Canadian Cardiovascular Society Antiplatelet Guidelines USE OF ANTIPLATELET

Canadian Cardiovascular Society Antiplatelet Guidelines USE OF ANTIPLATELET THERAPY IN PATIENTS WITH DIABETES Working Group: Maria E. Wolfs, MD, FRCP; Rmi Rabasa-Lhoret, MD, PhD Leadership. Knowledge. Community. Objectives Interpret the Canadian Cardiovascular Society Guideline recommendations regarding the use of antiplatelet therapy in patients with diabetes. Appropriately use antiplatelet agents for primary and secondary vascular prevention. Recognize the difference in the effect of antiplatelet agents in patients with and without diabetes. Evaluate the evidence regarding the use of antiplatelet agents in patients with diabetes. 2011 - TIGC

Case A 65 year old man suffering from type 2 diabetes for 15 years Currently taking ramipril 10 mg OD, rosuvastatin 20 mg OD and metformin 500 mg TID He has no history of CAD, CVD or PAD. The physical examination is unremarkable. He is concerned about not taking any ASA. 2011 - TIGC Antiplatelet management What antiplatelet therapy, if any, would you suggest ? A. No antiplatelet therapy B. ASA 80 mg

C. Clopidogrel 75 mg D. ASA 80 mg + Clopidogrel 75 mg 2011 - TIGC Mechanisms contributing to platelet dysfunction In patients with diabetes mellitus HYPERGLYCAEMIA Increased P-selectin expression ASSOCIATED METABOLIC CONDITIONS DEFICIENT INSULIN

ACTION Impaired response to NO and PGI2 Osmotic effect Decreased membrane fluidity by glycation of surface proteins PLATELET Obesity IRS-dependent factors: Increased intracellular Ca++ degranulation Activation of PKC OTHER CELLULAR

ABNORMALITIES Dyslipidemia ENDOTHELIAL DYSFUNCTION Increased platelet turnover Inflammation Increased intracellular Ca++ Upregulation of P2Y12 signalling Oxydative stress H2O PKC IRS-1

Ca++ Increased P-selectin and GP expression P2Y 12 AD P ROS/NOS Increased production of TF Decreased NO and PGI2 production TF

NO PGI2 Endothelial cells Ferreiro JL, Angiolllo DJ. Circulation 2011; 123: 798-813 A Roussin Diabetes in primary prevention Antiplatelet agents The proportion of diabetic patients in primary prevention studies is SMALL. PPP: 17% HOT: 8% PHS: 2% BMD: 2%

TPT: 2% < 20 % Hayden M et al. U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:161-172 Diabetes inprimary prevention: Antiplatelet agents Antithrombotic Trialists Collaboration 2002 % odds reduction 7% Much of the new information comes from the early treatment diabetic retinopathy study, in which 3711 people with diabetes (and, generally, no history of myocardial infarction or stroke) were allocated to receive 650 mg aspirin dailyor placebo. BMJ 2002, vol 24: 71-86 A Roussin

Early treatment diabetic retinopathy Study report 14 CAD baseline: 8% ETDRS Investigators. JAMA 1992; 268: 1292-1300 2011 - TIGC ASA and diabetes: 2008 JPAD 2011 - TIGC Ogawa H et al. JAMA 2008 (300) 18; 2134-2141 ASA and diabetes: 2008 JPAD: Baseline clinical characteristics Ogawa H et al. JAMA 2008 (300) 18; 2134-2141

2011 - TIGC ASA and diabetes: 2008 JPAD: Primary end point Ogawa H et al. JAMA 2008 (300) 18; 2134-2141 2011 - TIGC ASA and diabetes: 2008 JPAD: Secondary end point Ogawa H et al. JAMA 2008 (300) 18; 2134-2141 2011 - TIGC ASA and diabetes: 2008 JPAD: Primary end point if 65 years or older Ogawa H et al. JAMA 2008 (300) 18; 2134-2141

2011 - TIGC ASA and diabetes: 2008 JPAD: Subgroup analysis Ogawa H et al. JAMA 2008 (300) 18; 2134-2141 2011 - TIGC ASA and diabetes: 2008 POPADAD (with PAD) Belch J et al. BMJ 2008 2011 - TIGC ASA and diabetes: 2008 POPADAD (with PAD) Belch J et al. BMJ 2008

