1. Prevention of Periop MI: Where are we now; & where are we going? H Yang Department of Anesthesiology

2. Perioperative Ischemia n Pre-op (%) Intra- op (%) Post- op (%) Mangano NEJM 1990 474202540 Raby JAMA 1992 115201830

3. POISE. Lancet 2008; 371:1839-47 POISE Primary Outcome Events

4. POISE. Lancet 2008; 371:1839-47 Risk 0.0 0.02 0.04 0.06 0.08 0102030 HR(95%CI)=0.83(0.70-0.99), p=0.035 4177391538733853 4174395939093879 # at Risk M P Metoprolol Placebo POISE Primary Outcomes

5. POISE. Lancet 2008; 371:1839-47 0.0 0.02 0.04 0.06 0.08 0102030 Days Metoprolol Placebo HR(95%CI)=0.70(0.56-0.86), p=0.0007 4177392338823859 4174397639223889 M P POISE Non-fatal MI Risk

6. POISE. Lancet 2008; 371:1839-47 All Death Risk 0.0 0.01 0.02 0.03 0102030 Days Metoprolol Placebo HR(95%CI)=1.33(1.02-1.74), p=0.032 4177411640914069 4174411340664038 No. at Risk M P

7. POISE. Lancet 2008; 371:1839-47 Risk 0.0 0.005 0.010 0.015 0.020 0102030 Days Metoprolol Placebo HR(95%CI)=2.17(1.26-3.73), p=0.005 4177410240764055 4174408540384011 No. at Risk M P POISE Strokes

8. POISE. Lancet 2008; 371:1839-47 Independent Predictors of Periop MI Independent predictorAssociation with perioperative MI Adjusted Odds Ratio (95% confidence interval) Every 10 bpm increase in baseline heart rate1.29 (1.13-1.50) Prior history of stroke2.24 (1.20-4.20) Undergoing major vascular surgery2.21 (1.15-4.25) Preoperative serum creatinine >175  mol/L (> 2.0 mg/dl) 4.33 (2.32-8.09) Age per deciles increase1.53 (1.20-1.95) emergent/urgent surgery2.94 (1.65-5.26) clinically important bleeding3.62 (2.07-6.36) MI = myocardial infarction; bpm = beats per minute; clinically important bleeding (i.e., bleeding that was disabling or required > 2 units of blood)

9. POISE. Lancet 2008; 371:1839-47 2.20-5.413.45 asymptomatic MI 1.78-6.153.31 symptomatic MI 9.93-36.2518.97stroke 1.14-2.441.67bleeding 1.37-3.322.13 bradycardia 3.62-6.814.97hypotension 95% CI Adjusted OR Predictor Independent postoperative predictors of death

10. Lancet 2008; 371: 1839–47 1.19-4.042.19AFIB 1.44-6.663.10clopidogrel 1.07-4.452.18hypotension 1.46-8.303.48bleeding Postoperative predictors 1.66-4.702.80stroke/TIA 95% CI HR Preoperative predictor 60 strokes – 49 ischemic, 3 hemorrhagic, 8 uncertain Stroke

11. Where we are CertainCertain –Incidence of Periop MI can be reduced with periop β- blockers ControversialControversial –Beta-blocker increases periop all-cause mortality & CVA SoSo –Is it a problem with POISE –Is it the question of the right magic pill –Is there something else going on; i.e. postop

12. J Clin Pharmacol 2005; 45:6 - 24 Bioavailability of Metoprolol CR Bioavailability after first pass effectBioavailability after first pass effect –Metoprolol tartrate (conventional) 78% –Metoprolol succinate (CR) 71% Metoprolol CR 200 mgMetoprolol CR 200 mg = metoprolol 65 mg q12h

13. J Clin Pharmcol 2005; 45:6 - 24

14. J Clin Pharm Ther 1997; 22:171-9

15. J Cardiac Failure 2001; 7:311 - 7

16. Clin Pharmacol Ther 2004; 76:536 – 44 CYP2D6 genotypeCYP2D6 genotype –Impacts on cytochrome P450 & metoprolol metabolism 50 HBP patients - No correlation between genotypes and BP or adverse effects50 HBP patients - No correlation between genotypes and BP or adverse effects Pharmacogenomics

17. Pharmacogenomics 2009; 9:175 - 84 Pharmacogenomics 52 patients: 27 – 2 functional alleles; 22 – 1 function allel; 3 no functional allele52 patients: 27 – 2 functional alleles; 22 – 1 function allel; 3 no functional allele Median dose-adjusted S-metoprolol concentrations 6.3 & 3.2 X higher in 0 or 1 versus 2 functional allelesMedian dose-adjusted S-metoprolol concentrations 6.3 & 3.2 X higher in 0 or 1 versus 2 functional alleles “no relationships between CYP2D6 genotype and dose or clinical effects could be shown”“no relationships between CYP2D6 genotype and dose or clinical effects could be shown”

