β-Blockers and Cardiac Events in

Noncardiac Surgery
Lessons from DECREASE-IV
M Chadi Alraies, MD
Department of Hospital Medicine Grand Round
Cleveland Clinic Foundation

M C Alraies 1
 Agenda
• Perioperative cardiac events
• RCRI
• ACC/AHA Guidelines for perioperative BB use.
• What is already known about perioperative β-
blockers
• Literature review
• DECREASE-IV study

M C Alraies 2
 Introduction
• About 20 million Americans undergo surgery
with general anesthesia each year.1
• Cardiac events (MI or Cardiac death) result in
perioperative mortality rate of 3-6%

1. July 20, 2005 Los Angeles Times

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 Incidence of Perioperative Myocardial Infarction After Noncardiac Surgery

Goldman et al. NEJM 1977 5.8%

Mangano et al. NEJM 1990 3.0% perioperative MI

4.7-5.6% in patients with known coronary

Shah et al. Anesth Analg 1990
disease

1.8% perioperative MI in men over the

Ashton et al., Ann Intern Med 1993
age of 40
1.4%, 3.2%, to 6.9% in successive surgical
Mangano et al., NEJM 1995
patients

Deveraux et al., CMAJ 2005 ~3%

non-fatal MI in POISE trial in the placebo group

Deveraux et al., Lancet 2008 was 5.1% at 30 days.

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 Perioperative cardiac events
• The most common reason for preoperative
evaluation.
• Associated with increased mortality and
results in higher costs

M C Alraies 5
Prognosis of perioperative MI after noncardiac surgery

• 15-25% in-hospital mortality, of which

perioperative MI accounts for 2/3
• Nonfatal perioperative MI predisposes to
death, ACS, or progressive angina:
– Post-op troponin I > 1.5 mcg/L: increased 6-mo
mortality (OR 5.9)
– Post-op troponin I > 0.6 mcg/L: increased 32-mo
mortality (OR 2.15)

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 Pathophysiology of Perioperative MI
• Multifactorial
• Myocardial oxygen demand/supply mismatch
due to:
– Perioperative surgical stress
– Tachycardia
– Hypertension
– Pain
• Coronary plaque instability and subsequent
rupture also lead to infarction.
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 ACC/AHA 2007 Guidelines on
Perioperative Cardiovascular Evaluation
and Care for Noncardiac Surgery

ACC/AHA Guideline JACC 2007;50:159-241 M C Alraies 8

 Revised Cardiac Risk Index (RCRI)
Five independent predictors of major cardiac complications*
History of ischemic heart disease
History of compensated or prior HF
History of cerebrovascular disease
Diabetes mellitus requiring treatment with insulin
Preoperative serum creatinine >2.0 mg/dL (177 mol/L)

Rate of cardiac death, nonfatal myocardial infarction, and nonfatal cardiac arrest
according to the number of predictors ¥
No risk factors - 0.4 percent (95% CI 0.1-0.8 percent)
One risk factor - 1.0 percent (95% CI 0.5-1.4 percent
Two risk factors - 2.4 percent (95% CI 1.3-3.5 percent
Three or more risk factors - 5.4 percent (95% CI 2.8-7.9 percent)

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M C Alraies 10
 Applying Classification of
Recommendations and Level of Evidence
Level A Class I Class IIa Class IIb Class III

Multiple (3-5) • Recommen- • Recommen- • Recommen- • Recommen-

population risk dation that dation in favor of dation’s dation that
strata evaluated procedure or treatment or usefulness/ procedure or
treatment is procedure being efficacy less well treatment not
Level B useful/ effective useful/ effective established useful/effective
• Sufficient • Some conflicting • Greater and may be
evidence from evidence from conflicting harmful
Limited (2-3) multiple multiple evidence from • Sufficient
population risk randomized trials randomized trials multiple evidence from
strata evaluated or meta-analyses or meta-analyses randomized trials multiple
or meta-analyses randomized trials
Level C or meta-analyses

