Perioperative Beta-Blockers in Non-cardiac Surgery and the POISE

Perioperative Beta-blockers in Perioperative Beta-blockers in non-cardiac surgery and the non-cardiac surgery and the

POISE trial: evidence revisitedPOISE trial: evidence revisited

Moises Auron MD FAAPMoises Auron MD FAAP

Hospital MedicineHospital Medicine

Cleveland ClinicCleveland Clinic

OutlineOutline

IntroductionIntroduction EpidemiologyEpidemiology Pathophysiology of perioperative ischemia and Pathophysiology of perioperative ischemia and

rationale for betablockade userationale for betablockade use Trials supporting use of betablockers.Trials supporting use of betablockers. Trials suggesting no benefit from addition of Trials suggesting no benefit from addition of

betablockersbetablockers POISE TrialPOISE Trial ConclusionsConclusions

IntroductionIntroduction

Increased peri-operative Beta-blocker use Increased peri-operative Beta-blocker use was based on limited evidence in the was based on limited evidence in the 1990’s suggesting a cardio-protective 1990’s suggesting a cardio-protective effect in patients with known or suspected effect in patients with known or suspected CAD.CAD.

Safe practice quality measure: AHRQSafe practice quality measure: AHRQNot supported by recent small trialsNot supported by recent small trials

IntroductionIntroduction

Change in evidence in the beginning of the Change in evidence in the beginning of the centurycenturyPrompted to a more conservative approachPrompted to a more conservative approach2007 AHA/ACC guidelines modified 2007 AHA/ACC guidelines modified

accordinglyaccordinglyPOISE trial – largest placebo-controlledPOISE trial – largest placebo-controlled

Showed deleterious effects from peri-Showed deleterious effects from peri-operative beta-blocker use. operative beta-blocker use.

EpidemiologyEpidemiology

> 20 million surgeries per year in USA> 20 million surgeries per year in USAPeri-operative MI is a major cause of Peri-operative MI is a major cause of

complications and death in patients complications and death in patients undergoing non-cardiac surgeryundergoing non-cardiac surgeryRate of 1 - 5%Rate of 1 - 5%Up to 30% - vascular surgeryUp to 30% - vascular surgeryMortality rate - Mortality rate - up to 60% per eventup to 60% per event

Prolonged hospitalization and increased Prolonged hospitalization and increased cost.cost.

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

EpidemiologyEpidemiology

Autopsy studies of peri-operative MIAutopsy studies of peri-operative MI50 - 90% associated with plaque rupture and 50 - 90% associated with plaque rupture and

thrombusthrombusRemaining cases are associated with Remaining cases are associated with

sustained mismatch in DOsustained mismatch in DO22/VO/VO22

Dawood MM, et al. Int J Cardiol. 1996; 57:37-44.

Cohen MC, Aretz TH. Cardiovasc Pathol. 1999; 8:133-139.

Pathophysiology of perioperative ischemiaPathophysiology of perioperative ischemia

Increased sympathetic toneIncreased sympathetic tone

Increased cathecolamine releaseIncreased cathecolamine release

Increased cortisol Increased cortisol

↑ ↑ Myocardial VOMyocardial VO22

Inflammatory stateInflammatory state

- TNFTNF

- CRPCRP

- IL-1 and IL-6IL-1 and IL-6

- FFAFFA

↑ ↑ Platelet functionPlatelet function

Endothelial dysfunctionEndothelial dysfunction

• AnesthesiaAnesthesia

• Fluid-shifts, anemiaFluid-shifts, anemia

• PainPain

• Increased metabolic demandsIncreased metabolic demands

++

Increased plaque shear stressIncreased plaque shear stress

Plaque rupturePlaque rupture

Tissue ↓OTissue ↓O22

Non – Q MINon – Q MI

Sir James BlackSir James Black

Nobel Prize 1988Nobel Prize 1988 Discovery of Beta-Discovery of Beta-

blockers (Propranolol)blockers (Propranolol)

