DECLARATION OF CONFLICT OF INTEREST

DECLARATION OF CONFLICT OF INTEREST

How to manage antiplatelet treatment in patients with diabetes in acute coronary syndrome Lars Wallentin Professor of Cardiology, Chief Researcher Cardiovascular Science Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden

Disclosures for Lars Wallentin AstraZeneca Boehringer Ingelheim Bristol-Myers Squibb GlaxoSmithKline Schering-Plough Eli Lilly & Co. Research grant Research grant Research grant Research grant Research grant Research grant Regado Biosciences Athera Biotechnologies Evolva Consultancy Consultancy Consultancy

Acute Coronary Syndrome ECG. Troponin. Aspirin + P2Y12 inhib Beta-blocker + Nitrate ACC/AHA/ESC ACS treatment guidelines Persistent ST-segment elevation Primary PCI + GpIIb/IIIa inh Or Thrombolysis High risk + GpIIb/IIIa inh. Cor angio urgent PCI/CABG No persistent ST-elevation + Fonda/LMWH UFH/Bivalirudin Intermediate risk Cor angio 1 7 days Aspirin + P2Y12 inhib + Betablocker + Statin + ACE-inhib Low risk Stress test Pos Neg Aspirin (+ Statin)

Prospective study of glucose metabolism in patients with Acute Myocardial Infarction in Sweden Age < 80 years At hospital discharge At 3 months after discharge 28% 20% 20% 32% Norhammar et al, Lancet 2002; 359: 2140

Diabetes mellitus in IHD 399,006 patients in RIKS-HIA

Prevalence of Diabetes Mellitus in Patients with STEMI According to International Registers Hospitals: RIKS-HIA 67 (85%); BLITZ 296 (87%); NRMI 1432 (19%); EuroHeart 103 in 25 Eur countries; ENACT 390 in 29 Eur countr.

Mortality, % Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS Diabetes Subgroup Analysis 11 TIMI Trials, >62,000 pts 10,613 diabetics (17.1%) 14 STEMI Diabetes No Diabetes UA/STEMI Diabetes No Diabetes 12 10 P<0.0001 STEMI 8 6 4 2 P<0.0001 P<0.0001 P<0.0001 UA/NSTEMI 0 No. at Risk STEMI Diabetes 7156 6508 2947 2653 2118 1610 No diabetes 39421 37136 16685 15274 12276 9351 UA/NSTEMI Diabetes 3457 3313 2923 2339 1317 924 No diabetes 12002 11658 10505 8191 5141 4008 Donahoe SM et al. JAMA. 2007;298:765-75. 0 30 90 180 270 360 Days after ACS

Probability of death One year mortality.45.40.35.30.25.20.15.10.05 Kaplan-Meier 1- survival analysis in all patients Adjusted RR = 1.48 (1.3 1.60); p<0.001 Diabetes n = 4 700 No diabetes n = 19 846 0.00 0 60 120 180 240 300 360 days

1-year mortality (%) in three different age groups of AMI patients. % 40 35 30 25 20 15 10 5 0 5 No Diabetes OR = 2.7 13 OR = 1.8 15 24 24 <65 65-74 >=75 Age (years) Diabetes OR = 1.7 Norhammar et al. European Heart Journal 2003; 24: 838 844 36

Randomised trials N patients Composite endpoint of MI, stroke, and cardiovascular death RR (95% CI) Fibrinolytic ACE-inhibitor Aspirin Clopidogrel 4496 38847 FTTC 3577 5720 4502 42333 2840 9722 HOPE ATC CURE Beta-blocker Statin GPIIb/IIIa 413 5778 20536 1462 5072 MIAMI HPS Epic, Epilog, Epistent Diabetes Yes No 0.4 0.6 0.8 1.0 1.2 Therapy better Therapy worse

Multiple adjusted treatment effects on one year mortality Reperfusion Heparin/Lmwh Aspirin Betablockade Lipidlowering ACE-inhibition Revasc <14 d 0 0.5 1 2.0 OR 0.67 0.69 0.69 0.64 0.50 0.57 0.65 0.52 0.70 0.55 0.90 0.79 0.53 0.60 Diabetes Yes No

Probability of death or MI FRISC II: Diabetes mellitus.30 DM Noninvasive (n=144).25.20.15.10 DM Invasive (n=155) Noninvasive (n=1091).05 Invasive (n=1067) 0.00 0 60 120 180 240 300 360 Lancet 2000; 356: 9-16

Odds/hazard ratio Diabetes as Predictor of Stent Thrombosis at 1 Year in the Era of DES 5 4 OR=2.0 (0.8-4.9) OR=2.8 (1.7-4.3) HR=3.7 (1.7-7.9) HR=2.03 (1.07-3.83) 3 2 1 0 IDDM IDDM Diabetes Diabetes Kuchulakanti et al. Circulation 2006 Urban et al. Circulation 2006 Iakovou et al. JAMA 2005 Daemen et al. Lancet 2007

