Department of O UTCOMES R ESEARCH. Perioperative Myocardial Infarction Daniel I. Sessler, M.D. Michael Cudahy Professor and Chair Department.

Department of OUTCOMES RESEARCH

Perioperative Myocardial Infarction

www.or.org

Daniel I. Sessler, M.D.

Michael Cudahy Professor and ChairDepartment of OUTCOMES RESEARCH

Cleveland Clinic

No personal financial interestsrelated to this presentation

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

Causes of Death

Bartels, et al., 2013, Anesthesiology

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?

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

Troponin T Predicts Mortality

“Prognosis define diagnosis”

Even slight troponin elevations predict death•Population attributable risk = 34%

Peak Troponin (ng/ml)

30-day Mortality (%)

Time to death (days)

<0.01 1 —

0.02 4 13

0.03-0.29 9 9

≥0.3 17 6

MINS (Troponin Increase)

Outcome No MINS(n = 13,822), %

MINS(n = 1,194), %

OR (95% CI)

Nonfatal cardiac arrest

0.1 0.8 14.6 (5.7-37.0)

CCF 1.0 9.4 10.3 (8.0-13.4)

Stroke 0.4 1.9 4.7 (2.9-7.6)

Death 1.1 9.8 10.1 (7.8-13.0)

Composite 2.4 18.8 9.6 (8.0-11.5)

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

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

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

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

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)

10,000 Randomized Patients

99.9% complete follow-up

Patient Characteristics, Aspirin

Aspirin(N=4998)

Placebo(N=5012)

Age – (years) 69 69

Male (%) 52 53

Known vascular disease (%)

33 33

History of PCI (%) 4.7 4.7

Similar for clonidine

Aspirin, Death & MI

POISE-2 Results, AspirinOutcome Aspirin

(4998)Placebo(5012)

HR (95% CI)

P

1O outcome:death or nonfatal MI

351 (7.0) 355 (7.1) 0.99 (0.86-1.15)

0.92

Major bleed 229 (4.6) 187 (3.7) 1.23 (1.01-1.49)

0.04

Stroke 16 (0.3) 19 (0.4) 0.84 (0.43-1.64)

0.62

No interaction with clonidine

POISE-2 Results, Clonidine

%

POISE-2, Clonidine Results

Outcome Clonidine(5009)

Placebo(5001)

HR (95% CI)

P

Clinically important hypotension

2385 (48) 1854 (37) 1.32 (1.24-1.40)

<0.001

Clinically important bradycardia

600 (12) 403 (8) 1.49 (1.32-1.69)

<0.001

Stroke 18 (0.4) 17 (0.3) 1.06 (0.54-2.05)

0.87

No interaction with aspirin

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

Association with MAP

Mascha, Anesthesiology, in press

Rare Outcomes: AKI and MI

Walsh, 2013

MAP < 55 mmHg

SIRS Background & DesignBackground•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

SIRS ResultsOutcomes Steroid

N=3755PlaceboN=3752

RR (95% CI) p-value

First Co-Primary: Death

155 (4.1) 176 (4.7)0.88 (0.71-

1.09)0.23

Second Co-Primary: Composite death, MI, stroke, AKI, respiratory failure

908 (24) 869 (23)1.04 (0.96-

1.13)0.30

New atrial fib (%) 821 (21.9) 846 (22.5)0.97 (0.89-

1.06)0.53

MI  500 (13.3) 408 (10.9) 1.22 (1.08-

1.38) 0.001

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

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

Department of OUTCOMES RESEARCH