Protective effects of Protective effects of ββ-blockers-blockers

↓ ↓ HR and contractilityHR and contractility ↓ ↓ VO2VO2 Modulation of β-Modulation of β-

receptorsreceptors ↓ ↓ apoptosis signalingapoptosis signaling ↓ ↓ RAASRAAS Anti-ischemic and Anti-ischemic and

anti-arrhythmic effectanti-arrhythmic effect

Improvement in Improvement in synthesis of myocardial synthesis of myocardial proteinsproteins

Shift from FFA Shift from FFA glucose metabolismglucose metabolism

Peripheral vasodilationPeripheral vasodilation AntioxidantAntioxidant Anti-inflammatoryAnti-inflammatory

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

Evidence supporting BB useEvidence supporting BB use

Mangano, et al. NEJM 1996Mangano, et al. NEJM 1996

N = 200N = 200 San Francisco VASan Francisco VA >> 2 risk factors for CAD (tobacco, hyperlipidemia, 2 risk factors for CAD (tobacco, hyperlipidemia,

HTN, age >65, DM).HTN, age >65, DM). Randomization to receive either atenolol (i.v and Randomization to receive either atenolol (i.v and

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

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

AtenololAtenolol PlaceboPlacebo PP

6 mo6 mo 00 88 < 0.001< 0.001

12 mo12 mo 33 1414 0.0050.005

24 mo24 mo 1010 2121 0.0190.019

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

The overlooked editorialThe overlooked editorial

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

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

Evidence supporting BB use: Evidence supporting BB use: DECREASE trialDECREASE trial

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

Poldermans, et al. NEJM.1999Poldermans, et al. NEJM.1999

N = 112N = 112Vascular surgeryVascular surgeryUNBLINDEDUNBLINDED Initially N = 1351; and 846 had DSE. Initially N = 1351; and 846 had DSE.

173 had positive results on DSE. 173 had positive results on DSE. Fifty-three were already on BB, and 8 had Fifty-three were already on BB, and 8 had

extensive wall-motion abnormalities.extensive wall-motion abnormalities.59 – bisoprolol and 53 – standard care.59 – bisoprolol and 53 – standard care.

Bisoprolol started 7 days before surgeryDose Dose titrated to HR 60x’Continued for 30 days


BisoprololBisoprolol PlaceboPlacebo PP

Cardiac causesCardiac causes 2 (3.4%)2 (3.4%) 9 (17%)9 (17%) 0.0020.002

Non-fatal MINon-fatal MI 00 9 (17%)9 (17%) < 0.001< 0.001

End-pointEnd-point 3.4%3.4% 34%34% < 0.001< 0.001


UnblindedStudy terminated early due to 90% lower Study terminated early due to 90% lower

rate of non-fatal MI and cardiac death at rate of non-fatal MI and cardiac death at 30 days. 30 days.

Intensive post-operative monitoring.Intensive post-operative monitoring.Excluded the absolutely sickest 5% of Excluded the absolutely sickest 5% of

patientspatients


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

Evidence supporting BB use: Evidence supporting BB use: DECREASE trialDECREASE trial

• Regression analysis using Lee index

Boersma, et al. JAMA 2001Boersma, et al. JAMA 2001

It is not a RCTIt is not a RCTDid not find a protective effect of statinsDid not find a protective effect of statinsDid not considered many perioperative Did not considered many perioperative

issues:issues: Intraoperative blood loss and/or transfusionIntraoperative blood loss and/or transfusionLength of surgeryLength of surgeryType of anesthesiaType of anesthesia

Boersma, et al. JAMA 2001Boersma, et al. JAMA 2001

Heart rate control vs. stress testHeart rate control vs. stress test

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

Cardiac stress-testing (n = 386) Cardiac stress-testing (n = 386) No testing. No testing.