2011 - TIGC Asymptomatic PAD and diabetes ASA ineffective (but ABI 0.9) POPADAD Belch J et al. BMJ 2008 2011 - TIGC Meta-analysis in primary prevention 2009 ASA and diabetes De Berardis G et al. BMJ 2009; 399 2011 - TIGC Meta-analysis in primary prevention 2009 ASA and diabetes: Studies, dose and Tx duration De Berardis G et al. BMJ 2009; 399

Meta-analysis in primary prevention 2009 ASA and diabetes: Major CV events De Berardis G et al. BMJ 2009; 399 De Berardis G et al. BMJ 2009; 399 2011 - TIGC Meta-analysis in primary prevention 2009 ASA and diabetes: MI De Berardis G et al. BMJ 2009; 399 2011 - TIGC Meta-analysis in primary prevention 2009 ASA and diabetes: Stroke 2011 - TIGC De Berardis G et al. BMJ 2009; 399

Meta-analysis in primary prevention 2009 ASA and diabetes: CV death De Berardis G et al. BMJ 2009; 399 2011 - TIGC Meta-analysis in primary prevention 2009 ASA and diabetes: Total mortality De Berardis G et al. BMJ 2009; 399 2011 - TIGC ASA and primary prevention Comparison diabetics and non-diabetics Calvin AD et al. Diabetes Care 2009; 32: 2300-6 2011 - TIGC

26 Antiplatelet therapy in patients with diabetes Primary prevention 1. There is currently no evidence to recommend routine use of ASA at any dose for the primary prevention of vascular ischemic events in patients with diabetes (Class III, Level A). 2. For patients with diabetes aged more than 40 years and at low risk for major bleeding, low-dose ASA (75-162 mg daily) may be considered for primary prevention in patients with other cardiovascular risk factors for which its benefits are established (Class IIb, Level B). Antiplatelet therapy in patients with diabetes Primary prevention

27 Case A 65 year old man suffering from type 2 diabetes for 15 years is currently taking ramipril 10 mg OD, rosuvastatin 20 mg OD and metformin 500 mg TID. He has no history of CAD, CVD or PAD. The physical examination is unremarkable. He is concerned about not taking any ASA. 2011 - TIGC Antiplatelet management What antiplatelet therapy, if any, would you suggest ? A. No antiplatelet therapy B. ASA 80 mg

C. Clopidogrel 75 mg D. ASA 80 mg + Clopidogrel 75 mg 2011 - TIGC Diabetes and Secondary Prevention: CAPRIE 1996 Clopidogrel and ASA to reduce MI, IS and VD/ yr High-risk Population ASA Event rate % Clopidogrel RRR (%)

ARR (%) NNT Total CAPRIE population 5.83 8.7 0.51 196 Patients with PAD 4.86 23.8 1.15

87 Patients with multivascular territory involvement 10.74 22.7 2.39 42 Patients with a history of more than one ischemic event NA NA

NA NA Patients with diabetes NA NA NA NA Patients with previous CABG 9.1 36 3.3

30 Patients taking lipid-lowering agents NA NA NA NA A Roussin Diabetes and secondary prevention: CAPRIE 1996 Reduction MI, IS, VD and Hosp for isch or bleeding events/yr ASA High-risk Population

Event rate % Clopidogrel RRR (%) ARR (%) NNT Total CAPRIE population 13.67 8.1 1.1 90 Patients with PAD

NA NA NA NA Patients with multivascular territory involvement NA NA NA NA Patients with a history of more

than one ischemic event 36.5 / 3yr 10.7 3.9 26 Patients with diabetes 17.7 11.8 2.1 48 Patients with previous CABG

22.3 28.7 6.4 16 Patients taking lipid-lowering agents 14.6 18.5 2.7 37 A Roussin

Clopidogrel vs ASA in secondary prevention CAPRIE: Diabetic patient subgroup Annual event rate (%) ASA Clopidogrel Events prevented / 1000 pts/yr over aspirin 25 21 20 9 15

17,7 % p = 0.032 38 21,5 % 17,7 % 15,6 % 10 12,7 % 11,8 % 5 0 non-diabetic

All diabetics With insulin Events : MI, IS, VD, hospitalization for ischemic event / bleeding Bhatt et al. AJC 2002 Sep 15;90(6):625-8 A Roussin CHARISMA 2006: Clopidogrel + ASA vs ASA only Primary endpoint (MI, IS and VD) by subgroups Characteristic Hazard Ratio and 95% CI Diabetes Yes No Hypertension

Yes No Hypercholesterolemia Yes No History of CABG Yes No History of PCI Yes No History of MI Yes No History of Stroke Yes No RF Only (Asymptomatic) Documented AT (Symptomatic) RF= Risk Factors AT= Atherothrombosis

