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hronic kidney disease (CKD) is frequently encountered among patients presenting with acute coronary syndrome (ACS). Recent data from the National
Cardiovascular Data RegistryAcute Coronary Treatment and
Intervention Outcomes Network (NCDR-ACTION) reported
CKD (defined as estimated creatinine clearance [CrCl]
<60mLmin11.73m2) prevalence rates of 30.5% among
patients presenting with ST-segmentelevation myocardial
infarction (STEMI) and 42.9% among patients presenting with nonST-segmentelevation myocardial infarction
(NSTEMI).1 The presence of CKD among patients presenting
with ACS has been associated with worse outcomes, including
higher rates of mortality and bleeding.24 Despite the increased
risk for adverse outcomes, CKD patients presenting with ACS
are less likely to receive evidence-based therapies, including
medications.1 In addition, patients with CKD have been underrepresented in randomized controlled trials of ACS pharmacotherapy.5,6 Thus, the net effect is a relative lack of evidence and
potential for uncertainty in selecting medications in this highrisk population. The purpose of this scientific statement is to
provide a comprehensive review of the published literature
and provide recommendations on the use of evidence-based
pharmacotherapies in CKD patients presenting with ACS.
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship
or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete
and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on September 15, 2014. A copy of the
document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase
additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.
The American Heart Association requests that this document be cited as follows: Washam JB, Herzog CA, Beitelshees AL, Cohen MG, Henry TD,
Kapur NK, Mega JL, Menon V, Page RL 2nd, Newby LK; on behalf of the American Heart Association Clinical Pharmacology Committee of the Council
on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, Council on Functional Genomics and Translational Biology, Council on the
Kidney in Cardiovascular Disease, and Council on Quality of Care and Outcomes Research. Pharmacotherapy in chronic kidney disease patients presenting
with acute coronary syndrome: a scientific statement from the American Heart Association. Circulation. 2015;131:.
Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines
development, visit http://my.americanheart.org/statements and select the Policies and Development link.
Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express
permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/CopyrightPermission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page.
(Circulation. 2015;131:000-000. DOI: 10.1161/CIR.0000000000000183.)
2015 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIR.0000000000000183
A2
A3
Normal to
mildly
increased
Moderately
increased
Severely
increased
<30 mg/g
<3 mg/mmol
30-300 mg/g
3-30 mg/mmol
>300 mg/g
>30 mg/mmol
90
G1
Normal or high
G2
Mildly decreased
60-89
G3a
Mildly to moderately
decreased
45-59
G3b
Moderately to
severely decreased
30-44
G4
Severely decreased
15-29
G5
Kidney failure
<15
90%
eGFR
90
76%
80%
Frequency (%)
88%
67%
65%
70%
58%
56%
60%
66%
60%
60%
46%
50%
38%
40%
31%
30%
20%
41%
37%
29%
25%
22%
15%
10%
10%
3%
15%
12%
11%
6%
0%
Chest pain
Killip II
STEMI
LBBB
NSTEMI
Figure 3. Relation of renal function to presentation, symptoms, and ECG changes in patients presenting with acute coronary syndrome.
Data from the SWEDEHEART Registry (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart
Disease Evaluated According to Recommended Therapies). eGFR indicates estimated glomerular filtration rate; LBBB, left bundle branch
block; NSTEMI, nonST-segmentelevation myocardial infarction; and STEMI, ST-segmentelevation myocardial infarction. Reprinted
from Szummer et al15 with permission of the publisher. Copyright 2010, Blackwell Publishing Ltd.
