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 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
 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
• Pain Increased cathecolamine release

• Increased metabolic demands

Increased cortisol

Inflammatory state
- TNF ↑ Myocardial VO2
- 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 Beta-
blockers (Propranolol)
 Protective effects of β-blockers
↓ HR and contractility  Improvement in
 ↓ VO2 synthesis of myocardial
 Modulation of β- proteins
 Shift from FFA 
receptors
 ↓ apoptosis signaling glucose metabolism
 Peripheral vasodilation
 ↓ RAAS
 Antioxidant
 Anti-ischemic and
 Anti-inflammatory
anti-arrhythmic effect
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 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.”

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

Bisoprolol Placebo P
Cardiac causes 2 (3.4%) 9 (17%) 0.002
Non-fatal MI 0 9 (17%) < 0.001
End-point 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
 Itis not a RCT
 Did not find a protective effect of statins
 Did not considered many perioperative
issues:
 Intraoperativeblood 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 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).
 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 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.
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%)
 Metoprolol49/53 (92%)
(
 Placebo (34/44 (77%) (P = 0.0004)

 Bradycardia < 50x

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

 Inotrope requirement
 Metoprolol47/53 (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
 Firstlarge double-blind RCT with placebo
 190 hospitals in 23 countries
 N = 8351 (intended to be 10,000)
 Metoprololsuccinate – 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:
 Intrathoracicor 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
 Startingthe 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.
 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
 Ifunable 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.
 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. Meta-
analyses were done with Rev Man version 4.2.
Results
Results
Results
Results
 Results
Primary outcome MI
Results
 Results
Stroke Death
Results

HR1.94 (CI 1.01-

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.
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-hocmultivariate 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
 Bluntedhaemodynamic response
 Decreased antibiotics delivery
 Devereaux quoted
 "Ifeven 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
 “….Ithink 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?)

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

 Use of long acting BB (B1 selective)

 Use smaller doses of BB