Myocardial Injury after Noncardiac Surgery (MINS): What is it and what can we do to help patients suffering this event? PJ Devereaux, MD, PhD

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1 Myocardial Injury after Noncardiac Surgery (MINS): What is it and what can we do to help patients suffering this event? PJ Devereaux, MD, PhD

2 Disclosure Member of research group with policy of not accepting honorariums or other payments from industry for own personal financial gain Accept honorariums/payments from industry to support research endeavors and reimbursement of costs to participate in meetings Based on study questions I originated and grants I wrote I have received grants from Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Roche Diagnostics, Stryker I have participated in advisory boarding meeting GlaxoSmithKline expert panel meeting AstraZeneca

3 Goals Discuss concept of myocardial injury after noncardiac surgery (MINS) Learn about treatment options for MINS Learn about first large how to manage MINS trial MANAGE Trial

4 Magnitude of problem Worldwide >200 million adults annually undergo major noncardiac surgery VISION Study >10% incidence of 30-day major vascular complications Despite magnitude of problem neglected area of research

5 VISION design and methods Prospective, international, cohort study Eligibility criteria >45 yrs undergoing in-hospital noncardiac surgery Sampling method representative sample Participating countries North and South America, Europe, Asia, Africa, Australia Sample size 40,000 patients after first 15,000 patients event rate was >3 X expected switched from 4 th gen Trop T to 5 th gen (hs) Trop T report results related to 4 th generation Trop T

6 Results Recruitment period for 4 th generation Trop T August 2007 to January 2011 Among 15,133 patients included in Trop T analyses median number of troponin measurements 3 (IQR 2-4) 40 patients did not complete 30 day f/u 99.7% with complete 30 day f/u censored on day of last contact

7 Age Baseline clinical variable Age years old years old 75 years old Participants (N=15,133) 7697 (50.9%) 3779 (25.0%) 3657 (24.2%)

8 Impact of troponin elevations after noncardiac surgery on 30 day mortality

9 Timing of death Peak TnT value Median days to death (IQR) 0.02 µg/l 13.5 (8.5-20) µg/l 9.0 (3.5-16) P value >0.30 µg/l 6.5 (1.5-15) 26.6% of patients who died did so after hospital discharge median time from discharge to death was 11.0 days; IQR, days

10 MINS diagnostic criteria Cox regression analysis dependent variable 30-day mortality independent variables preop and surgical variables independently associated with death in 1 st analyses time dependent post op variables (stroke, PE, DVT, pneumonia, sepsis, infection) proposed MINS variables post-op peak TnT 0.04 with clinical feature post-op peak TnT 0.04 with no clinical feature, post-op peak TnT = 0.03, post-op peak TnT =0.02 post-op peak TnT <0.01) Excluded 99 patients for non-ischemic elevated TnT and 13 patients for missing predictor information

11 Cox model based on 15,065 patients and 260 deaths Proposed MINS variables Peak TnT 0.04 with clinical feature Peak TnT 0.04 with no clinical feature Peak TnT = 0.03 Peak TnT = 0.02 Adjusted HR (95% CI) 4.82 ( ) 3.30 ( ) 4.30 ( ) 1.61 ( ) Therefore definition of MINS is TnT 0.03 due to ischemic etiology

12 Preop variables predicting death Age yrs 75 yrs at 30 days after surgery Incidence (%) Adjusted HR (95% CI) PAR (95% CI) 3754 (24.9) 3625 (24.1) 1.62 ( ) 2.66 ( ) 42.1% ( ) Urgent/Emerg Sx 2117 (14.1) 3.58 ( ) 33.3% ( ) Cancer 3993 (26.5) 2.17 ( ) 22.7% ( ) General Sx 3033 (20.1) 1.58 ( ) 15.7% ( ) Hx of COPD 1262 (8.4) 1.79 ( ) 10.8% ( ) Hx of stroke 693 (4.6) 1.72 ( ) 7.5% ( ) Hx of PVD 793 (5.3) 1.89 ( ) 6.9% ( ) Neurosurgery 888 (5.9) 2.03 ( ) 5.6% ( ) Recent high risk CAD 171 (1.1) 2.51 ( ) 4.1% ( )