Very limited (1-2)

population risk
strata evaluated
Class I Class IIa Class IIb Class III
Benefit >>> Risk Benefit >> Risk Benefit ≥ Risk Risk ≥ Benefit
Additional studies with Additional studies with No additional studies
focused objectives broad objectives needed; needed
What it needed Additional registry data
would be helpful
means IT IS REASONABLE
SHOULD be performed/ MAY BE SHOULD NOT
administered to perform procedure/
administer CONSIDERED NOT HELPFUL
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MAY BE HARMFUL
 ACC/AHA Recommendation for Beta Blockers
• Class I
– Patients on BB should remain on these agents [level C]
– BB should be given to patients undergoing vascular surgery who are at high cardiac
risk owing to the finding of ischemia on preop testing [level B]
• Class IIa
– BB probably recommend those undergoing vascular surgery preop testing notes
CHD [level B]
– BB probably recommend high cardiac risk with more than 1 clinical risk factor [level
B]
– BB probably recommend preop assessment identifies CHD or high cardiac risk with
> 1 risk factor and undergoing intermediate risk surgery or vascular surgery [level B]
• Class IIb
– BB uncertain in patient with a single risk factor undergoing intermediate or vascular
surgery [level C]
– BB uncertain in patient with no risk factors undergoing vascular surgery [level B]
• Class III
– Beta blockers should not be given to patients undergoing surgery who have absolute
contraindications to beta blockade. [level C]

ACC/AHA Guideline JACC 2007;50:159-241 M C Alraies 12

 ACC/AHA Recommendation for Beta Blockers

ACC/AHA Guideline JACC 2007;50:159-241 M C Alraies 13

ACC/AHA guidelines Recommendations
for Statin Therapy
CLASS I
• For patients currently taking statins and scheduled for
noncardiac surgery, statins should be continued. (B)

CLASS IIa
• For patients undergoing vascular surgery with or without
clinical risk factors, statin use is reasonable. (B)

CLASS IIb
• For patients with at least 1 clinical risk factor who are
undergoing intermediate-risk procedures, statins may be
considered. (C)

ACC/AHA Guideline JACC 2007;50:159-241 M C Alraies 14

Perioperative β-Blockers

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 Mechanism of Beta-blockers?
• Decrease myocardial oxygen demand
– Heart rate
– Myocardial contractility
• Reduce the adrenergic activity
• Reduce levels of free fatty acid
• Increase myocardial glucose uptake
• Coronary plaque stability – requires weeks
– Anti-inflammatory
– Progression of atherosclerosis
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● Most trials are inadequately powered.
● Few randomized trials of medical therapy to prevent
perioperative MACE have been performed.
● Few randomized trials have examined the role of perioperative
beta-blocker therapy, and there is particularly a lack
of trials that focus on high-risk patients.
● Studies to determine the role of beta blockers in
intermediate- and low-risk populations are lacking.
● Studies to determine the optimal type of beta blockers are
lacking.
● No studies have addressed care-delivery mechanisms in the
perioperative setting, identifying how, when, and by whom
perioperative beta-blocker therapy should be implemented
and monitored.

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Review of literature

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 Effect of Atenolol on Mortality and Cardiovascular
Morbidity after Noncardiac Surgery. Mangano 1996

Participants 200 patients.

Surgery Elective non-cardiac surgery
Intervention Atenolol (100mg PO or 10 IV) vs. placebo
Administration Before anesthesia & Immediately after surgery for 7 days
Median follow-up 24 months
Primary outcome composite all-cause mortality, MI, UA, CHF

Mangano DT, Layug EL, Wallace A, et al; for Multicenter Study of Perioperative Ischemia Research Group. Effect of atenolol on mortality and
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cardiovascular morbidity after noncardiac surgery. N Engl J Med. 1996;335:1713–1720. 19
 Mangano 1996
83%

68%

P = 0.008

Overall Survival in the Two Years after Noncardiac Surgery among 192 Patients in the Atenolol and
Placebo Groups Who Survived to Hospital Discharge.

Mangano DT. N Engl J Med. 1996;335:1713–1720.

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 Mangano 1996

90%

79%

Event-free Survival in the Two Years after Noncardiac Surgery among 192 Patients in the Atenolol
and Placebo Groups Who Survived to Hospital Discharge. N Engl J Med. 1996;335:1713–1720.

