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Perioperative Beta Blockers in non-cardiac surgery and POISE

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Information about Perioperative Beta Blockers in non-cardiac surgery and POISE

Published on January 31, 2009

Author: mauron

Source: slideshare.net

Description

Review of the evidence that supported the use of Beta-blockers in the peri-operative setting and the data from the POISE trial.
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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

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

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 peri-operative beta-blocker use.

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 peri-operative 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 hospitalization and increased cost. Poldermans. NEJM. 353(4): 412 - 414. Auerbach. AHRQ. http://www.ahrq.gov/clinic/ptsafety/chap25.htm

> 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 hospitalization and increased cost.

Epidemiology Autopsy studies of peri-operative MI 50 - 90% associated with plaque rupture and thrombus Remaining cases are associated with sustained mismatch in DO 2 /VO 2 Dawood MM, et al. Int J Cardiol. 1996; 57:37-44. Cohen MC, Aretz TH. Cardiovasc Pathol. 1999; 8:133-139.

Autopsy studies of peri-operative MI

50 - 90% associated with plaque rupture and thrombus

Remaining cases are associated with sustained mismatch in DO 2 /VO 2

Pathophysiology of perioperative ischemia Increased sympathetic tone Increased cathecolamine release Increased cortisol ↑ Myocardial VO 2 Inflammatory state TNF CRP IL-1 and IL-6 FFA ↑ Platelet function Endothelial dysfunction Anesthesia Fluid-shifts, anemia Pain Increased metabolic demands + Increased plaque shear stress Plaque rupture Tissue ↓O 2 Non – Q MI

Inflammatory state

TNF

CRP

IL-1 and IL-6

FFA

↑ Platelet function

Anesthesia

Fluid-shifts, anemia

Pain

Increased metabolic demands

Sir James Black Nobel Prize 1988 Discovery of Beta-blockers (Propranolol)

Nobel Prize 1988

Discovery of Beta-blockers (Propranolol)

Protective effects of β -blockers ↓ HR and contractility ↓ VO2 Modulation of β-receptors ↓ 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.

↓ HR and contractility

↓ VO2

Modulation of β-receptors

↓ 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

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).

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 Atenolol 10 3 0 0.019 21 24 mo 0.005 14 12 mo < 0.001 8 6 mo P Placebo All cause death (%)

 

“ Whether one should routinely give beta-blockers 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 .” The overlooked editorial Eagle KA, Froehlich JB. NEJM. 1996; 335(23): 1761-1763

“ Whether one should routinely give beta-blockers 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 .”

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.

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.

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.

Bisoprolol started 7 days before surgery Dose titrated to HR 60x’ Continued for 30 days 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 P Placebo Bisoprolol < 0.001 34% 3.4% End-point < 0.001 9 (17%) 0 Non-fatal MI 0.002 9 (17%) 2 (3.4%) Cardiac causes

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 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 JAMA. 2001; 285(14): 1865 - 1873 Regression analysis using Lee index

Regression analysis using Lee index

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 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.

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).

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.

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

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.

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

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). 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 of 22 trials N = 2437

Metaanalysis of 22 trials

N = 2437

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).

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. 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 meta-analysis assessing the effect of POBB on 30 day risk of major perioperative CV events in patients having non-cardiac surgery. Cumulative evidence is inconclusive

Current recommendations Circulation. 1999; 100: 1043 – 1049.

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

Retrospective cohort study N = 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

Retrospective cohort study

N = 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.

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.

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

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.

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)

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.)

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.

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.)

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%)

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.

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).

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

Uses same risk factors as Lee index but considers surgical risk separately 2007 AHA/ACC Perioperative guidelines

Uses same risk factors as Lee index but considers surgical risk separately

Finally… Devereaux PJ, et al. Lancet 2008; 371: 1839 – 47. PeriOperative ISchemic Evaluation

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.

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)

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)

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. 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 2 nd or 3 rd 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.

Heart rate < 50 bpm

2 nd or 3 rd 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 controlled-release metoprolol once daily: a comparison with conventional metoprolol tablets twice daily. Eur J Clin Pharmacol 1988; 33 (suppl): S45–49.

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).

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.

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).

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 post-op.

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 post-op.

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.

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.

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.

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. Meta-analyses were done with Rev Man version 4.2.

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. Meta-analyses were done with Rev Man version 4.2.

Results

Results

Results

Results

Results Primary outcome MI

Results

Results Death Stroke

 

Results HR1.94 (CI 1.01-3.69; 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 –71.6 + 12 vs. 78.6 + 11.8 bpm; P<0.0001 BP 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.

Median length of hospital stay was similar as well as ICU or CCU stay.

At hospital discharge:

Mean HR (metoprolol vs. placebo)

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

BP 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.

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.

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

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 &quot; 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…. &quot;

&quot; 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…. &quot;

“….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 .&quot; 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 .&quot;

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

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

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