13 Post-op variables predicting death at 30 days after surgery Incidence (%) Adjusted HR (95% CI) PAR (95% CI) MINS (TnT 0.03) 1200 (8.0) 3.87 ( ) 34.0% ( ) Sepsis 812 (5.4) 7.18 ( ) 30.5% ( ) stroke 81 (0.5) 3.50 ( ) 4.5% ( ) PE 95 (0.6) 6.11 ( ) 3.5% ( )

14 12 month impact of MINS on mortality

15 Should you monitor periop trops? MINS that would probably go undetected without trop monitoring MINS without chest discomfort, other possible symptoms (i.e., arm, neck, or jaw discomfort, shortness of breath), or pulmonary edema 84.2% 9.0% 30-day risk of mortality 3 rd Universal Definition of MI now recommends monitoring troponins after Sx POISE analyses suggest ASA and statins decrease mortality in these patients

16 How are MINS that probably would go undetected managed Medication Preop usage During first 3 days after Sx At discharge from hospital At 30 days post-op ASA 26% 33% 37% 37% Statin 32% 31% 35% 34% ACE-I/ARB 45% 39% 44% 44%

17 Pathophysiology Growing evidence supporting coronary artery thrombosis post-operative environment pro-coagulant, pro-inflammatory, elevated catecholamines Cath study - consecutive PACS patients and randomly selected non-operative ACS patients and stable CAD patients PACS Non-op ACS Stable CAD Outcome n=120 n=120 n=240 Ambrose s II lesions 45% 57% 16% Time to cath 5.5 days 1.3 days Death 15% 4%

18 Short-term impact of antithrombotic on non-op MI Acute NSTEMI RCTs of heparin + ASA vs. ASA alone meta-analysis 2919 patients heparin reduced 7 day risk of death, MI» OR 0.53; 95% CI, Acute STEMI treated with lytic and ASA addition of LMWH vs control meta-analysis 16,943 patients LMWH reduced risk of in hospital» MI - OR 0.72; 95% CI, )» Death - OR, 0.90; 95% CI, 0.80 to 0.99

19 Long-term impact of antithrombotic on non-op MI Warfarin +ASA vs. ASA alone M-A 7836 patients after ACS f/u 3 months to 5 yrs reduction in death, MI, stroke OR, 0.73; 95% CI, increased risk of bleeding OR, 2.32; 95% CI,

20 Rational for dabigatran 110 mg BID Non-inferior to warfarin in preventing thromboembolic events No difference to warfarin in preventing MI Less unstable angina Less bleeding major life-threatening in comparison to warfarin intracranial for MANAGE major and GI in comparison to 150 mg dabigatran

21 Rational for omeprazole in MANAGE Major bleeding after MI increases mortality and major vascular complications 7.6% of MINS patients suffer GI bleed in first 30 days ASA and dabigatran increase risk of gastrointestinal bleeding and dyspepsia Omeprazole reduces risk of GI bleeds and dyspepsia and increases drug compliance

22 MANAGE Trial Primary efficacy objectives In MINS patients, to determine effect of dabigatran versus placebo on risk of major vascular complication omeprazole versus placebo on risk of major upper GI complication

23 Trial design RCT of 3200 MINS patients randomized to dabigatran 110 mg BID or placebo Partial 2X2 factorial design patients not already on PPI (n~1900) randomize to omeprazole 20 mg OD or placebo Blind investigator initiated trial F/U 6-24 months

24 Conclusions Troponin is strong independent predictor of 30-day mortality after noncardiac surgery 3 rd Universal Definition of MI now recommends monitoring troponins after Sx Worldwide 8 million MINS cases annually MANAGE Trial will inform treatment and pathophys Status quo is not acceptable We need your help to conduct MANAGE Trial