8th Platelet Colloquium dddd8th Platelet Colloquium The Diabetic Patient and the Optimal Antiplatelet Therapy Dominick J. Angiolillo, MD, PhD Director of Cardiovascular Research Associate Professor of Medicine

Dominick J. Angiolillo, MD, PhD Honoraria/Lectures: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., Advisory Board: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Merck, Evolva Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, Astra Zeneca, Johnson&Johnson, Bristol Myers Squibb, Sanofi-Aventis

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%) STEMI UA/STEMI Diabetes Diabetes No Diabetes No Diabetes 14 12 10 P<0.0001 STEMI 8 P<0.0001 Mortality, % 6 P<0.0001 UA/NSTEMI 4 2 P<0.0001 0 30 90 180 270 360 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 Days after ACS Donahoe SM et al. JAMA. 2007;298:765-75.

Mechanisms Involved in Platelet Dysfunction in Diabetes Mellitus Hyperglycemia Deficient Insulin Action Associated Metabolic Conditions Other Cellular Abnormalities Increased P-selectin expression Impaired response to NO and PGI2 Platelet Endothelial Dysfunction Osmotic effect Obesity IRS-dependent factors: Increased intracellular Ca++ Degranulation Activation of PKC Dyslipidemia Decreased membrane fluidity by glycation of surface proteins Inflammation Increased platelet turnover Increased intracellular Ca++ Upregulation of P2Y12 signaling Oxidative stress H2O Increased P-selectin and GP expression Increased production of TF Decreased NO and PGI2 production Endothelial Cells ACP=adenosine disphosphate; GP=glycoprotein; IRS-1=insulin receptor substrate-1; NO=nitric oxide; PGI2=prostacyclin; PKC= protein kinase C; TF=tissue factor. Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011 123:798-813.

Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Acute Phase of Treatment Long-term Phase of Treatment 80 P=0.002 DM No-DM P<0.0001 P=0.04 60 8% 38% 14% Platelet aggregation (%) 56% 40 78% 6% 24 hrs post 300 mg LD 20 Non-responders (Platelet inhibition <10%) Low responders (Platelet inhibition 10-29%) DM No DM DM No DM ADP 20M ADP 6M Responders (Platelet inhibition >30%) Angiolillo DJ et al. Diabetes. 2005;54:2430-5. Angiolillo DJ et al. J Am Coll Cardiol. 2006;48:298-304.

Overcoming suboptimal antiplatelet drug response in diabetic patients Play smarter with what we have Adding other agents with antiplatelet properties Use new drugs

Overcoming suboptimal antiplatelet drug response in diabetic patients Play smarter with what we have Adding other agents with antiplatelet properties Use new drugs

Pathways of oxidative stress associated with diabetes mellitus Increased Turnover Tackling the DM platelet: 1) oxidative stress 2) Give aspirin bid Ferroni P et al. J Thromb Haemost 2004

Influence of intensive insulin treatment Urinary 11-dehydro-TXB2 nmol/day NS P < 0.01 Before Tight Unsuccessful Metabolic Control Davì G et al, NEJM 1990; 322: 1769-74

Schematic of circadian release of platelets into bloodstream from bone marrow and impact of a single daily dose of aspirin on newly generated platelets in type 2 DM Capodanno D et al. Circ Cardiovasc Interv. 2011;4:180-7.

Impact of once vs twice daily aspirin dosing on platelet reactivity LTA –collagen (2mg/mL) VerifyNow ASA P = 0.02 P = 0.02 P = 0.006 P = NS P = 0.046 P = NS Capodanno D et al. Circ Cardiovasc Interv. 2011;4:180-7.

OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus) Impact of high clopidogrel maintenance dosing on platelet function in DM patients with suboptimal clopidogrel response VerifyNow P2Y12 substudy %IPA PRU 20 40 60 80 75 mg 150 mg Platelet inhibition (%) p=0.009 P2Y12 Reactivity Units 50 100 150 200 250 300 p=0.007 Only ~40% of patients reach therapeutic target! Angiolillo DJ et al. Circulation. 2007;115:708-16. Angiolillo DJ et al. Am J Cardiol. 2008;101:440-5.

