1. Pre-op and Post-op Beta Blockers Alla Kotlyanskaya, Pharm.D. Clinical Pharmacist – Critical Care Woodhull Medical Center, Brooklyn, New York Adjunct Professor of Pharmacology College of Nursing Graduate Programs SUNY Downstate College of Nursing And Adjunct Professor of Pharmacotherapy Physician Assistant Program

2. Objectives  Discuss the protective effects of β-blockers in setting of perioperative beta blockade  Present standards of care for use of peri- operative β-blocker therapy  Describe the benefits & limitations of β-blockers in surgical population  Deliver final recommendations on when to use and why to avoid β-blockers in select patients

3. Magnitude of Risks of Non-Cardiac Surgery  NON -cardiac surgery  risk of CARDIAC mortality  Adverse outcomes of post-op myocardial infarction (MI)   LOS & healthcare costs  Results in 15 - 25% of all in-hospital mortality   Cardiac death or non-fatal MI in next 6 months

4. Why is Non-Cardiac Surgery Associated with Cardiac Complications  100 million have non-cardiac surgery each year  Huge at-risk population  1 million suffer perioperative cardiac event  huge burden of disease  Frequently silent  Few interventions proven to lower risk

5. Barriers Surrounding a Silent Myocardial Infarction  Frequency of silent MI  Chest pain (14%)  Single symptom or sign (50%)  Numerous explanations for under-diagnosis  Opioids administration for surgical pain  Residual effect of anesthesia  Other reasons for  BP,  HR, SOB, N&V  Different pathophysiology of perioperative MI?

6. Pathophysiology PMI TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting InflammationHypercoagulabilityStress stateHypoxic state Plaque Rupture Plaque Rupture Coronary thrombosis  O2 demand  O2 delivery Myocardial ischemia

7. Initial Risk Assessment  In 1977 Goldman et al developed a preoperative cardiac risk index  9 Individual risk factors and their scores  Risk Index:  Class I = 0-5 points (low)  Class II = 6-12 points (intermediate)  Class III = 13-25 pts (high)  Class IV  25 pts (very high) Risk FactorScore 3 rd Heart sound (S3) 11 Elevated JV pressure 11 MI in past 6 months 10 ECG: premature atrial contractions or any rhythm other than sinus 7 ECG shows >5 premature ventricular contractions per minute 7 Age >70 years 5 Emergency Procedure 4 Intra-thoracic, intra- abdominal or aortic surgery 3 Poor general status, metabolic or bedridden 3 N Engl J Med 1977;297:845-850

8. Goldman Cardiac Risk Index Risk of Death and Major Cardiac Complications Based on the Goldman Index Class CLASS I1.3% CLASS II4.7% CLASS III15.3% CLASS IV56% N Engl J Med 1977;297:845-850

9. Cardiac Risk Stratification Proposals  Goldman: 1977  Detsky: 1986  Eagle: 1989  Lee:1999

10. ACC/AHA Guidelines Am Coll Cardiol. 2007 Oct 23;50(17):e159-241. Risk stratification according to major, intermediate or minor clinical predictors

11. Surgery ACC/AHA Guideline Summary : Major Clinical Predictors Acute or recent MI (7-30 d) Unstable coronary syndrome Decompensated CHF Significant Arrhythmias Severe Valvular Disease High Risk: Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.

12. ACC/AHA Guideline Summary : Clinical Risk Factors 3 or more risk factors & Vascular surgery History of heart disease Compensated or prior CHF Cerebrovascular disease Diabetes Mellitus Renal Insufficiency Proceed Cautiously With: Consider testing 1 – 2 risk factors Proceed with surgery or consider testing Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.

13. ACC/AHA Guideline Summary : Minor Clinical Predictors Reasonable to proceed with surgery Low risk surgery Good functional capacity No cardiac symptoms No “active cardiac conditions” No clinical risk factors Low Risk: Am Coll Cardiol. 2007 Oct 23;50(17):e159-241.

