleeding, weight loss, choking, chest pain, and epigastric mass.
These symptoms warrant immediate referral for more invasive testing.
e. Aggravating factors: Recumbency (gravity), increased intra-abdominal pressure, reduced
gastric motility, decreased lower esophageal sphincter (LES) tone, and direct mucosal
irritation
f. Long-term complications: Esophageal erosion, strictures/obstruction, Barrett esophagus,
and reduction in patients quality of life (Aliment Pharmacol Ther 2003;18:76776)
B. Diagnosis
1. Symptoms
a. Patient description of classic GERD symptoms, such as pyrosis, is often enough to
consider it an initial diagnosis; invasive testing is therefore not indicated in
uncomplicated cases.
b. The AGA guidelines state that it is reasonable to assume a diagnosis of GERD in patients
who respond to initial acid-suppressive therapy, particularly proton pump inhibitors
(PPIs).
c. Symptoms do not predict the degree of esophagitis or complications secondary to GERD,
if present.
d. Patients presenting with extraesophageal symptoms should be assessed on a case-by-case
basis to consider the need for referral or alternative/invasive testing.
e. Cardiac etiologies (ischemic) should be considered and explored before arriving at a
diagnosis of reflux chest pain syndrome.
2. Endoscopy. (See guidelines on endoscopy in GERD. Gastroenterology 2006;131:131536.)
a. Considered the technique of choice to identify Barrett esophagus (with biopsy) or
complications of GERD; findings of typical symptoms in association with endoscopic
mucosal changes are about 97% specific for the diagnosis of GERD; however, most
patients with typical/atypical symptoms will have normal-appearing esophageal mucosa
on endoscopy. Biopsies should be performed in areas of suspected metaplasia, dysplasia,
or malignancy.
b. Used in patients older than 45 years, those presenting with alarm symptoms (particularly
troublesome dysphagia), and those refractory to initial treatment, as well as in those with
a preoperative assessment or possibly when extraesophageal symptoms are present (grade
B)
c. Routine endoscopy to assess disease progression is not recommended (grade D).
d. Routine screening for Barrett esophagus in patients 50 years or older with more than
510 years of Heartburn is not recommended (evidence grade: insufficient).
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3. Manometry
a. Used to evaluate peristaltic function of the esophagus in patients with normal endoscopic
findings
b. Should be used before pH testing to rule out esophageal motility disorders and to help
localize the LES for subsequent pH testing (grade B)
4. pH testing. (See review in Aliment Pharmacol Ther 2005;22(suppl 3):29)
a. The main outcome measure of esophageal pH monitoring is the percentage of time the
pH value is less than 4 in a 24-hour period.
b. Ambulatory pH testing is useful in the following clinical situations:
i. Patients with no mucosal changes on endoscopy and normal manometry who have
continued symptoms (both typical and atypical) (grade B)
ii. Patients who are refractory to therapeutic doses of appropriate pharmacologic agents
iii. Monitoring of reflux control in patients with continued symptoms on drug therapy
c. Sensitivity/specificity of 96% reported
d. The PPIs should be withheld for 7 days before pH testing, if possible, for the most
accurate results.
5. Role of H. pylori testing and eradication is controversial in patients presenting with GERD
symptoms; should be assessed on the basis of patient presentation and risk factors for gastric
cancer. A 4-week trial of a twice-daily PPI can be considered for patients thought to have
reflux chest pain syndrome before manometry or pH testing (grade A). Reported sensitivity
and specificity of a short course of PPIs are 80% and 74% for diagnosing reflux chest pain
syndrome.
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i.
Step-down treatment: Starting with maximal therapy, such as therapeutic doses of
PPIs, is always appropriate as a first-line strategy in patients with documented
esophageal erosion. Advantages: Rapid symptom relief, avoidance of
over-investigation. Disadvantages: Potential overtreatment, higher drug cost,
increased potential of adverse effects
ii. Step-up treatment: Starting with lower-dose OTC products. Advantages: Avoids
overtreatment, has lower initial drug cost. Disadvantages: Potential undertreatment
(partial symptom relief), may take longer for symptom control, may lead to
over-investigation
b. AGA guideline recommendations (Gastroenterology 2008;135:138391)
i. Empiric drug therapy is appropriate for patients with uncomplicated heartburn.
ii. Use of antisecretory drugs for patients with esophageal GERD symptoms, with or
without esophagitis, is strongly recommended (grade A).
iii. PPIs are more effective than histamine-2 receptor antagonists (H2RAs), which are, in
turn, better than placebo for patients with esophageal GERD symptoms.
iv. All PPIs are similar in efficacy when used for patients with esophageal GERD
symptoms. Selection of drugs is based on adverse effects, onset of action, and
prescription plan coverage. For instance, changing to an alternative PPI or lowering
the dose if a patient experiences adverse effects is a reasonable approach.
v. Data are weak to support using PPIs or H2RAs above standard doses. However,
twice-daily dosing of PPIs is appropriate in patients who continue to have symptoms
on once-daily PPI therapy (grade B).
vi. Rapid-acting drugs should be used for patients who wish to take the drug in response
to symptoms. Antacids are the fastest-acting agents available and may be combined
with both PPIs and H2RAs. The PPIs and H2RAs are more effective at preventing
heartburn.
vii. Maintenance therapy is appropriate for patients with esophagitis in whom PPIs have
been effective (grade A). Titration to the lowest effective dose is recommended.
Most patients with nonerosive disease will continue on maintenance therapy if
they initially respond, but it may not be possible to down-titrate them to on-demand
therapy. On-demand therapy is not appropriate for patients with erosive esophagitis.
viii. Dosing PPIs less than once daily as maintenance therapy is ineffective for patients
who initially had erosive esophagitis (grade D).
ix. No evidence of improved efficacy by adding a bedtime dose of H2RA to twice-daily
PPI therapy (evidence grade: insufficient)
x. Data are weak to support the use of PPIs in patients with extraesophageal symptoms.
c. AGA guideline recommendations for the management of extraesophageal symptoms
i. The presence of extraesophageal GERD syndromes in the absence of esophageal
GERD syndromes is rare. Chronic cough, laryngitis, and asthma all have definite
associations with GERD.
ii. Evidence is fair for the use of once- or twice-daily PPI therapy in patients with an
extraesophageal syndrome and a concomitant esophageal GERD syndrome (grade
B). A 2-month trial of twice-daily PPI therapy would be an appropriate therapy for
these patients.
iii. Evidence is for the use of once- or twice-daily PPI therapy in patients with an
extraesophageal syndrome in the absence of an esophageal GERD syndrome (grade
D).
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iv. Evidence is insufficient to recommend once- or twice-daily PPI therapy for patients
with suspected reflux cough syndrome.
d. Pharmacologic agents
i. Calcium-, aluminum-, and magnesium-based products are available OTC in a wide
variety of formulations (capsules, tablets, chewable tablets, and suspensions).
(a) Neutralizing acid and raising intragastric pH results in decreased activation of
pepsinogen and increased LES pressure; rapid onset of action but short duration,
necessitating frequent dosing
(b) Some products (Gaviscon) contain the anti-refluxant alginic acid, which forms a
viscous layer on top of gastric contents to act as a barrier to reflux (variable added
efficacy).
(c) Used as first-line therapy for intermittent (less than 2 times/week) symptoms or as
breakthrough therapy for those on PPI/H2RA therapy; not appropriate for healing
established esophageal erosions
(d) Adverse reactions: Constipation (aluminum), diarrhea (magnesium), accumulation
of aluminum/magnesium in renal disease with repeated dosing
(e) Drug interactions: Chelation (fluoroquinolones, tetracyclines), reduced absorption
because of increases in pH (ketoconazole, itraconazole, iron, atazanavir,
delavirdine, indinavir, nelfinavir) or increases in absorption leading to potential
toxicity (raltegravir, saquinavir)
ii. Histamine-2 receptor antagonists
(a) Reversibly inhibit histamine-2 receptors on the parietal cell
(b) All agents available as prescription and OTC products; a variety of formulations
available; generics exist for all prescription products
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(c) OTC H2RA products may be used for on-demand therapy for intermittent
mild-moderate GERD symptoms; preventive dosing before meals or exercise is
also possible for all agents. Higher prescription doses are often required for more
severe symptoms or for maintenance dosing. Prolonged use may result in the
development of tolerance and reduced efficacy (tachyphylaxis).
(d) Therapy with H2RAs is less efficacious than therapy with PPIs in healing erosive
esophagitis.
(e) Adverse effects: Most are well tolerated. Central nervous system (CNS) effects
such as headache, dizziness, fatigue, somnolence, and confusion are the most
common. Elderly patients and those with reduced renal function are more at risk.
Prolonged cimetidine use is associated with the rare development of
gynecomastia.
(f) Drug interactions: May affect the absorption of drugs dependent on lower gastric
pH, such as ketoconazole, itraconazole, iron, atazanavir, delavirdine, indinavir,
and nelfinavir, or increases in absorption leading to potential toxicity (raltegravir,
saquinavir). Cimetidine also inhibits cytochrome P450 (CYP) enzymes 1A2,
2C9, 2D6, and 3A4. Warfarin, theophylline, and other agents metabolized by
these enzymes may be affected. Cimetidine may also compete with medications
and creatinine for tubular secretion in the kidney.
iii. Proton pump inhibitors
(a) irreversibly inhibit the final step in gastric acid secretion; greater degree of acid
suppression achieved and typically longer duration of action than H2RAs
(b) Most effective agents for short- and long-term management of GERD, as well as
for management of erosive disease (Aliment Pharmacol Ther 2003;18:55968)
(c) Most costly agents: Omeprazole and lansoprazole now available as a generic
prescription-strength product and OTC. The OTC products are considered safe
and effective for intermittent short-term (2 weeks) use in patients with typical
heartburn symptoms. Long-term use of OTC products should be discussed with
prescriber to prevent loss of follow-up or to assess for potential undertreatment
(Digestion 2009;80:22634). Pantoprazole and esomeprazole are available in
intravenous formulations.
(d) Most effective when taken orally before meals; for divided dosing, give evening
dose before evening meal instead of at bedtime.
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(f) Adverse reactions: Overall, well tolerated; possible adverse effects include
headache, dizziness, nausea, diarrhea, and constipation. Long-term use is not
associated with significant increases in endocrine neoplasia or symptomatic
vitamin B12 deficiency.
(1) A cohort study of 364,683 users of both PPIs and H2RAs found an elevated
risk of community-acquired pneumonia with these agents. The adjusted
relative risk of pneumonia was 1.89 (95% confidence interval [CI],
1.362.62) with PPI use and 1.63 (95% CI, 1.072.48) for H2RA use.
Patients at risk of community-acquired pneumonia include the
immunocompromised, the elderly, children, and those with asthma or chronic
obstructive pulmonary disease. Acid suppression should be used for these
patients only if necessary and only at the lowest possible dose (JAMA
2004;292:195560).
(2) A recent large prospective cohort study of hospitalized patients revealed an
increased risk of hospital-acquired pneumonia in nonventilated patients who
were prescribed PPIs (OR = 1.3; 95% CI, 1.11.4) (JAMA
2009;301:21208).
(3) Another recent study revealed a higher incidence of fracture in patients
receiving higher doses of PPIs for longer durations (OR = 1.44; 95% CI,
1.31.59) (JAMA 2006;296:294753). This may be attributable to reductions
in the absorption of calcium in patients receiving potent acid suppression or,
possibly, interference with osteoclast function.
(4) New U.S. Food and Drug Administration (FDA) labeling for PPIs as of May
2010 stating that PPIs may increase the risk of hip and spine fracture
(www.fda.gov/
Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvider
s/ ucm213206.htm#SafetyAnnouncement). The 2008 AGA guidelines cite
insufficient evidence to recommend bone density screening or calcium
supplementation because of PPI use. Screening for osteoporosis in
populations at risk, such as the elderly, is recommended regardless of PPI
use.
(5) Studies have revealed an association of overgrowth of Clostridium difficile in
patients receiving PPIs, particularly in the hospital setting. Odds ratios were
reported as 2.1 (95% CI, 1.332.25) (J Hosp Infect 2003;54:2435, CMAJ
2004;171:338).
(6) FDA warning in 2011 regarding risk of hypomagnesemia is patients
receiving PPIs (www.fda.gov/Drugs/DrugSafety/ucm245011.htm)
(A) Most often associated with use greater than 1 year
(B) May lead to tetany, arrhythmias, or seizures
(C) May require discontinuation of PPIs and/or magnesium supplementation
(D) Consider checking a baseline serum magnesium concentration in patients
receiving diuretics or digoxin or requiring long-term PPI use.
(g) Drug interactions: Drugs with pH-dependent absorption (e.g., ketoconazole,
itraconazole, protease inhibitors); omeprazole inhibits the metabolism of
diazepam through CYP2C19. Recent data suggest a reduced effectiveness of
clopidogrel through CYP2C19-mediated inhibition of conversion to active
metabolite by omeprazole and esomeprazole.
(1) Recommendations are to avoid omeprazole, esomeprazole, and cimetidine
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A. Classification of PUD
1. Duodenal ulcer
a. Common causes: H. pylori infection (95%), NSAIDs, low-dose aspirin
b. Uncommon causes: Zollinger-Ellison syndrome, hypercalcemia, granulomatous diseases,
neoplasia, infections (cytomegalovirus, herpes simplex, tuberculosis), ectopic pancreatic
tissue
c. Clinical signs/symptoms: Epigastric pain, possibly worse at night; often, pain occurs 13
hours after a meal and may be relieved by eating. Pain may also be episodic. Associated
symptoms may include heartburn, belching, a bloated feeling, nausea, and anorexia.
2. Gastric ulcer:
a. Common causes: NSAIDs, H. pylori infection
b. Uncommon causes: Crohn disease (CD), infections (cytomegalovirus, herpes simplex)
c. Clinical signs/symptoms: Epigastric pain, which is often made worse by eating; associated
symptoms may include heartburn, belching, a bloated feeling, nausea, and anorexia
3. Complications of PUD
a. Bleeding
b. Gastric outlet obstruction
c. Perforation
4. Patients at risk of NSAID-induced GI toxicity (Am J Gastroenterol 2009;104:72838)
a. Some NSAIDs (e.g., ibuprofen, diclofenac, nabumetone) are intrinsically less toxic to the
GI tract than naproxen, which is considered moderate risk. Other agents, such as piroxicam
or ketorolac, are considered high-risk drugs.
b. Duration of NSAID use (higher risk in first 3 months). Presence of chronic debilitating
disorders such rheumatoid arthritis or CV disease may also contribute to the increased GI
toxicity of NSAIDs, but these are not generally considered independent risk factors.
c. H. pylori infection is thought to confer additive risk of GI toxicity in NSAID users.
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5. Diagnosis
a. Symptom presentation
b. Testing for H. pylori infection: Practitioners must be willing to treat if testing is positive
because H. pylori is a known carcinogen.
i. Testing is indicated for patients with active ulcer disease, history of PUD, or gastric
mucosaassociated lymphoid tissue lymphoma.
ii. The test-and-treat strategy for identifying H. pyloripositive patients is also
acceptable for patients with unevaluated dyspepsia who have no alarm symptoms and
are younger than 55 years (Am J Gastroenterol 2007;102:180825).
c. Diagnostic tests for H. pylori infection (Aliment Pharmacol Ther 2003;16(suppl
1):1623)
i. invasive (endoscopic)
(a) Histology: 90%95% sensitive, 98%99% specific, subject to sampling error
(b) Rapid urease tests (CLOtest, Hpfast, and PyloriTek): Detect the presence of
ammonia (NH3) on a sample generated by H. pylori urease activity; 80%95%
sensitive, 95%100% specific. False negatives may result from a partly treated
infection, GI bleeding, achlorhydria, or use of PPIs, H2RAs, or bismuth. Patients
should discontinue antisecretory agents for at least 1 week before test is
performed.
(c) Culture: Costly, time-consuming, and technically difficult, although 100%
specific
ii. Noninvasive
(a) Serologic tests (QuickVue H. pylori gII, FlexSure HP): Detect immunoglobulin
(Ig)G to H. pylori in the serum by ELISA (enzyme-linked immunosorbent assay);
85% sensitive, 79% specific. Cannot distinguish between active infection and
past exposure. Because antibodies persist for long periods after eradication,
cannot use to test for eradication after treatment. Newly available tests will detect
the presence of CagA or VacA antibodies.
(b) Urea breath test (BreathTek UBT, PYtest): Detects the exhalation of radioactive
CO2 after the ingestion of 13C- or 14C-radiolabeled urea. H. pylori hydrolysis of
the radiolabeled urea results in CO production; 97% sensitive, 95% specific.
Used to make a diagnosis and to test for eradication. Recent use of antibiotics or
PPIs may result in false negatives in up to 40% of patients. Patients should
discontinue antisecretory agents or antibiotics at least 2 weeks before UBT
testing or wait 4 weeks after treatment has ended before having the UBT
performed.
(c) Stool antigen tests (Premier Platinum HpSA, ImmunoCard STAT! HpSA):
Polyclonal or monoclonal antibody tests that detect the presence of H. pylori in
the stool; 88%92% sensitive, 87% specific. Can be used to make a diagnosis
and confirm eradication. Recent use of bismuth, antibiotics, or PPIs may also
result in false negatives. Patients should discontinue antisecretory agents or
antibiotics at least 2 weeks before UBT testing or wait 4 weeks after treatment
has ended before having the UBT performed.
6. Treatment of H. pyloriassociated ulcers (Am J Gastroenterol 2007;102:180825)
a. General recommendations, based on the American College of Gastroenterology (ACG)
guidelines, are to include an antisecretory agent (preferably a PPI) plus at least two
antibiotics (clarithromycin and amoxicillin or metronidazole) in the eradication regimen.