0.5 1 Clopidogrel Better Placebo Better Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press. 1.5 A Roussin Antiplatelet therapy in patients with diabetes Secondary prevention 3. Low-dose ASA therapy (75-162 mg daily) may be considered for secondary prevention in patients with diabetes and manifest vascular disease for which its benefits are established (Class I,

Level A). 4. Clopidogrel 75 mg daily may be considered for secondary prevention in patients with diabetes who are unable to tolerate ASA (Class IIa, Level B). 34 Antiplatelet therapy in patients with diabetes Secondary prevention 35 What if ACS The same 65 year old man comes back to your office after a hospitalization for ACS with two coated stents implanted. He is mixed up about his antiplatelet regimen and understands that ASA is important.

How would that change your choice of antiplatelet therapy? 2011 - TIGC KaplanMeier curves for prasugrel versus clopidogrel Patients with DM vs no DM from the TRITON-TIMI 38 trial No DM DM No DM TIMI Major Bleeding Primary End Point DM A Roussin KaplanMeier curves for

prasugrel versus clopidogrel Patients with diabetes mellitus from the TRITON-TIMI 38 trial 18 18 End Point Point (%) (%) End 16 16 14 14 n=3,146 n=3,146 Primary Primary Efficacy Efficacy End

End Point Point Clopidogrel Clopidogrel 17.0 17.0 HR HR 0.70; 0.70; p<0.001 p<0.001 12.2 12.2 12 12 Prasugrel Prasugrel

10 10 88 66 44 22 00 Timi Timi Major Major Non-CABG Non-CABG Bleeds Bleeds Clopidogrel Clopidogrel Prasugrel Prasugrel 00 30

30 60 60 90 90 270 270 180 180 360 360 2.6 2.6 2.5 2.5 450 450 Days

Wiviott SD et al. Circulation 2008;118(16):162636 A Roussin PLATO (ticagrelor vs. clopidogrel) Diabetes substudy primary end point 2011 - TIGC James S et al. European Heart Journal 2010 A Roussin PLATO (ticagrelor vs. clopidogrel) Diabetes substudy Total mortality James S et al. European Heart Journal 2010 2011 - TIGC

PLATO (ticagrelor vs. clopidogrel) Diabetes substudy Major bleeding James S et al. European Heart Journal 2010 2011 - TIGC PLATO (ticagrelor vs. clopidogrel) Diabetes substudy Primary end point according to baseline HbA1c James S et al. European Heart Journal 2010 2011 - TIGC PLATO (ticagrelor vs. clopidogrel) Diabetes substudy

Major bleeding according to baseline HbA1c James S et al. European Heart Journal 2010 2011 - TIGC Efficacy of Antiplatelet Therapies in ACS Results in the Diabetes Mellitus Subgroups (Adapted from Ferreiro JL et al. Circulation 2011; 123: 798-813) Study # pts Regimen 12 562 ASA+CL VS ASA 2 658 ASA+CL VS ASA

CREDO 2 116 ASA+CL VS ASA COMMI T 45 852 Cure PCICURE CLARIT Y PCICLARIT Y

Primary endpoint Results overall CV death, non fatal MI, stroke at 1 yr 9.3 vs 11.4% RR= 0.80 Cv death, MI or urgent TVR at 30 days 4.5 vs 6.4% RR= 0.70 Death, MI or stroke at

1 yr ASA+CL VS ASA 3 491 ASA+CL VS ASA 1 863 ASA+CL VS ASA # pts DM Results in DM

2 840 14.2 vs 16.7% RR=0.84 ns 504 12.9 vs 16.5% RR=0.77 ns 8.5 vs 11.5% RRR=26.9% 560 % NA

RRR=11.2% ns Death, reinfarct or stroke at discharge or 28 days 9.2 vs 10.1% OR=0.91 NA NA Occluded infarctrelated artery on angiography or death or recurrent MI before angiography 15 vs

21.7% OR=0.64 575 NA CV death, recurrent MI or stroke at 30 days 3.6 vs 6.2% OR=0.54 282 6 vs 10.1% OR=0.61 ns A Roussin Ongoing Studies

ASCEND and ACCEPT - D ASCEND UK ASA 100 mg and Omega-3 Randomized double blind for 5 years 10,000+ patients > 40 yrs ACCEPT D Italy ASA 100 mg + simvastatine 20-40 mg Randomized open for 5 years 5170 patients > 50 yrs 2011 - TIGC 2011 - TIGC