Mangano DT, N Engl J Med. 1996;335:1713–1720. M C Alraies 21

 Mangano 1996
• In patients who have or are at risk for CAD +
noncardiac surgery, treatment with atenolol
reduce mortality and the incidence of MACE
for two years after surgery.

Mangano DT, N Engl J Med. 1996;335:1713–1720. M C Alraies 22

The effect of bisoprolol on perioperative mortality and
myocardial infarction in high-risk patients undergoing
vascular surgery Poldermans D 1999

Participants 112 patients.

Stress test Positive dobutamine echocardiography
Surgery Elective non-cardiac surgery
Intervention Bisoprolol (5 mg titrated to 10mg) vs. placebo
Administration Daily for 1 week before surgery and QD for 30 days post surgery.
Dose titration Yes (1 week interval)
Median follow-up 24 months
Primary outcome composite all-cause mortality, MI, UA, CHF

Poldermans D, Boersma E, Bax JJ, et al; for Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography
Study Group. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular
surgery. N Engl J Med. 1999;341: 1789–1794.
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 Poldermans D,1999

Kaplan–Meier Estimates of the Cumulative Percentages of Patients Who Died of Cardiac Causes
or Had a Nonfatal Myocardial Infarction during the Perioperative Period.

Poldermans D,. N Engl J Med. 1999;341: 1789–1794. M C Alraies 24

 Poldermans D,1999

Bisoprolol reduces the perioperative incidence of

death from cardiac causes and nonfatal myocardial
infarction in high-risk patients who are undergoing
major vascular surgery.

Poldermans D,. N Engl J Med. 1999;341: 1789–1794. M C Alraies 25

 β-Blockers and Reduction of Cardiac Events in
Noncardiac Surgery, scientific review. Auerbach 2002

Auerbach AD, Goldman L. Beta-Blockers and reduction of cardiac events in noncardiac surgery: scientific review. JAMA. 2002;287:1435–1444
M C Alraies 26
1. β-blockers work the best in high risk patients.
2. Need more studies for patients with stable coronary
disease and are undergoing elective surgery?
3. What is the optimal duration of therapy?
4. Which agent is the best?
5. When to start BB therapy?

M C Alraies Auerbach AD. JAMA. 2002;287:1435–144427

 Perioperative -blockade (POBBLE) for patients undergoing
infrarenal vascular surgery: Results of a randomized double-blind
controlled trial. Brady et al 2005, UK

Participants 103 patients – median age 73 yrs

Surgery Infrarenal vascular surgery
Intervention Metoprolol (50 mg BID) vs. Placebo
Administration Day before surgery twice daily & Continued for 7-14 days
Dose titration No
Median follow-up 30 days
Primary outcome composite all-cause mortality, MI, UA, CHF

Brady AR, Gibbs JS, Greenhalgh RM, et al. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular
surgery: results of a randomized double-blind controlled trial. J Vasc Surg. 2005;41:602– 609.
28
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 POBBLE trial 2005

• lower-risk vascular surgical patients,

perioperative β-blockade does not reduce 30-
day cardiovascular morbidity and mortality
but, facilitate earlier patient discharge.

Brady AR. J Vasc Surg. 2005;41:602– 609.

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 The effects of perioperative betablockade: results of
the Metoprolol after Vascular Surgery (MaVS) study, a
randomized controlled trial. Yang et al 2006

Participants 500 vascular patients – mean age 66 yrs

Surgery Vascular surgery only
Intervention Metoprolol (50-100mg) vs. placebo
Administration 2 hours before anesthesia induction then daily for 5 days.
Dose titration No
Median follow-up 30 days and 6 months
Primary outcome composite all-cause mortality, MI, UA, CHF

Yang H, Raymer K, Butler R, et al. The effects of perioperative betablockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a
randomized controlled trial. Am Heart J. 2006;152:983–990 30
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 Outcomes at 30 days postoperative

Yang H. Am Heart J. 2006;152:983–990

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 Cumulative risk primary outcomes at 6 months.

Yang H. Am Heart J. 2006;152:983–990

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 MaVS trial 2006

• Metoprolol has no effect in reducing the

cardiac event rate in vascular patients at 30
days postoperative or at 6 months.

