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Prevention of Periop MI: Where are we now; & where are we going?

Prevention of Periop MI: Where are we now; & where are we going?. H Yang Department of Anesthesiology. Pre-op. Intra-. Post-. n. (%). op (%). op (%). Mangano. 474. 20. 25. 40. NEJM. 1990. Raby. 115. 20. 18. 30. JAMA. 1992. Perioperative Ischemia.

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Prevention of Periop MI: Where are we now; & where are we going?

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

  2. Pre-op Intra- Post- n (%) op (%) op (%) Mangano 474 20 25 40 NEJM 1990 Raby 115 20 18 30 JAMA 1992 Perioperative Ischemia

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

  4. POISE Primary Outcomes 0.08 HR(95%CI)=0.83(0.70-0.99), p=0.035 0.06 0.04 Risk Metoprolol 0.02 Placebo 0.0 0 10 20 30 # at Risk 4177 3915 3873 3853 P 4174 3959 3909 3879 M POISE. Lancet 2008; 371:1839-47

  5. POISE Non-fatal MI 0.08 HR(95%CI)=0.70(0.56-0.86), p=0.0007 0.06 0.04 Risk 0.02 Metoprolol Placebo 0.0 0 10 20 30 Days 4177 3923 3882 3859 P 4174 3976 3922 3889 M POISE. Lancet 2008; 371:1839-47

  6. All Death HR(95%CI)=1.33(1.02-1.74), p=0.032 0.03 0.02 Risk 0.01 Metoprolol Placebo 0.0 0 10 20 30 Days No. at Risk 4177 4116 4091 4069 P 4174 4113 4066 4038 M POISE. Lancet 2008; 371:1839-47

  7. POISE Strokes 0.020 HR(95%CI)=2.17(1.26-3.73), p=0.005 0.015 Metoprolol Placebo 0.010 Risk 0.005 0.0 0 10 20 30 Days No. at Risk 4177 4102 4076 4055 P 4174 4085 4038 4011 M POISE. Lancet 2008; 371:1839-47

  8. Independent Predictors of Periop MI MI = myocardial infarction; bpm = beats per minute; clinically important bleeding (i.e., bleeding that was disabling or required > 2 units of blood) POISE. Lancet 2008; 371:1839-47

  9. Independent postoperative predictors of death Adjusted OR Predictor 95% CI stroke 18.97 9.93-36.25 hypotension 4.97 3.62-6.81 symptomatic MI 3.31 1.78-6.15 asymptomatic MI 3.45 2.20-5.41 bradycardia 2.13 1.37-3.32 bleeding 1.67 1.14-2.44 POISE. Lancet 2008; 371:1839-47

  10. Preoperative predictor HR 95% CI clopidogrel 3.10 1.44-6.66 stroke/TIA 2.80 1.66-4.70 Postoperative predictors bleeding 3.48 1.46-8.30 AFIB 2.19 1.19-4.04 hypotension 2.18 1.07-4.45 Stroke 60 strokes – 49 ischemic, 3 hemorrhagic, 8 uncertain Lancet 2008; 371: 1839–47

  11. Where we are • Certain • Incidence of Periop MI can be reduced with periop β-blockers • Controversial • Beta-blocker increases periop all-cause mortality & CVA • So • 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. Bioavailability of Metoprolol CR • Bioavailability after first pass effect • Metoprolol tartrate (conventional) 78% • Metoprolol succinate (CR) 71% • Metoprolol CR 200 mg = metoprolol 65 mg q12h J Clin Pharmacol 2005; 45:6 - 24

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

  17. Pharmacogenomics • 52 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 alleles • “no relationships between CYP2D6 genotype and dose or clinical effects could be shown” Pharmacogenomics 2009; 9:175 - 84

  18. Pharmacogenomics • 121 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 HR • No association with side effects except cold extremities and sexual dysfunctiion Clin Pharmacol Ther 2005; 78: 378 - 87

  19. Pharmacogenomics Pharmacokinetics Pharmacodynamics

  20. Β-blockers & strokes • Cardiac Insufficiency Bisoprolol Study II (CIBIS II) • Strokes 31 vs 16, p=0.04 • 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. Meta-analyses • 13 RCTs (105,951 patients) comparing β-blockers with other antihypertensives • 7 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 19% lower for β-blockers than for placebo (95% CI 7 – 29%) Lindholm et al. Lancet 2005; 366:1545 - 53

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

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

  24. ARMYDA-ACS • 171 ACS, NSTEMI, statin-naïve patients for angioplasty • Atorvastatin 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 = 0.01 • Mostly driven by reduction in MI: 5% in atorvastatin; 15% in placebo; p = 0.04 JACC 2007; 49(12):1272 - 8

  25. Statins • Kertai 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 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” • 50 atorvastatin: 50 placebo • Cardiac deaths, non-fatal MI, unstable angina, strokes • 4 (8%) atorvastatin: 13 (26%) placebo (p = 0.031) • DECREASE 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 postop • Grop 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 times • Primary 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. DECREASE IV • Bisoprolol & 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; • Results • 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 Ann Surg 2009; 249:921 - 6

  30. Incidence of hospitalized rhabdomyolysis • 252460 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 JAMA 2004; 292:2585-90

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

  32. Prophylaxis with α2 agonists • 1980 – 2002, randomized trials • Comparing preop, intraop, postop 48 hours • Use of clonidine, dexmedetomidine, or mivazerol • Results • 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] Am J Med 2003; 114:742-52

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

  34. Pre-op Intra- Post- (%) op (%) op (%) Perioperative Ischemia n Mangano 474 20 25 40 NEJM 1990 Raby 115 20 18 30 JAMA 1992

  35. 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 death • Nadir Hb – lowest Hb in first 3 days postop • 1:1 Propensity Analysis with matching • 4387 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<0.0001 • Non-BB: RR 2.17; CI 0.97 – 4.86, p=0.0533 Anesthesiology 2010; 112:25 - 33

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

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

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

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

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