1. Department of OUTCOMES RESEARCH

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

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
“Myocardial Injury after Non-cardiac Surgery” = MINS

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%
Peak Troponin (ng/ml)
30-day Mortality (%)
Time to death (days)
<0.01 1 —
0.02 4 13 9
≥0.3 17 6
Population attributable risks: Age – 40%, MINS – 34%, and sepsis – 30%.

8. 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 ( )
CCF
1.0
9.4
10.3 ( )
Stroke
0.4
1.9
4.7 ( )
Death
1.1
9.8
10.1 ( )
Composite
2.4
18.8
9.6 ( )

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 Aspirin ± statins
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 Hypothesis
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 Aspirin Clonidine
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
Placebo
(N=5012)
Age – (years) 69
Male (%) 52 53
Known vascular disease (%) 33
History of PCI (%)
4.7
Similar for clonidine

17. Aspirin, Death & MI

18. POISE-2 Results, Aspirin
Outcome
Aspirin
(4998)
Placebo
(5012) HR
(95% CI) P
1O outcome:
death or nonfatal MI
351 (7.0)
355 (7.1)
0.99 ( )
0.92
Major bleed
229 (4.6)
187 (3.7)
1.23 ( )
0.04
Stroke
16 (0.3)
19 (0.4)
0.84 ( )
0.62
No interaction with clonidine

19. POISE-2 Results, Clonidine%

20. POISE-2, Clonidine Results
Outcome
Clonidine
(5009)
Placebo
(5001) HR
(95% CI) P
Clinically important hypotension
2385 (48)
1854 (37)
1.32 ( )
<0.001
Clinically important bradycardia
600 (12)
403 (8)
1.49 ( )
Stroke
18 (0.4)
17 (0.3)
1.06 ( )
0.87
No interaction with aspirin

21. POISE-2 Conclusions Aspirin Clonidine
Does not prevent death or MI
Increases life-threatening bleeding
Should not be used for MI prophylaxis
Clonidine
Causes clinically important hypotension
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
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 First Co-Primary: Death 155 (4.1) 176 (4.7)
Outcomes
Steroid
N=3755
Placebo
N=3752
RR (95% CI)
p-value
First Co-Primary: Death
155 (4.1)
176 (4.7)
0.88 ( )
0.23
Second Co-Primary: Composite death, MI, stroke, AKI, respiratory failure
908 (24)
869 (23)
1.04 ( )
0.30
New atrial fib (%)
821 (21.9)
846 (22.5)
0.97 ( )
0.53 MI
 500 (13.3)
408 (10.9)
 1.22 ( )
 0.001

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 No known safe prophylaxis
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 OUTCOMES RESEARCH