A pooled analysis of 16
710 patients enrolled in the
Thrombolysis in Myocardial Infarction (TIMI)-10A, TIMI10B, TIMI-14, and Intravenous NPA for the Treatment of
Infarcting Myocardium Early (InTIME-II) trials was conducted to assess the impact of baseline renal function (SCr and
CrCl) on outcomes in patients receiving fibrinolytic therapy.30
A stepwise increase in mortality was seen with worsening renal
Renal
Elimination
NS
No adjustment
Bivalirudin26
20%
Enoxaparin26,27
40%
U
A/NSTEMI: 1 mg/kg SC every 12 h
S TEMI patients <75 y of age receiving fibrinolytic
therapy: 30-mg single IV bolus plus a 1-mg/kg
SC dose followed by 1 mg/kg SC every 12 h
S TEMI patients 75 y of age receiving fibrinolytic
therapy: No bolus, 0.75 mg/kg SC every 12 h
Eptifibatide7,26
50%
Fondaparinux26,27
75%
Abciximab26,27
(Continued)
Renal
Elimination
Unfractionated
heparin26,27
Tirofiban26
NS
65%
No adjustment recommended
CrCl 60 mL/min:
PCI: 25 g/kg IV over 3 min followed by an infusion
of 0.075 gkg1min1 for up to 18 h post-PCI
ACS indicates acute coronary syndrome; aPTT, activated partial thromboplastin time; CKD, chronic kidney disease; CrCl, creatinine clearance; IV, intravenous; NS,
not significant; NSTEMI, nonST-segmentelevation myocardial infarction; PCI, percutaneous coronary intervention; SC, subcutaneous; STEMI, ST-segmentelevation
myocardial infarction; and UA, unstable angina.
Hobbach
et al31
Keough-Ryan
et al32
Study Design
Population
Observational
cohort
Observational
cohort (ICONS
registry)
End Points
Mortality (30 d)
Angiographic outcomes
(TIMI flow grade, corrected
TIMI frame count)
Results
A stepwise increase in 30-d mortality was seen
in patients with normal, mildly, moderately, and
severely impaired renal function with rates of
2.2%, 5.2%, 13.8%, and 30.7%, respectively
(P<0.0001).
In patients who had angiographic assessment,
the rates of TIMI flow grade 2 or 3 at 90 min
were 80.7%, 80.2%, 85.5%, and 93.3%
(P=0.11 for trend) in the normal, mildly,
moderately, and severely impaired groups,
respectively.
ICH
Dragu et al34
Study Design
Observational
cohort (GRACE
registry)
Observational
cohort (ACSIS)
Population
12532 patients with ST-segment
elevation or LBBB. Patients stratified
into groups based on estimated GFR*:
normal, 60 mLmin11.73 m2 (n=9082);
moderate, 3059 mLmin11.73 m2
(2982); and severe renal dysfunction,
<30 mLmin11.73 m2.
End Points
Mortality (in-hospital and
6 mo)
Reinfarction
Results
In this analysis, mortality increased as GFR
decreased (P<0.001). The adjusted ORs
(95% CIs) for in-hospital mortality in patients
receiving fibrinolysis vs patients receiving no
reperfusion were as follows: normal, 1.06
(0.781.44); moderate, 1.35 (1.011.80);
severe renal dysfunction, 1.11 (0.57-2.14).
Major bleeding
Mortality (7 d, 30 d, 1 y)
ACS indicates acute coronary syndrome; ACSIS, Acute Coronary Syndromes Israeli Survey; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine
clearance; CRI, chronic renal insufficiency; ESRD, end-stage renal disease; GFR, glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; HR, hazard
ratio; ICH, intracranial hemorrhage; ICONS, Improved Cardiac Outcomes in Nova Scotia; LBBB, left bundle branch block; OR, odds ratio; PCI, percutaneous coronary
intervention; SCr, serum creatinine; STEMI, ST-segmentelevation myocardial infarction; and TIMI, Thrombolysis in Myocardial Infarction.
*GFR calculated by the modified Modification of Diet in Renal Disease equation.
Antiplatelet Therapy
Aspirin
Current guidelines recommend aspirin should be initiated as
soon as an ACS is suspected and should be continued indefinitely, unless a contraindication develops.26,27 Given that
patients with renal insufficiency have an increased bleeding
risk, there is some trepidation regarding the use of antiplatelet
therapy in these patients. Although patients with CKD were
excluded from most randomized trials of aspirin therapy in
ACS, data on observational studies evaluating aspirin therapy
in patients with renal impairment are shown in Table3.