H. pylori eradication has been shown to have a relative risk reduction of 54% for
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duodenal ulcer recurrence and a 38% relative risk reduction for gastric ulcer recurrence
(Cochrane Database Syst Rev 2006;2:CD003840).
b. Therapy duration is 714 days, depending on the regimen chosen. The ACG guidelines
state that 14 days is preferred. Most regimens last for 10 days.
c. Follow-up testing for eradication should be performed in patients with a history of ulcer
complication, gastric mucosaassociated lymphoid tissue lymphoma, early gastric cancer,
or recurrence of symptoms.
d. UBTs or stool antigen tests are preferred for confirming eradication (should wait at least
4 weeks after treatment for both).
e. Quadruple-based therapy with bismuth subsalicylate, metronidazole, tetracycline, and a
PPI can be used for 14 days as initial therapy if triple-based therapy fails or if the patient
has an intolerance of or allergy to components of the triple-drug therapy. Use of Pylera, a
quadruple-based therapy formulated with tetracycline, bismuth, and metronidazole in 1
capsule, received FDA label approval in 2007. This product contains bismuth subcitrate
salt rather than subsalicylate salt.
f. Sequential therapy is a relatively new type of treatment in which a PPI and amoxicillin
are given first for the first 5 days, followed by a PPI, clarithromycin, and tinidazole for an
additional 5 days. This therapy requires further validation before widespread use will be
accepted.
g. A bismuth-based quadruple therapy for 14 days or a levofloxacin-based triple therapy for
10 days can be used in patients who have not responded to initial regimens as salvage
therapy.
a,b
Table 5. H. pylori Treatment Regimens
Duration Efficacy
Regimen (days) (%)c
Lansoprazole 30 mg BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID 1014 8186
Esomeprazole 40 mg once daily + amoxicillin 1000 mg BID + clarithromycin 500 mg BID 1014 7085
Omeprazole 20 mg BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID 1014 7085
Rabeprazole 20 mg PO BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID 7 7085
Bismuth subsalicylate 525 mg QID + metronidazole 500 mg TID + tetracycline 500 mg 14 7590
QID + PPI BID
Bismuth subcitrate 420 mg + tetracycline 375 mg + metronidazole 375 mgd + PPI BID 10 8592
Sequential therapy
PPI + amoxicillin 1 g BID for 5 days; then PPI, clarithromycin 500 mg BID + tinidazole 10 (5 each > 90
500 mg BID for 5 days treatment)
a
Pantoprazole 40 mg BID or dexlansoprazole does not have an FDA-approved indication for H. pylori eradication; however, it
could be substituted in any of the 10- to 14-day regimens.
b
Metronidazole 500 mg BID can be substituted for amoxicillin or clarithromycin in patients with penicillin or macrolide allergy
for the triple-drug regimens. Treat for 14 days in this instance.
c
Rates are based on intention to treat.
d
Triple-capsule formulation.
BID = 2 times/day; FDA = U.S. Food and Drug Administration; PO = orally; PPI = proton pump inhibitor; QID = 4 times/day;
TID = 3 times/day.
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e. Misoprostol (Cytotec) should be given at full doses (800 mcg/day in divided doses);
however, this therapy is poorly tolerated because of excessive nausea, vomiting, diarrhea,
and abdominal cramping.
f. Concomitant use of antiplatelet agents and NSAIDs: Recent guidelines from a consensus
cardiology and GI group (ACCF [American College of Cardiology
Foundation]/ACG/AHA [American Heart Association]) (Circulation 2008;118:1894-909)
i. Need for antiplatelet therapy should first be evaluated.
ii. If antiplatelet therapy is deemed necessary, then assess for the presence of GI risk
factors (see Table 4 above). These guidelines also cite dyspepsia or GERD symptoms
as risk factors.
iii. Test and treat for H. pylori in patients with a history of a nonbleeding ulcer and in
those with a history of an ulcer-related complication. Eradicating H. pylori before
beginning long-term antiplatelet therapy is optimal.
iv. PPIs are the preferred gastroprotective agents for both the treatment and prevention
of aspirin- and NSAID-associated GI injury.
v. Gastroprotective therapy should be prescribed for patients with GI risk factors who
require the use of any NSAID (including OTC and cyclooxygenase-2 [COX-2]
inhibitors) in conjunction with cardiac-dose aspirin.
vi. Gastroprotective therapy should be prescribed for patients with GI risk factors who
require preventive doses of aspirin. Aspirin doses greater than 81 mg/day should not
be used in patients with GI risk factors during the long-term phase of aspirin therapy.
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vii. PPIs should be prescribed for patients receiving concomitant aspirin and
anticoagulant therapy (unfractionated heparin, low-molecular-weight heparin, and
warfarin).
viii. A target INR of 2.02.5 should be used in patients for whom warfarin is added to
concomitant aspirin and clopidogrel therapy. The combination of both aspirin and
clopidogrel with warfarin should only be used when benefit outweighs risk.
ix. Clopidogrel is not recommended as a substitute for patients with recurrent ulcer
bleeding. Aspirin plus a PPI is superior to clopidogrel.
x. The health care provider who decides to discontinue aspirin therapy in patients with
short-term bleeding episodes should weigh the risks of subsequent GI or cardiac
events.
xi. For patients receiving dual antiplatelet therapy (aspirin plus clopidogrel) who require
elective endoscopy (particularly colonoscopy and polypectomy), consider deferring if
patient is at high risk of cardiac events. Elective endoscopy should be deferred for 1
year after the placement of drug-eluting stents.
8. Treatment/secondary prevention of NSAID-induced ulcers (Am J Gastroenterol
1998;93:203746, Aliment Pharmacol Ther 2004;19:197208)
a. Risk factor modification
b. Discontinue/lower dose of NSAID if possible. Ulcers will heal with appropriate
treatment, but it may take longer with continued NSAID use.
c. Test for H. pylori and treat if present.
d. Drug therapy
i. PPIs: Drugs of choice for healing and secondary prevention of NSAID-induced
ulcers (N Engl J Med 1998;338:71926, N Engl J Med 1998;338:72734). New
combination product Vimovo contains esomeprazole with naproxen in the same
tablet (375 mg/20 mg or 500 mg/20 mg).
ii. Misoprostol: Appears to be as effective as PPIs for healing/secondary prevention (N
Engl J Med 1998;338:72734); however, it necessitates several doses per day and is
poorly tolerated because of the high incidence of diarrhea and abdominal pain
iii. Cyclooxygenase inhibitors: Celecoxib was shown to have rates of ulcer recurrence
and bleeding comparable with a diclofenac and omeprazole combination; use of
celecoxib may be limited by its recent association with CV effects (N Engl J Med
2002;347:210411). Use of celecoxib is uncertain in combination with low-dose
aspirin for secondary prevention of GI events.
iv. Combination of a COX-2 inhibitor and a PPI is not well studied but may be
considered in high-risk patients such as the elderly, especially if they are receiving
aspirin plus steroids or warfarin or have a history of a recent complicated GI event
and require continued NSAID or aspirin use.
v. The H2RAs: Inferior to misoprostol and PPIs in healing and preventing recurrence
vi. Clopidogrel is not recommended as a substitute in patients with recurrent ulcer
bleeding. Aspirin plus a PPI is superior to clopidogrel (Circulation
2008;118:1894909).
e. CV safety of COX-2 inhibitors and NSAIDs
i. The main theory underlying the development of excess thrombotic events with
COX-2 inhibitor use is that by reducing COX-2mediated prostacyclin production,
the prothrombic prostaglandin thromboxane A2 continues to be produced by COX-1,
leading to the development of a prothrombic state. The degree of development of
these events does not appear to be equal across the class of COX-2 inhibitors.
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ii. Guidelines for appropriate use and safety of NSAIDs, aspirin, and COX-2 inhibitors
have been published by both the AHA (Circulation 2007;115:163442) and a
multidisciplinary clinical group (Clin Gastroenterol Hepatol 2006;4:10829).
iii. Celecoxib was not associated with increases in CV events until the APC (Adenoma
Prevention with Celecoxib) trial for cancer prevention was terminated in December
2004. Daily doses of 400 and 800 mg of celecoxib conferred a 2.5- and 3.4-fold
higher risk of fatal and nonfatal myocardial infarction, which suggests a dose-related
response for this toxicity (N Engl J Med 2005;352:107180).
iv. A stepped approach is recommended for patients with CV disease or risk factors for
ischemic heart disease who require analgesic treatment of musculoskeletal symptoms
based on recommendations from the AHA (Circulation 2007;115:163442).
(a) Consider using acetaminophen, aspirin, tramadol, or short-term narcotics first.
(b) Nonacetylated salicylates can be considered next.
(c) NonCOX-2-selective NSAIDS can be used next, followed by NSAIDs with
some COX-2 activity. Use the lowest dose possible to control symptoms.
(d) The COX-2 inhibitors should be reserved as last line. In patients at increased risk
of thromboembolic events, coadministration with aspirin and a PPI may be
considered.
(e) Routinely monitor BP, renal function, and signs of edema or GI bleeding.
v. Methods to reduce CV risk such as tobacco cessation, BP and lipid control, and
glucose control are recommended for NSAID users but have not been proved to
reduce NSAID-associated CV risk. In patients for whom the risk of GI bleeding
outweighs the CV risk, lower-risk NSAIDs such as ibuprofen, etodolac, diclofenac,
or celecoxib should be used. In patients for whom the CV risk outweighs the risk of
GI bleeding, COX-2 inhibitors should be avoided. Limit the dose and therapy
duration if possible (Clin Gastroenterol Hepatol 2006;4:10829).
vi. An FDA article also reviews the effects of ibuprofen on the attenuation of aspirins
antiplatelet effects (www.fda.gov/cder/drug/infopage/ibuprofen/science_ paper.htm).
The AHA (Circulation 2007;115:163442) recommends that ibuprofen be taken at
least 30 minutes after or 8 hours before the ingestion of immediate-release low-dose
aspirin to prevent this interaction.
A. Background: Prevalence is 170 cases/100,000 adults; associated annual costs are about $750
million, and mortality is 6%10%.
B. Causes of Upper GI Bleeding
1. Peptic ulcer disease (40%70%)
a. NSAIDs and low-dose aspirin use
b. H. pylori
2. Esophagitis
3. Erosive disease
4. Esophageal varices
5. Mallory-Weiss tear
6. Neoplasm
7. Stress ulcers (critically ill patients)
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Table 7. Clinical Predictors of Death Associated with Nonvariceal UGIB (Ann Intern Med 2003;139:84357)
Advanced age (> 75 years highest risk) Red blood on rectal examination
Shock/hypotension Elevated serum urea
> 1 comorbid condition Serum creatinine > 150 micromoles/L (1.7 mg/dL)
Continued bleeding/rebleeding Elevated aminotransferases
Blood in gastric aspirate Sepsis
Hematemesis Onset of bleeding during hospitalization for other causes
UGIB = upper gastrointestinal bleeding.
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b. Recommended in patients in an intensive care unit setting with the following risk factors:
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iii. Oral or intravenous routes may be used. Alternative formulations exist for patients
with difficulty swallowing or with feeding tubes (see section on GERD).
iv. Oral PPIs are also as efficacious as intravenous PPI therapy for maintaining
equivalent pH (Am J Gastroenterol 2001;96:205865, Aliment Pharmacol Ther
1998;12:102732, Aliment Pharmacol Ther 2001;15:180717, Aliment Pharmacol
Ther 2003;18:70511).
v. Intravenous PPI therapy is generally considered equivalent to high-dose intravenous
H2RA therapy.
vi. Recent associations with C. difficile infections in hospitalized patients
Table 11. Model for End-Stage Liver Disease (MELD) (Hepatology 2007;45:797805)
Version Calculation Comment
Original 9.57 ln(creatinine) + 3.78 ln(total Score ranges from 6 to 40
bilirubin) + 11.2 ln(INR) + 6.43 Higher number indicates more severe disease
Used to predict mortality and prioritize patients for liver
transplantation
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A. Ascites
1. Definition: Free fluid in the abdominal cavity secondary to increased resistance within the
liver (forces lymphatic drainage into the abdominal cavity) and reduced osmotic pressure
within the bloodstream (hypoalbuminemia); develops at a 5-year cumulative rate of 30% in
compensated liver disease
2. Clinical features: Protuberant abdomen, shifting dullness, fluid wave, bulging flanks,
abdominal pain
3. Diagnosis
a. Clinical features
b. Abdominal ultrasonography
c. Paracentesis. Can use serum ascites albumin gradient, calculated by subtracting the
ascites albumin concentration from the serum albumin concentration; a value greater than
1.1 indicates ascites secondary to portal hypertension
4. Treatment (Hepatology 2009;49:2087107)
a. Attainment of negative sodium balance
i. Dietary sodium restriction (less than 2000 mg/day), fluid restriction to less than 1.5
L/day if serum sodium is less than 120125 mmol/L
ii. Goal is excretion greater than 78 mmol/day of sodium. A random spot urine
sodium concentration greater than the potassium concentration (ratio greater than 1)
correlates with a 24-hour sodium excretion of greater than 78 mmol/day with 90%
accuracy.
iii. Diuretics
(a) Patients with minimal fluid overload may be treated with spironolactone alone
(doses up to 400 mg/day); however, a combination of furosemide and
spironolactone is preferable as initial therapy in most patients.
(b) When used in combination, a ratio of 40 mg of furosemide to every 100 mg of
spironolactone is an appropriate starting regimen. Amiloride 1040 mg/day may
be substituted for spironolactone in patients who develop tender gynecomastia.
(c) If tense ascites is present, may use large-volume paracentesis. Administer
albumin at a dose of 68 g/L of ascitic fluid removed (if more than 5 L is
removed at one time).
iv. No upper limit of weight loss if massive edema is present, 0.5 kg/day in patients
without edema
v. The goal is to achieve 78 mmol or more urinary sodium excretions per day with
diuretics.
vi. Monitor for electrolyte imbalances, renal impairment, and gynecomastia
(spironolactone).
b. Discontinue drugs associated with sodium/water retention such as NSAIDs
B. Hepatic Encephalopathy
1. Definition: Disturbance in CNS function secondary to hepatic insufficiency, resulting in a
broad range of neuropsychiatric manifestations
a. Thought to be secondary to the accumulation of nitrogenous substances (mainly NH3)
arising from the gut; overall, NH serum concentrations do not correlate well with mental
status
b. Other theories are related to the activation of -aminobutyric acid receptors by
endogenous benzodiazepine-like substances, possible zinc deficiency, or altered cerebral
metabolism.
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2. Clinical features
a. May result in acute encephalopathy with altered mental status and progress to coma if
untreated; asterixis (hand flap) is a classic physical finding
b. May be precipitated by various factors including constipation, GI bleeding, infection,
hypokalemia, dehydration, hypotension, and CNS-active drugs
(benzodiazepines/narcotics)
3. Treatment (Am J Gastroenterol 2001;96:196876)
a. Assess need for airway support and remove possible precipitating factors.
b. Main treatments targeted at reducing the nitrogen load in the gut
c. Lactulose
i. Nonabsorbable disaccharide: Metabolized by colonic bacteria to acetic and lactic
acid; NH3 present in the GI lumen is reduced to ammonium ion (NH4+) through the
reduction in pH (ammonia trapping) and is therefore unable to diffuse back into the
bloodstream. Lactulose may also alter bacterial metabolism, resulting in increased
uptake of NH3.
ii. Dose: 45 mL orally every 12 hours until the patient has a loose bowel movement;
then titrate to two or three loose bowel movements a day (typically, a 15- to 45-mL
dose 2 or 3 times/day); may also administer as an enema (300 mL plus 700 mL of
water retained for 1 Hour). Powder formulation (KRISTALOSE) in 10- and 20-g
packets that may be dissolved in 4 oz of water (10 g = 15 mL of traditional lactulose).
This formulation is more palatable than the traditional syrup.
iii. May be continued over the long term for the prevention of recurrent encephalopathy
iv. Flatulence, diarrhea, and abdominal cramping are common adverse effects.
d. Antibiotics
i. Targeted at reducing the number of intraluminal urease-producing bacteria that may
be associated with excess NH3 production
ii. Neomycin (36 g/day in three or four divided doses 12 weeks; then 12 g/day
maintenance) or metronidazole (250 mg orally 2 times/day) may be used; neomycin
is considered as effective as lactulose.
iii. From 1% to 3% of neomycin is absorbed, so use caution with long-term use in
patients.
Having renal insufficiency; long-term metronidazole use may result in
peripheral neuropathy.
iv. Rifaximin is as effective as lactulose and other nonabsorbable antibiotics and may be
better tolerated. Approved dose for reduction in overt encephalopathy in patients 18
years and older is 550 mg 2 times/day. Drug cost may be greater, but this may be
offset by fewer hospitalizations and shorter lengths of stay. Previous studies in the
short-term setting have used 400 mg 3 times/day (Pharmacotherapy
2008;28:101932).
e. Other possible treatments
i. Benzodiazepine antagonists such as flumazenil may be used in cases of suspected
benzodiazepine overdose.
ii. Zinc supplementation should used in patients with documented zinc deficiency.
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Table 12. Most Commonly Isolated Bacteria Responsible for Spontaneous Bacterial Peritonitis
Gram-negative Bacilli (50%) Gram-positive Bacilli (17%)
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(a) The presence of more than 250 polymorphonuclear cells/mm3 is diagnostic for SBP.
(b) Lactate dehydrogenase, glucose, and protein values may help distinguish it from
secondary peritonitis.
iii. Blood cultures positive in 50%70% of cases; ascitic fluid cultures positive in 67%
of cases
iv. Gram stain of ascitic fluid is typically low yield.
4. Treatment of acute SBP (Hepatology 2009;49:2087107)
a. Because of the high associated mortality, treatment should be initiated promptly in
patients with clinical and laboratory features consistent with SBP.
b. Up to 86% of ascetic fluid cultures may be negative if one dose of an antibiotic is given
before cultures are drawn.
c. Predictors of poor outcomes include bilirubin more than 8 mg/dL, albumin less than 2.5
g/dL, creatinine more than 2.1 mg/dL, hepatic encephalopathy, hepatorenal syndrome,
and upper GI bleeding.
d. Antibiotic therapy plus albumin if patient meets criteria for use (see below)
i. Empiric therapy targeting enteric gram-negative organisms should be instituted.
ii. Third-generation cephalosporins have been studied the most and are considered first
line: Cefotaxime (2 g every 812 hours) or ceftriaxone (2 g/day intravenously)
iii. Other agents such as fluoroquinolones may be used.
iv. Avoid aminoglycosides because of the high risk of renal failure in patients with
cirrhosis and SBP.
v. Treatment duration: 510 days; most studies suggest that a 5-day treatment period is
as effective as a 10-day period
e. Albumin
i. Rationale: The hemodynamics of patients with cirrhosis reflect a state of
intravascular hypovolemia and organ hypoperfusion; SBP is thought to enhance this
effect, resulting in progressive renal hypoperfusion and precipitation of renal failure
or hepatorenal syndrome.
ii. The regimen most commonly used is based on one study (N Engl J Med
1999;341:4039).
