Department of O UTCOMES R ESEARCH

1. Department of OUTCOMESRESEARCH

2. Daniel I. Sessler, M.D. Michael Cudahy Professor and Chair Department of OUTCOMES RESEARCH Cleveland Clinic No personal financial interests related to this presentation Perioperative Myocardial Infarction www.or.org

3. Perioperative Mortality • Intraoperative mortality rare • Thirty-day postoperative mortality • 1% nationwide in United States • 2% worldwide for inpatients ≥45 years old • 80% during initial hospitalization • Mostly cardiovascular or consequent

4. Causes of Death Bartels, et al., 2013, Anesthesiology

5. Postoperative MIs are Common • ≈230 million non-cardiac operations / year • MI incidence 8% among inpatients >45 years • ≈10 million postoperative infarctions per year • Nearly all non-ST segment elevation • Plaque rupture? • Supply-demand mismatch? • Thrombus? • Postoperative MI poorly understood • Etiology? • Prediction? • Prevention? (today’s focus) • Treatment?

6. Silent and Deadly • Most MIs only detected by troponin • Only 15% report chest pain • 65% entirely asymptomatic • Mortality identical after apparent & silent MIs • It’s not just “troponitis” • Mortality is 10% at 30 days • Twice as high as non-operative infarctions • Different? • Unrecognized? • Untreated? VISION: Devereaux JAMA 2012 and Botto, Anesthesiology 2014

7. Troponin T Predicts Mortality • “Prognosis define diagnosis” • Even slight troponin elevations predict death • Population attributable risk = 34%

8. MINS (Troponin Increase)

9. Universal Definition of MI* • “Most patients who have a perioperative MI will not experience ischemic symptoms. Nevertheless, asymptomatic perioperative MI is as strongly associated with 30-day mortality as symptomatic MI. Routine monitoring of cardiac biomarkers in high-risk patients … after major surgery is therefore recommended.” *Thygeson, Circulation 2012

10. Elevated Troponin? • Cardiology consult • Some patients need catheterization ± angioplasty • Discussion of risk • Aspirin ± statins • Heart rate and hypertension control • Lifestyle • Smoking cessation • Reasonable diet • Exercise

11. ENIGMA-2 • Background • N2O increases plasma homocysteine • N2O impairs endothelial function • Hypothesis • N2O increases 30-day death or major CV events • MI required troponin elevation & clinical event • Randomized trial in 7,000 high-risk patients • 70% nitrous oxide • 70% nitrogen Myles, Lancet, 2014

13. POISE-2 Background • Surgery • Inflammatory response activates platelets • Promotes tachycardia • Aspirin • Impairs platelet aggregation • Prevents non-operative primary & secondary MI • Clonidine • Moderates central sympathetic activation • Heart rate control • Less hypotension than beta blockers • Analgesic Devereaux, NEJM (2 papers) 2014

14. POISE-2 Design • Inpatients >45 years at cardiovascular risk • Blinded 2 X 2 factorial trial • Aspirin 100 mg/day vs. placebo for 7 or 30 days • Clonidine 75 µg/day vs. placebo for 72 hours • Primary outcome • Death or MI within 30 days • MI required troponin elevation and clinical events • Safety outcomes • Life-threatening bleeding (i.e., required reoperation) • Clinically important hypotension (syst < 90 mmHg & Rx) • Clinically important bradycardia (HR <55/min & Rx)

15. 10,000 Randomized Patients 99.9% complete follow-up

16. Patient Characteristics, Aspirin Similar for clonidine

17. Aspirin, Death & MI

18. POISE-2 Results, Aspirin No interaction with clonidine

19. POISE-2 Results, Clonidine %

20. POISE-2, Clonidine Results No interaction with aspirin

21. POISE-2 Conclusions • Aspirin • Does not prevent death or MI • Increases life-threatening bleeding • Should not be used for MI prophylaxis • Clonidine • Does not prevent death or MI • Causes clinically important hypotension • Should not be used for MI prophylaxis • A safe and effective way to prevent perioperative myocardial infarctions remains unknown

22. Association with MAP Mascha, Anesthesiology, in press

23. Rare Outcomes: AKI and MI MAP < 55 mmHg Walsh, 2013

24. SIRS Background & Design • Background • In-hospital mortality after cardiac surgery ≈5% • Inflammation believed to contribute • Small studies suggest that steroids help • Patients • 7,500, high-risk cardiac surgery (Euroscore ≥6) • Surgery with bypass • Intervention • 500 mg methylprednisilone vs. placebo, N=7,500 • Major outcomes • 30-day mortality • Myocardial infarction • Atrial fibrillation Whitlock, in review

25. SIRS Results

26. SIRS Conclusions • Methylprednisolone in high-risk cardiac surgery • Does not reduce death • Does not reduce composite major morbidity • Does not reduce atrial fibrillation • Steroids increase perioperative MI by 20% • Do not use prophylactic methylprednisolone

27. Summary • MI after non-cardiac surgery • Common, mostly silent, and deadly • No known safe prophylaxis • Beta blockers work, but cause strokes • Nitrous oxide has no effect • Aspirin: no benefit and increased bleeding • Clonidine: no benefit and hypotension • Consider keeping MAP >55 mmHg

28. Department of OUTCOMESRESEARCH