14. Functional Capacity  Determined by how much physical activity a patient can tolerate without severe exertion  Provides valuable prognostic information  Patients with good functional status have a lower risk of complications

15. How to stratify itHow to modify it ß BlockerOther New Agents Perioperative MI

16. The Evolution of ß -Blockers 1960s1970s1980s-1990s2007 Non-SelectiveNon-Selective Vasodilating Vasodilating Non- Selective Non- Selective Propranolol Atenolol Metroprolol Carvedilol Labetalol Nebivolol

17. Protective Effect of β-Blockers  Decrease sympathetic CNS outflow  ↓ Heart rate and ↓ contractility  ↓ Myocardial oxygen demand  Membrane stabilizing effect  Antiarrhythmic property  Anti-renin/antgiotensin properties  Inhibit renin release  Anti-inflammatory effect  Possible ↑ plaque stability * Schouten O et al. Cardiovascular Anesthesia 2007 ; 104(1):8-10. Cruickshank JM. European Heart Journal 2000 ; 21:354-364. Ohtsuka T et al. J Am Coll Cardiol 2001 ; 37(2):412-417. *With long-term use

18. Protective Effect of  -blockers Against Cardiac Events During and After Surgery TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting InflammationHypercoagulabilityStress stateHypoxic state Plaque Rupture Plaque Rupture Coronary thrombosis  O2 demand  O2 delivery Myocardial ischemia PMI

19. Protective Effect of  -blockers Against Cardiac Events During and After Surgery TRIGGERS: surgery, anaesthesia, analgesia, intubation, extubation, pain, hypothermia, bleeding, anaemia, fasting Stress state Plaque Rupture Coronary thrombosis  O2  demand Myocardial ischemia PMI  Catechols/cortisol Coronary artery shear stress  HR, BP, FFAs

20. Reducing Myocardial Ischemia  Avoid tachycardia & hypertension  Avoid hypotension  Avoid pain  Avoid hypercoagulation  Avoid vasospasm  Avoid tissue injury

21. Does Perioperative Beta Blockade Work? Perioperative β-Blockers 1995 to 2005  Mangano et al. at 1996 1  Atenolol study  Poldermans et al. at 1999 2  DECREASE trial Perioperative β -blockers 2005–2008  Yang et al. at 2006 4  MaVS study  Juul et al. at 2006 5  DiPoM trial

22. Effect of Atenolol on Mortality and Cardiovascular Morbidity After Noncardiac Surgery Mangano DT, Layug EL, Wallace A, et al. N Engl J Med. 1996; 335: 1713-1720

23. Mangano Trial: Overview  Randomized, double-blind, placebo-controlled trial  200 patients included VA (Veterans’ Admin) patients with >= 2 risk factors for CAD  Age >65 y/o  Total cholesterol >240 mg/dL  Hypertension  Diabetes mellitus  Current smoking  Surgeries were:  Major vascular (~40%)  “Intraabdominal” (~20%)  Neurosurgery, general, plastic surgery and head and neck surgery

24. Mangano Trial: Study Design Surgery PO Atenolol 50 mg Patients were followed over the subsequent two years IV Atenolol 5 mg Placebo BeforeAfter Placebo For the Duration of Hospitalization N Engl J Med. 1996; 335: 1713-1720

25. Mangano Trial: Postoperative Mortality Reduction Number of death during Follow up N Engl J Med. 1996; 335: 1713-1720

26. The Effect of Bisoprolol on Perioperative Mortality and Myocardial Infarction in High-risk Patients Undergoing Vascular Surgery Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group Poldermans D, Boersma E, Bax JJ, et al. N Engl J Med 1999; 341:1789–1794

27. The DECREASE Trial : Overview  European, multicentered, unblinded RCT  112 high risk patients undergoing major vascular surgery were randomized to  Bisoprolol 5mg orally (min. of 7 days before surgery) (n = 59)  Standard care (n = 53)  The study was stopped early