(a) Albumin dosing: 1.5 g/kg on admission; 1 g/kg on hospital day 3
(b) In addition, should give antibiotic treatment; cefotaxime was used in this study
(c) The incidence of renal failure was reduced to 10% versus 33% for placebo
(p=0.002).
(d) In-hospital mortality was 10% for albumin versus 29% for placebo (p=0.01).
(e) 30-day mortality was reduced to 21% with albumin versus 41% for placebo
(p=0.03).
(f) Recent guidelines suggest using this albumin regimen with antibiotics if SCr is
more than 1 mg/dL, BUN more than 40 mg/dL, or total bilirubin more than 4
mg/dL (Hepatology 2009;49:2087107).
5. Prevention (Hepatology 2009;49:2087107)
a. Prophylactic oral antibiotics are used to prevent SBP in high-risk patients to reduce the
number of enteric organisms in the GI tract (GI decontamination), with the hope of
reducing the chance of bacterial translocation.
b. Antibiotic regimens are similar for both primary and secondary prevention:
i. Fluoroquinolones: Norfloxacin or ciprofloxacin
ii. Trimethoprim/sulfamethoxazole 1 double-strength tablet 5 times/week (Monday
through Friday)
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c. Primary prevention
i. For acute upper GI bleeding (7-day course during hospitalization only), give
ceftriaxone or norfloxacin 400 mg 2 times/day.
ii. May also consider for indefinite use in patients without GI bleeding if ascitic fluid
protein concentration is less than 1.5 g/dL and at least one of the following is present:
SCr more than 1.2 mg/dL, BUN more than 25 mg/dL, sodium less than 130 mg/dL,
or Child-Pugh score more than 9 with bilirubin more than 3 mg/dL
iii. Use norfloxacin 400 mg once daily or trimethoprim/sulfamethoxazole.
d. Secondary prevention
i. All patients recovering from an initial episode of SBP should be treated with oral
prophylactic antibiotics (norfloxacin or trimethoprim/sulfamethoxazole) indefinitely.
ii. Consider patient for liver transplantation because 2-year survival is 25%30% after
recovery.
A. For all hepatitis virus infections, acute hepatitis is defined as infection for less than 6 months,
whereas chronic infection is infection for greater than 6 months.
B. Hepatitis A Virus
1. Background
a. An RNA virus that is associated with the development of self-limited hepatitis
b. Transmission occurs mainly through the fecal-oral route.
i. Areas of poor sanitation; also associated flooding, leading to increased spread
ii. Foodborne: Shellfish, water, milk, vegetables
iii. Person-to-person contact: Sexual, day care, intravenous drug use, household,
restaurant workers
c. After exposure, incubation for 1450 days takes place; patients may show general,
nonspecific symptoms such as nausea, vomiting, diarrhea, myalgia, fever, abdominal
pain, and jaundice.
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d. Most patients have self-limited disease lasting less than 2 months; death of the hepatocyte
results in elimination of the virus.
e. Hepatitis A virus is associated with very low mortality (less than 1%) and is not
associated with the development of chronic hepatitis. Fulminant hepatitis may occur in
some instances.
2. Diagnosis
a. Clinical signs/symptoms such as nausea, abdominal pain, jaundice, fever, malaise, or
anorexia. Some patients may have mild asymptomatic disease.
b. Recent possible exposures
c. Laboratory data
i. igM antibody to HAV (anti-HAV): Detectable in the serum 510 days before the
onset of symptoms; once the infection clears, the IgM antibody is replaced by IgG
antibodies during a 2- to 6-month period; these antibodies confer lifelong protective
immunity against subsequent infection
ii. Elevation of aminotransferases
d. Management of acute HAV infection is mainly supportive; avoid hepatotoxic
medications such as acetaminophen.
3. Preexposure prophylaxis
a. Active (vaccination) or passive (immune globulin) prophylaxis can be used.
b. Havrix (GlaxoSmithKline) and Vaqta (Merck) are the two available HAV vaccines;
Twinrix is a combination HAV and HBV product (GlaxoSmithKline).
c. Populations requiring preexposure prophylaxis with HAV vaccine:
i. All children older than 1 year
ii. Children living in areas where hepatitis rates are above twice the national average
iii. People working in or traveling to countries with high or intermediate endemicity
(may take up to 4 weeks for full protection)
iv. Men who have sex with men
v. illegal drug users
vi. Those with occupational risk of exposure (exposure to sewage)
vii. Patients with chronic liver disease
viii. Patients with clotting factor disorders
ix. Optional: Food handlers, workers in institutions
d. Populations requiring preexposure prophylaxis with HAV immune globulin
ii. Children younger than 1 year (vaccine not approved for this age group)
iii. Doses: 0.02 mL/kg intramuscularly (3 months coverage or more); 0.06 mL/kg
intramuscularly (35 months coverage); repeat every 5 months if travel or exposure
is prolonged
4. Postexposure prophylaxis
a. immune globulin can be given at a dose of 0.02 mL/kg intramuscularly within 2 weeks of
exposure. Hepatitis A vaccine may also be used. Efficacy approaches that of immune
globulin, but it is recommended only in patients 12 months to 40 years of age.
b. Offer to those not previously vaccinated in the following situations:
i. Close personal contact with a documented infected person
ii. Staff or attendees of day care centers if one or more cases are recognized in children
or employees or if cases are recognized in two or more households of attendees
iii. Common sources of exposure:
(a) If a food handler receives a diagnosis of HAV, vaccine or immune globulin
should be administered to other food handlers at the same establishment.
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(a) Most patients will have hepatitis B early antigen (HBeAg)-positive disease.
(b) HBeAg-negative disease: Mutation in the precore or core promoter regions.
These variants are known as precore mutants; these mutations do not allow
monitoring of loss of E antigen as a clinical marker of suppressed replication.
Monitor reduction in HBV DNA in these patients; patients infected with these
variants also tend to have lower serum HBV DNA and more fluctuating liver
function tests.
(c) Centers for Disease Control and Prevention guidelines for screening for HBV
infection (MMWR 2008;57(RR-08):120). The serologic assay for HBV surface
antigen (HBsAg) should be the serologic screening test used for the following
populations. Additional HBVs are needed in combination with the HBsAg for
select populations as listed below.
(1) People born in geographic regions with HBsAg prevalence of more than
2%, regardless of vaccination history
(2) Men who have sex with men; also test for anti-HBc or anti-HBs
(3) Past or current intravenous drug users; also test for anti-HBc or anti-HBs
(4) Individuals receiving cytotoxic chemotherapy or immunosuppressive
therapy related to organ transplantation or rheumatologic or GI disorders. In
addition, test for anti-HBc or anti-HBs.
(5) U.S.-born person not vaccinated as infant whose parents were born in
regions with HBV endemicity more than 8%
(6) People with elevated ALT/AST of unknown etiology
(7) Donors of blood, plasma, organs, tissues, or semen. In addition, test for
anti-HBc and HBV DNA.
(8) Pregnant women (during each pregnancy, preferably in the first trimester)
(9) Infants born to HBsAg-positive mothers
(10) Household, needle-sharing, or sex contacts of individuals known to be
HBsAg positive. In addition, test for anti-HBc or anti-HBs.
(11) Individuals who are the sources of blood or bodily fluid for exposures that
might require postexposure prophylaxis
(12) Individuals who are human immunodeficiency virus (HIV) positive. In
addition, test for anti-HBc or anti-HBs.
v. Clinical definitions
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(b) PEG -2a (Pegasys): 180 mcg subcutaneously once weekly 48 weeks (duration
is same for HBeAg-negative and HBeAg-positive disease)
iv. In general, response to traditional IFN is poor; 37% loss of HBsAg, 33% loss of
HBeAg with 1224 weeks of treatment; this equates to about 20% better than placebo.
Some trials suggest that PEG-IFN has only slightly better efficacy in HBeAg-positive
disease, with 25% loss of HBV DNA and 30% loss of HBeAg at 48 weeks. Adherence
may be better because of less-frequent dosing.
v. if a response is obtained, it is usually long lasting (more than 48 years).
vi. Treatment with IFN typically results in an increase in ALT 48 weeks into treatment.
This is an expected response; it should not be viewed as an adverse effect of therapy.
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(c) Dose: 0.5 mg orally once daily for individuals older than 16 years and nucleoside
naive; 1 mg orally once daily for patients older than 16 years with HBV viremia
while receiving lamivudine or in lamivudine-resistant HBV
(d) Dose adjustments required for renal impairment
(e) Toxicity: Similar to lamivudine with headache, cough, upper respiratory
infection, abdominal pain; possibly fewer ALT flares. Rare lactic acidosis.
Resistance reported as similar to 1% at 5 years
vi. Telbivudine (Tyzeka)
(a) Indicated for HBeAg-negative and HbeAg-positive patients with persistently
elevated AST/ALT or histologically active disease
(b) Not effective in lamivudine-resistant YMDD mutants
(c) A direct comparison with lamivudine (GLOBE trial) showed greater efficacy in
both HBeAg-negative and HBeAg-positive patients.
(d) Reduces HBV DNA by up to 6.45 logs in HBeAg-positive, naive patients and by
5.2 logs in HBeAg-negative patients
(e) Dose: 600 mg orally once daily. Dose adjustments required for renal impairment
(f) Toxicity: Similar to lamivudine; small incidence of myopathy. Creatine kinase
elevations greater than 7 times the ULN; for telbivudine, 9% versus 3% with
lamivudine in the GLOBE study. Rare lactic acidosis. Resistance reported as
25% at 2 years
vii. Tenofovir (Viread)
(a) Nucleotide analog, formulated as tenofovir disoproxil fumarate indicated for
chronic HBV infection
(b) Effective for lamivudine-resistant HBV
(c) A direct comparison with adefovir for 48 weeks showed greater viral suppression
to less than 400 copies/mL plus histologic improvement for tenofovir compared
with adefovir in HBeAg-positive patients (66% vs. 12%; p<0.001) and
HBeAg-negative patients (71% vs. 49%; p<0.001) (N Engl J Med
2008;359:244255). Dose: 300 mg orally once daily. Dose adjustments required
for renal impairment
(d) Toxicity: Overall, well tolerated. Headache, nausea, and nasopharyngitis most
commonly reported. Potential renal toxicity, so periodic monitoring of SCr
recommended. Potential ALT flares on withdrawal. Rare lactic acidosis
Table 16. Summary of Treatment Recommendations for Chronic HBV Infection in Adults
HBV Population Preferred Treatment Options Duration Comments
HBeAg positive Entecavir and tenofovir are preferred Minimum Preferred if contraindications or
oral agents of 1 year nonresponse to INF
Use of the other oral reverse
transcriptase inhibitors is possible but
not preferred
INF 16 weeks If contraindication or no response,
PEG-INF 48 weeks use entecavir and tenofovir
HBeAg negative Entecavir and tenofovir are preferred > 1 year Preferred if contraindications or no
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Table 16. Summary of Treatment Recommendations for Chronic HBV Infection in Adults
HBV Population Preferred Treatment Options Duration Comments
oral agents response to INF
Use of the other oral reverse
transcriptase inhibitors is possible but
not preferred
INF 1 year If contraindication or nonresponse,
PEG-INF use entecavir and tenofovir
Development of Lamivudine or telbivudine resistance: Confirm resistance with genotypic
resistant HBV Add adefovir or tenofovir or change to N/A testing
entecavir Reinforce adherence to therapy
Adefovir resistance: Add lamivudine
Entecavir resistance: Change to
tenofovir
HBeAg = hepatitis B early antigen; HBV = hepatitis B virus; INF = interferon alfa; N/A = not applicable; PEG = pegylated.
4. Preventive strategies
a. vaccination (preexposure); indicated in the following groups:
i. All infants born to HBsAg-negative mothers
ii. Adolescents with high-risk behavior (intravenous drug abuse, multiple sex partners)
iii. Workers with possible occupational risk of exposure
iv. Staff and clients at institutions for the developmentally disabled
v. Hemodialysis patients
vi. Patients receiving clotting factor concentrates
vii. Household contacts and sex partners of infected patients
viii. Adoptees from countries where HBV infection is endemic
ix. International travelers (more than 6 months travel in an endemic area, short-term
travel if contact with blood in a medical setting is expected, or sexual contact with
residents in areas of intermediate- to high-endemic disease); series of vaccinations
started 6 months before travel
x. injection drug users
xi. Sexually active homosexual or bisexual men, as well as heterosexual men and
women
xii. Patients seeking treatment of a sexually transmitted disease
xiii. Inmates of long-term correctional facilities
xiv. Patients with chronic HIV infection or chronic liver disease
xv. All other individuals seeking protection from HBV infection
b. Available HBV vaccines (dose schedules vary by age)
i. Dose schedules
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ii. Obtain titers 12 months after the third dose of the series for health care personnel.
iii. Hepatitis B vaccines are available as combination products with HAV (Twinrix),
DTP/IPV (Pediarix), and Hib (Comvax). Avoid Twinrix in patients with HIV.
c. Postexposure prophylaxis
i. Exposure may result in the need for HBV vaccine and/or immune globulin.
ii. Doses of HBV immune globulin are 0.06 mL/kg intramuscularly and must be given
within 7 days of exposure.
iii. Patient populations requiring postexposure prophylaxis
(a) Perinatal transmission
(1) Children born to HBsAg-positive mothers should receive vaccine plus HBV
immune globulin within 12 hours of birth.
(2) Children born to mothers with unknown HBsAg status (but suspected)
should receive vaccine within 12 hours of birth; testing should be performed
on child, and if positive, HBV immune globulin should be administered
within 1 week.
(3) Infants weighing less than 2 kg at birth whose mothers are documented to be
HBsAg negative should receive the first dose of vaccine 1 month after birth
or at hospital discharge, whichever comes first.
(b) Sexual contact or household contact with an infected person: Should receive
HBV immune globulin plus vaccine series if exposed person is previously
unvaccinated
(c) Sexual contact or household contact with an HBV carrier: Should receive vaccine
series if exposed person was previously unvaccinated
D. Hepatitis C Virus
1. Background
a. RNA virus: Six genotypes (50 subtypes)
i. Genotype 1 (subtypes 1a, 1b, and 1c) accounts for 70%75% of infections in the
United States.
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ii. Genotypes 2 (subtypes 2a, 2b, and 2c) and 3 (3a and 3b) are common in the United
States.
iii. Genotype helps determine therapy duration and likelihood of responding to therapy.
b. Leading cause of liver disease and liver transplantation in the United States; also, a
common cause of hepatocellular carcinoma
c. viral replication occurs in the hepatocyte (virus is not directly cytopathic).
d. Transmission: Mainly bloodborne (transfusion, intravenous drug abuse)
i. High risk: Transfusion, intravenous drug abuse
ii. Low risk:
(a) Snorting cocaine or other drugs
(b) Occupational exposure
(c) Body piercing and acupuncture with unsterilized needle
(d) Tattooing
(e) From pregnant mother to child
(f) Nonsexual household contacts (rare)
(g) Sharing razors and/or toothbrushes
(h) Sexual transmission
e. Associated with acute and chronic infection; after acute infection, most patients
(60%85%) will develop chronic infection
2. Clinical features: About 30% of patients are asymptomatic.
a. Acute infection: Symptoms present 412 weeks after exposure; most patients are
asymptomatic and seldom progress to fulminant disease; those who develop symptoms
have nonspecific findings such as malaise, weakness, anorexia, and jaundice.
b. Chronic infection: Defined as the presence of viral RNA in the serum for 6 months or
more
i. May be associated with the long-term development of end-stage liver disease,
cirrhosis, hepatocellular carcinoma
ii. Progression to complications and end-stage liver disease may be accelerated by
concurrent alcohol use and coinfection with HIV; younger females have slower
progression.
c. Extrahepatic manifestations: Rheumatoid symptoms, glomerulonephritis,
cryoglobulinemia
3. Diagnosis and monitoring
a. Clinical signs/symptoms such as nausea, abdominal pain, jaundice, fever, malaise, or
anorexia. Many patients have asymptomatic disease.
b. Laboratory
i. Serum anti-HCV antibodies: 99% sensitivity/specificity (enzyme immunoassays).
Used as an initial screening for HCV; presence of anti-HCV antibody does not confer
protective immunity from subsequent infection
ii. Serum HCV RNA
(a) Obtain in patients who test positive for anti-HCV antibodies.
(b) Quantitative: Viral load is typically polymerase chain reaction reported in
international units per milliliter; obtain for patients who will receive treatment;
for use in monitoring treatment response. Preferred assays for diagnosis and
monitoring of drug therapy
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(c) Qualitative: Typically, polymerase chain reaction; lower limit of detection is 50 IU/mL
(equivalent to 100 copies/mL) preferred (specificity is about 98%); typically used to
confirm diagnosis in patients who are HCV antibody positive. The American Association
for the Study of Liver Diseases (AASLD) guidelines state that there is no longer a need
for qualitative assays. Quantitative assays are preferred.
Table 18. Definitions and Monitoring of Chronic HCV Treatment Based on HCV RNA
Parameter Definition
Rapid virologic Undetectable HCV RNA at week 4 of treatment
response (RVR)
Early virologic > 2-log reduction in HCV RNA compared with baseline or undetectable HCV RNA at 12
response (EVR) weeks
End-of-treatment Undetectable HCV RNA at the end of a 24- or 48-week course depending on genotype
response (ETR)
Sustained virologic Undetectable HCV RNA 24 weeks after finishing treatment
response (SVR)
Breakthrough Reappearance of HCV RNA while on treatment
Relapse Reappearance of HCV RNA after finishing a course of treatment
Nonresponder Failure to clear HCV RNA from serum after 24 weeks of therapy
Null responder Failure to decrease HCV RNA by < 2 logs after 24 weeks of therapy
Partial responder Decrease in HCV RNA by > 2 logs after 24 weeks of therapy but HCV RNA still detectable
HCV = hepatitis C virus.
iii. Liver biopsy: Consider if patient and health care provider wish to obtain information
regarding fibrosis stage or prognostic purposes or to make a decision regarding
treatment. ALT: Nonspecific; may fluctuate with chronic disease (should decrease
with treatment)
iv. Genotyping: Genotype 1 is the most common genotype in the United States; it is also
the least responsive to treatment. Genotypes 2 and 3 are the other most common
genotypes in the United States.
v. Treatment response depends on other factors such as race, age, or coinfection.