18. Clin Pharmacol Ther 2005; 78: 378 - 87 Pharmacogenomics 121 patients enrolled in prospective 6-week multi- center study on metoprolol121 patients enrolled in prospective 6-week multi- center study on metoprolol –5 ultra-rapid CYP2D6 metabolizers; 91 extensive metabolizers; 21 intermediate metabolizers; 4 poor metabolizers –UMs 0.0088 ng/mL, EMS 0.047 ng/mL, IMs 0.34 ng/mL, and PMs 1.34 ng/mL (P <.0001) No association with BP or HRNo association with BP or HR No association with side effects except cold extremities and sexual dysfunctiionNo association with side effects except cold extremities and sexual dysfunctiion

19. Pharmacogenomics Pharmacokinetics Pharmacodynamics

20. Β-blockers & strokes Cardiac Insufficiency Bisoprolol Study II (CIBIS II)Cardiac Insufficiency Bisoprolol Study II (CIBIS II) –Strokes 31 vs 16, p=0.04 Nordic Diltiazem Trial (NORDIL)Nordic Diltiazem Trial (NORDIL) –Diltiazem vs diuretics + β-blockers for HBP –Fatal & non-fatal strokes 159 vs 196 (6.4 vs 7.9 events per 1000 patient-years, 0.80 [0.65 – 0.99], p=0.04)

21. Lindholm et al. Lancet 2005; 366:1545 - 53 Meta-analyses 13 RCTs (105,951 patients) comparing β-blockers with other antihypertensives13 RCTs (105,951 patients) comparing β-blockers with other antihypertensives 7 RCTs (27,443 patients) comparing β-blockers with placebo7 RCTs (27,443 patients) comparing β-blockers with placebo Strokes RR 16% higher for β-blockers than for other drugs (95% CI 4 – 30%)Strokes RR 16% higher for β-blockers than for other drugs (95% CI 4 – 30%) Strokes RR 19% lower for β-blockers than for placebo (95% CI 7 – 29%)Strokes RR 19% lower for β-blockers than for placebo (95% CI 7 – 29%)

22. Where we are going Other candidates for prophylaxisOther candidates for prophylaxis –Statins –Alpha-2 agonists –ASA

23. Statins: Magical CancerCancer Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells J Endocrinol. 2011/04/08 ePub Airway inflammationAirway inflammation Inhibition of Inflammatory Mediators: Role of Statins in Airway Inflammation Otolaryngol.Head Neck Surg. 2011/04/05 ePub AsthmaAsthma Statins in the Treatment of Acute Ischemic Stroke Curr.Pharm.Biotechnol. 2011/04/06 ePub

24. JACC 2007; 49(12):1272 - 8 ARMYDA-ACS 171 ACS, NSTEMI, statin-naïve patients for angioplasty171 ACS, NSTEMI, statin-naïve patients for angioplasty Atorvastatin 80 mg 12 hrs before & 40 mg 2 hrs before PCI versus placeboAtorvastatin 80 mg 12 hrs before & 40 mg 2 hrs before PCI versus placebo RR reduction of MACE of 88%: 5% in atorvastatin; 17% in placebo; p = 0.01RR reduction of MACE of 88%: 5% in atorvastatin; 17% in placebo; p = 0.01 Mostly driven by reduction in MI: 5% in atorvastatin; 15% in placebo; p = 0.04Mostly driven by reduction in MI: 5% in atorvastatin; 15% in placebo; p = 0.04

25. Statins Kertai et alKertai et al –Database cohort study –570 patients for AAA 1991 – 2001 –30-day mortality or MI in 51 (8.9%) patients –O.R. 0.24 (0.11 – 0.54) Poldermans et alPoldermans et al –Case-controlled study –2816 vascular patients 1991 – 2000 –Case subjects 160 (5.8%) mortality –Control subjects 2 : 1 –O.R. 0.22 (0.10 – 0.47)

26. Statins “Reduction in Cardiovascular Events after vascular surgery with Atorvastatin: a randomized trial”“Reduction in Cardiovascular Events after vascular surgery with Atorvastatin: a randomized trial” –50 atorvastatin: 50 placebo –Cardiac deaths, non-fatal MI, unstable angina, strokes 4 (8%) atorvastatin: 13 (26%) placebo (p = 0.031)4 (8%) atorvastatin: 13 (26%) placebo (p = 0.031) DECREASE IIIDECREASE III –250:247 fluvastatin vs placebo + β-blockers –Myocardial Ischemia: 27/250 (10.8%) fluvastatin vs 47/247 (10.9%) placebo –CV death: 4/250 (1.6%) fluvastatin vs 8/247 (3.2%) placebo –MI: 8/250 (3.2%) fluvastatin vs 17/247 (6.9%) placebo