Similar incidence of the primary end point as those assigned to testing (1.8%(1.8% vs. 2.3%; [OR] 0.78; 95% [CI] 0.28-2.1; P=0.62). 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 remainingthan the remaining patients (1.3% vs. 5.2%; OR patients (1.3% vs. 5.2%; OR 0.24; 95% CI 0.09 to 0.66; p 0.003).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 High dose BB and rate control in vascular surgeryvascular surgery

Observational cohort studyN = 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/dBisoprolol - 0.330 mg/kg/dMetoprolol 6.670 mg/kg/dCarvedilol 0.417 mg/kg/dPropranolol 10.700 mg/kg/dLabetalol 40.700 mg/kg/d

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

In multivariate analysis,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 High dose BB and rate control in vascular surgeryin vascular surgery

The start of disbeliefThe start of disbelief

BMJ. 2005; 331: 313-321.

Devereaux, et al. BMJ 2005.Devereaux, et al. BMJ 2005.

Metaanalysis of 22 trialsN = 2437


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).


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 recommendationsCurrent recommendations

Circulation. 1999; 100: 1043 – 1049.

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

Retrospective cohort studyRetrospective cohort studyN = 782,969N = 782,96918% received Betablockers in the first 2 18% received Betablockers in the first 2

days. days. Propensity-score matchingPropensity-score matching – compare – compare

differences between groups (BB vs no BB)differences between groups (BB vs no BB)Multivariable logistic modeling – compared Multivariable logistic modeling – compared

mortalitymortality

Lindenauer, NEJM 2005.Lindenauer, NEJM 2005.

Lindenauer, NEJM, 2005. Lindenauer, NEJM, 2005.

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

Abdominal aortic surgery and infrainguinal or Abdominal aortic surgery and infrainguinal or axillofemoral revascularizations.axillofemoral revascularizations.

Double blind RCTDouble blind RCTN = 500 (246 metoprolol; 250 placebo)N = 500 (246 metoprolol; 250 placebo)Start Start metoprolol 2 h pre-op until D/C or until D/C or

maximum maximum 5 days post-op..Primary outcome: post-op 30 days incidence of Primary outcome: post-op 30 days incidence of

non-fatal MI, UA, new CHF, new arrhythmias non-fatal MI, UA, new CHF, new arrhythmias or cardiac death. or cardiac death.

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

MaVS StudyMaVS Study

MaVS StudyMaVS Study

Primary outcome events at 30 daysPrimary outcome events at 30 days Metoprolol: 25 (10.2%)Metoprolol: 25 (10.2%) Placebo: 30 (12.0%) Placebo: 30 (12.0%) P = 0.57 No significant difference at 6 months No significant difference at 6 months (P = 0.81)

Metoprolol Metoprolol Increased risk of complications Increased risk of complications Intraoperative bradycardia 53/246 vs. 19/250 (P = 53/246 vs. 19/250 (P =

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

0.0045)0.0045)

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

POBBLE TrialPOBBLE 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.



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).



Perioperative hypotension (SBP drop > 25%) (SBP drop > 25%) Metoprolol 49/53 ( 49/53 (92%) Placebo (34/44 (77%) (P = 0.0004)Placebo (34/44 (77%) (P = 0.0004)

Bradycardia < 50x < 50x Metoprolol – Metoprolol – 57% Placebo – 14% (P < 0.0001)Placebo – 14% (P < 0.0001)

Inotrope requirement requirement Metoprolol 47/53 (Metoprolol 47/53 (92%) Placebo 28/44 (64%)Placebo 28/44 (64%)


DIPOM (Diabetes Postoperative DIPOM (Diabetes Postoperative Mortality and Morbidity) TrialMortality and Morbidity) Trial

BMJ. 332 (7556):1482-88

DIPOM TrialDIPOM Trial RCT, double blind, placebo controlled RCT, double blind, placebo controlled N = 921 N = 921 DM > 39 y/o > 39 y/o major non-cardiac surgery. . 100 mg metoprolol controlled and extended release or 100 mg metoprolol controlled and extended release or

placebo – 1d before surgery to maximum 8d post-op. placebo – 1d before surgery to maximum 8d post-op. Composite primary outcome measure was time to all Composite primary outcome measure was time to all

cause mortality, acute myocardial infarction, unstable cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure. angina, or congestive heart failure.