% 2,0 Stenttrombos i SCAAR 1,5 Diabetes n=7722 1,0 No diabetes n=32730 0,5 0,0 0 1 År 2

CURE: Outcomes With Clopidogrel in Various Subgroups Characteristic Percentage of Patients with Event No. of Patients Clopidogrel + ASA Placebo + ASA Overall 12562 9.3 11.4 Associated MI 3283 11.3 13.7 No associated MI 9279 8.6 10.6 Male sex 7726 9.1 11.9 Female sex 4836 9.5 10.7 65 yr old 6354 5.4 7.6 > 65 yr old 6208 13.3 15.3 ST-segment deviation 6275 11.5 14.3 No ST-segment deviation 6287 7.0 8.6 Enzymes elevated at entry 3176 10.7 13.0 Enzymes not elevated at entry 9386 8.8 10.9 Diabetes 2840 14.2 16.7 No diabetes 9722 7.9 9.9 Low risk 4187 5.1 6.7 Intermediate risk 4185 6.5 9.4 High risk 4184 16.3 18.0 History of revascularization 2246 8.4 14.4 No history of revascularization 10316 9.5 10.7 Revascularization after randomization 4577 11.5 13.9 No revascularization after randomization 7985 8.1 10.0 0.4 0.6 0.8 1.0 1.2 Yusf S et al. N Engl J Med. 2001;345:494-502. Relative Risk (95% CI) Clopidogrel Better Placebo Better

Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach TRITON-TIMI 38 17.0 12.2 0.70 (0.58 0.85) PLATO 16.2 14.1 0.88 (0.76 1.03) CURRENT OASIS 7 5.6 4.9 0.87 (0.66 1.15) (PCI Cohort) 0 0.5 1 1.5 New Drug/Approach Better Standard Clopidogrel Better CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Platelet Inhibition and Patient Outcomes; TRITON- TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction. Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011. In press

TRITON TIMI-38: CV Death/MI/Stroke by Diabetic Status Pras Clop Reduction in Risk No DM 9.2% 10.6% 14% DM No Insulin 11.5% 15.3% 26% DM on Insulin 14.3% 22.2% 37% 0.3 1 2 Prasugrel better Clopidogrel better Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:1626-36.

Endpoint (%) 18 16 14 12 10 8 6 4 2 0 TRITON: Diabetic Subgroup CV Death / MI / Stroke TIMI Major NonCABG Bleeds HR 0.70 P<0.001 NNT = 21 0 30 60 90 180 270 360 450 Days N=3146 Clopidogrel Prasugrel Prasugrel 17.0 12.2 Clopidogrel 2.6 2.5

CV death, MI, or stroke (%) 20 15 PLATO diabetes: Primary composite endpoint Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.88(0.76 1.03) 16.2% 14.1% 10 p for interaction = 0.49 10.2% 8.4% 5 0 Days after randomisation No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.83(0.74 0.93) 0 60 120 180 240 300 360 Primary endpoint benefit with ticagrelor was consistent with the overall PLATO trial results No interaction between diabetes status and treatment was observed (p=0.49) CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. James S, et al. Eur Heart J 2010;31:3006 3016.

All-cause mortality (%) 10 8 6 4 PLATO diabetes: All-cause mortality Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.82(0.66 1.01) p for interaction = 0.66 8.7% 7.0% 5.0% 3.7% 2 0 Days after randomisation CI, confidence interval; HR, hazard ratio. James S, et al. Eur Heart J 2010;31:3006 3016. No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.77(0.65 0.91) 0 60 120 180 240 300 360 All-cause mortality benefit with ticagrelor was consistent with the overall PLATO trial results No interaction between diabetes status and treatment was observed (p=0.66)

Major bleeding (%) 15 PLATO diabetes: Major bleeding 14.8% 14.1% 10 p for interaction = 0.21 10.8% 10.0% 5 Diabetes Ticagrelor (n=2305) Clopidogrel (n=2316) HR (95% CI) = 0.95(0.81 1.12) No diabetes Ticagrelor (n=6928) Clopidogrel (n=6870) HR (95% CI) = 1.08(0.97 1.20) 0 0 60 120 180 240 300 360 Days after randomisation Bleeding occurred with similar frequency in the ticagrelor and clopidogrel groups, independent of diabetes status No interaction between diabetes status and treatment was observed (p=0.21) CI, confidence interval; HR, hazard ratio. James S, et al. Eur Heart J 2010;31:3006 3016.

Conclusions Diabetes mellitus patients with ACS have 1.5-2.7 times higher mortality women <60 years 5 times higher have same or better effect of platelet inhibitors and other ACS treatments might be undertreated with platelet inhibition and other ACS treatments

Treatment of arterial thrombosis Risk for ischemic events Risk for bleeding