β-blockers And Cardiac Events In Noncardiac Surgery

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 βblockers • 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

M C Alraies

3

Incidence of Perioperative Myocardial Infarction After Noncardiac Surgery Goldman et al. NEJM 1977

5.8%

Mangano et al. NEJM 1990

3.0% perioperative MI

Shah et al. Anesth Analg 1990

4.7-5.6% in patients with known coronary disease

Ashton et al., Ann Intern Med 1993

1.8% perioperative MI in men over the age of 40

Mangano et al., NEJM 1995

1.4%, 3.2%, to 6.9% in successive surgical patients

Deveraux et al., CMAJ 2005

~3%

Deveraux et al., Lancet 2008

non-fatal MI in POISE trial in the placebo group was 5.1% at 30 days.

M C Alraies

4

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)

M C Alraies

6

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. M C Alraies

7

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)

M C Alraies

9

M C Alraies

10

Applying Classification of Recommendations and Level of Evidence Level A

Multiple (3-5) population risk strata evaluated Level B

Limited (2-3) population risk strata evaluated

Class I

Class IIa

Class IIb

Class III

• Recommen• Recommendation that dation in favor of procedure or treatment or treatment is procedure being useful/ effective useful/ effective • Sufficient • Some conflicting evidence from evidence from multiple multiple randomized trials randomized trials or meta-analyses or meta-analyses

• Recommendation’s usefulness/ efficacy less well established • Greater conflicting evidence from multiple randomized trials or meta-analyses

• Recommendation that procedure or treatment not useful/effective and may be harmful • Sufficient evidence from multiple randomized trials or meta-analyses

Class I

Class IIa

Class IIb

Class III

Benefit >>> Risk

Benefit >> Risk Additional studies with focused objectives needed

Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful

Risk ≥ Benefit No additional studies needed

SHOULD be performed/ administered

IT IS REASONABLE to perform procedure/ administer M C Alraies

MAY BE CONSIDERED

SHOULD NOT NOT HELPFUL 11 MAY BE HARMFUL

Level C

Very limited (1-2) population risk strata evaluated

What it means

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

M C Alraies

15

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 M C Alraies

16

● 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. M C Alraies

17

Review of literature

M C Alraies

18

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 M C Alraies 19 cardiovascular morbidity after noncardiac surgery. N Engl J Med. 1996;335:1713–1720.

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.

M C Alraies

20

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.

M C Alraies

23

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.

M C Alraies

28

POBBLE trial 2005 • lower-risk vascular surgical patients, perioperative β-blockade does not reduce 30day cardiovascular morbidity and mortality but, facilitate earlier patient discharge.

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

M C Alraies

29

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

M C Alraies

Outcomes at 30 days postoperative

Yang H. Am Heart J. 2006;152:983–990

M C Alraies

31

Cumulative risk primary outcomes at 6 months.

Yang H. Am Heart J. 2006;152:983–990

M C Alraies

32

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

M C Alraies

33

Pooled RRR of all four trials

Yang H. Am Heart J. 2006;152:983–990

M C Alraies

34

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.

M C Alraies

35

Kaplan-Meier plot of time to primary outcome measure

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

36 M C Alraies

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.

M C Alraies

37

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.

M C Alraies

38

PeriOperative Ischemia Evaluation (POISE) Participants

8351 patients. 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

Intervention

Metoprolol XL 100 mg 2-4 hours before induction Metoprolol XL 100 mg 0-6 hours after surgery 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

Comment

75 centers, 9 countries Goal 10000 patients (final enrollment 8351)

Devereaux PJ, (POISE trial). Lancet. 2008;371:1839 –1847.

39 M C Alraies

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 before surgery and

4177 Patients Placebo

200mg/day for 30 days

Cardiovascular death, nonfatal myocardial infarction, or non-fatal cardiac arrest

Cardiovascular death, nonfatal myocardial infarction, or 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

Devereaux PJ,. Lancet. 2008;371:1839 –1847.

40

Kaplan-Meier estimates of the primary outcome (A), myocardial infarction (B), stroke (C), and death (D)

Primary

MIs

Primary

MIs

Death

Strokes

Strokes

Death

Devereaux et al. POISE . Lancet. 2008;371:1839 –1847.

M C Alraies

41

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) Devereaux et al. POISE . Lancet. 2008;371:1839 –1847.

M C Alraies

42

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.

M C Alraies

46

DECREASE-IV Participants

1066 patients. Risk for a perioperative MACE 1-6% (RCRI 2-3)

Surgery

elective noncardiovascular surgery

Mean age

65 yrs

Intervention

Bisoprolol starting at 2.5 mg po daily Dose modified by 1.25 or 2.5 mg per day 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.

M C Alraies

47

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.

M C Alraies

48

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.

M C Alraies

50

Incidence of primary study end point by treatment group

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

M C Alraies

51

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

52

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 M C Alraies

53

POISE

DECREASE - IV

Type of BB

Metoprolol XL

Bisoprolol

Starting dose

100 mg 2 hours preop Then 200 mg daily

2.5 mg daily 30 days Preop 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 M C Alraies

55

Questions

M C Alraies

56