4. Treatment
a. Acute HCV infection
i. Patients with acute HCV should be considered for IFN-based therapy, preferably
with PEG-IFN for 1224 weeks. Adding ribavirin may be considered, but it is
unclear whether this improves sustained virologic response (SVR) rates.
ii. Alternatively, treatment may be delayed for 812 weeks to assess for spontaneous
resolution.
iii. Main benefit of treatment is prevention of chronic infection.
b. Chronic infection (Hepatology 2009;49:133564, 2009;39:114771)
i. Therapy goal is to attain an SVR.
ii. Indications for the treatment of patients who are treatment naive
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(a) Age older than 18 years and positive serum HCV RNA
(b) Portal or bridging fibrosis with at least moderate inflammation/necrosis on
biopsy
(c) Compensated liver disease, acceptable hemoglobin (13 g/dL men, 12 g/dL
women) and neutrophils (more than 1500/mm3), SCr less than 1.5 mg/dL
(d) Willingness to be treated and be adherent
(e) No contraindications to therapy
iii. Difficult patient populations that require individualized therapy
(a) Normal ALT (treatment dependent on genotype, degree of fibrosis, symptoms)
(b) Liver biopsy indicating no or mild fibrosis
(c) Advanced liver disease (fibrosis or decompensated cirrhosis)
(d) Recurrence after liver transplantation
(e) Patients younger than 18 years
(f) Coinfection with HIV or HBV
(g) Chronic kidney disease
(h) Users of alcohol or illicit drugs who are willing to participate in substance abuse
treatment programs
(i) Nonresponder or relapser
iv. Contraindications to treatment of chronic HCV
(a) Major uncontrolled depressive disorder
(b) Solid-organ transplantation (renal, heart, lung)
(c) Autoimmune hepatitis or other autoimmune conditions
(d) Untreated thyroid disease
(e) Pregnant or unwilling to adhere to adequate contraception
(f) Severe concurrent medical disease (hypertension, heart failure, coronary heart
disease, poorly controlled diabetes mellitus, chronic obstructive pulmonary
disease)
(g) Age younger than 2 years
(h) Hypersensitivity to IFN or ribavirin
c. Ribavirin in the treatment of HCV infection
i. Oral nucleoside analog
ii. Available as 200-mg tablets (Copegus) or capsules (Rebetol) (generic now available)
iii. Significant adverse effect profile
(a) Hemolytic anemia: May occur in up to 10% of patients (usually within 12
weeks of initiating therapy): may worsen underlying cardiac disease; monitor
complete blood cell count (CBC) at baseline, 2 weeks, 4 weeks, and periodically
thereafter. In patients with no cardiac history, decrease dose to 600 mg/day when
hemoglobin drops to 10 g/dL or less, and discontinue when hemoglobin drops to
8.5 g/dL or less. In patients with a cardiac history, decrease dose to 600 mg/day if
hemoglobin drops more than 2 g/dL in any 4-week period during treatment.
Discontinue if hemoglobin drops to less than 12 g/dL 4 weeks after dose
reduction. May use epoetin or darbepoetin to stimulate red blood cell production,
improve anemia (J Clin Gastroenterol 2005;39:S9S13), and sustain initial
starting dose. Also need to confirm iron studies are normal and within range
during treatment
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Table 19. Protease Inhibitors Used in the Treatment of Chronic HVC Infection
Telaprevir (Incivek) Boceprevir (Victrelis)
FDA-approved Long-term HCV therapy (genotype 1) in Chronic HCV genotype 1 infection, in
indication combination with PEG-IFN and ribavirin in combination with peginterferon alfa
patients with compensated liver disease and ribavirin, in adult patients ( 18
Not studied in Child-Pugh class B or C years old) with compensated liver
disease, including cirrhosis, who were
previously untreated or who have not
responded to previous interferon and
ribavirin therapy
Dose and formulation 750 mg orally 3 times/day for at least 12 weeks, 800 mg orally 3 times/day
followed by PEG-IFN and ribavirin for 12 Give doses 79 hours apart; give with
weeks if undetectable HCV RNA at weeks 4 meal or light snack
and 12 200-mg capsules
Give doses 79 hours apart; give with meal that Take missed doses if within 2 hours
has at least 20 g of fat ingested 20 minutes
prior
375-mg tablets
Take missed doses if within 4 hours
Contraindications Pregnant women or male partners of pregnant Pregnant women or male partners of
women (category B, but must be used with pregnant women (category B, but must
ribavirin, which is category X) be used with ribavirin, which is
CYP3A4 substrates or inducers category X) CYP3A4 substrates or
Alfuzosin, rifampin, DHE, St. Johns wort, inducers
atorvastatin, lovastatin, simvastatin, Alfuzosin, rifampin, DHE, St. Johns
pimozide, sildenafil, tadalafil, oral triazolam wort, atorvastatin. lovastatin,
or midazolam simvastatin, pimozide, sildenafil,
Several other drug-drug interactions that may tadalafil, oral triazolam, or midazolam
require dose adjustment of interacting drug Several other drug-drug interactions
(see package insert) that may require dose adjustment of
interacting drug (see package insert)
Adverse effects Rash (56%), DRESS syndrome, or Anemia, neutropenia, fatigue, dysgeusia
Stevens-Johnson syndrome Anemia, pruritus,
nausea
CYP = cytochrome P450; DHE = dihydroergotamine; DRESS = drug reaction/rash with eosinophilia and systemic symptoms;
HCV = hepatitis C virus.
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e. Recommendations from the AASLD guidelines for the treatment of chronic HCV
infection
i. First-line therapy: PEG-IFN plus ribavirin
ii. Efficacy: 42%46% SVR for genotype 1; 76%82% SVR for genotype 2 or 3
iii. Factors associated with increased response: Genotype other than 1, lower initial HCV
RNA (less than 600,000 IU/mL), minimal fibrosis/inflammation on biopsy, lower
body weight or surface area, and nonAfrican Americans
f. Dosing of HCV treatment regimens
i. Pegylated interferon
(a) Pegasys: 180 mcg/week subcutaneously
(b) PEG-Intron: 11.5 mcg/kg/week subcutaneously
ii. Ribavirin (Rebetol or Copegus 200-mg tablets or capsules); generic products are now
available as well
(a) Genotype 1:
(1) Copegus with Pegasys: 1200 mg/day in two divided doses (more than 75 kg);
1000 mg/day in two divided doses (less than 75 kg/day)
(2) Rebetol with PEG-Intron: 800 mg/day if less than 65 kg, 1000 mg/day if
6580 kg, 1200 mg/day for 81105 kg, 1400 mg/day if more than 105 kg
(b) Genotype 2 or 3: 800 mg/day in two divided doses
iii. Protease inhibitors for genotype 1 (see table above for dosing)
iv. Treatment duration
(a) Genotype 1:
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REFERENCES
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children, and adolescents. MMWR 7. Ghany MG, Strader DB, Thomas DL, et al.
2005;54(RR-16):123. Diagnosis, management, and treatment of
5. Centers for Disease Control and Prevention. hepatitis C: an update. Hepatology
A comprehensive immunization strategy to 2009;49:133564.
eliminate transmission of hepatitis B virus 8. Ghany MG, Nelson DR, Strader DB, et al.
infection in the United States: An update on treatment of genotype 1
recommendations of the Advisory chronic hepatitis C virus infection: 2011
Committee on Immunization Practices practice guideline by the American
(ACIP). Part II. Immunization of adults. Association for the Study of Liver Diseases.
MMWR 2006;54(RR-16):140. Hepatology 2011;54:143344.
6. Centers for Disease Control and Prevention. 9. 4. Ramkumar D, Rao SSC. Efficacy and
Recommendations for identification and safety of traditional medical therapies for
public health management of persons with chronic constipation: systematic review. Am
chronic hepatitis B virus infection. MMWR J Gastroenterol 2005;100:93671.
2008;57(RR-08):120.
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Learning Objectives:
1. Given a patient with hypertension, outline the optimal pharmacologic management on the
basis of practice guidelines and clinical trial evidence.
2. Identify and determine the appropriate therapeutic goals for a patient with dyslipidemia on
the basis of cardiovascular (CV) risk factors.
3. Develop a pharmacotherapy treatment plan for a patient with dyslipidemia on the basis of
various cholesterol targets as well as CV risk factors.
4. Develop a pharmacotherapy treatment plan for a patient with peripheral arterial disease
(PAD).
5. Demonstrate an understanding of the pathophysiology, prognosis, and economic impact of
PAD.
6. Create an evidence-based drug regimen for a patient with coronary artery disease in both the
presence and absence of stable angina.
7. Distinguish between the different acute coronary syndromes (ACSs), ST-segment elevation
myocardial infarction, nonST-segment elevation myocardial infarction, and unstable angina
by diagnosis as well as treatment.
8. Develop a pharmacotherapy treatment plan for a patient presenting with the various ACSs.
9. Recommend patient-specific pharmacologic management of chronic heart failure, with an
emphasis on mortality-reducing drugs and their target dosages.
10. Develop an appropriate pharmacologic and monitoring plan for a patient with atrial
fibrillation.
11. Discuss indications for warfarin and goal INR for specific patients, and adjust therapy
according to INR, other clinical findings, and/or patient factors.
12. Describe how to design a treatment plan for a patient receiving warfarin who needs to
undergo an invasive procedure.
13. Determine the appropriate immunizations for an adult given his/her age and medical
conditions.
I. Hypertension
A. Background
1. Definition: Hypertension is considered a blood pressure (BP) of 140/90 mm Hg or
higher.
2. Statistics
a. Most common chronic disease in the United States
b. Affects 50 million Americans
c. The normotensive 50-year-old lifetime risk of developing hypertension is 90%.
d. For each 20-mm Hg increase in systolic BP and 10-mm Hg increase in diastolic
BP, there is a 2-fold increased risk of cardiovascular (CV) disease (e.g., stroke,
MI).
e. Only 31% of patients with hypertension have it under adequate control.
3. Etiology
a. Essential hypertension: 90% (no identifiable cause)
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i. Contributed to by obesity
ii. Evaluate sodium (Na) intake.
b. Secondary hypertension
i. Primary aldosteronism
ii. Renal parenchymal disease
iii. Thyroid or parathyroid disease
iv. Medications (e.g., cyclosporine, nonsteroidal anti-inflammatory drugs
[NSAIDs], sympathomimetics)
4. Diagnosis
a. Periodic screening for all individuals older than 21 years
b. Patient should be seated quietly in chair for at least 5 minutes.
c. Use appropriate cuff size (bladder length at least 80% the circumference of the
arm).
d. Take BP at least twice, separated by at least 2 minutes.
e. The average BP on two separate visits is required to diagnose hypertension
accurately.
5. Benefits of lowering BP
a. 40% decrease in stroke
b. 25% decrease in myocardial infarction (MI)
c. 50% decrease in heart failure (HF)
6. Effects of lifestyle modifications on BP
Table 1.
Approximate
Systolic BP
Modification Recommendation Reduction
Weight reduction Attain/maintain BMI less than 25 kg/m2 520 mm Hg per 10-
(if more than 25 kg/m2) kg weight loss
Adopt DASH eating Consume a diet rich in fruits, vegetables, and low-fat 814 mm Hg
plan (includes dairy products with a reduced content of saturated and
substantial potassium total fat
intake)
Dietary sodium Reduce dietary sodium intake to no more than 2.4 g of 28 mm Hg
restriction sodium
Physical activity Engage in regular aerobic physical activity such as 49 mm Hg
brisk walking (at least 30 minutes/day most days of the
week)
Moderation of alcohol Limit consumption to: 24 mm Hg
consumption Men: 2 drinks/day
Women: 1 drink/day
BMI = body mass index; BP = blood pressure; DASH = Dietary Approaches to Stop Hypertension.
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B. Therapeutic Management
1. Patient classification and management in adults: Primary classification based on
systolic BP
Table 2.
Systolic BP (mm Lifestyle
BP Classification Hg) Diastolic BP (mm Hg) Modification
Normal < 120 AND < 80 Encourage
Prehypertension 120139 OR 8089 Yes
Stage 1 hypertension 140159 OR 9099 Yes
Stage 2 hypertension 160 OR 100 Yes
BP = blood pressure.
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Figure 1.
NOTE: Strength of recommendation (A, B, and C = good, moderate, and poor evidence to support
recommendation) and quality of evidence [1 = Evidence from more than 1 properly randomized,
controlled trial. 2 = Evidence from at least 1 well-designed clinical trial with randomization, from cohort
or case-controlled analytic studies; or dramatic results from uncontrolled experiments or subgroup
analyses. 3 = Evidence from opinions of respected authorities, based on clinical experience, descriptive
studies, or reports of expert communities] are in brackets.
Modified from Saseen JJ, MacLaughlin EJ. Hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM, eds. Pharmacotherapy: A Pathophysiological Approach, 8th ed. New York: McGraw-Hill,
2008:chap 19.
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker.
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enzyme (ACE) inhibitors, ARBs, and calcium channel blockers; use caution in
patients at high risk of diabetes mellitus (e.g., family history, obese)
iii. May assist in the management of osteoporosis by preventing urine calcium
loss
c. ACE inhibitors and ARBs
i. Contraindicated in pregnancy
ii. Contraindicated with bilateral renal artery stenosis
iii. Monitor potassium (K) closely, especially if renal insufficiency exists or
another K-sparing drug is in use.
iv. The presence of diabetic nephropathy should influence the choice of an ACE
inhibitor versus an ARB.
d. Aliskiren
i. A direct rennin antagonist
ii. When combined with losartan (100 mg/day) in patients with hypertension,
type 2 diabetes mellitus, and nephropathy (albumin-to-creatinine ratio greater
than 300 mg/g or greater than 200 mg/g), aliskiren showed renoprotective
effects independently of its BP effects (N Engl J Med 2008;358:243346).
iii. Whether this combination is superior to ACE inhibitor/ARB combinations is
unknown.
Table 3.
Type Nephropathy Agent
1 Any level of proteinuria ACEI
2 Microalbuminuria ACEI or ARB
2 Macroalbuminuria and renal insufficiency (i.e., elevated SCr) ARB
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; SCr = serum creatinine.
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continued in pregnancy.
6. Monitoring
a. Have the patient return in 4 weeks to assess efficacy.
b. May have patient follow up sooner if BP is particularly worrisome
c. If there is an inadequate response from the first agent (and adherence verified)
and no compelling indication exists, initiate therapy with a drug from a different
class.
II. Dyslipidemia
A. Diagnosis
1. Complete fasting lipoprotein profile preferred (i.e., total cholesterol [TC], low-density
lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TG])
2. After 912 hours of fasting (however, with the availability of measuring direct LDL,
fasting not always necessary)
Classification National Institutes of Health National Heart, Lung and Blood Institute.
Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). Available at
www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
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D. Main Positive Risk Factors (exclusive of LDL) That Modify LDL Goals
1. Cigarette smoking
2. Hypertension (BP 140/90 mm Hg or higher or taking an antihypertensive drug)
3. Low HDL (less than 40 mg/dL)
4. Family history of premature CHD
a. CHD in male first-degree relative younger than 55 years
b. CHD in female first-degree relative younger than 65 years
5. Age (men 45 years or older; women 55 years or older)
E. Main Negative Risk Factors (exclusive of LDL) That Modify LDL Goals: High HDL
(more than 60 mg/dL) (subtract 1 from the total number of risk factors)
F. Risk Assessment
1. For patients with several (two or more) risk factors, perform a Framingham 10-year
CHD risk assessment.
2. For patients with zero or one risk factor, a 10-year risk assessment is not required.
3. A 10-year CHD risk assessment is based on Framingham tables.
a. Sex
b. Age
c. Total cholesterol
d. Smoking
e. High-density lipoprotein
f. Systolic BP
Table 4. Goal LDL According to Risk Category and LDL Concentration to Start
Pharmacotherapy
Risk Categorya LDL Goal (mg/dL) LDL to Start Pharmacotherapy (mg/dL)
CHD and CHD risk < 100 (optional < 70) 130; 100 optional ( 100 or < 100)
equivalents
(10-year risk > 20%)
Several (2+) risk factors < 130 (optional < 100) 130 ( 100)
(10-year risk 10%20%)
Several (2+) risk factors < 130 160
(10-year risk < 10%)
0 or 1 risk factor < 160 190; 160 optional
a
Risk factors: See item D above. The LDL concentrations in parentheses are from Grundy SM, et al. Implications of recent
clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227
39. Only concentrations that are different from the National Cholesterol Education Panel guidelines are included in parentheses.
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Consider less than 70 for everyone at very high CHD risk or with stable CHD, based on PROVE-IT (N Engl J Med 2004;350)
and TNT (N Engl J Med 2005;352:142535) studies, which were published after the 2004 ATP (Adult Treatment Panel) III
update.
CHD = coronary heart disease; LDL = low-density lipoprotein.
Classification National Institutes of Health National Heart, Lung and Blood Institute. Third Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Available at
www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
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K. Elevated C-Reactive Protein in Low-Risk Individuals: JUPITER study (Ridker PM, et al. N Engl
J Med 2008;359:2195207)
1. More than 15,000 subjects with no prior coronary artery disease (CAD) or diabetes mellitus,
with normal LDL (less than 130 for inclusion; median, 108), high C-reactive protein (2 mg/L
or greater) (median C-reactive protein, 4.24.3)
2. Rosuvastatin 20 mg versus placebo
3. Trial was terminated early because of significant reduction in CV death and CV events
(hazard ratio = 0.56; 95% confidence interval, 0.460.69)
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Figure 2.
1. Efficacy
a. Drugs of choice for high LDL and/or CHD or CHD risk
b. When selecting a statin, consider the percentage of LDL reduction needed.
i. (current LDL goal LDL)/current LDL 100
ii. Select an initial dose to achieve an LDL reduction of 30%40% if possible.
c. Reduce LDL 24%60%.
d. Reduce TG 7%40%.
e. Raise HDL 5%15%.
f. Reduce major coronary events.
g. Reduce CHD mortality.
h. Reduce coronary procedures (percutaneous transluminal coronary angioplasty/coronary
artery bypass graft).
i. Reduce stroke.
j. Reduce total mortality.