The Antithrombotic Trialists Collaboration performed
a meta-analysis of 287 randomized trials that included
135000 patients and compared various antiplatelet therapies versus control.37 Some of those trials included patients
undergoing hemodialysis. Among those undergoing hemodialysis, antiplatelet therapy reduced the risk of serious
Study Design
Population
End Points
Results
Antithrombotic
Trialists
Collaboration37
Meta-analysis
of randomized
trials
Keough-Ryan
et al32
Observational
cohort
McCullough
et al21
Observational,
prospective
cohort study
In-hospital mortality
Berger et al19
Observational,
retrospective
analysis of CCP
and USRDS
Mortality (30 d)
Yan et al38
Observational,
prospective
cohort study
1-y Survival
Wright et al2
Observational,
retrospective
cohort study
Sciahbasi et al39
Retrospective
review
ACS, acute coronary syndrome; AMI, acute myocardial infarction; CCP, Cooperative Cardiovascular Project; CI, confidence interval; CKD, chronic kidney disease; CrCl,
creatinine clearance; CRI, chronic renal insufficiency; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; NSTEMI,
nonST-segmentelevation myocardial infarction; OR, odds ratio; RR, relative risk; SE, standard error; STEMI, ST-segmentelevation myocardial infarction; and USRDS,
United States Renal Data System.
*GFR calculated by the modified Modification of Diet in Renal Disease equation.
CrCl calculated via Cockcroft-Gault equation.
Most of the published observational data show similar benefits of aspirin therapy in ACS patients across the spectrum of
renal function (Table3). However, one study did find a significant interaction between discharge aspirin therapy and renal
function, with an attenuated benefit with increasing degree of
CREDO,
200345,46
Study Design
Population
Subgroup analysis
of an RCT
Major or life-threatening
bleeding
Subgroup analysis
of an RCT
End Points
Results
TRITON-TIMI
38, 200749
Subgroup analysis
of an RCT
PLATO,
200950,51
Subgroup analysis
of an RCT
Major bleeding
ACS indicates acute coronary syndrome; CI, confidence interval; CKD, chronic kidney disease; CLARITY-TIMI 28, Clopidogrel as Adjunctive Reperfusion Therapy
Thrombolysis in Myocardial Infarction 28; CrCl, creatinine clearance; CREDO, Clopidogrel for the Reduction of Events During Observation; CURE, Clopidogrel in Unstable
Angina to Prevent Recurrent Events; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary
intervention; PLATO, Study of Platelet Inhibition and Patient Outcomes; RCT, randomized controlled trial; RR, relative risk; TIMI, Thrombolysis in Myocardial Infarction;
and TRITON-TIMI 38, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38.
*Calculated by modified Modification of Diet in Renal Disease equation.
Calculated via Cockcroft-Gault equation.
Table 5. Summary of GP IIb/IIIa Receptor Antagonist Studies in Patients With ACS and CKD
Study
PRISM-PLUS56
Best et al57
ESPRIT58
Study Design
Population
Observational cohort
Subgroup analysis
of an RCT
End Points
Results
7-d death/MI/refractory
ischemia (primary
composite)
Composite of death or MI
Frilling et al60
TARGET61
EARLY ACS62
Study Design
Population
Observational,
cohort study
Single-center registry
Subgroup analysis
of an RCT
Subgroup analysis
of an RCT
End Points
Results
In-hospital mortality
Composite of all-cause
mortality, MI, and TVR
at 30 d
Primary composite:
death, MI, recurrent
ischemia requiring urgent
revascularization, or
thrombotic bailout at 96 h
Death or MI at 30 d
Rates of non-CABG
related TIMI major
bleeding and GUSTO
severe/moderate bleeding
ACS indicates acute coronary syndrome; CABG, coronary artery bypass grafting; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance;
EARLY ACS, Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome; ESPRIT, Enhanced Suppression of the Platelet IIb/IIIa Receptor
With Integrilin Therapy; GP, glycoprotein; GUSTO, Global Utilization of Streptokinase and tPA for Occluded Arteries; HR, hazard ratio; MACCE, major adverse cardiac or
cerebrovascular event; MI, myocardial infarction; NSTEMI, nonST-segmentelevation myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention;
PRISM-PLUS, Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; RCT, randomized controlled trial;
SCr, serum creatinine; TARGET, Do Tirofiban and ReoPro Give Similar Efficacy Outcome; TIMI, Thrombolysis in Myocardial Infarction; TVR, target-vessel revascularization;
and UA, unstable angina.
