Perioperative Beta-blockers In Non-cardiac Surgery And The Poise

Perioperative Beta-blockers in non-cardiac surgery and the POISE trial: evidence revisited Moises Auron MD FAAP Hospital Medicine Cleveland Clinic

Outline  Introduction  Epidemiology  Pathophysiology

of perioperative ischemia and rationale for betablockade use  Trials supporting use of betablockers.  Trials suggesting no benefit from addition of betablockers  POISE Trial  Conclusions

Introduction  Increased

peri-operative Beta-blocker use was based on limited evidence in the 1990’s suggesting a cardio-protective effect in patients with known or suspected CAD.  Safe practice quality measure: AHRQ  Not supported by recent small trials

Introduction  Change

in evidence in the beginning of the century  Prompted

to a more conservative approach  2007 AHA/ACC guidelines modified accordingly  POISE

trial – largest placebo-controlled

 Showed

deleterious effects from perioperative beta-blocker use.

Epidemiology >

20 million surgeries per year in USA  Peri-operative MI is a major cause of complications and death in patients undergoing non-cardiac surgery  Rate

of 1 - 5%  Up to 30% - vascular surgery  Mortality rate - up to 60% per event  Prolonged

cost.

hospitalization and increased

Poldermans. NEJM. 353(4): 412 - 414. Auerbach. AHRQ. http://www.ahrq.gov/clinic/ptsafety/chap25.htm

Epidemiology  Autopsy

studies of peri-operative MI

 50

- 90% associated with plaque rupture and thrombus  Remaining cases are associated with sustained mismatch in DO2/VO2

Dawood MM, et al. Int J Cardiol. 1996; 57:37-44. Cohen MC, Aretz TH. Cardiovasc Pathol. 1999; 8:133-139.

Pathophysiology of perioperative ischemia • Anesthesia

Increased sympathetic tone

• Fluid-shifts, anemia Increased cathecolamine release

• Pain • Increased metabolic demands

Increased cortisol

Inflammatory state

↑ Myocardial VO2

- TNF - CRP - IL-1 and IL-6 - FFA

Increased plaque shear stress

Tissue ↓O2

↑ Platelet function

+ Endothelial dysfunction

Plaque rupture

Non – Q MI

Sir James Black  Nobel

Prize 1988  Discovery of Betablockers (Propranolol)

Protective effects of β-blockers ↓

HR and contractility  ↓ VO2  Modulation of βreceptors  ↓ apoptosis signaling  ↓ RAAS  Anti-ischemic and anti-arrhythmic effect

 Improvement

in synthesis of myocardial proteins  Shift from FFA  glucose metabolism  Peripheral vasodilation  Antioxidant  Anti-inflammatory

Schouten O, et al. Anesth and Analg. 2007; 104(1): 8-10. Zaugg M, et al. Br J Anaesth. 2002; 88: 101-123. Eur Rev Med Pharmacol Sci. 2002; 6: 115-126.

Evidence supporting BB use

Mangano, et al. NEJM 1996 N

= 200  San Francisco VA  > 2 risk factors for CAD (tobacco, hyperlipidemia, HTN, age >65, DM).  Randomization to receive either atenolol (i.v and p.o.) or placebo  before

the induction of anesthesia 5-10 mg iv,  after surgery – first post-op morning – po 50-100 mg.  daily throughout their hospital stay (up to 7 days).

Mangano, et al. NEJM 1996 All cause death (%) Atenolol

Placebo

P

6 mo

0

8

< 0.001

12 mo

3

14

0.005

24 mo

10

21

0.019

The overlooked editorial  “Whether

one should routinely give betablockers to patients with cardiac risk factors but no signs of underlying coronary disease remains unclear and cannot be inferred from the results of the study by Mangano et al.”

Eagle KA, Froehlich JB. NEJM. 1996; 335(23): 1761-1763

N

= 200 patients  Non-cardiac surgery  Atenolol versus placebo (7 days)  Atenolol iv before induction of anesthesia and every 12 h post-op until the patient could take p.o. Then switched to p.o. q.day adjusting dose to BP and HR.

Wallace, A, et al. Anesthesiology. 1998; 88: 7-17.