2. Mechanism of action: Inhibits enzyme responsible for converting HMG-CoA to mevalonate
(rate-limiting step in production of cholesterol)
3. Main adverse effects/monitoring
a. Myopathy (check creatine kinase at baseline and then only if muscle symptoms occur; no
regular monitoring)
b. Increased liver enzymes
c. Liver function tests (LFTs) at baseline, 3 months, and yearly
4. Contraindications
a. Absolute: Severe liver disease (AST/ALT [aspartate aminotransferase/alanine
aminotransferase] more than 3 ULN [upper limits of normal])
b. Relative: Use with certain medications (strong cytochrome P450 [CYP] 3A4 inhibitors).
5. Drug interactions
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Cholestyramine 48 9
812 13
1216 17
1620 21
2024 28
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N. Niacin
1. Main actions
a. Lowers LDL 15%26%
b. Lowers TG 20%50%
c. Raises HDL 15%26%
d. Reduces major coronary events
e. Possibly reduces total mortality
f. Lowers lipoprotein(a)
2. Mechanism of action: Inhibits mobilization of free fatty acids from peripheral adipose tissue
to the liver, so reduces VLDL synthesis (LDL and TG)
3. Adverse effects: Flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity;
monitor LFTs at baseline, every 612 weeks, and then yearly
4. Sustained release appears to be more hepatotoxic than other preparations (e.g., over-the-
counter drugs). Available as Slo-Niacin or 2 times/day generic niacin over the counter. Use
of these products should be avoided
5. Extended release and sustained release are less likely to cause flushing.
6. Contraindications: Liver disease, severe gout, active peptic ulcer
7. Flushing can be minimized by taking ASA 30 minutes before niacin, taking at bedtime with
food, and avoiding hot beverages, spicy foods, and hot showers around the time of
administration.
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O. Fibrates
1. Main actions
a. Lower LDL 5%20% (with normal TG)
b. May raise LDL to 45% (with very high TG)
c. Lower TG 30%55%
d. Raise HDL 18%22%
e. Reduce progression of coronary lesions
f. Reduce major coronary events
2. Mechanism of action: Reduce rate of lipogenesis in the liver
3. Adverse effects: Dyspepsia, gallstones, myopathy, increased hepatic transaminases; monitor
LFTs every 3 months during first year and then periodically
4. Contraindications: Severe renal or hepatic disease
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A. Definition
1. Peripheral arterial disease (PAD) is a generic term that encompasses vascular insufficiencies
caused by noncoronary arteries secondary to atherosclerotic occlusions. The arteries affected
supply bloodflow to the brain, visceral organs, and limbs.
a. FunctionalCaused by spasm of the vessels. Ex. Raynaud disease
b. OrganicCaused by structural changes in blood vessels. Ex. Fatty buildup in the arteries
2. In North America and Europe, around 27 million people are affected by the disease. About
10.5 million people are symptomatic, and 16.5 million are asymptomatic. The incidence
increases with age, with about 20% of patients older than 70 years affected.
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C. Diagnosis
1. Ankle brachial index (ABI): BP is measured in the arms and ankles using a regular BP cuff
and a Doppler. The two pressures are then compared, and a determination is made on the
adequacy of bloodflow. The specific index or reference number is determined by dividing the
ankle systolic pressure by the arm systolic pressure.
a. May be done with or without a treadmill
b. Calculation of ABI
i. Right ABI = Higher right ankle pressure/higher brachial pressure
ii. Left ABI = Higher left ankle pressure/higher brachial pressure
2. Pulse volume recordingUsed to establish initial lower extremity diagnosis (localization and
severity)
3. Duplex ultrasonographyUsed to assess anatomic location and the degree of stenosis. Often
used as a follow-up procedure after a femoral-popliteal or femoral-tibial pedal bypass
4. Continuous wave Doppler ultrasoundUsed to determine the location of the diseased
segment as well as the severity. Can be helpful to monitor disease progression
5. Magnetic resonance imagingUsed to assess anatomic location and disease severity. Most
useful in assessing patients for endovascular intervention
6. Computed tomographic angiographyUsed to determine the location of the stenosis as well
as the degree of stenosis
7. Contrast angiographyProvides detail on the anatomy of the arteries and is used to assess
patients possibly undergoing revascularization
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D. TreatmentGeneral
1. Diet
2. Exercise
3. Smoking cessationApplicable to all forms of tobacco
a. Single most important intervention
b. People who smoke receive a diagnosis of PAD as much as 10 years before a nonsmoker.
4. Drug therapy
a. Statins initiationGoal LDL cholesterol (LDL-C) of less than 70 mg/dL for patients
deemed very high risk
b. Fibric acid agentsUsed for patients with low high-density lipoprotein cholesterol
(HDL-C), normal low-density lipoprotein cholesterol (LDL-C), and high triglycerides
(TG)
c. AntihypertensivesGoal BP of less than 140/90 mm Hg if nondiabetic and less than
130/80 mm Hg if diabetic or with chronic kidney disease
i. -Blockers
ii. ACE inhibitors
d. Diabetes control including proper foot careGoal hemoglobin A1C less than 7%
e. Homocysteine
f. Folic acid and B12 vitamin supplements
g. Antiplatelet agents
i. Recommended for all patients with lower extremity disease
ii. Aspirin 75325 mg orally daily is effective.
iii. Clopidogrel 75 mg orally daily is an alternative to ASA.
iv. WarfarinNot indicated
E. TreatmentClaudication
1. Cilostazol (Pletal)
a. Mechanism of actionA phosphodiesterase type 3 inhibitor that causes an increase in
cyclic adenosine monophosphate. It has both vasodilatory and antiplatelet effects.
b. Precise mechanism in claudication is unknown.
c. Dose100 mg orally 2 times/day
d. This agent improves symptoms and increases walking distance.
e. Avoid use in patients with heart failure (HF).
2. Pentoxifylline (Trental)
a. Mechanism of actionA methylxanthine derivative; reduces blood and plasma viscosity,
inhibits neutrophil adhesion and activation, increases erythrocyte and leukocyte
deformability, and lowers plasma fibrinogen levels
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A. Overview
Coronary artery disease (CAD) is a general term that does not discriminate between the various
phases the individual may cycle between for several decades. These phases include asymptomatic
disease, stable angina, progressive angina, unstable angina (UA), ST-segment elevation
myocardial infarction (STEMI), and non-STEMI (NSTEMI).
On the basis of a patients manifestations, some therapies may be added or modified. However,
several basic treatment rules apply to all individuals with CAD, regardless of the symptoms they
may experience.
The following mnemonic, developed for patients with chronic stable angina, can be applied to all
patients with CAD.
Although not all patients with CAD have diabetes or smoke cigarettes, the mnemonic is a way to
remember the primary areas that should be addressed, as applicable, in all patients with CAD.
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2. Therapy goals
a. Unstable angina (UA)/nonST-segment elevation myocardial infarction (NSTEMI) goals
i. Prevent total occlusion of the infarct-related artery.
(a) Glycoprotein (GP) IIb/IIIa inhibitors, other antiplatelet agents, and anticoagulants
(b) Percutaneous coronary intervention (PCI) can be either or both:
(1) Percutaneous transluminal coronary angioplasty (i.e., balloon)
(2) Stent implantation
(c) Thrombolytics have no role and have an increased bleeding risk.
ii. Control chest pain and associated symptoms.
b. STEMI goals
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C. Initial Management
1. MONA in UA/NSTEMI, MONA plus -blocker in STEMI
N = Nitroglycerin Nitroglycerin spray or SL tablet 0.4 mg x 3 doses to relieve acute chest pain (if pain is
unrelieved after 1 dose, call 911)
Nitroglycerin IV 510 mcg/minute, titrate to chest pain relief or 200 mcg/minute if pain
unrelieved by morphine and SL NTG
Hold if MAP < 80 mm Hg
Used in first 48 hours for treatment of persistent chest pain, HF, and HTN
Use should not preclude other mortality-reducing therapies (ACE inhibitor, -blocker)
No mortality benefits but high placebo crossover rate
Contraindication: Sildenafil or vardenafil use within 24 hours or tadalafil use within 48
hours; SBP < 100 mm Hg or 30 mm Hg below baseline, HR < 50 beats/minute, HR > 100
beats/minute in absence of symptomatic HF or right ventricular infarction
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ACE inhibitors Indicated orally within first 24 hours if HF, LVEF < 40%, type 2 diabetes mellitus, or CKD
IV therapy contraindicated because of risk of hypotension
Consider in all patients with CAD
Indicated indefinitely in all patients with LVEF < 40%
ARB indicated if contraindication to ACE inhibitor
Contraindication: Hypotension
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a
Table 21. STEMI Algorithm
Symptoms 12 hours
Clopidogrel or prasugrel Clopidogrel
Primary PCI Fibrinolysis
UFH with abciximab (alternatively eptifibatide or IV UFH for at least 48 hours or
tirofiban) or bivalirudin alone IV and SC enoxaparin for hospitalization, up to 8 days
(preferred, selected patients) or
IV and SC fondaparinux for hospitalization, up to 8 days
a
Algorithm for patients with symptoms for 12 hours or less. If symptoms for more than 12 hours, administer clopidogrel with PCI
or coronary artery bypass grafting or fibrinolysis for selected patients. If PCI, administer UFH or enoxaparin with abciximab or
eptifibatide or bivalirudin alone at time of PCI.
IV = intravenous; PCI = percutaneous coronary intervention; SC = subcutaneous; STEMI = ST-segment elevation myocardial
infarction; UFH = unfractionated heparin.
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a
Target ACT 250300 seconds for primary PCI without GP IIb/IIIa inhibitor and 200250 seconds in patients given a
concomitant GP IIb/IIIa inhibitor.
b
If STEMI status is post-fibrinolytics, UFH dosesame as UA/NSTEMI and enoxaparin doseif younger than 75 years, 30 mg
IVB, followed immediately by 1 mg/kg subcutaneously 2 times/day (first two doses maximum 100 mg if more than 100 kg); if
older than 75 years, no IVB, 0.75 mg/kg subcutaneously 2 times/day (first two doses maximum 75 mg if more than 75 kg).
ACT = activated clotting time; aPTT = activated partial thromboplastin time; BID = twice daily; DTI = direct thrombin inhibitor;
GP = glycoprotein; HIT = heparin-induced thrombocytopenia; IV = intravenous; IVB = intravenous bolus; LMWH = low-
molecular-weight heparin; NSTEMI = nonST-elevation myocardial infarction; PCI = percutaneous coronary intervention; QD =
once daily; SC = subcutaneously; STEMI = ST-elevation myocardial infarction; UA = unstable angina; UFH = unfractionated
heparin.
Tenecteplase < 60 kg, 30 mg IV; 6069 kg, 35 mg IV; 7079 kg, 40 mg IV; 8089 kg, 45 mg
(TNK-tPA, TNKase) IV, > 90 kg, 50 mg IV (about 0.5 mg/kg)
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D. Long-term Management
1. -Blockers
a. Indicated for all patients unless contraindicated
b. Initiate within a few days of event, if not acute, and continue indefinitely.
c. If moderate or severe left ventricular (LV) failure, initiate with gradual titration.
2. ACE inhibitors
a. Indicated for all patients even if no LV dysfunction, HTN, or diabetes mellitus
b. Give oral ACE inhibitor in low doses to all patients during the first 24 hours of anterior
STEMI, HF signs (pulmonary congestion), or LV ejection fraction (LVEF) less than
40%, provided no hypotension exists (systolic BP less than 100 mm Hg) or other
contraindication, to reduce mortality and remodeling.
c. ARB if ACE inhibitor intolerant
d. Avoid intravenous ACE inhibitor post-MI to prevent hypotension.
3. Aldosterone receptor blockers: Indicated if post-MI with LVEF less than 40%, symptomatic
HF, or diabetes mellitus and receiving ACE inhibitor; however, contraindicated if creatinine
clearance less than 30 mL/minute or K more than 5 mEq/L
4. WarfarinIndicated either without (international normalized ratio [INR] 2.53.5) or with
low-dose ASA (7581 mg/day, INR 22.5) if high CAD risk and low bleeding risk if patient
does not require, or is intolerant of, clopidogrel
5. Lipid managementStatins indicated with an LDL goal less than 100 mg/dL, with a goal of
less than 70 mg/dL reasonable
6. Other goalsHemoglobin A1c less than 7%, smoking cessation, body mass index 18.524.9
kg/m2, exercise 3 or 4 times/week
A. Background: Heart failure is a complex clinical syndrome that can result from any structural or
functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.
1. Systolic dysfunction (decreased ejection fraction [EF] less than 40%)
a. Impaired wall motion
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b. Dilated ventricle
c. Two-thirds attributable to coronary artery disease (CAD)
d. One-third attributable to nonischemic cardiomyopathy
i. Hypertension
ii. Thyroid disease
iii. Valvular disease
iv. Cardiotoxins
(a) Alcohol
(b) Chemotherapeutic agents
(1) Anthracyclines
(2) Cyclophosphamide
(3) 5-Fluorouracil
(4) Trastuzumab
v. Myocarditis
vi. Idiopathic
2. Diastolic dysfunction (preserved/normal EF greater than 40%, greater than 45%, or greater
than 50%)
a. Accounts for about 30% of patients with heart failure (HF)
b. Impaired ventricular relaxation and filling
c. Normal wall motion
d. Most are caused by hypertension and age-related decreases in the elastic properties of the
cardiovascular system.
e. Some are caused by various cardiomyopathies (e.g., restrictive, infiltrative, hypertrophic).
3. Primary symptoms
a. Dyspnea
b. Fatigue
c. Edema
d. Exercise intolerance
4. Stages of HF
Table 27.
ACC/AHA Description Patient Population
Stage
A At high risk of HF but without Patients with hypertension, atherosclerotic disease,
structural heart disease or symptoms diabetes mellitus, obesity, or metabolic syndrome OR
of HF patients using cardiotoxins or having a family history of
cardiomyopathy
B Structural heart disease but without Patients with a previous MI, left ventricular remodeling,
signs or symptoms of HF left ventricular hypertrophy, or asymptomatic valvular
disease
C Structural heart disease with prior or Patients with known structural heart disease and
current symptoms of HF shortness of breath, fatigue, and/or reduced exercise
tolerance
D Refractory HF requiring specialized Patients who have marked symptoms at rest despite
interventions maximal medical therapy (e.g., those who are recurrently
hospitalized or cannot be safely discharged from the
hospital without specialized interventions)
HF = heart failure; MI = myocardial infarction.
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Table 28.
NYHA Functional Class Description
Figure 3.
H2O = water; Na = sodium; TNF = tumor necrosis factor alpha.
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Table 29.
Diuretic Class Examples Increase in Sodium Excretion (%)
Loop Furosemide, bumetanide, torsemide 2530
Thiazide Hydrochlorothiazide, metolazone, chlorthalidone 58
Potassium sparing Amiloride, triamterene, spironolactone 23
3. Neurohormonal blockade
a. ACE inhibitors
i. Benefits of ACE inhibitor
(a) Decreased mortality (about 25% relative risk reduction vs. placebo)
(b) Decreased hospitalizations (about 30% relative risk reduction vs. placebo)
(c) Symptom improvement
(d) Improved clinical status
(e) Improved sense of well-being
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Table 30.
Drug Starting Dosage Target Dosage Maximal Dosage
v. Monitoring
(a) SCr, BP, and K in 12 weeks after starting or increasing the dose, especially in
high-risk individuals (e.g., those with systolic BP less than 90 mm Hg, those with
serum sodium concentrations less than 130 mEq/L, or those receiving high doses
of loop diuretics)
(1) SCr may rise (up to a 0.5-mg/dL increase is acceptable) because of renal
efferent artery dilation (results in a slightly decreased glomerular filtration
rate).
(A) Rarely, acute renal failure occurs, especially if the patient is
intravascularly depleted (be careful to avoid overdiuresis).
(B) Use cautiously in patients with a baseline SCr more than 3.0 mg/dL
(NOT a contraindication; they should still be used, just with smaller
dosage changes and increased monitoring).
(2) Monitor BP and symptoms of hypotension (e.g., dizziness, light-headedness).
(A) BP may be low to begin with because of low cardiac output.
BP = CO SVR (CO = cardiac output, SVR = systemic vascular resistance)
(B) In HF, as cardiac output increases because of decreased SVR, BP may
decrease slightly or remain about the same.
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(C) Symptoms of hypotension are often not present with small dose
increases. Remember to treat the patient, not the number.
(3) Potassium (K)may rise because of decreased glomerular filtration rate and
decreased aldosterone.
(A) Use cautiously in those with a baseline K greater than 5.0 mEq/L.
(B) Monitor K within 3 days of beginning therapy.
(b) 90% of people tolerate ACE inhibitors.
(1) Angioedema (less than 1%)Could switch to ARBs (cross-reactivity is
2.5%) or hydralazineisosorbide dinitrate
(2) Cough (20%)Could switch to ARBs (less than 1%)
b. -Blockers
i. Benefits of -blockade (when added to an ACE inhibitor)
(a) Decreased mortality (about 35% relative risk reduction vs. placebo)
(b) Decreased hospitalizations (about 25% relative risk reduction vs. placebo)
(c) Symptom improvement
(d) Improved clinical status
(e) Improved sense of well-being
ii. Mechanism of action
(a) Blocks the effect of norepinephrine and other sympathetic neurotransmitters on
the heart and vascular system
(1) Decreases ventricular arrhythmias (sudden death)
(2) Decreases cardiac hypertrophy and cardiac cell death
(3) Decreases vasoconstriction and HR
(b) Carvedilol also provides 1-blockade.
(1) Further decreases SVR (afterload)
(2) Will have a greater reduction in BP compared with metoprolol
iii. Place in therapy
(a) Should be used in all stable patients (e.g., those not receiving intravenous inotropic
or diuretic therapy, those without significant peripheral and pulmonary congestion)
with LV dysfunction (even if asymptomatic)
(b) Can be used safely in those with depression, diabetes, and heart block with a pacer
iv. Dosing considerations
(a) Added to existing ACE inhibitor therapy (at least at a low dose) when HF
symptoms are stable and patients are euvolemic
(b) Start low and increase (double) the dose every 24 weeks (or slowly, if needed)
to target dose.