28. The DECREASE Trial: Postoperative Cardiac Events Poldermans et al. NEJM 1999;341:1789.

29. “ “There are still very few RCTs … and they do not provide enough data from which to draw firm conclusions. Current studies, however, suggest that …  -blockers reduce perioperative ischaemia, and may reduce the risk of MI and death in high-risk patients” RECOMMENDATIONS Class I 1. Beta-blockers required in the recent past to control symptoms of angina or patients with symptomatic arrhythmias or hypertension 2. Beta-blockers: patients at high cardiac risk owing to the finding of ischemia on preoperative testing who are undergoing vascular surgery Eagle KA, et.al. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery: executive summary. J Am Coll Cardiol. 2002;39:542–553

30.  22 RCTs published between 1980 and 2004  Median sample size: 61patients (total = 2437)  Variety of patients and surgeries  Treatment duration: 1 dose  30 days  Length of follow-up: PACU discharge  30 days  Overall quality of trials was acceptable  4 trials inadequate blinding  2 trials stopped early  1 trial inadequate randomization concealment

31. Devereaux et al.: Metaanalysis Results Relative risks for major perioperative cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal cardiac arrest)

32. Devereaux et al.: Metaanalysis Results Relative risks for bradycardia needing treatment

33. Devereaux et al.: Metaanalysis Conclusion  Growing evidence suggests BB may reduce the risk of major perioperative cardiovascular events  However, increases the risk of bradycardia and hypotension requiring treatment  Evidence indicates that more further studies are needed

34. Perioperative β -blockers 2005 – 2007 StudyPatients and ProtocolFindings Yang et al 2006 (MaVS study)  496 vascular surgery patients  Metoprolol begun immediately before surgery, continued through to discharge  No impact on in-hospital cardiac events or deaths  Cardiac events in patients given β-blockers vs patients given placebo: at 6 months, 0% vs 8%, P< 0.001; at 2 years, 10% vs 21%, P< 0.019 Juul et al 2006 (DiPoM trial)  921 patients with diabetes who were undergoing major noncardiac surgery  100 mg metoprolol controlled and ER or placebo administered from the day before surgery to a maximum of 8 perioperative days  All-cause deaths, cardiac deaths, and major cardiac events at 30 days in patients given –blockers vs patients given placebo:  21% vs 20%, P = NS

35. Does Perioperative Beta Blockade Increase Risk ? Perioperative -blockade (POBBLE) for patients undergoing infrarenal vascular surgery: Results of a randomized double-blind controlled trial. POBBLE Trial Investigators, London, United Kingdom Brady AR, et.al. J Vasc Surg 2005; 41:602–609

36.  Double-blind randomized placebo-controlled trial  Included low risk patients  Treatment  Metoprolol 50 mg PO BID or placebo ( from admission until 7 days after surgery)  Primary endpoint  30 day cumulative risk of cardiac death, non-fatal MI, unstable angina, VT or stroke  Patient group (n = 103 [stopped early]) POBBLE Trial Overview Brady AR, et.al. J Vasc Surg 2005; 41:602–609

37. Control (n = 48) Treatment (n = 55) P value Cardiac Events15 (34%)17 (32%)0.57 Heart rate (4 hr after)77 ± 1565 ± 100.0001 Bradycardia7 (14%)31 (57%)0.0001 Hypotension34 (77%)49 (92%)0.0001 POBBLE Trial Results and Conclusion OR (CV event or death) = 0.93 (95% CI: 0.53-1.64) This trial indicates that in lower-risk patients, perioperative β-blockade does not reduce cardiovascular mortality BUT may have adverse intraoperative effects Brady AR, et.al. J Vasc Surg 2005; 41:602–609

38. RECOMMENDATIONS Class I 1.Beta blockers should be continued in patients undergoing surgery who are previously receiving beta blockers to treat angina, symptomatic arrhythmias, hypertension, or other ACC/AHA class I guideline indications. ( Level of Evidence: C ) 2.Beta blockers should be given to patients undergoing vascular surgery who are at high cardiac risk owing to the finding of ischemia on preoperative testing. Fleisher LA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary. Anesth Analg 2008;106:685–712.