Yang H. Am Heart J. 2006;152:983–990

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 Pooled RRR of all four trials

Yang H. Am Heart J. 2006;152:983–990

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 Effect of perioperative blockade in patients with diabetes
undergoing major non-cardiac surgery: randomized placebo
controlled, blinded multicentre (DIPOM) trial
Participants 921 diabetic patients.
Surgery Major (over 1 hr) non-cardiac surgery (majority orthopedic)
Mean age 64 yrs
Intervention Metoprolol XL 50 mg day before surgery
Metoprolol XL 100 mg 2 hours before induction, then
Metoprolol XL 100 mg daily x 8 days.
Administration Day of surgery for 8 days post op
Titration of therapy No
Median follow-up 18 months
Primary outcome composite all-cause mortality, MI, UA, CHF
Comment Followed Mangano’s inclusion criteria and protocol.
(2.5 x bigger sample size)

Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery:
randomized placebo controlled, blinded multicentre trial. BMJ. 2006;332:1482. 35
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 Kaplan-Meier plot of time to primary outcome measure

Juul AB. DIPOM. BMJ. 2006;332:1482.

36
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 Diabetic Postoperative Mortality and Morbidity
(DIPOM) 2006
• Heart rate lower with metoprolol (72 vs 78
bpm)
• Primary outcome: 21% metoprolol group vs.
20% placebo group
• Metoprolol XL (100 mg a day for up to eight
perioperative days) for diabetics does not
affect long term mortality and cardiac
morbidity. (But wide CI)

Juul AB. DIPOM. BMJ. 2006;332:1482.

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 Effects of extended-release
metoprolol succinate in patients
undergoing non-cardiac surgery
(POISE trial)

Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE
trial): a randomized controlled trial. Lancet. 2008;371:1839 –1847. 38
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 PeriOperative Ischemia Evaluation (POISE)
8351 patients.
Participants Hx: CAD, PVD, CVA, CHF within 3 yrs of surgery, or vascular
surgery
Surgery Major non-cardiac surgery – majority vascular surgeries
Mean age 69 yrs

Metoprolol XL 100 mg 2-4 hours before induction

Metoprolol XL 100 mg 0-6 hours after surgery
Intervention
Metoprolol XL 200 mg daily for 30 days following surgery
Metoprolol 15mg IV every 6 hours if NPO

Administration Day of surgery & for 8 days post op

Median follow-up 18 months
Titration of therapy No
Primary outcome composite all-cause mortality, MI, UA, CHF
75 centers, 9 countries
Comment
Goal 10000 patients (final enrollment 8351)
39
Devereaux PJ, (POISE trial). Lancet. 2008;371:1839 –1847.
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 Effects of study treatment on primary and secondary outcomes at 30 days

8351 Patients
Hx: CAD, PVD, CVA, CHF
Major vascular surgery

4174 Patients
Metoprolol XL 100mg 2-4 hours 4177 Patients
before surgery and Placebo
200mg/day for 30 days

Cardiovascular death, non- Cardiovascular death, non-

fatal myocardial infarction, or fatal myocardial infarction, or
non-fatal cardiac arrest non-fatal cardiac arrest
5.8% 6.9%

Total mortality Total mortality

3.1% 2.3%

Stroke 1% Stroke 0.5%

Non-fatal stroke 0.6% Non-fatal stroke 0.3%

M C Alraies 40
Devereaux PJ,. Lancet. 2008;371:1839 –1847.
 Kaplan-Meier estimates of
the primary outcome (A), myocardial infarction (B), stroke (C), and death (D)

MIs
Primary

MIs
Primary

Death
Strokes

Strokes

Death

M C Alraies 41
Devereaux et al. POISE . Lancet. 2008;371:1839 –1847.
 PeriOperative Ischemia Evaluation (POISE)