(c) Avoid abrupt discontinuation; can precipitate clinical deterioration
(d) Patient may notice improvement in several months.
(e) Benefits of high versus low doses
Table 31.
Agent Starting Dosage Target Dosage
Bisoprolol 1.25 mg/day 10 mg/day
Carvedilol 3.125 mg BID 25 mg BIDa
Metoprolol succinate XLb (metoprolol CR/XL) 12.525 mg/day 200 mg/day
a
50 mg 2 times/day if weight is more than 85 kg.
b
Few or no data exist with metoprolol tartrate.
BID = 2 times/day; CR = controlled release; XL = extended release.
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v. Monitoring
(a) BP, HR, and symptoms of hypotension (monitor in 12 weeks)
(1) Significant hypotension, bradycardia, or dizziness occurs in about 1% of
patients on -blocker therapy when titrated slowly. If these appear, lower the
dose by 50%. Discontinue the drug only if the patient has heart block or is in
cardiogenic shock.
(2) Of importance, remember that higher -blocker doses are associated with
increased reduction in mortality. Therefore, if hypotension alone is the
problem, try reducing the dose of the ACE inhibitor first.
(3) With carvedilol, dizziness and hypotension are more common, usually
occurring within 2448 hours of a dosage increase.
(4) The net decrease in HR at goal doses of -blocker is only 1015 beats/minute
from baseline.
(b) Increased edema/fluid retention (monitor in 12 weeks)
(1) From 1% to 2% more common than placebo (in euvolemic, stable patients)
(2) Responds to diuretic increase
(c) Fatigue or weakness
(1) From 1% to 2% more common than placebo
(2) Usually resolves spontaneously in several weeks
(3) May require dosage decrease or discontinuation
c. Aldosterone blockade
i. Patient population
(a) Class III and IV HF
(b) Left ventricular dysfunction immediately after MI
ii. Benefits of spironolactone in class III and IV HF
(a) Decreased mortality (30% relative risk reduction vs. placebo)
(b) Decreased hospitalizations for HF (35% relative risk reduction vs. placebo)
(c) Improved symptoms
iii. Benefits of eplerenone in class II HF
(a) Decreased death from cardiovascular causes or hospitalization from HR (46%
relative risk reduction vs. placebo)
(b) Decreased mortality (24% relative risk reduction vs. placebo)
iv. Benefits of eplerenone (a selective aldosterone blocker) with LV dysfunction after
MI
(a) Decreased mortality (15% relative risk reduction vs. placebo)
(b) Decrease in the composite of death from cardiovascular causes or hospitalization
for cardiovascular events (13% relative reduction vs. placebo)
v. Mechanism of action: Blocks effects of aldosterone in the kidneys, heart, and
vasculature
(a) Decreases K and Mg loss: Decreases ventricular arrhythmias
(b) Decreases Na retention: Decreases fluid retention
(c) Eliminates catecholamine potentiation: Decreases BP
(d) Blocks direct fibrotic actions on the myocardium
vi. Place in therapy
(a) Should be considered in all patients with class III and IV HF who are receiving
background therapy with an ACE inhibitor, diuretic, and -blocker or after an MI
with LV dysfunction
(b) Avoid use in combination with both ACE inhibitor and ARB; the effects of all
three agents on K have not been adequately characterized.
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4. Digoxin
a. Benefits of digoxin
i. Improved symptoms
ii. Improved exercise tolerance
iii. Decreased hospitalizations
iv. No effect on mortality
b. Mechanism of action (in HF) by Na-K adenosine triphosphatase inhibition
i. Decreases central sympathetic outflow by sensitizing cardiac baroreceptors
ii. Decreases renal reabsorption of Na
iii. Minimal increase in cardiac contractility because of the inhibition of Na-K adenosine
triphosphatase. This is not thought to cause beneficial effects in HF.
c. Place in therapy: Should be considered in patients with symptomatic LV dysfunction
despite optimal ACE inhibitor (or ARB), -blocker, spironolactone (if appropriate), and
diuretic therapy
d. Dosing considerations and monitoring
i. Serum concentrations of 0.51.0 ng/dL are effective in HF.
(a) Minimizes the risk of adverse effects and ventricular arrhythmias associated with
increased concentrations
(b) Risk of toxicity increases with age and renal dysfunction.
(c) Risk of toxicity increases in the presence of hypokalemia or hypomagnesemia.
ii. SCr as the drug is cleared more than 95% renally
iii. For most patients, 0.125 mg/day is adequate to achieve the desired serum
concentration. Loading doses are not recommended in those with HF.
iv. Useful initial agent for patient with concomitant AF
v. Drug interactions. Digoxin concentrations are increased with concomitant:
(a) Clarithromycin, erythromycin
(b) Amiodarone, dronedarone
(c) Itraconazole, posaconazole, voriconazole
(d) Cyclosporine, tacrolimus
(e) Verapamil
5. Hydralazineisosorbide dinitrate
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a. Benefits
i. Decreases mortality 39% versus placebo
ii. Decreases hospitalizations 33% versus placebo
b. Mechanism of action
i. Hydralazine
(a) Vasodilator
(b) Enhances effect of nitrates
ii. Isosorbide dinitrate
(a) Stimulates nitric acid signaling in the endothelium
(b) Effective in reducing preload
c. Place in therapy
i. African Americans with NYHA class IIIV HF, already receiving an ACE inhibitor
(or ARB), -blocker, and diuretic therapy
ii. Decreases mortality versus placebo risk reduction in death compared with
hydralazineisosorbide dinitrate
iii. A reasonable alternative in patients unable to take an ACE inhibitor or ARB because
of severe renal insufficiency, hyperkalemia, or angioedema
d. Dosing consideration
i. Hydralazine (2575 mg orally 3 or 4 times/day); isosorbide dinitrate (1040 mg
orally 3 times/day). Titrate on the basis of BP.
ii. Fixed-dose BiDil (hydralazine 37.5 mg plus isosorbide dinitrate 20 mg) with a goal
dose of 2 tablets 3 times/day
e. Monitoring
i. Headache
ii. Hypotension
iii. Drug-induced lupus with hydralazine
6. Angiotensin II receptor blockers
a. Have never been proved superior to ACE inhibitors at target HF dosages
b. Current role: As ACE inhibitor substitutes for patients unable to take ACE inhibitors
because of cough. Possibly if patient has experienced ACE inhibitorinduced
angioedema
c. The best ARB to use on the basis of available data is candesartan 32 mg/day or valsartan
160 mg 2 times/day (target doses).
C. Nonpharmacologic Therapy
1. Prevent further cardiac injury
a. Discontinue smoking.
b. Reduce weight if obese.
c. Control hypertension.
d. Control diabetes mellitus.
e. Minimize alcohol to 2 or fewer drinks a day for men, 1 or fewer drinks a day for women.
f. Eliminate alcohol if cardiomyopathy is alcohol induced.
2. Limit Na to 2 g/day.
3. Restrict fluid intake to 2 L/day if serum sodium is less than 130 mEq/L or if there is fluid
retention despite aggressive diuresis and dietary Na restriction.
4. Modest exercise program benefits
a. Possible modest effects on all-cause hospitalization and all-cause mortality,
cardiovascular death or cardiovascular hospitalization, cardiovascular death or HF
hospitalization (ACTION-HF studyJAMA 2009;301:143950)
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In contrast to the large number of trials and the patients with systolic dysfunction who have been studied,
there is a lack of objective data to guide therapy for patients with diastolic dysfunction. The following
recommendations are based primarily on the consensus opinion of cardiovascular experts.
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2. Control tachycardia.
a. Tachycardia decreases the time for the ventricles and coronary arteries to fill with blood.
b. Control of HR improves symptoms of HF.
c. Can use -blockers, non-dihydropyridine calcium channel blockers, and/or digoxin
3. Reduce preload (but not too much!).
a. Ventricular filling pressure is primarily determined by central blood volume.
b. Patients with diastolic dysfunction are more preload-dependent for ventricular filling.
Decreasing the preload too much may cause unexpected hypotension.
c. Symptoms of breathlessness can be relieved by the use of diuretics or nitrates.
4. Aggressively investigate, repair, and treat myocardial ischemia.
a. Myocardial ischemia impairs ventricular relaxation.
b. Any ischemia possibly contributing to diastolic dysfunction warrants aggressive therapy.
A. Background
1. Prevalence
a. Most common arrhythmia: 2.2 million Americans
b. Prevalence increases with age.
c. Common comorbidity in patients with valvular heart disease or heart failure (HF)
2. Symptoms
a. Some patients have no symptoms.
b. At worst, an embolic event may occur, or symptoms of HF may be present.
c. Most patients have some degree of the following:
i. Palpitations
ii. Chest pain
iii. Dyspnea
iv. Fatigue
v. Light-headedness
d. Symptoms vary with ventricular rate, underlying LV functional status, AF duration, and
individual patient perceptions.
3. Classification (more than one of these may exist in a given patient):
a. Paroxysmalspontaneous self-termination within 7 days of onset
b. Persistentlasting more than 7 days
c. Permanenta commonly used but arbitrary classification
d. Recurrenttwo or more episodes
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B. Pathophysiology
1. Cardiac conduction
Figure 4.
2. Electrocardiogram findings
a. No P waves
b. Irregularly, irregular rhythm
c. Rate may be fast or slow (depending on the rate of atrioventricular node conduction).
Figure 5.
Table 32.
Atrial Distension High Adrenergic Tone
Chronic hypertension Alcohol withdrawal
Mitral valve disease Thyrotoxicosis
Cardiomyopathy Sepsis
Congenital defects Binge drinking
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C. Pharmacologic Therapy
1. Ventricular rate control
a. If patients have a rapid ventricular rate, atrioventricular node blockade is required.
b. The goal HR is 6080 beats/minute at rest and 90115 beats/minute during exercise.
However, the RACE-2 (Rate Control Efficacy in Permanent Atrial Fibrillation) trial
suggested that lenient rate control (HR less than 110 beats/minute) is not inferior to strict
rate control (HR less than 80 beats/minute) regarding the composite end point of death
from cardiovascular causes, hospitalization for HF, and stroke, systemic embolism,
bleeding, and life-threatening arrhythmic events.
c. Select the best agent on the basis of individual clinical response and concomitant disease
states that may increase or decrease the desirability of one of the three approaches.
d. These therapies have no effect on the cardioversion of AF:
i. -Blockers
(a) Any agent with -blockade can be used and dosed to the goal HR.
(b) Selective 1-antagonists, such as atenolol or metoprolol, may be preferred.
(c) Labetalol or carvedilol if additional -blockade is desirable (e.g., hypertension or
cocaine exposure)
(d) Sotalol (class III antiarrhythmic) or propafenone (class Ic antiarrhythmic) if
rhythm control is necessary
(e) Effective for controlling exercise-associated HR increases
(f) Can be considered in patients with stable HF
ii. Non-dihydropyridine calcium channel blockers: Verapamil or diltiazem
(a) Avoid use if there is concomitant systolic dysfunction.
(b) May be preferred over -blocker in patients with asthma/severe chronic
obstructive pulmonary disease
(c) Also effective for controlling exercise-associated HR increases
iii. Digoxin
(a) Often ineffective alone for controlling ventricular rate in AF, especially during
exercise or movement (because of minimal effectiveness with sympathetic
stimulation)
(b) Can be included in regimen if patient has systolic HF
(c) May also be effective if additional HR control is needed when a patient is
receiving a -blocker, diltiazem, or verapamil
2. Anticoagulation
a. The average annual stroke rate is 5% per year without anticoagulation.
i. A patients individual risk may vary from about 1% to 20% per year on the basis of
his or her risk factors.
ii. This risk is independent of current cardiac status (i.e., sinus rhythm or AF).
b. Risk stratification and treatment determination
c. Role of clopidogrel
i. ACTIVE A (N Engl J Med 2009;360:206678): Compared with aspirin alone, 75
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mg/day of clopidogrel and aspirin in patients with AF who had an increased risk of
stroke and for whom warfarin was unsuitable showed a significant reduction in major
vascular events but an increased risk of bleeding.
ii. ACTIVE W (Lancet 2006;367:190312): Compared with clopidogrel and aspirin,
warfarin had a significantly lower rate of vascular events in patients with AF plus one
or more risk factors for stroke. No difference existed in bleeding between groups.
d. Role of dabigatran
i. Direct thrombin inhibitor indicated to reduce the risk of stroke and systemic
embolism in patients with nonvalvular AF
ii. Dose: CrCl greater than 30 mL/minute150 mg 2 times/day; CrCl 1530
mL/minute75 mg 2 times/day; CrCl less than 15 mL/minuteno dosing
recommendations available; swallow capsules whole
iii. Missed doses: If a dose is not taken at the scheduled time, the dose should be taken as
soon as possible the same day; the missed dose should be skipped if it cannot be
taken at least 6 hours before the next scheduled dose. The dose of should not be
doubled to make up for a missed dose.
iv. Converting from or to warfarin
v. Drug interactions
(a) P-glycoprotein inducers (e.g., rifampin mentioned only in package labeling)
should be avoided; however, inducers such as ketoconazole, verapamil,
amiodarone, quinidine, and clarithromycin do not require dose adjustments.
(b) Proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change
the trough concentration of dabigatran.
vi. RE-LY (N Engl J Med 2009;361:113951): Dabigatran 110 mg 2 times/day was non-
inferior to INR-adjusted warfarin but superior at 150 mg 2 times/day for preventing
thromboembolic stroke in paroxysmal or permanent AF. Compared with warfarin,
dabigatran 110 mg 2 times/day had a statistically significant lower incidence of major
bleeding, with no difference seen with the 150-mg twice-daily dose.
e. Bleeding
i. Minor hemorrhage increased with therapeutic warfarin therapy.
ii. Major hemorrhage did not increase with warfarin therapy with INR 23.
iii. Risk of intracranial hemorrhage increased with INR greater than 4.
3. Rhythm control: Since the publication of the Atrial Fibrillation Follow-up Investigation of
Rhythm Management (AFFIRM) trial (N Engl J Med 2002;34:182533), it has been known
that maintaining sinus rhythm offers no advantage over controlling the ventricular rate (in the
typical elderly patient with AF). In fact, the rhythm control group had a higher incidence of
hospitalizations, gastrointestinal adverse effects, and symptoms of HF. However, in specific
patients with intractable and intolerable symptoms or in patients for whom adequate
ventricular rate control cannot be achieved, despite adequate rate control (dyspnea and
palpitations), restoration and maintenance of sinus rhythm may be desirable.
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Table 33.
Pros Cons
Rate control Easy to achieve and maintain; Electrical and structural remodeling because
strategy out-of-hospital therapy typical; and of continued AF makes future attainment of
end point relatively easy to achieve SR virtually impossible; safety unproved for
younger patients
Rhythm control If patient is symptomatic with fatigue and Adverse effects of medications, cost of
strategy exercise intolerance, these may improve if SR medications and monitoring, likelihood of
is attained (especially in the patient with HF); AF recurrence; in-hospital stay may be
minimized structural atrial changes; acceptable required; and high recurrence rate
for all age groups
AF = atrial fibrillation; HF = heart failure; SR = normal sinus rhythm.
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(8) Compared with placebo in the ATHENA trial (N Engl J Med 2009;360:668
78), high-risk patients with a history of paroxysmal or persistent AF or atrial
flutter within the past 6 months receiving dronedarone had a lower incidence
of hospitalization for cardiovascular causes or death from any cause; risk of
cardiovascular death; death from arrhythmias; and incidence of stroke.
(9) On the basis of the ANDROMEDA study (N Engl J Med 2008;358:2678
87), dronedarone compared with placebo showed an increased mortality in
patients with HF (LVEF less than 35% and NYHA classes IIIV).
(10) One meta-analysis (J Am Coll Cardiol 2009;54:108995) found dronedarone
less effective than amiodarone for the maintenance of sinus rhythm, but with
fewer adverse effects.
(11) Drug interactions
(A) Digoxin: Increased digoxin exposure; lower dose of digoxin by 50%
(B) Diltiazem, verapamil, -blockers: Excessive bradycardia and increased
exposure of these agents; initiate these drugs at lowest dose. Diltiazem
and verapamil can increase dronedarone exposure, so monitor the
electrocardiogram.
(C) Statins with CYP3A metabolism: Increased statin exposure. Follow
statin package labeling for CYP3A4 inhibitors.
(D) CYP3A4 inhibitors: AVOID.
