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Perioperative Beta Blockers in non-cardiac surgery and POISE

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

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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    • 1. Perioperative Beta-blockers in non-cardiac surgery and the POISE trial: evidence revisited Moises Auron MD FAAP Hospital Medicine Cleveland Clinic
    • 2. 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
    • 3. 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
    • 4. 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.
    • 5. 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
    • 6. 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.
    • 7. 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
    • 8. Sir James Black
      • Nobel Prize 1988
      • Discovery of Beta-blockers (Propranolol)
    • 9. 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.
    • 10. Evidence supporting BB use
    • 11. 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).
    • 12. 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 (%)
    • 13.  
    • 14.
      • “ 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
    • 15.
      • 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.
    • 16.  
    • 17. Wallace, A, et al. Anesthesiology. 1998; 88: 7-17.
    • 18. Evidence supporting BB use: DECREASE trial NEJM. 1999; 341(24): 1789-1794
    • 19. 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.
    • 20.
      • Bisoprolol started 7 days before surgery
      • Dose titrated to HR 60x’
      • Continued for 30 days
      Poldermans, et al. NEJM.1999
    • 21. 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
    • 22.
      • 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
    • 23. Evidence supporting BB use: DECREASE trial JAMA. 2001; 285(14): 1865 - 1873
      • Regression analysis using Lee index
    • 24. Boersma, et al. JAMA 2001
    • 25.
      • 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
    • 26.  
    • 27. 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.
    • 28. Feringa HHH, et al. Circulation . 2006;114[suppl I]:I-344 –I-349.
    • 29. 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.
    • 30. 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.
    • 31.
      • 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
    • 32. The start of disbelief BMJ. 2005; 331: 313-321.
    • 33. Devereaux, et al. BMJ 2005.
      • Metaanalysis of 22 trials
      • N = 2437
    • 34. 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).
    • 35. 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
    • 36. Current recommendations Circulation. 1999; 100: 1043 – 1049.
    • 37. N Engl J Med 2005;353: 349-61.
    • 38.
      • 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
    • 39. Lindenauer, NEJM 2005.
    • 40. 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.
    • 41. Yang H, et al. Am Heart J. 2006; 152: 983 – 90.
    • 42.
      • 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.
    • 43. 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)
    • 44. Powell JT, et al. J Vasc Surg 2005;41:602-9.)
    • 45. 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.)
    • 46. 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.)
    • 47. 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.)
    • 48. DIPOM (Diabetes Postoperative Mortality and Morbidity) Trial BMJ. 332 (7556):1482-88
    • 49. 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.
    • 50. 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).
    • 51. Current recommendations Circulation 2007;116;e418-e499
    • 52. 2007 AHA/ACC Perioperative guidelines
    • 53. 2007 AHA/ACC Perioperative guidelines
    • 54.
      • Uses same risk factors as Lee index but considers surgical risk separately
      2007 AHA/ACC Perioperative guidelines
    • 55. Finally… Devereaux PJ, et al. Lancet 2008; 371: 1839 – 47. PeriOperative ISchemic Evaluation
    • 56. 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.
    • 57. 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)
    • 58.
      • 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
    • 59. 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.
    • 60. POISE
    • 61. 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.
    • 62. 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.
    • 63. 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).
    • 64. 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.
    • 65. 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.
    • 66. POISE
    • 67. 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.
    • 68. 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.
    • 69. 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.
    • 70. Results
    • 71. Results
    • 72. Results
    • 73. Results
    • 74. Results Primary outcome MI
    • 75. Results
    • 76. Results Death Stroke
    • 77.  
    • 78. Results HR1.94 (CI 1.01-3.69; P = 0.0450)
    • 79. Results
    • 80. 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.
    • 81. Results
    • 82.  
    • 83. RR 1.29, 95% CI 1.02–1.62; P = 0.03
    • 84. Discussion RR 1.29, 95% CI 1.02–1.62; P = 0.03
    • 85. 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.
    • 86. 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.
    • 87. 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
    • 88. 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;
    • 89.
      • “….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
    • 90. 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

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