Evidence supporting BB use: DECREASE trial

NEJM. 1999; 341(24): 1789-1794

Poldermans, et al. NEJM.1999 N

= 112  Vascular surgery  UNBLINDED  Initially N = 1351; and 846 had DSE.  173

had positive results on DSE.  Fifty-three were already on BB, and 8 had extensive wall-motion abnormalities.  59

– bisoprolol and 53 – standard care.

Poldermans, et al. NEJM.1999  Bisoprolol

started 7 days before surgery  Dose titrated to HR 60x’  Continued for 30 days

Poldermans, et al. NEJM.1999

Cardiac causes Non-fatal MI End-point

Bisoprolol

Placebo

P

2 (3.4%)

9 (17%)

0.002

0

9 (17%)

< 0.001

3.4%

34%

< 0.001

Poldermans, et al. NEJM.1999  Unblinded  Study

terminated early due to 90% lower rate of non-fatal MI and cardiac death at 30 days.  Intensive post-operative monitoring.  Excluded the absolutely sickest 5% of patients

Evidence supporting BB use: DECREASE trial

• Regression analysis using Lee index

JAMA. 2001; 285(14): 1865 - 1873

Boersma, et al. JAMA 2001

Boersma, et al. JAMA 2001  It

is not a RCT  Did not find a protective effect of statins  Did not considered many perioperative issues:  Intraoperative

blood loss and/or transfusion  Length of surgery  Type of anesthesia

Heart rate control vs. stress test N

= 1,476 – all on betablockers.  Intermediate (n = 770)  Cardiac

stress-testing (n = 386)  No testing.  Similar

incidence of the primary end point as those assigned to testing (1.8% vs. 2.3%; [OR] 0.78; 95% [CI] 0.28-2.1; P=0.62).  Surgery done almost 3 weeks earlier.

 Patients

with a HR 65 beats/min had lower risk than the remaining patients (1.3% vs. 5.2%; OR 0.24; 95% CI 0.09 to 0.66; p 0.003). Poldermans D, et al. JACC. 2006; 48(5): 964-9.

Feringa HHH, et al. Circulation. 2006;114[suppl I]:I-344 –I-349.

High dose BB and rate control in vascular surgery  Observational

cohort study

N

= 272  Beta-blocker dose was optimized.  Continuous ECG 1 d prior to 2 d post-op.  Serial post-op troponin T

Feringa HHH, et al. Circulation. 2006;114[suppl I]:I-344 –I-349.

Maximum Recommended Therapeutic Dose (MRTD)  Atenolol

- 3.330 mg/kg/d  Bisoprolol - 0.330 mg/kg/d  Metoprolol 6.670 mg/kg/d  Carvedilol 0.417 mg/kg/d  Propranolol 10.700 mg/kg/d  Labetalol 40.700 mg/kg/d

Feringa HHH, et al. Circulation. 2006;114[suppl I]:I-344–I349.

High dose BB and rate control in vascular surgery 

In multivariate analysis, higher B-blocker doses (per 10% ↑)  ↓ myocardial ischemia ( [HR] 0.62; 95% [CI] 0.51 to 0.75)  ↓ troponin T release (HR, 0.63; 95% CI, 0.49 to 0.80),  ↓ long-term mortality (HR, 0.86; 95% CI, 0.76 to 0.97).



Higher HR in ECG (per 10-bpm increase)  ↑ myocardial ischemia (HR, 2.49; 95% CI, 1.79 to 3.48)  ↑ troponin T release (HR, 1.53; 95% CI, 1.16 to 2.03)  ↑ long-term mortality (HR, 1.42; 95% CI, 1.14 to 1.76).

The start of disbelief

BMJ. 2005; 331: 313-321.

Devereaux, et al. BMJ 2005.  Metaanalysis N

= 2437

of 22 trials

Devereaux, et al. BMJ 2005.  Composite

outcome of cardiovascular mortality, non-fatal myocardial infarction, and non-fatal cardiac arrest – RR 0.44 (95% CI 0.20 - 0.97), (99% CI 0.16 - 1.24)  Bradycardia needing treatment – RR 2.27 (95% CI 1.53 - 3.36, 99% CI 1.36 - 3.80)  Hypotension needing treatment – RR 1.27 (95% CI 1.04 to 1.56, 99% CI 0.97 to 1.66).