(E) Cyclosporine, tacrolimus, sirolimus: Increased exposure of these agents,
monitor serum concentrations closely
(12) U.S. Food and Drug Administration Risk Evaluation and Mitigation
Strategy. See the following Web site:
www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformat
ionforPatientsandProviders/UCM187494.pdf
(b) Vernakalant: Unique ion channel blocker currently under investigation
4. The choice of agent may depend on the comorbidities.
5. Nonpharmacologic therapies
a. Electrical cardioversion (low-energy cardioversion, sedation highly desirable, can be
used in an emergency if patient is hemodynamically unstable)
b. Atrioventricular nodal ablation: Ablate atrioventricular node and chronically pace the
ventricles.
c. Pulmonary vein ablation: Ablates the origin of the abnormal atrial foci, which is often
near the pulmonary veinatrial tissue intersection
Table 34. Antiarrhythmic Drug Properties and Dosing (class I and III agents only)
Adverse Effects, Contraindications, Drug
Drug Interactions, Pharmacokinetics Dosing by Indication
Class IA Na+ channel blockers
Quinidine AEs: Nausea/vomiting/diarrhea (30%), AF conversion:
(Quinidex, cinchonism(CNS and GI symptoms, Avoid use because of GI AEs
Quinaglute) tinnitus), AF maintenance:
TdP (first 72 hours) Sulfate: 200400 mg PO every 6 hours
DIs: Warfarin, digoxin Gluconate (CR): 324 mg PO every 812 hours
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Table 34. Antiarrhythmic Drug Properties and Dosing (class I and III agents only)
Adverse Effects, Contraindications, Drug
Drug Interactions, Pharmacokinetics Dosing by Indication
Procainamide AEs: Lupuslike syndrome (30% if > 6 months), AF conversion:
(Pronestyl) hypotension (IV use, 5%), TdP 1 g IV for 30 minutes; then 2 mg/minute
CI: LVEF < 40% (1-hour efficacy 51%)
PK: Reduce dose in renal and liver dysfunction AF maintenance:
(active metabolite NAPA [class III effects] No oral agent
may accumulate) VT conversion:
20 mg/minute IV until 17 mg/kg, arrhythmia
ceases, or QRS widens > 50%
VT maintenance:
24 mg/minute
Lidocaine AEs: CNS (perioral numbness, seizures, Pulseless VT/VF conversion or VT with a pulse:
(Xylocaine) confusion, blurry vision, tinnitus) 11.5 mg/kg IVB; repeat 0.50.75 mg/kg
CI: Third-degree AV heart block every 35 minutes (maximum 3 mg/kg)
PK: Reduce dose in those with HF, liver (If LVEF < 40%: 0.50.75 mg/kg IVP)
disease, low body weight and renal (Amiodarone DOC in pulseless VT/VT
dysfunction and in the elderly lidocaine acceptable if amiodarone not
DI: Amiodarone (increased lidocaine available)
levels) VT maintenance: 14 mg/minute
Mexiletine AEs: CNS (tremor, dizziness, ataxia, VT maintenance: 200300 mg every 8 hours
(Mexitil) nystagmus)
CI: Third-degree AV heart block
Class IC Na+ channel blockers (Note: Avoid in patients with HF or post-MIIncreased risk of sudden death)
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Table 34. Antiarrhythmic Drug Properties and Dosing (class I and III agents only)
Adverse Effects, Contraindications, Drug
Drug Interactions, Pharmacokinetics Dosing by Indication
Propafenone AEs: Metallic taste, dizziness, ADHF, AF conversion:
(Rythmol, bronchospasm, bradycardia, heart block 600 mg PO 1 (efficacy 45% at 3 hours)
Rythmol CR) (negative inotropy and b-blocking properties) AF maintenance:
CIs: HF (NYHA IIIIV), liver disease, HCl: 150300 mg PO every 812 hours
valvular disease HCl (SR): 225425 mg PO every 12 hours
DIs: Digoxin by 70%; warfarin by 50% as
well as drugs that inhibit CYP 2D6, 1A2, 3A4
(increased propafenone
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Table 34. Antiarrhythmic Drug Properties and Dosing (class I and III agents only)
Adverse Effects, Contraindications, Drug
Drug Interactions, Pharmacokinetics Dosing by Indication
DIs: CYP3A4 inhibitors and drugs secreted 250 mcg PO BID (4060 mL/minute)
by kidney (cimetidine, ketoconazole, 125 mcg PO BID (2040 mL/minute)
verapamil, trimethoprim, prochlorperazine, Contraindicated < 20 mL/minute (efficacy 12% at 1
megestrol), HCTZ month)
CI: Baseline QTc > 440 milliseconds or AF maintenance:
CrCl < 20 mL/minute Titrate down based on QTc NTE 500 milliseconds or
PK: Renally eliminated > 15% in QTc
* Hospitalization mandatory for initiation,
obtain QTc 23 hours after each of the first
5 doses, reduce 50% if QTc > 15%; NTE
QTc > 500 milliseconds
* Does not increase mortality in patients
with HF
Ibutilide AEs: TdP 8%, heart block (-blocking AF conversion:
(Covert) properties) 1 mg IV ( 60 kg)
DIs: CYP3A4 inhibitors or QT-prolonging or 0.01 mg/kg IV (< 60 kg),
drugs repeat in 10 minutes if ineffective
CIs: Baseline QTc > 440 milliseconds, LVEF < (efficacy 47% at 90 minutes)
30%, concomitant antiarrhythmic drugs
*ECG monitoring during and 4 hours
after CV
Dronedarone AEs: Worsening HF, QT prolongation, AF maintenance:
(Multaq) hypokalemia or hypomagnesemia with 400 mg PO BID
potassium-sparing diuretics Discontinue if QTc 500 milliseconds
DIs: CYP3A4 inhibitors, QT-prolonging drugs,
simvastatin, tacrolimus-sirolimus, and other
CYP3A4 substrates with narrow therapeutic
range, digoxin and other pgp substrates
CIs: QTc 500 milliseconds or PR 280
milliseconds, NYHA class IV HF or NYHA
class IIIII HF with recent ADHF, severe
hepatic impairment, second- or third-degree
AVB or HR < 50 beats/minute
PK: Half-life 1319 hours
ADHF = acute decompensated heart failure; AE = adverse effect; AF = atrial fibrillation; AV = atrioventricular; AVB =
atrioventricular block; BID = twice daily; CAD = coronary artery disease; CI = contraindication; CNS = central nervous system;
CR = controlled release; CrCl = creatinine clearance; CV = cardioversion; CYP = cytochrome P450; D5W = dextrose 5%; DI =
drug interactions; DOC = drug of choice; ECG = electrocardiogram; GI = gastrointestinal; HCL = hydrochloride; HCTZ =
hydrochlorothiazide; HF = heart failure; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; HR = heart rate; IR = immediate
release; IV = intravenous; IVB = intravenous bolus; IVP = intravenous push; LVEF = left ventricular ejection fraction; MI =
myocardial infarction; MOA = mechanism of action; NS = normal saline; NTE = not to exceed; NYHA = New York Heart
Association; pgp = P-glycoprotein; PK = pharmacokinetics; PO = oral; QD = once daily; QOD = once every other day; TdP =
torsades de pointes; VF = ventricular fibrillation; VT = ventricular tachycardia.
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VIII. ANTICOAGULATION
A. Warfarin Products
1. Brands: Coumadin, Jantoven, and many generics (Barr, Geneva, Taro)
2. Strengths: 1-, 2-, 2.5-, 3-, 4-, 5-, 6-, 7.5-, and 10-mg tablets. All are scored.
B. Mechanism of Action
1. Inhibits vitamin Kdependent clotting factors II, VII, IX, and X
2. Inhibits anticoagulant proteins C and S
3. Racemic mixture of R- and S-isomers
a. S-isomer more potent vitamin K antagonist
b. S-isomer metabolized primarily by cytochrome P450 (CYP) 2C9
c. R-isomer metabolized primarily by CYP3A4
C. Indications
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Bioprosthetic heart valve with 2.5 (23) Until 1C If systemic embolism, reassess at 3 months
LA thrombus at surgery documented
thrombus
resolution
Mechanical prosthetic heart 2.5 (23) Long term 1B If normal LA size and in sinus rhythm. Valves: St.
valve: aortic Jude bileaflet, Carbomedics bileaflet, Medtronic
tilting disk. 2.53.5 if AF or LA enlargement
Mechanical prosthetic heart 3 (2.5 Long term 1B Tilting disk or bileaflet
valve: mitral 3.5)
Any mechanical valve plus 3 (2.5 Long term 1B PLUS ASA 50100 mg/day
other risk factors OR 3.5) Risk factors: AF, hypercoagulable state, low EF,
Any mechanical valve with 2C atherosclerotic vascular disease
systemic embolism with For systemic embolism with therapeutic INR, add
therapeutic INR (2C) ASA and/or increase target INR range by 0.5
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E. Adverse Effects
1. Bleeding
a. Incidence
i. All: 2.4%29%
ii. Fatal or life threatening: 2%8%
b. Epistaxis, hematuria, gastrointestinal hemorrhage, bleeding gums
c. Easy bruising often occurs with therapeutic INR.
2. Skin necrosis (rare)
a. Extensive thrombosis of venules and capillaries within subcutaneous fat, involving
abdomen, buttocks, thighs, or breasts
b. Caused by protein C or protein S deficiency induced by warfarin early in therapy
c. Occurs between days 1 and 10
d. If occurs, discontinue warfarin and initiate heparin. Reinitiate warfarin at a low dose
(e.g., 2 mg/dose), and increase gradually for several weeks.
3. Purple toe syndrome (rare)
a. Mechanism of action: Anticoagulation treatment may enhance the release of
atheromatous plaque emboli to cause systemic cholesterol microembolism.
b. Occurs 310 weeks after warfarin is begun
c. Toes painful, purple, fluctuating from hour to hour
d. If occurs, discontinue warfarin; may take weeks to months for discoloration to disappear
4. Teratogenicity (category X)
a. First-trimester exposure: Nasal hypoplasia, small nares, chondrodysplasia
b. Second- and third-trimester exposure: Mental retardation, blindness, spasticity, seizures
c. If pregnant, subcutaneous heparin or LMWH is safe to use.
d. Breastfeeding: Can use warfarin because not excreted in breast milk
F. Patient Education
1. Indication and expected therapy duration
2. Bleeding symptoms/signs
3. Management of bleeding complicationsWhen to call health care provider
4. Need for and importance of frequent blood tests and INR goals
5. Drug interactions (especially OTCs [over-the-counter medications] and herbals)
6. Dosing/importance of adherence/pillbox
7. How to take; what to do if a dose missed
8. Dietary instructions; keep intake of vitamin Kcontaining foods consistent
9. Teratogenicity; need for reliable contraception if of childbearing age
10. Wear medic alert bracelet/necklace or carry identification card.
**Drug interactions are very common with warfarin. The magnitude of interactions varies
considerably; for some, concomitant use is contraindicated; others require a warfarin dose
adjustment; for others, more frequent monitoring of the INR is sufficient.**
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No significant Lower dose OR omit dose, monitor more often, and reinitiate at a lower dose
<5 and bleeding or need when INR approaches 3. If INR is only minimally above the therapeutic
for rapid reversal range, no dose reduction may be required
In need of rapid Give oral vitamin K1 (24 mg) with the expectation that a reduction in the
<9 and reversal (e.g., INR will occur within 24 hours. If the INR remains high at 24 hours, an
before surgery) additional dose of 12 mg of oral vitamin K1 can be given
No bleeding and no Omit one or two doses of warfarin, and monitor INR more often. Reinitiate
5 risk factors warfarin at a lower dose when the INR falls into the therapeutic range
and and
<9 No bleeding, but at Omit one dose of warfarin and give oral vitamin K1 ( 5 mg; generally 1
risk of bleeding 2.5 mg)
No clinically Omit the next several warfarin doses and give oral vitamin K1 (510 mg),
9 significant bleeding with the expectation that the INR will be reduced substantially by about 24
and
48 hours. Monitor INR closely and repeat vitamin K1, if necessary. Resume
warfarin at a lower dose when INR is in the desired range
Serious bleeding at Hold warfarin, give vitamin K1 10 mg by slow IV infusion over 2030
any INR elevation minutes, and supplement with FFP or prothrombin complex concentrate
or warfarin (alternative: recombinant factor VIIa) (depending on urgency). If needed,
overdosage repeat vitamin K1 injection every 12 hours. If continued warfarin therapy is
indicated after high doses of vitamin K1, can give heparin until the patient is
responsive to warfarin
Life-threatening Interrupt warfarin and give prothrombin complex concentrate supplemented
bleeding or with vitamin K (10 mg by slow IV infusion); recombinant factor VIIa may
warfarin overdose be considered an alternative to prothrombin complex concentrate; repeat if
necessary, depending on INR
FFP = fresh frozen plasma; INR = international normalized ratio; IV = intravenous.
Adapted from: Hirsh J, Guyatt G, Albers GW, Harrington R, Schunemann HJ. Chest 2008 Guidelines. Antithrombotic and
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Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest
2008;133:110S112S.
I. Disease Interactions: May result in increased INR and a lower warfarin dose requirement
1. Malnourished/nothing by mouth
2. Recent major surgery
3. Chronic heart failure (especially decompensated)
4. Liver disease
5. Hyperthyroidism (increased clearance of clotting factors)
6. Prolonged fever (increased clearance of clotting factors)
7. Diarrhea
J. Monitoring Parameters
1. Signs and symptoms of bleeding
a. Mild: Nosebleeds, bleeding gums, easy bruising
b. More severe (evaluation needed): Hematuria, hematemesis, hemoptysis, melena,
hematochezia, bright red blood per rectum
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REFERENCES:
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Learning Objectives:
1. Select and monitor appropriate acute and preventive treatment for pediatric and adult patients with
asthma and adult patients with chronic obstructive pulmonary disease (COPD), depending on
patient-specific factors.
2. Classify a patient according to his or her asthma severity class, and assess his or her control,
according to the current National Institutes of Health, National Heart Lung and Blood Institute
guidelines.
3. Educate a patient about his or her therapy for asthma and COPD, including proper use of inhalers and
holding chambers.
I. ASTHMA
Guidelines:
National Institutes of Health (NIH) National Heart Lung and Blood Institute (NHLBI). National Asthma
Education and Prevention Program (NAEPP) Guidelines. NAEPP Expert Panel Report 3. NIH
Publication 08-5846. July 2007. Available at www.nhlbi.nih.gov/guidelines/index.htm. Accessed
December 19, 2011.
A. Definition: Asthma is a chronic inflammatory disorder of the airways causing recurrent episodes
of wheezing, breathlessness, cough, and chest tightness, particularly at night or early in the
morning. During episodes, there is variable airway obstruction, often reversible spontaneously or
with treatment. There is also increased bronchial hyperresponsiveness to a variety of stimuli.
B. Diagnosis
1. Episodic symptoms of airflow obstruction are present.
2. Airway obstruction is reversible (forced expiratory volume in 1 second [FEV1]; improves by
12% or more after short-acting 2-agonists [SABAs])
3. Alternative diagnoses are excluded. Asthma versus chronic obstructive pulmonary disease
(COPD)
a. Cough is usually nonproductive with asthma and productive with COPD.
b. FEV is reversible with asthma but not with COPD.
c. Cough is worse at night and early in the morning with asthma; throughout the day with
COPD
d. Asthma is often related to allergies/environmental triggers; COPD has a common history
of smoking.
e. Asthma can be reversible; lung damage from COPD is irreversible.
4. Exercise-induced bronchospasm
a. Presents with cough, shortness of breath, chest pain or tightness, wheezing, or endurance
problems during exercise
b. Diagnosed with an exercise challenge, in which a 15% decrease in FEV or peak
expiratory flow (PEF) is seen before and after exercise, measured at 5-minute intervals
for 2030 minutes
c. Prevention and treatment of symptoms
i. Long-term control therapy, if otherwise appropriate (initiate or step-up)
ii. Pretreatment with SABA before exercise
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b
Normal FEV1/FVC: ages 819 years: 85%, 2039 years: 80%, 4059 years: 75%, 6080 years: 70%.
c
Episodes lasting more than 1 day and risk factors for persistent asthma.
d
For ages 511, initial step 3 therapy should be medium-dose ICS.
FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; SABA = short-acting 2-agonist.
Adapted from NIH Asthma Guidelines. National Institutes of Health National Heart Lung and Blood Institute. National Asthma Education and
Prevention Program (NAEPP) Guidelines. NAEPP Expert Panel Report 3. NIH P ublication 08-5846. Available at
www.nhlbi.nih.gov/guidelines/index.htm. Accessed December 19, 2011.
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D. Treatment Goals
1. Minimal or no chronic symptoms day or night
2. Minimal or no exacerbations
3. No limitations on activities; no school/work missed
4. Maintain (near) normal pulmonary function.
5. Minimal use of SABA
6. Minimal or no adverse effects from medications
E. Treatment Guidelines
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Beclomethasone MDI QVAR (HFA) See ICS dosing table INHALED ICSs are first line for persistent asthma
40 mcg/puff Oral candidiasis Use HOLDING CHAMBERS only if
80 mcg/puff Hoarseness needed for technique; not well studied
May slow bone growth in with HFA inhalers; holding chambers are
Fluticasone MDI Flovent HFA children but similar adult only for MDIs cannot be used for DPIs;
44 mcg/puff height holding chambers with a mask can be
110 mcg/puff used for young children
220 mcg/puff SYSTEMIC RINSE MOUTH with water after
Cushing effects inhalations
Fluticasone DPI Flovent Diskus Growth retardation Use corticosteroid inhaler as
50 mcg/puff Osteoporosis SCHEDULED, not as needed
100 mcg/puff Hypertension Onset of improvement is 57 days.
250 mcg/puff Cataracts Additional benefit may be seen over
Glucose intolerance several weeks
Mometasone DPI Asmanex
Skin thinning Consider calcium and vitamin D
220 mcg/puff Twisthaler
Myopathy supplements in adults, particularly in
Budesonide DPI Pulmicort Euphoria perimenopausal women
90 mcg/dose Flexhaler and Depression Pulmicort Respules only nebulized
180 mcg/dose Respules steroid available
0.25-, 0.5-, and
1-mg/2-mL nebs
Anticholinergics
Ipratropium MDI Atrovent HFA 24 puffs TIDQID (up Headache Used mainly for COPD or for acute
17 mcg/puff to 12 puffs/24 hours) Flushed skin asthma exacerbations requiring emergency
Blurred vision treatment
Tachycardia Duration: 28 hours
Palpitations Also available as a solution for
nebulization
Tiotropium DPI Spiriva Inhale 1 capsule/day Used for COPD; not currently
18 mcg recommended for asthma.