*Calculated via Cockcroft-Gault equation.
Anticoagulants
Unfractionated Heparin
UFH has been a mainstay in the treatment of ACS for several
decades.63 Current guidelines recommend UFH as an anticoagulant option across the spectrum of ACS presentations.26,42
Once administered, the primary route of UFH elimination is
via the reticuloendothelial system, with renal clearance being
a minor route for elimination.64 Few data are available from
early placebo-controlled trials on the treatment effect of UFH
therapy in CKD patients presenting with ACS. In addition,
given that UFH has often been the standard anticoagulant
with which newer agents have been compared, the outcome
data for UFH use in CKD patients will be discussed in the
sections below.
Low-Molecular-Weight Heparin
Enoxaparin
Enoxaparin is the most widely studied low-molecular-weight
heparin (LMWH) in the setting of ACS. Current guidelines
recommend enoxaparin as an anticoagulant option in UA/
NSTEMI patients being managed with either an early invasive (Class I recommendation) or initial conservative (ClassI
recommendation) strategy.42 For patients presenting with
STEMI, current guidelines recommend enoxaparin as an
adjunctive anticoagulant option in conjunction with fibrinolytic therapy (Class I recommendation).26 Enoxaparin elimination is largely dependent on renal function, with 40% of
a dose being eliminated by glomerular filtration. The current
US Food and Drug Administrationapproved dose for enoxaparin in ACS patients with CrCl <30 mL/min is 1 mg/kg subcutaneously every 24 hours. However, patients with CrCl <30
mL/min have been routinely excluded from randomized trials
of enoxaparin in ACS; therefore, limited data are available
from randomized controlled trials on the use of enoxaparin
in this population. Data from randomized trials and observational studies on the use of enoxaparin in ACS patients with
CKD are shown in Table6.
A number of studies have shown increased anti-Xa activity in ACS patients with renal insufficiency receiving therapeutic doses of enoxaparin. In a substudy performed in 445
ACS patients enrolled in the TIMI 11A trial, the effect of renal
function and other patient characteristics on the pharmacokinetics and pharmacodynamics of enoxaparin was examined.70
In this analysis, CrCl was the most influential factor on pharmacokinetic and pharmacodynamic parameters of enoxaparin. Patients with CrCl <40 mL/min had higher peak and
trough anti-Xa activity than patients with CrCl 40 mL/min
and were more likely to have a major hemorrhagic event.70
Several clinical trials evaluating the use of enoxaparin in UA/
NSTEMI patients have provided data on the outcomes of
CKD patients receiving enoxaparin or UFH. A pooled analysis of CKD patients with severe renal impairment (defined
as CrCl 30 mL/min) enrolled in the Efficacy and Safety of
Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events
(ESSENCE) and TIMI 11B trials was performed to assess
Collet et al66
ExTRACT-TIMI
25 Trial67
SYNERGY68
OASIS-569
Study Design
Pooled
subgroup
analysis of 2
RCTs
Observational
cohort (GRACE
registry)
Double blind
RCT
Open-label
RCT
Double-blind
RCT
Population
7081 NSTE ACS patients enrolled in ESSENCE
(n=3171) and TIMI 11B (n=3910) randomized
to enoxaparin or UFH. CrCl 30 mL/min was
an exclusion in 1 trial (ESSENCE), whereas
SCr >2.0 mg/dL was an exclusion in the other
(TIMI 11B). Severe renal impairment (CrCl* 30
mL/min) was found in 74 UFH-treated patients
and 69 patients receiving enoxaparin (2%). The
enoxaparin dose was 1 mg/kg every 12 h.