39. Perioperative Beta Blockade After Another heated debate about the pros and cons of using beta blockers perioperatively in noncardiac surgery

40.  RCT of metoprolol versus placebo (30 d)  Non-cardiac surgery  With or at risk of IHD  Sample size  10,000 patients  Primary outcome  30 day cumulative risk of cardiac death, nonfatal MI and non-fatal cardiac arrest Devereaux PJ,et al. Am J Heart 2006; 152: 223-30

41. 8,351 Patients Recruited 3548 1506 406 886 191 sites 23 countries 2005

42. Trial Flow Diagram 8351 randomized 4174 allocated to metoprolol CR 8 lost to follow-up 4177 allocated to matching placebo 12 lost to follow-up 99.8% complete 30 day follow-up and include in intention-to-treat analysis

43. Criteria (%)Metoprolol (n = 4174) Placebo (n = 4177) Coronary artery disease43.342.7 Peripheral vascular disease41.540.3 Stroke14.915.4 Chronic heart failure admission2.72.6 Major vascular surgery35.735.6 Three of 7 risk factors18.318.8 82% of participants had atherosclerotic disease Risk Criteria

44. Primary Outcome Metoprolol (n = 4174) Placebo (n = 4177) HR (95% CI) P value Primary outcome 243 (5.8%) 290 (6.9%) 0.83 (0.70-0.99) 0.04 Non-fatal MI* 151 (3.6%) 215 (5.1%) 0.70 (0.56-0.86) 0.0007 68% of MIs were asymptomatic

45. Secondary Outcomes  60 strokes reported  49 ischemic, 3 hemorrhagic and 8 uncertain  Of non-fatal strokes  59 % patients in the metoprolol group required help to perform daily activities OutcomeMetoprolol (n = 4174) Placebo (n = 4177) HR (95% CI) P value Total mortality129 (3.1%) 97 (2.3%) 1.33 (1.02-1.74) 0.03 Significant hypotension 626 (15.0%) 404 (9.7%) 1.55 (1.38-1.74) <0.0001 Significant bradycardia 274 (6.6%) 101 (2.4%) 2.71 (2.17-3.39) <0.0001 Stroke41 (1.0%) 19 (0.5%) 2.17 (1.26-3.73) 0.005

46. Predictors of Stroke Predictor of strokeHR (95% CI) Bleeding3.48 (1.46-8.30) Clopidogrel3.10 (1.44-6.66) Prior stroke/TIA2.80 (1.66-4.70) Atrial fibrillation2.19 (1.19-4.04) Hypotension2.18 (1.07-4.45)

47. OutcomeMetoprolol (n = 4174) Placebo (n = 4177) HR (95% CI) P value Revascularisation11 (0.3%) 27 (0.6%) 0.41 (0.20-0.82) 0.01 Atrial fibrillation91 (2.2%) 120 (2.9%) 0.76 (0.59-0.99) 0.04 Congestive heart failure 132 (3.2%) 116 (2.8%) 1.14 (0.89-1.45) 0.30 More Secondary Outcomes

48. After the POISE Study  For every 1,000 patients treated, metoprolol would prevent  15 MIs  7 cases of new onset AF  3 post-op CABGs  …. And there would be  8 excess deaths  5 excess strokes  53 patients with significant hypotension  No effect on total mortality

49.  Continue β-blockers in patients who are on them already  Start β -blockers perioperatively only in patients who need lifelong β-blocker therapy  Coronary ischemia who are undergoing vascular surgery  Starting β-blockers immediately before surgery may be harmful  Start β-blockers as early before surgery as possible  7 - 30 days before procedure After the POISE Study … Cont’d

50.  After surgery focus shifts to continuing β-blockers appropriately  Assess for infection, pain, hypovolemia, or bleeding  If discontinuing β-blockers  Titrate  Restart as soon as unstable issues are resolved After the POISE Study … Cont’d

51. Conclusion  The data suggests that Beta Blockers are beneficial in patients with major cardiac risk  Beta Blockers associated with severe bradycardia and hypotension leading to stroke and death  Patients with low cardiac risk may exhibit a higher risk/benefit ratio  Intermediate risk patient need to undergo for further work up