Long acting; not for rapid relief
Duration: > 24 hours
Albuterol MDI Proventil HFA 2 puffs every 46 hours Tremor Used for acute bronchospasm; regular use
90 mcg/puff Ventolin HFA PRN Tachycardia indicates poor control
ProAir HFA Hypokalemia - Also available as solution for
Hypomagnesemia nebulization
Hyperglycemia - Duration of effect (MDI): 34 hours (up to
Tachyphylaxis 6)
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Salmeterol DPI Serevent Diskus Inhale 1 blister/puff Tremor Not for acute symptoms
50 mcg/puff BID Tachycardia Should NOT be used as monotherapy for
Electrolyte asthma
effects rare Duration: 812 hours
Formoterol DPI Foradil Aerolizer Inhale 1 capsule BID Onset of action 13 minutes, but not acute
12-mcg capsule therapy
Perforomist Should NOT be used as monotherapy
Formoterol 20 mcg BID nebs for asthma
20 mcg/2-mL nebs Duration of MDI: 812 hours
Brovana Formoterol Aerolizer is indicated to prevent
Arformoterol 15 mcg BID exercise-induced bronchospasm; should be
15 mcg/2-mL nebs nebs used at least 15 minutes before exercise
Arformoterol is the R,R-isomer of racemic
formoterol
Indacaterol inhalation Arcapta Neohaler Inhale 1 capsule once Indacaterol is only indicated for COPD
powder daily NOT indicated for use in asthma at all
75-mcg capsule Approved by the FDA in July 2011
Duration of action: 24 hours
Combination inhalers
Albuterol 103 mcg/puff Combiventb 2 puffs QID Primarily used for COPD
plus Combivent Respimat (newly approved
ipratropium propellant-free mist inhaler) will be available
18 mcg/puff MDIb starting mid-2012
- 100 mcg of albuterol/20 mcg of ipratropium
Combination solution for nebulization is also
available as DuoNeb or generic
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Methylxanthine
Zafirlukast Accolate 20 mg BID Hepatotoxicity Monitor LFTs Drug interactions: Warfarin, erythromycin,
10-mg tablet (baseline, every month 3 theophylline
20-mg tablet months, every 23 months For 5 years
for 1 year for montelukast Bioavailability decreases with food; take 1
and zafirlukast) hour before or 2 hours after meals
Headache
Montelukast Singulair 510 mg/day GI upset Drug interactions: Phenobarbital
Oral 10-mg tablet FDA-approved for use in 1 year old; used
Chewable 4- and 5-mg *Risk of neuropsychiatric in 6 months and older
tablets events (behavior and mood Churg-Strauss syndrome associated with
Oral granules 4-mg/packet changes: aggression, tapering doses of steroids
agitation, anxiousness, dream
Zileuton Zyflo CR 1200 mg BID Drug interactions: Warfarin and theophylline
abnormalities, hallucinations,
600-mg CR tablet Only for those 12 years and older
depression, insomnia,
irritability, restlessness,
suicidal thinking and
behavior, tremor)
Monoclonal antibody
Omalizumab Xolair 150375 mg SC every Injection site reactions MOA: Inhibits IgE binding to high-affinity
24 weeks Urticaria IgE receptors on mast cells and basophils
Dose and frequency Thrombocytopenia Used in severe persistent allergy-related
based on baseline IgE (transient) asthma
and weight in Anaphylaxis (rare) Use in 12 years
kilograms Malignancy Half-life: 26 days
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a
The following MDIs have been discontinued by the manufacturers and are no longer available: AeroBid (flunisolide) MDI (June 2011), Azmacort
(triamcinolone) MDI (December 2009), Intal (cromolyn) MDI (August 2009), Intal (cromolyn) nebulization solution (June 2008), and Tilade (nedocromil) MDI
(April 2008). They are not included in this table. OTC Primatene Mist has also been discontinued, and it is no longer available as of 12/31/2011.
b
These inhalers, which still contain CFCs, are being phased out by the manufacturers. They may no longer be sold after the following dates: Maxair
(pirbuterol) (12/31/2013) and Combivent (albuterol/ipratropium) (12/31/2013).
BID = 2 times/day; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; CR = controlled release; DOC = drug of choice; DPI =
dry powder inhaler; FDA = U.S. Food and Drug Administration; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HFA = hydrofluoroalkane;
IBW = ideal body weight; ICS = inhaled corticosteroid; IgE = immunoglobulin E; LABA = long-acting 2-agonist; LFT = liver function test; MDI = metered
dose inhaler; MOA = mechanism of action; nebs = nebulizers; PRN = as needed; QID = 4 times/day; SC = subcutaneously; SVT = supraventricular
tachycardia; TID = 3 times/day.
Budesonide N/A 180400 180600 N/A > 400800 > 600-1200 N/A > 800 > 1200
(Pulmicort DPI 90, 180)
Fluticasone
Flovent HFA 44,110, 220 176 88176 88264 > 176352 > 176352 > 264440 > 352 > 352 > 440
Flovent DPI 50, 100, 250 N/A 100200 100300 N/A > 200400 > 300500 N/A > 400 > 500
Beclomethasone N/A 80160 80240 N/A > 160320 > 240480 N/A > 320 > 480
(QVAR HFA 40, 80)
Mometasone (Asmanex 100b 100b 200 100b 100b 400 100b 100b > 400
DPI 110, 220): delivers (age 4 only) (age 4 (age 4
100 and 200 mcg/puff) only) only)
Ciclesonidec N/A N/A 160 N/A N/A 320 N/A N/A 640
(Alvesco HFA 80, 160)
Budesonide suspension for 0.250.5 mg 0.5 mg N/A > 0.51 mg 1 mg N/A > 1 mg 2 mg N/A
nebulization
a
Effective December 31, 2009: Azmacort (triamcinolone) MDI (12/31/2009) and Aerobid (flunisolide) MDI (6/30/2011) have been discontinued by the
manufacturers and are no longer available.
b
The guidelines state the delivered dose of mometasone, not the actual dose; indicated in ages 411 after guidelines published; doses are estimated
from package insert for children 04 and 511 years.
c
Ciclesonide was not available when the National Asthma Education and Prevention Program guidelines were published. The dose ranges are estimated
from package insert.
CFC = chlorofluorocarbon; DPI = dry powder inhaler; HFA = hydrofluoroalkane; MDI = metered dose inhaler.
Adapted from NIH asthma guidelines. National Institutes of Health National Heart Lung and Blood Institute. National Asthma Education and
Prevention Program (NAEPP) Guidelines. NAEPP Expert Panel Report 3. NIH Publication 08-5846. Available at
www.nhlbi.nih.gov/guidelines/index.htm. Accessed December 19, 2011.
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G. Long-Acting -Agonists (LABAs): The U.S. Food and Drug Administration (FDA) issued a
safety announcement because of safety concerns with LABAs. This is largely because of the
results from the SMART trial (Nelson HS, et al. Chest 2006;129:1526).
1. Use of a LABA alone without another long-term asthma control medication such as an
inhaled corticosteroid (ICS) is contraindicated.
2. LABAs should not be used in patients whose asthma is adequately controlled on low- or
medium-dose ICSs.
3. LABAs should only be used as additional therapy for patients who are currently taking, but
not adequately controlled on, a long-term asthma control medication (e.g., an ICS).
4. Once asthma control is achieved and maintained, patients should be assessed at regular
intervals and stepped-down (e.g., discontinue LABA), if possible, and the patient should
continue to be treated with a long-term asthma control medication, such as an ICS.
a. Regular follow-up every 16 months.
b. Consider step-down if well controlled for 3 months or more.
5. Pediatric and adolescent patients who require a LABA and an ICS should use a combination
product, to ensure adherence to both medications.
H. New Data in Asthma Treatment
(not included in the current guidelines; more data needed before using in clinical practice)
1. Tiotropium for persistent asthma
a. A recent study evaluated adding tiotropium versus adding LABA (salmeterol) versus
doubling the ICS dose in patients uncontrolled on low-dose beclomethasone (Peters SP,
et al. TALC study. N Engl J Med 2010;363:1715-26)
b. Results: Adding tiotropium resulted in significantly greater improvements in PEF and
FEV, symptom control as well as the number of asthma control days than did doubling
the ICS dose.
c. Adding tiotropium was at least noninferior to adding LABA for all outcomes studied, and
it increased prebronchodilator FEV more than did salmeterol (p=0.003).
d. Conclusion: Adding tiotropium to low-dose ICS is an option if asthma uncontrolled,
noninferior to adding LABA and superior to doubling ICS
2. ICS/SABA for rescue treatment in children
a. Randomized, double-blind, placebo-controlled trial of children/adolescents with mild
persistent asthma randomized to four different groups (TREXA study; Lancet
2011;377:650-7):
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and proceed to the emergency department (ED) if the distress is severe and
unresponsive to treatment; consider calling 9114. Red zone
a. Medical alert; marked coughing, wheezing, and/or dyspnea; inability to speak more than
short phrases; use of accessory respiratory muscles; drowsiness (or PEFR less than 50%
of personal best)
b. Begin treatment and consult clinician immediately.
c. Use SABA: 26 puffs by MDI or 1 nebulizer treatment; repeat every 20 minutes up to 3
times; add an OCS burst.* Higher dose of 46 puffs SABA MDI usually recommended
d. If incomplete or poor response, repeat SABA immediately; proceed to the ED or call 911
if distress is severe and unresponsive to treatment
e. Call 911 or go to the ED immediately if lips or fingernails are blue or gray or if the
patient has trouble walking or talking because of shortness of breath.
f. Continue to use a SABA every 34 hours regularly for 2448 hours.
*Oral prednisone burst: 4060 mg/day for 510 days (adults) or 12 mg/kg/day (maximum
60 mg/ day) for 310 days (children).
5. After initial treatment, immediate medical attention is required if patient is at high risk of a
fatal attack. Risk factors:
a. Asthma: History of severe attack (previous intubation or intensive care unit admission for
asthma), two or more asthma hospitalizations for asthma in past year, three or more ED visits
for asthma in past year, hospitalization or ED visit for asthma in past month, use of more than
two canisters of a SABA per month, difficulty perceiving asthma symptoms
b. Social: Low socioeconomic status or inner-city residence, illicit drug use, major
psychosocial problems
c. Comorbidities: Cardiovascular disease (CVD), other chronic lung disease, chronic
psychiatric disease
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a. Holding chambers reduce oropharyngeal deposition and improve lung deposition with
CFC MDIs (almost 2-fold); not well studied with HFA MDIs.
b. Technique same as with MDIs, but can inhale up to 5 seconds after actuation
c. 1 puff into chamber per inhalation
d. For facemask: 5 inhalations/exhalations per puff
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L. Monitoring
1. Peak flow monitoring
a. Both symptom-based and peak flowbased monitoring have similar benefits; either is
appropriate for most patients. Symptom-based monitoring is more convenient.
b. Consider daily home peak flow monitoring for moderate-severe persistent asthma, if
history of severe exacerbations or if poor perception of worsening asthma symptoms
c. Personal best PEFR should be determined if using peak flowbased asthma action plan,
not predicted PEFR.
i. Personal best PEFR is the highest number obtained after daily monitoring for 2
weeks two times/day when asthma is under good control.
ii. Predicted PEFR is based on population norms using sex, height, and age.
2. Spirometry (if 5 years or older)
a. At initial assessment
b. After treatment has started and symptoms have stabilized
c. If prolonged or progressive loss of asthma control
d. At least every 12 years or more often, depending on response to therapy
Guidelines:
Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Diagnosis, Management and
Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 Revision.
Available at www.goldcopd.org/. Accessed March 1, 2012.
Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and Management of Stable Chronic Obstructive
Pulmonary Disease: A Clinical Practice Guideline Update from the American College of Physicians,
American College of Chest Physicians, American Thoracic Society, and European Respiratory Society
(ACP/ACCP/ATS/ERS Guidelines). Ann Intern Med 2011;155:179-91.
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4. Presence of comorbidities
D. Therapy Goals
1. Relieve symptoms.
2. Reduce the frequency and severity of exacerbations.
3. Improve exercise tolerance.
4. Improve health status.
5. Minimize adverse effects from treatment.
GOLD Guidelines
C Nonrandomized trials
Observational studies
ACP/ACCP/ATS/ERS Guidelines
2. Existing medications for COPD have not been shown to modify the long-term decline in lung
function, the hallmark of this disease (Evidence A). Therefore, pharmacotherapy for COPD is
used to decrease symptoms, complications, or both.
3. Smoking cessation is a critical component of COPD management.
4. Bronchodilator medications are central to the symptomatic management of COPD (Evidence
A).
a. They are given on an as-needed or regular basis to prevent or reduce symptoms.
b. The principal bronchodilator treatments are -agonists, anticholinergics, or a
combination of these drugs (Evidence A). Theophylline is a bronchodilator given on a
regular basis.
c. Inhaled therapy is preferred.
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(b) Reduced annual number of exacerbations; rate for both moderate and severe
exacerbations was significant
(c) Benefit was consistent in all major subgroups and over 1year.
(d) Significantly fewer patients taking tiotropium withdrew early.
vi. Conclusion: Tiotropium may be more effective than a LABA as initial long-acting
bronchodilator therapy.
b. Chronic azithromycin for prevention of COPD exacerbations
i. Albert RK, et al. N Engl J Med 2011;365:689-98
ii. 1577 subjects at increased risk of exacerbations (stage IImoderate or worse COPD
either on continuous O or received systemic corticosteroids in past year, and history
of a COPD exacerbation requiring ED visit or hospitalization; no history of hearing
impairment
iii. Subjects randomized to daily azithromycin 250 mg or placebo for 1 year
iv. Results:
(a) Median time to exacerbation: 266 days (azithromycin group) versus 174 days
(placebo) (p<0.001)
(b) Rate of acute exacerbation: 1.48 versus 1.83 for azithromycin versus placebo
(p=0.01)
(c) Number needed to treat to prevent one acute exacerbation of COPD: 2.86
(d) Quality of life improved more with azithromycin than with placebo (based on St.
Georges Respiratory Questionnaire; p=0.03)
(e) However, hearing decrements (by audiometry) were more common with
azithromycin versus placebo (25% vs. 20%, p=0.04) (number needed to harm =
20), and in azithromycin group, there was an increased incidence of colonization
with macrolide-resistant organisms (81% vs. 41%, p<0.001).
v. Conclusion: Daily azithromycin lengthens time to first exacerbation, decreases rate of
exacerbations, and improves quality of life in patients with COPD at increased risk of
exacerbations, with the expense of risk of hearing decrements and increasing
macrolide-resistant organism colonization. The most recent GOLD guidelines still do
not recommend treatment with antibiotics, except when indicated during acute
exacerbations.
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G. Vaccinations: All patients with COPD should receive the influenza vaccine yearly and the
polysaccharide pneumococcal vaccine once before age 65; then, a one-time revaccination with
pneumococcal vaccine 5 years or more after the first vaccination
Table 12. Agencies/Associations Specific to Asthma, COPD, and/or Smoking Cessation with
Resources/Educational Programs for the Public
Web Site/
Agency/Association Telephone Numbers Programs/Resources
American Lung www.lungusa.org Information on management of asthma, COPD, and smoking
Association (ALA) cessation
Can enter zip code and search for local associations
Many local programs available
Better Breathers Club (COPD), Breathe Well/Live Well
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Table 12. Agencies/Associations Specific to Asthma, COPD, and/or Smoking Cessation with
Resources/Educational Programs for the Public
Web Site/
Agency/Association Telephone Numbers Programs/Resources
Self-Management Program (asthma), Freedom From Smoking
Online program
Lung help line 1-800-LUNGUSA to help with any questions on
asthma, COPD, smoking cessation
Can also do an online CHAT
Asthma and Allergy www.aafa.org Educational programs (online, classroom), resources, materials,
Association of tools (e.g., asthma action plans/cards), publications, educational
America (AAFA) materials, etc.
Local educational support groups, including parent support groups
Allergy and Asthma www.aanma.org Ask a Nurse patient support center, educational tools and
Network; Mothers of materials, asthma and allergy topics in the news, etc.
Asthmatics (AANMA) Help for parents dealing with children with asthma and allergies
National Heart Lung www.nhlbi.gov Area for public; includes information on asthma, COPD, and
and Blood Institute smoking cessation
(NHLBI) National Asthma Control Initiative
Publications, fact sheets
Demonstration projects around the country addressing implementing
guidelines and dealing with asthma disparities
Nicotine Anonymous www.nicotine-anony 12-step program offering support to those who want to quit
mous.org smoking; similar to AA
Links to local support groups and meetings; information on
telephone meetings
AA = Alcoholics Anonymous; COPD = chronic obstructive pulmonary disease; NCI = National Cancer Institute.
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V. PRACTICE MANAGEMENT
Table 13. Examples of Quality Measures for Asthma and COPD More Specific to Pharmacy
Asthma Quality Measuresa COPD Quality Measuresb
Documentation of asthma severity classification Pneumococcal vaccination
Use of inhaled corticosteroids for persistent asthma Influenza vaccination
Provision of asthma action plans Number (or percentage) of
Patients have been educated on managing their asthma and avoiding triggers patients who received smoking
Influenza vaccines given cessation counseling
Smoking cessation counseling completed Number (or percentage) of patients
Daily symptom burden prescribed long-acting
- Frequency of symptoms and 2-agonist use (per week) bronchodilators in patient group B
- Number of days of (or free from) asthma symptoms in past month Number (or percentage) of
- Days with nocturnal symptoms in past month patients prescribed inhaled
- Number of school/workdays missed in past month corticosteroids in patient groups
- Frequency of urgent care or acute office visits C and D
- Frequency of ED visits or hospitalization
Number of full 2-agonist canisters used in past 3 months
Number (or percentage) of patients who have been taught how to use an MDI
or DPI by a health professional
a
From the Agency for Healthcare Research and Quality. Available at www.ahrq.gov/qual/asthmacare/asthmod4.htm. Accessed
December 21, 2011.
b
Adapted from Heffner JE, Mularski RA, Calverley PM. COPD performa measures: missing opportunities for improving care. Chest
2010;137:11819.
COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; ED = emergency department; MDI = metered dose inhaler.
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A. For Asthma and COPD, All Inhalers are Brand Name (not available generically). Cost
may be an issue for many patients.
D. Some Manufacturers Offer Coupons on Their Web sites (e.g., GlaxoSmithKline offers
$10 coupons that can be printed and used each month and can be applied toward full
price or even co-pays).
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REFERENCES
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The American College of Clinical Pharmacy and the faculty of the Pharmacotherapy Review Program for Advanced
Clinical Pharmacy Practice would like to express their appreciation to the authors of the original previously
published material that has been adapted here into this text:
Anna Legreid Dopp, Pharm.D. Robert L. Page II, Pharm.D., FCCP, FAHA, BCPS
University of Wisconsin University of Colorado Schools of Pharmacy and
Madison, Wisconsin Medicine
Aurora, Colorado
Edward F. Foote, Pharm.D., FCCP,
BCPS Wilkes University Jo E. Rodgers, Pharm.D., FCCP, BCPS
Wilkes Barre, Pennsylvania University of North Carolina School of
Pharmacy Chapel Hill, North Carolina
Ila M. Harris, Pharm.D., FCCP, BCPS
University of Minnesota Medical Curtis L. Smith, Pharm.D., BCPS
School Bethesda Family Medicine Ferris State University
St. Paul, Minnesota Grand Ledge, Michigan
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