End Points
Results
All-cause death,
recurrent MI, and
urgent revas
cularization at 43 d
Major hemorrhage
Mortality (30 d)
In-hospital major
bleeding
All-cause death or
nonfatal recurrent MI
within 30 d
Major bleeding
All-cause death or
nonfatal MI (30 d)
Major bleeding
ACS indicates acute coronary syndrome; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESSENCE,
Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events; ExTRACT-TIMI 25, Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction
TreatmentThrombolysis In Myocardial Infarction 25; GRACE, Global Registry of Acute Coronary Events; HR, hazard ratio; LMWH, low-molecular-weight heparin; MI, myocardial
infarction; NSTE, nonST-segment elevation; NSTEMI, nonST-segmentelevation myocardial infarction; OASIS-5, Organization for the Assessment of Strategies for Ischemic
Syndromes 5; OR, odds ratio; RCT, randomized controlled trial; SCr, serum creatinine; STEMI, ST-segmentelevation myocardial infarction; SYNERGY, Superior Yield of the New
Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors; TIMI, Thrombolysis in Myocardial Infarction; UA, unstable angina; and UFH, unfractionated heparin.
*Cockcroft-Gault Formula.
eGFR assessed by Modification of Diet in Renal Disease formula.
Factor Xa Inhibitors
Fondaparinux
Fondaparinux is an indirect factor Xa inhibitor that has
recently been evaluated in the management of patients presenting with ACS. Current guidelines for fondaparinux in ACS
patients include a Class I recommendation for fondaparinux
use as an adjunctive anticoagulant for STEMI patients receiving fibrinolytic therapy and a Class I recommendation for UA/
NSTEMI patients being managed with either an invasive or
conservative strategy.26,73 In addition, the guidelines recommend fondaparinux as the preferred anticoagulant in UA/
NSTEMI patients being managed with a conservative strategy
who have an increased risk of bleeding.73 Fondaparinux is primarily excreted unchanged through renal elimination, and is
contraindicated in the United States for patients with severe
CKD (CrCl <30 mL/min).74
The Organization for the Assessment of Strategies for
Ischemic Syndromes (OASIS) 5 trial compared fondaparinux
to enoxaparin in 20
078 patients with nonST-segment
elevation ACS randomized to fondaparinux 2.5 mg subcutaneously once daily or enoxaparin 1 mg/kg subcutaneously twice
daily (dose adjusted to 1 mg/kg once daily in patients with
CrCl <30 mL/min).75 Although patients with SCr >3 mg/dL
were excluded, a specific analysis was designed to examine
efficacy and safety outcomes by quartiles of GFR (as estimated by the MDRD formula).69 This study showed a direct
relationship between degree of renal impairment and the
risk of death, MI, refractory ischemia, and bleeding. Among
patients with a GFR 58 mLmin11.73 m2, no significant
difference was seen between treatment groups in the primary
composite outcome of death, MI, or refractory ischemia at 9
days. However, at 30 days, the rate of the primary composite outcome was significantly lower among patients with a
GFR <58 mLmin11.73 m2 with fondaparinux (HR, 0.81;
95% CI, 0.690.96). Fondaparinux treatment was associated
with lower rates of major bleeding events at 9 days among
patients with a GFR <58 mLmin11.73 m2 (HR, 0.42; 95%
CI, 0.320.56). In addition, in the subgroup of patients with
CrCl <30 mL/min, the rates of major bleeding at 9 days were
Anti-Ischemic Therapies
-Blockers
-Blockers are recommended for all patients with ACS unless
contraindicated.86,87 Metoprolol, atenolol, and propranolol have
been studied in the setting of AMI, and carvedilol has been studied in the setting of AMI with left ventricular dysfunction.8892
Atenolol is renally eliminated and requires dose adjustment in
those with renal impairment. Dose adjustment is recommended
Study Design
Chew et al
79
REPLACE-280
Delhaye et al81
ACUITY82
HORIZONS-AMI83
Population
Meta-analysis
of 3 trials: the
Bivalirudin
Angioplasty Study,
CACHET trial and
REPLACE-1
Subgroup analysis
of an RCT
Retrospective
analysis of
single-center
registry
Subgroup analysis
of an RCT
Subgroup analysis
of an RCT
End Points
Results
Bleeding (definition
varied by trial)
Major bleeding
Composite ischemic
end point of death,
MI, or unplanned
revascularization
Non-CABG-related
major bleeding
NonCABG-related
major bleeding (30 d)
ACS indicates acute coronary syndrome; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; CABG, coronary artery bypass grafting; CACHET,
Comparison of Abciximab Complications With Hirulog for Ischemic Events Trial; CI, confidence interval; CKD, chronic kidney disease; CrCl, creatinine clearance; GP,
glycoprotein; HORIZONS-AMI, Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; HR, hazard ratio; MACE, major adverse cardiac
events; MI, myocardial infarction; NACE, net adverse clinical events; OR, odds ratio; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; REPLACE,
Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events; RR, relative risk; SCr, serum creatinine; TIMI, Thrombolysis in Myocardial Infarction; TVR,
target-vessel revascularization; UA, unstable angina; and UFH, unfractionated heparin.