Secondary outcome measures were time to all cause Secondary outcome measures were time to all cause mortality, cardiac mortality, and non-fatal cardiac mortality, cardiac mortality, and non-fatal cardiac morbidity. morbidity.

DIPOM TrialDIPOM 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 recommendationsCurrent recommendations

Circulation 2007;116;e418-e499

2007 AHA/ACC Perioperative guidelines2007 AHA/ACC Perioperative guidelines

2007 AHA/ACC Perioperative 2007 AHA/ACC Perioperative guidelinesguidelines

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

2007 AHA/ACC Perioperative guidelines2007 AHA/ACC Perioperative guidelines

Finally…Finally…

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

PeriOperative ISchemic Evaluation

POISEPOISE

First large double-blind RCT with placebo190 hospitals in 23 countries190 hospitals in 23 countriesN = 8351 (intended to be 10,000)N = 8351 (intended to be 10,000)

Metoprolol succinate – 4174Metoprolol succinate – 4174Placebo – 4177Placebo – 4177

Primary endpoint - composite of CV death, - composite of CV death, non-fatal MI, and non-fatal cardiac arrest.non-fatal MI, and non-fatal cardiac arrest.

Analyses were by intention to treat.Analyses were by intention to treat.

Inclusion criteriaInclusion criteria Non-cardiac surgeryNon-cardiac surgery Age Age >> 45 y/o 45 y/o Expected length of hospital stay of at least 24 hExpected length of hospital stay of at least 24 h Any of the following criteria: Any of the following criteria:

CADCAD PVDPVD CVACVA Hospitalisation for CHF within previous 3 yearsHospitalisation for CHF within previous 3 years Undergoing major vascular surgery (except AV shunt, Undergoing major vascular surgery (except AV shunt,

vein stripping procedures, and carotid vein stripping procedures, and carotid endarterectomies)endarterectomies)

Any 3 of 7 risk criteria:Any 3 of 7 risk criteria: Intrathoracic or intraperitoneal surgeryIntrathoracic or intraperitoneal surgeryHistory of CHFHistory of CHFTIA, TIA, DM,DM,Serum creatinine >175 μmol/LSerum creatinine >175 μmol/LAge >70 yearsAge >70 yearsEmergent or urgent surgery.Emergent or urgent surgery.

Inclusion criteriaInclusion criteria

Exclusion criteriaExclusion 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.

POISEPOISE

POISEPOISE Regimen was influenced by practicality Regimen was influenced by practicality

Starting the study drug 2–4 h before surgeryStarting the study drug 2–4 h before surgery Evidence - Evidence - extended-release metoprolol 200 mg daily

had a had a more even reduction in exercise HR and SBPmore even reduction in exercise HR and SBP vs. vs. Atenolol 100 mg dailyAtenolol 100 mg daily

Better anti-anginal effectsBetter anti-anginal effects than metoprolol 100 mg BID. than metoprolol 100 mg BID. Review of confidential blinded safety data on the Review of confidential blinded safety data on the

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

Blomqvist I, Westergren G, Sandberg A, Jonsson UE, Lundborg P. Pharmacokinetics and pharmacodynamics of Blomqvist I, Westergren G, Sandberg A, Jonsson UE, Lundborg P. Pharmacokinetics and pharmacodynamics of controlled-release metoprolol: a comparison with atenolol. controlled-release metoprolol: a comparison with atenolol. Eur J Clin Pharmacol Eur J Clin Pharmacol 1988; 33 (suppl): S19–24.1988; 33 (suppl): S19–24.

Egstrup K, Gundersen T, Harkonen R, Karlsson E, Lundgren B. The antianginal effi cacy and tolerability of controlled-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. release metoprolol once daily: a comparison with conventional metoprolol tablets twice daily. Eur J Clin Pharmacol Eur J Clin Pharmacol 1988; 33 (suppl): S45–49.1988; 33 (suppl): S45–49.