BB prevents
15 MI
3 Revasc
7 Atrial Fib

BB causes:
8 Deaths
5 Stroke (1.0% vs. 0.5%, HR 2.17, p = 0.005)
53 Hypotension (15.0% vs. 9.7%, p < 0.0001)
42 Bradycardia (6.6% vs. 2.4%, p < 0.0001)
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Devereaux et al. POISE . Lancet. 2008;371:1839 –1847.
 POISE observations
• BB decreased non-fatal MI and CV mortality
• Evidence does not support initiation of BB in
most pts undergoing surgery with (RCRI <3)
• Benefit of BB for:
– High risk patients (RCRI 3+)
– Pts with evidence of ischemia by stress testing
• However, most patients at highest CV risk
have independent indications for B-B therapy
M C Alraies 43
 POISE limitations
• Significant hypotension more often in BB
group (15% vs. 9.7%)
• Fixed dose, not titrated
• Started treatment only 2-4 hrs prior to surgery
• High starting dose of oral metoprolol may
have contributed to hypotension/stroke rate.

M C Alraies 44
 Bisoprolol and Fluvastatin for the Reduction of Perioperative
Cardiac Mortality and Myocardial Infarction in Intermediate-Risk
Patients Undergoing Noncardiovascular Surgery
A Randomized Controlled Trial
(DECREASE-IV)

Dunkelgrun M, Boersma E, Schouten O, Koopman-van Gemert AW, van Poorten F, Bax JJ,
Thomson IR, Poldermans D; Dutch Echocardiographic Cardiac Risk Evaluation Applying
Stress Echocardiography Study Group.
Departments of Vascular Surgery, Erasmus Medical Centre, Rotterdam, the Netherlands.

Annals of Surgery. 2009 Jun;249(6):921-6.

M C Alraies 45
 Objective
• This study evaluated the beta-blockers and
statins for the prevention of perioperative
cardiovascular events in intermediate-risk
patients undergoing noncardiovascular
surgery.

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6. 46

M C Alraies
 DECREASE-IV
1066 patients.
Participants
Risk for a perioperative MACE 1-6% (RCRI 2-3)
Surgery elective noncardiovascular surgery
Mean age 65 yrs
Bisoprolol starting at 2.5 mg po daily
Dose modified by 1.25 or 2.5 mg per day
Intervention Maximum dose of 10 mg po dialy
Metoprolol IV every 6 hours if NPO
Fluvastatin XL 80 mg po daily (NGT if unable to swallow)
Administration Median 34 days before surgery & 30 days after surgery
Median follow-up 30 days
Titration of therapy Yes (Target: heart rate of 50-70 bpm)
Primary end point Cardiac death, all-cause mortality, non-fatal MI
Secondary end point Cardiac arrhythmias, Acute heart failure, Coronary revascularization
Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6. 47
M C Alraies
 Methods
• A prospective
• Open-label 2 x 2 factorial design
• Multicenter
• Randomized
• Controlled trial

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

48
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 Safety End Points
• Stroke
• Significant bradycardia & hypotension
• Significant liver and muscles markers
– ALT 3 times upper limit of normal
– CK level more than 10 times upper limit of normal
– Myopathy
– Rhabdomyolysis

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

M C Alraies 49
Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6. 50
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 Incidence of primary study end point by treatment group

Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.

51
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 M C Alraies 52
Dunkelgrun al. DECREASE-IV. Annals of Surgery. 2009 Jun;249(6):921-6.
 Limitations
• Majority of patients (RCRI 2-3) had an
independent indication for beta-blockade
prior to surgery
• Early termination for slow recruitment
– 78% of the patient who met the inclusion criteria
were already on beta-blockers and/or statin
• Only 1% of the study population were actually
titrated.
• Not blinded: Beta-blocker therapy cannot be
titrated to heart rate
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 POISE DECREASE - IV
Type of BB Metoprolol XL Bisoprolol
Starting dose 100 mg 2 hours preop 2.5 mg daily 30 days Preop
Then 200 mg daily Titrated to 10 mg po daily
Initiation time 1 day 30 days
Dose titration No Yes (only in 1%)
Dose adjustment for HR No yes
Withdrawal of therapy Early (7 days) Late (30 days)
Sample size 8351 1066
Age (mean) 69 yrs 65 yrs
Type of surgery Non-cardiac Non-cardiovascular
M C Alraies 54
Thank you

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Questions

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