*CrCl calculated by the Cockcroft-Gault formula.
94
Study Design
Population
End Points
All-cause mortality
(primary)
Cardiovascular
mortality, HF mortality
Results
No statistically significant interactions were
observed between the randomized treatment
and the study type for each clinical outcome.
Adjusted HRs (95% CI) for carvedilol treatment
were as follows: All-cause mortality: eGFR >60:
0.59 (0.430.81); eGFR 60: 0.78 (0.64-0.95).
In the subgroup with eGFR <45, HR was 0.94
(95% CI, 0.721.23). Cardiovascular mortality:
eGFR >60: 0.59 (0.42-0.82); eGFR 60: 0.77
(0.620.94).
HF mortality: eGFR >60: 0.58 (0.34-0.99);
eGFR 60: 0.68 (0.520.88); in the subgroup
with eGFR <45: 0.86 (0.611.21).
Yan et al38
Observational,
prospective
cohort study
One-year survival
Wright et al2
Observational, retro
spective cohort study
Bae et al95
Observational,
retrospective analysis
of KAMIR cohort
Keough-Ryan
et al32
Observational cohort
Death, secondary
outcomes length
of stay, surgical
interventions
Berger et al19
Observational,
retrospective analysis
of CCP and USRDS
Mortality (30 d)
McCullough
et al21
Observational,
prospective
cohort study
In-hospital mortality
ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAPRICORN, Carvedilol Postinfarct Survival Control
in Left Ventricular Dysfunction; CCP, Cooperative Cardiovascular Project; CI, confidence interval; CKD, chronic kidney disease; COPERNICUS, Carvedilol Prospective
Randomized, Cumulative Survival; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; HR, hazard
ratio; hs-CRP, high-sensitivity C-reactive protein; KAMIR, Korean Acute Myocardial Infarction Registry; MACE, major adverse cardiovascular events; MI, myocardial
infarction; OR, odds ratio; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; RR, relative risk; STEMI, ST-segmentelevation myocardial
infarction; and USRDS, United States Renal Data System.
*Glomerular filtration rate calculated by the modified Modification of Diet in Renal Disease equation.
CrCl calculated via Cockcroft-Gault equation.
Corrected CrCl calculated as (140age)/serum creatinine, multiplied by 0.85 if female.
Study Design
Population
End Points
Results
Frances etal,
2000118
Observational,
retrospective cohort
of the CCP database
All-cause
mortality (1 y)
Shlipak et al,
2001122
Observational,
retrospective
analysis of the CCP
database
All-cause
mortality (1 y)
Berger et al,
200319
Observational,
retrospective cohort
using ESRD and CCP
database
All-cause
mortality (30 d)
CATS119
Change in GFR*
from baseline over
a 12-mo period
SAVE121
All-cause and
cardiovascular
mortality and morbidity
stratified
by GFR* (4 y)
Krause et al,
2004120
Observational,
retrospective cohort
of the CCP
300400-d all-cause
mortality
Reddan et al,
2005103
Association between
The interaction between use of ACE inhibitors
CrCl and 90-d all-cause and CrCl was significantly associated with
mortality
improved outcomes, with the greatest
benefit in seen in patients with CrCl of 3059
mLmin11.73 m2 (P=0.0005 for interaction).
ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; CATS, Captopril and Thrombolysis Study; CKD, chronic kidney disease; CCP, Cooperative
Cardiovascular Project; CI, confidence interval; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GFR, glomerular
filtration rate; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; RCT, randomized controlled trial; SAVE, Survival And Ventricular Enlargement
study; SCr, serum creatinine; and SYMPHONY, Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-Acute Coronary Syndromes.
*GFR calculated by the modified Modification of Diet in Renal Disease equation.
GFR calculated via Cockcroft-Gault equation.
CrCl calculated by modified Modification of Diet in Renal Disease equation.
Study Design
Population
Lim et al
Observational,
retrospective analysis
of KAMIR cohort
Death and
complications during
hospital course
CARE135
Death of coronary
disease or symptomatic
nonfatal MI confirmed
by CK
Keough-Ryan
et al32
Observational cohort
Death, secondary
outcomes length
of stay, surgical
interventions
Szummer
etal133
Observational analysis
of the SWEDEHEART
registry
Mortality at 1y
Shibui et al134
Observational cohort
132
End Points
Results
ACS indicates acute coronary syndrome; AMI, acute myocardial infarction; CARE, Cholesterol and Recurrent Events trial; CI, confidence interval; CK, creatine kinase;
CKD, chronic kidney disease; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; HR, hazard ratio; KAMIR, Korean Acute Myocardial Infarction Registry;
MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; and SWEDEHEART, Swedish Web System for Enhancement and
Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies.
*Glomerular filtration rate calculated via Cockcroft-Gault equation.
CrCl calculated by modified Modification of Diet in Renal Disease equation.
Glomerular filtration rate calculated by the modified Modification of Diet in Renal Disease equation.
Summary
Aspirin
Available data suggest aspirin should be used in patients with CKD presenting with ACS
Fibrinolytic
Available data suggest fibrinolytic therapy should be considered as a treatment strategy in STEMI patients with CKD
presenting within 12 h of symptom onset when primary PCI is not available. Observed rates of ICH were higher in CKD
patients receiving fibrinolytics than in non-CKD patients
Available data suggest these agents should be considered in CKD patients presenting with ACS. Data from RCTs of newer
agents (prasugrel and ticagrelor) suggest these agents should be considered in CKD patients not requiring dialysis.
Available data suggest glycoprotein IIb/IIIa receptor antagonist therapy, within the context of labeled dosing modifications
and exclusions for each agent, can be considered as a treatment strategy in CKD patients presenting with ACS. The data
also suggest an increased rate of bleeding in patients with CKD.
Anticoagulant
Available data suggest anticoagulant therapy should be considered in CKD patients presenting with ACS. The data support
consideration for fondaparinux and bivalirudin as strategies with lower rates of bleeding in patients with stage 3 and 4
CKD (relatively few patients with stage 4 CKD were included in the randomized trials evaluating these agents). Relevant
labeled dosing modifications and contraindications should be considered for each agent.
-Blocker
Available data suggest -blocker therapy should be considered in CKD patients presenting with ACS who do not have a
contraindication to -blocker therapy.
ACE inhibitor/ARB
Available data suggest ACE inhibitor or ARB therapy should be considered in CKD patients presenting with ACS and LV
dysfunction. Potassium and SCr should be monitored closely.
Aldosterone blocker
Limited available data suggest aldosterone blocker therapy should be considered for CKD patients with post-MI LV
dysfunction (with either diabetes mellitus or heart failure signs or symptoms) and baseline SCr 2.5 mg/dL and serum
potassium <5.0 mmol/L. Serum potassium should be monitored closely.
Statin
Available data suggest statin therapy should be considered in CKD patients presenting with ACS.
ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; ICH, intracranial
hemorrhage; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; SCr, serum creatinine; and STEMI,
ST-segmentelevation myocardial infarction.
*A detailed discussion and all references can be found in the text of each respective drug section.
Summary/Future Directions
In patients presenting with ACS, declining renal function has
been associated with increased risk for adverse clinical outcomes,
including death, MI, and bleeding events. In spite of the high risk
of adverse events in this population, CKD patients have largely
been excluded from or underrepresented in randomized controlled
trials in patients presenting with ACS. This presents a challenging situation for clinicians to make evidence-based medication
choices, as well as for understanding the risk and benefits of different therapy combinations. Taken collectively, the available data
suggest that patients with CKD benefit from the evidence-based
medications routinely used in all patients presenting with ACS
(Table11); however, important considerations are necessary to
provide the greatest benefit while limiting the chance for harm.
These would include careful assessment of renal function, use of a
validated equation for dose adjustment of medications, avoidance
of medications that are contraindicated in patients with stage 4 and
5 CKD, and avoidance or limiting of the use of emerging medications that have not been formally studied in patients with CKD.
Currently, the US Food and Drug Administration provides
guidance and recommendations for the pharmaceutical industry on the design and conduct of pharmacokinetic studies in
patients with impaired renal function.137 However, moving forward, inclusion and better representation of patients with CKD
in randomized clinical trials will be necessary to accurately
assess the risks and benefits of medications in this population.
Disclosures
Writing Group Disclosures
Writing Group
Member
Employment
Research Grant
Other Research
Support
Speakers
Bureau/
Honoraria
Expert
Witness
None
None
None
None
None
None
None
None
None
Ownership Consultant/Advisory
Interest
Board
Jeffrey B.
Washam
L. Kristin
Newby
Duke University
Medical Center
Amber L.
Beitelshees
University of Maryland
None
None
None
None
None
None
None
Mauricio G.
Cohen
University of Miami
Miller School of
Medicine
None
None
None
None
None
Daiichi-Sankyo;
AstraZeneca;
The Medicines
Company*
None
Timothy D.
Henry
Cedars-Sinai Heart
Institute
None
None
None
None
None
Daiichi Sankyo*;
Eli Lilly*; The
Medicines
Company*
None
Charles A.
Herzog
Hennepin Healthcare
System, Inc
Venu Menon
Cleveland Clinic
Robert L.
Page II
University of Colorado
School of Pharmacy
None
None
Other
None
Amgen;
American
AstraZeneca*; Heart Journal*;
Cubist*; Daiichi Society of Chest
Sankyo*;
Pain Centers*;
Genentech*;
JAHA*
GlaxoSmithKline*;
Novartis*
Boston
Abbott*; Affymax*;
Scientific*;
Amgen;
Cambridge
CorMedix*;
Heart*;
FibroGen*;
Johnson & Fresenius*; Keryx*;
Johnson*; GlaxoSmithKline*;
Merck*
AbbVie*
None
None
None
None
None
None
None
None
Daiichi Sankyo;
AstraZeneca
None
None
None
None
Bayer*; Janssen*;
Portola*
None
AstraZeneca
None
None
None
None
None
None
None
None
None
None
None
None
None
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the
Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be significant if (a) the person
receives $10000 or more during any 12-month period, or 5% or more of the persons gross income; or (b) the person owns 5% or more of the voting stock or share of the
entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition.
*Modest.
Significant.
Other Research
Support
Speakers Bureau/
Honoraria
Expert Witness
Ownership
Interest
Consultant/
Advisory Board
Other
None
None
None
None
None
None
Mayo Clinic
None
None
None
None
None
None
None
NIH
Medtronic
None
Fresenius
None
Keryx*;
Medtronic*
None
None
None
None
None
None
None
None
Employment
Research Grant
Sripal Bangalore
Gregory Barsness
David Charytan
Peter McCullough
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure
Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during
any 12-month period, or 5% or more of the persons gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more
of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition.
*Modest.
Significant.
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