POISEPOISE 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.

POISEPOISE

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).

POISEPOISE

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.

POISEPOISE 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.

POISEPOISE

Statistical analysisStatistical analysis Assuming an event rate in the control group of 6% for the Assuming an event rate in the control group of 6% for the

primary outcomeprimary outcome 8000 patients - 85% power 8000 patients - 85% power 10 000 patients 10 000 patients - 92% power to detect a relative risk - 92% power to detect a relative risk

reduction of 25% (two-sided α=0·05).reduction of 25% (two-sided α=0·05).

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

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

Statistical analysisStatistical analysis All analyses used Cox proportional hazards models.All analyses used Cox proportional hazards models. χ² test was used to analyze new clinically significant χ² test was used to analyze new clinically significant

AFib, cardiac revascularisation, CHF, clinically significant AFib, cardiac revascularisation, CHF, clinically significant hypotension, and clinically significant bradycardia.hypotension, and clinically significant bradycardia.

Subgroup analyses - Cox proportional hazard models - Cox proportional hazard models that incorporated tests for interactions, designated to be that incorporated tests for interactions, designated to be significant at P<0.05.significant at P<0.05. Primary subgroup analysis was based on RCRI.Primary subgroup analysis was based on RCRI. Secondary subgroup analyses was based on sex, Secondary subgroup analyses was based on sex,

type of surgery, and use of an epidural or spinal type of surgery, and use of an epidural or spinal anaesthetic.anaesthetic.

Statistical analysisStatistical 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.

ResultsResults

ResultsResults

Primary outcome MI

ResultsResults

ResultsResults

DeathStroke

ResultsResults

HR1.94 (CI 1.01-3.69; P = 0.0450)

ResultsResults

ResultsResults

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

At hospital discharge:At hospital discharge:Mean HR (metoprolol vs. placebo)Mean HR (metoprolol vs. placebo)

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

BP in mmHg (metoprolol vs. placebo)BP in mmHg (metoprolol vs. placebo)129 129 ++ 18.9 / 72 18.9 / 72 ++ 11·1 11·1 vs. vs. 131.1 131.1 ++ 18.2 / 74.2 18.2 / 74.2 ++ 11.1; 11.1;

P<0·0001 for both SBP and DBP.P<0·0001 for both SBP and DBP.

ResultsResults

RR 1.29, 95% CI 1.02–RR 1.29, 95% CI 1.02–1.62; P = 0.031.62; P = 0.03

DiscussionDiscussion

RR 1.29, 95% RR 1.29, 95% CI 1.02–1.62; CI 1.02–1.62; P = 0.03P = 0.03

DiscussionDiscussion 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.


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

One had a cardiovascular deathOne had a non-fatal MIOne had a non-fatal cardiac arrestOn had a non-fatal stroke at 30-day follow-up.


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 quotedDevereaux quoted

""If even only 10% of physicians followed these guidelines —which incidentally in the United —which incidentally in the United States are used in quality assessments, where States are used in quality assessments, where you have people going around ranking hospitals you have people going around ranking hospitals in terms of whether or not they are giving in terms of whether or not they are giving perioperative beta blockers—and if the POISE perioperative beta blockers—and if the POISE data are true, 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…." "

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

Devereaux quotedDevereaux quoted

ConclusionsConclusions

Continue PBB in patients ALREADY on BBContinue PBB in patients ALREADY on BB Benefit from BB is limited to high risk patientsBenefit from BB is limited to high risk patients

RCRI RCRI >> 2 2 Positive stress test undergoing vascular surgeryPositive stress test undergoing vascular surgery

Early start of betablocker (7days?, 30 days?)Early start of betablocker (7days?, 30 days?) Careful titration to HR 60 – 65 bpmCareful titration to HR 60 – 65 bpm Continue for 30 days post-operatively.Continue for 30 days post-operatively.

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

Perioperative Beta-Blockers in Non-cardiac Surgery and the POISE

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