Devereaux, et al. BMJ 2005. Cumulative meta-analysis assessing the effect of POBB on 30 day risk of major perioperative CV events in patients having non-cardiac surgery. The Lan-DeMets sequential monitoring boundary, assumes a 10% control event rate and a 25% RR reduction with 80% power and a two sided = 0.01. Cumulative evidence is inconclusive

Current recommendations

Circulation. 1999; 100: 1043 – 1049.

N Engl J Med 2005;353: 349-61.

 Retrospective N

cohort study

= 782,969  18% received Betablockers in the first 2 days.  Propensity-score matching – compare differences between groups (BB vs no BB)  Multivariable logistic modeling – compared mortality

Lindenauer, NEJM 2005.

Lindenauer, NEJM, 2005.  Retrospective

design  Administrative database  No data on pre-operative medications.  Patients with CHF and COPD were excluded.  46% of surgeries were nonelective  RCRI

by Lee – elective surgery.

Yang H, et al. Am Heart J. 2006; 152: 983 – 90.

MaVS Study  Abdominal

aortic surgery and infrainguinal or axillofemoral revascularizations.  Double blind RCT  N = 500 (246 metoprolol; 250 placebo)  Start metoprolol 2 h pre-op until D/C or maximum 5 days post-op.  Primary outcome: post-op 30 days incidence of non-fatal MI, UA, new CHF, new arrhythmias or cardiac death.

Yang H, et al. Am Heart J. 2006; 152: 983 – 90.

MaVS Study  Primary

outcome events at 30 days

 Metoprolol:

25 (10.2%)  Placebo: 30 (12.0%) P = 0.57  No significant difference at 6 months (P = 0.81)  Metoprolol

 Increased risk of complications  Intraoperative

bradycardia 53/246 vs. 19/250 (P =

0.00001)  Intraoperative hypotension 114/246 vs. 84/250 (P = 0.0045)

Powell JT, et al. J Vasc Surg 2005;41:602-9.)

POBBLE Trial  Double-blind

RCT placebo-controlled trial  N = 103 patients without previous myocardial infarction who had infrarenal vascular surgery between July 2001 and March 2004.  55 – metoprolol; 48 – placebo  Oral metoprolol (50 mg bid supplemented by intravenous doses when necessary) or placebo from admission until 7 days post-op. Powell JT, et al. J Vasc Surg 2005;41:602-9.)

POBBLE Trial

Time from surgery to discharge Placebo - median of 12 days (95% confidence interval, 9-19 days) Metoprolol – median of 10 days (95% confidence interval, 8-12 days) group (adjusted HR 1.71; 95% CI 1.09-2.66; P < .02). Powell JT, et al. J Vasc Surg 2005;41:602-9.)

POBBLE Trial  Perioperative

hypotension (SBP drop > 25%)

 Metoprolol

49/53 (92%) (  Placebo (34/44 (77%) (P = 0.0004)  Bradycardia

< 50x

 Metoprolol

– 57%  Placebo – 14% (P < 0.0001)  Inotrope

requirement

 Metoprolol

47/53 (92%) (  Placebo 28/44 (64%) Powell JT, et al. J Vasc Surg 2005;41:602-9.)

DIPOM (Diabetes Postoperative Mortality and Morbidity) Trial

BMJ. 332 (7556):1482-88

DIPOM Trial    



RCT, double blind, placebo controlled N = 921 DM > 39 y/o  major non-cardiac surgery. 100 mg metoprolol controlled and extended release or placebo – 1d before surgery to maximum 8d post-op. Composite primary outcome measure was time to all cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac morbidity.

DIPOM Trial  Primary

outcome

 Metoprolol

– 99/462 (21%)  Placebo – 93/459 (20%) (HR 1.06, 0.80 to 1.41)  Median follow-up - 18 months (6-30)  All

cause mortality

 Metoprolol

- 74/462 (16%)  Placebo - 72/459 (16%) (HR 1.03, 0.74 to 1.42).

Current recommendations

Circulation 2007;116;e418-e499

2007 AHA/ACC Perioperative guidelines

2007 AHA/ACC Perioperative guidelines

2007 AHA/ACC Perioperative guidelines  Uses

same risk factors as Lee index but considers surgical risk separately

Finally…

PeriOperative ISchemic Evaluation

Devereaux PJ, et al. Lancet 2008; 371: 1839 – 47.