27. Atorvastatin & Postop CRP Group AAA (n=26): atorvastatin 7 days before, the day of, and for 7 days postopGroup AAA (n=26): atorvastatin 7 days before, the day of, and for 7 days postop Grop PAA (n=17): placebo for 7 days before, atorvastatin on the day of Sx, & for 7 days postopGrop PAA (n=17): placebo for 7 days before, atorvastatin on the day of Sx, & for 7 days postop Grooup PPP (n=17): placebo at all timesGrooup PPP (n=17): placebo at all times Primary Outcome: C-reactive Protein (CRP) levels at 48 hoursPrimary Outcome: C-reactive Protein (CRP) levels at 48 hours Neilipovitz et al. The Ottawa Hospital

28. Atorvastatin & CRP Neilipovitz et al. The Ottawa Hospital

29. Ann Surg 2009; 249:921 - 6 DECREASE IV Bisoprolol & fluvastatinBisoprolol & fluvastatin –2 X 2 open label factorial design –1066 intermediate risk scheduled for non-cardiovascular Sx –264 bisoprolol; 265 fluvastatin; 269 combined Rx; 268 to double control; ResultsResults –Bisoprolol lower incidnce of MI or cardiac death, 2.1% vs 6.0%, p = 0.002 –Fluvastatin lower incidence, 3.2% vs 4.9%, p = 0.17

30. JAMA 2004; 292:2585-90 Incidence of hospitalized rhabdomyolysis 252460 patients treated with lipid lowering drugs252460 patients treated with lipid lowering drugs –Prevastatin, simvastatin, atorvastatin 0.44 per 100000 –Cerivastatin 5.34 per 100000 –Fibrate 2.82 per 100000 –Combined prevastatin or simvastatin or atorvastatin with fibrate 5.98 per 100000 –Combined cerivastatin with fibrate 1035 per 100000 –Per year of Rx, NNT to see 1 case of rhabdomyolysis is 22727 with statin monotherapy

32. NEJM 1988; 318(1):47 - 8

33. Am J Med 2003; 114:742-52 Prophylaxis with α2 agonists 1980 – 2002, randomized trials1980 – 2002, randomized trials Comparing preop, intraop, postop 48 hoursComparing preop, intraop, postop 48 hours Use of clonidine, dexmedetomidine, or mivazerolUse of clonidine, dexmedetomidine, or mivazerol ResultsResults –23 trials included –Mortality RR 0.64 [0.42 – 0.99, p=0.05] –Myocardial ischemia RR 0.76 [0.63 – 0.91, p = 0.003]

34. POISE. Lancet 2008; 371:1839-47

35. Perioperative Ischemia n Pre-op (%) Intra- op (%) Post- op (%) Mangano NEJM 1990 474202540 Raby JAMA 1992 115201830

36. Anesthesiology 2010; 112:25 - 33 Acute Surgical Anemia Influences the Cardioprotective Effects of β-Blockade Retrospective Review of Records between Mar 2005 – Jun 2006, 1° outcomes: MI, non-fatal CA, in-hospital deathRetrospective Review of Records between Mar 2005 – Jun 2006, 1° outcomes: MI, non-fatal CA, in-hospital death Nadir Hb – lowest Hb in first 3 days postopNadir Hb – lowest Hb in first 3 days postop 1:1 Propensity Analysis with matching1:1 Propensity Analysis with matching 4387 patients with nadir Hb4387 patients with nadir Hb –1153 (26%) received β-blockers (BB) within 24 hr postop –Propensity matching in 827 –Major cardiac event 54 (6.5%) in BB & 25 (3.0%) in non-BB (RR 2.38; CI 1.43 – 3.96, p = 0.0009) –Hb drop > 35% BB: RR 3.5; CI 1.8 – 5.5, p<0.0001BB: RR 3.5; CI 1.8 – 5.5, p<0.0001 Non-BB: RR 2.17; CI 0.97 – 4.86, p=0.0533Non-BB: RR 2.17; CI 0.97 – 4.86, p=0.0533

37. Anesthesiology 2009; 111(5): 988-1001

38. NEJM 1999; 340:409 - 17 A MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL OF TRANSFUSION REQUIREMENTS IN CRITICAL CARE (TRICC) Transfusion strategiesTransfusion strategies Equivalency TrialEquivalency Trial 416 liberal strategy (100 g/L); 413 restrictive strategy (70 g/L)416 liberal strategy (100 g/L); 413 restrictive strategy (70 g/L) 30-day mortality 18.7 vs 23.3%, p=0.1130-day mortality 18.7 vs 23.3%, p=0.11 In-hospital mortality 22.2 vs 28.1%, p=0.05In-hospital mortality 22.2 vs 28.1%, p=0.05 Restrictive strategy much more prevalent since the TRICC trialRestrictive strategy much more prevalent since the TRICC trial

39. Criticial Care Medicine 2007; 35(6):1509-16 Subgroup Analysis of TRICC

40. Summary High RiskHigh Risk –Prophylactic β-blockers to reduce MI –Keep up Hb “Unfinished Symphony”“Unfinished Symphony” –Statins –Alpha-2 agonists –ASA Postop CarePostop Care –Hypotension –Bleeding –Others?