POISE  First

large double-blind RCT with placebo  190 hospitals in 23 countries  N = 8351 (intended to be 10,000)  Metoprolol

succinate – 4174  Placebo – 4177  Primary

endpoint - composite of CV death, non-fatal MI, and non-fatal cardiac arrest.  Analyses were by intention to treat.

Inclusion criteria  Non-cardiac

surgery  Age > 45 y/o  Expected length of hospital stay of at least 24 h  Any of the following criteria:  CAD  PVD  CVA  Hospitalisation

for CHF within previous 3 years  Undergoing major vascular surgery (except AV shunt, vein stripping procedures, and carotid endarterectomies)

Inclusion criteria  Any

3 of 7 risk criteria:

 Intrathoracic

or intraperitoneal surgery  History of CHF  TIA,  DM,  Serum creatinine >175 μmol/L  Age >70 years  Emergent or urgent surgery.

Exclusion criteria  Heart

rate < 50 bpm  2nd or 3rd degree heart block  Asthma  On βB or if PCP planned to start it perioperatively  Prior adverse reaction to a β blocker  CABG < 5 years and no cardiac ischaemia since  Low-risk surgical procedure  On verapamil  Previous enrolment in POISE.

POISE

POISE  Regimen

was influenced by practicality

 Starting

the study drug 2–4 h before surgery  Evidence - extended-release metoprolol 200 mg daily had a more even reduction in exercise HR and SBP vs. Atenolol 100 mg daily  Better anti-anginal effects than metoprolol 100 mg BID.  Review

of confidential blinded safety data on the first 10,000 pt included in COMMIT (RCT; N= 45,852; AMI randomised to early intravenous metoprolol and starting on day 2 extended-release metoprolol 200 mg daily vs placebo).

Blomqvist I, Westergren G, Sandberg A, Jonsson UE, Lundborg P. Pharmacokinetics and pharmacodynamics of controlled-release metoprolol: a comparison with atenolol. Eur J Clin Pharmacol 1988; 33 (suppl): S19–24. Egstrup K, Gundersen T, Harkonen R, Karlsson E, Lundgren B. The antianginal effi cacy and tolerability of controlledrelease metoprolol once daily: a comparison with conventional metoprolol tablets twice daily. Eur J Clin Pharmacol 1988; 33 (suppl): S45–49.

POISE   

  



First dose (oral extended-release metoprolol 100 mg or placebo) 2–4 h before surgery. HR > 50 bpm or SBP > 100 mmHg. If, at any time during the first 6 h post-operatively HR> 80 bpm or and SBP > 100 mmHg  first postoperative dose (extended-release metoprolol 100 mg or placebo) orally. Otherwise patients received their first postoperative dose at 6 h after surgery. Then, 12 h after the first postoperative dose, patients started taking oral extended-release metoprolol 200 mg or placebo every day for 30 days. If a patient’s heart rate was consistently < 45 bpm or SBP < 100 mmHg, study drug was withheld until those VS recovered.  Study drug - restarted at 100 mg once daily. Patients whose HR was consistently 45–49 bpm and SBP > 100 mmHg delayed taking the study drug for 12 h.

POISE  If

unable to take medications orally – iv infusion q6h.  Slow infusion - 15 mg in 25 mL NS over 60 min  HR

and BP were checked at 10, 30, and 60 min into the infusion.  If HR < 50 bpm or SBP < 100 mmHg - infusion was stopped and subsequent infusions - 10 mg.  Rapid

infusion - 5 mg over 2 min and repeated q5 min for a total of 15 mg. (If hemodynamic parameters met).

POISE  ECG

- 6–12 h postop, 24h, 48h and 30th days post-op.  Troponin or, CK-MB 6–12 h post-op, and on the first, second, and third days postop.

POISE 

 

The prespecifed primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal cardiac arrest at 30 days after randomisation. Outcome adjudicators were clinicians blinded to treatment allocation. Monitoring    

Central data consistency checks Statistical monitoring On-site monitoring - Hospitals that recruited > 40 or participants and all sites that stood out on statistical monitoring. Random review of participants with and without primary outcome events and independent monitors audited their hospital charts and all other supporting documents.

POISE

Statistical analysis 

Assuming an event rate in the control group of 6% for the primary outcome  8000 patients - 85% power  10 000 patients - 92% power to detect a relative risk reduction of 25% (two-sided α=0·05).



Study was terminated  > 8000 patients  Higher than predicted event rate  Remaining study drug expired in September, 2007.



Both groups were analyzed on an intention-to-treat basis.

Statistical analysis  



All analyses used Cox proportional hazards models. χ² test was used to analyze new clinically significant AFib, cardiac revascularisation, CHF, clinically significant hypotension, and clinically significant bradycardia. Subgroup analyses - Cox proportional hazard models that incorporated tests for interactions, designated to be significant at P<0.05.  Primary subgroup analysis was based on RCRI.  Secondary subgroup analyses was based on sex, type of surgery, and use of an epidural or spinal anaesthetic.

Statistical analysis   

The independent external safety, efficacy, and monitoring committee Two interim analyses were completed (2,500 and 5,000 pt). Thresholds in at least two consecutive analyses > 3 months apart before making a recommendation to consider stopping the trial:   

Primary outcome – 4 S.D. Adverse effect on mortality – 3 S.D. of the HR. α-level for the final analyses remained α=0.05   



Infrequent interim analyses, Extremely low α levels, Requirement for confirmation

Statistical analyses were done with SAS version 9.1 for Unix. Metaanalyses were done with Rev Man version 4.2.

Results

Results

Results

Results

Results Primary outcome

MI

Results

Results Stroke

Death

Results

HR1.94 (CI 1.013.69; P = 0.0450)

Results

Results  Median

length of hospital stay was similar as well as ICU or CCU stay.  At hospital discharge:  Mean

HR (metoprolol vs. placebo)

Metoprolol

 BP

–71.6 + 12 vs. 78.6 + 11.8 bpm; P<0.0001

in mmHg (metoprolol vs. placebo)

129

+ 18.9 / 72 + 11·1 vs. 131.1 + 18.2 / 74.2 + 11.1; P<0·0001 for both SBP and DBP.

Results

RR 1.29, 95% CI 1.02– 1.62; P = 0.03

Discussion

RR 1.29, 95% CI 1.02–1.62; P = 0.03

Discussion  Extended-release

metoprolol –for every 1000 with a similar risk profile undergoing non-cardiac surgery:  Prevent

15 MI  Prevent 4 cardiac revascularization  Prevent 7 clinically significant A Fib.  Cause

excess of 8 deaths,  5 new strokes  53 clinically significant hypotension  42 clinically significant bradycardia for every 1000 treated.

Discussion Number needed to harm (NNH):  For every 15 patients in POISE:  One

had a cardiovascular death  One had a non-fatal MI  One had a non-fatal cardiac arrest  On had a non-fatal stroke at 30-day follow-up.

Discussion  Post-hoc

multivariate analyses – β blockers increased the risk of death:  Clinically

significant hypotension  Bradycardia  Stroke  Sepsis

or infection

 Hypotension

 predisposed to nosocomial infection.  Delay the diagnosis and treatment  Blunted

haemodynamic response  Decreased antibiotics delivery

Devereaux quoted  "If

even only 10% of physicians followed these guidelines —which incidentally in the United States are used in quality assessments, where you have people going around ranking hospitals in terms of whether or not they are giving perioperative beta blockers—and if the POISE data are true, then in the past decade 800,000 people would have died prematurely and 500,000 would have had a major stroke perioperatively…."

Devereaux quoted  “….I

think this is a very similar signal to WHI (Woman's Health Initiative) on [hormone replacement therapy]— at times we are convinced by small trials that something does benefit, but lo and behold, we do a large trial and discover that, rather than preventing, we are causing."

Conclusions  Continue

PBB in patients ALREADY on BB  Benefit from BB is limited to high risk patients  RCRI

>2  Positive stress test undergoing vascular surgery  Early

start of betablocker (7days?, 30 days?)

 Careful

titration to HR 60 – 65 bpm  Continue for 30 days post-operatively.  Use

of long acting BB (B1 selective)  Use smaller doses of BB