Overcoming suboptimal antiplatelet drug response in diabetic patients Play smarter with what we have Adding other agents with antiplatelet properties Use new drugs

Upregulation of P2Y12 receptor signaling in type 2 diabetes mellitus Clopidogrel ATP ADP 15% active metabolite HOOC * HS N O Cl OCH3 N S O Cl CH3 C P2X1 P2Y1 Gastro-intestinal absorption Gq G12 “Rho” Ca2+ flux PIP2 Shape change P2Y12 Shape change PLCβ + Gi IP3 DAG Hepatic CYP Biotransformation PKC αi βγ Ca2+ mobilization MLCK-P AC PI3K 85% inactive metabolites (Esterases in blood) GP IIb/IIIa receptor activation Granule secretion PKB/Akt Rap1b Cilostazol GP IIb/IIIa receptor activation PDE-III Initiation of Platelet Aggregation cAMP Stabilization of Platelet Aggregation VASP VASP-P AC Gs PGE1 cAMP GP IIb/IIIa receptor activation Angiolillo DJ et al JACC 2007

OPTIMUS-2: p=0.002 p=0.0001 PRU P2Y12 inhibtion Impact of adjunctive treatment with cilostazol in Diabetes Mellitus patients on aspirin and clopidogrel VerifyNow P2Y12 assay PRU P2Y12 inhibtion p=0.002 p=0.0001 CILOSTAZOL PLACEBO CILOSTAZOL PLACEBO Angiolillo DJ et al. Eur Heart Journal 2008; 29:2202-11

P2Y12 Reactivity Index (PRI) Impact of adjunctive treatment with cilostazol according to Diabetes Mellitus status in patients on aspirin and clopidogrel P2Y12 Reactivity Index (PRI) * p between  = 0.039 p<0.0001 p<0.0001  = 23.1*  = 15.0* Angiolillo DJ et al. Thromb Haemost. 2011 May 26;106(2). [Epub ahead of print]

Triple versus Dual Antiplatelet Therapy Role for cilostazol in addition to aspirin and clopidogrel? Stent thrombosis @ 30 days (Lee SW et al JACC 2006) Triple therapy vs dual therapy 9/1597 (0.5%) vs 1/1415 (0.1%) p=0.024 DECLARE-DIABETES: Triple therapy significantly reduced late loss at 6 months after DES implantation and the occurrence of TLR and MACE at 9 months in patients with Diabetes (Lee SW et al JACC 2008)

Overcoming suboptimal antiplatelet drug response in diabetic patients Play smarter with what we have Adding other agents with antiplatelet properties Use new drugs

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) 0.5 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. 123:798-813.

Diabetic Subgroup N=3146 Clopidogrel CV Death / MI / Stroke 18 Clopidogrel 17.0 16 CV Death / MI / Stroke 14 12.2 12 HR 0.70 P<0.001 Endpoint (%) Prasugrel 10 NNT = 21 8 Patients with diabetes are of particular interest since they are known to have increased rates of events and more aggregable platelets. PRASUGREL REDUCED THE RATE OF THE PRIMARY ENDPOINT IN DIABETIC PATIENST FROM 17% with clopidogrel to 12.2% of prasugrel patients. 68 events were prevented. There was a 30% reduction in the HR with P < 0.001 As shown at the bottom of the slide these striking benefits in a high risk subgroup were achieved with prasugrel with a virtually identical rate of major non CABG bleeding compared with clopidogrel. 6 TIMI Major NonCABG Bleeds 4 Clopidogrel 2.6 2.5 2 Prasugrel 30 60 90 180 270 360 450 Days Wiviott, Braunwald, Angiolillo et al Circulation 2008 21

Wiviott, Braunwald, Angiolillo et al Circulation 2008 CV death/MI/stroke by diabetic status Pras Clop Reduction in Risk No DM 9.2% 10.6% 14% DM No Insluin 11.5% 15.3% 26% DM on Insulin 14.3% 22.2% 37% 0.3 1 2 Prasugrel Better Clopidogrel Better Wiviott, Braunwald, Angiolillo et al Circulation 2008 22

Verify Now®-P2Y12 % Inhibition OPTIMUS-3: Optimizing Antiplatelet Therapy in Diabetes Mellitus Prasugrel (standard dose) vs Clopidogrel (high dose) in DM patients Verify Now®-P2Y12 % Inhibition ***p<0.0001 Mean±SE Similar findings obtained with MPA to 5 and 20 µM ADP, VASP PRI, and Verify Now® PRU Angiolillo DJ et al. European Heart Journal 2011; 32: 838-46.

Diabetes N=4662 Primary endpoint 16.2% 14.1% CV death, MI or stroke (%) 10.2% 8.4% No diabetes Number at risk Diabetes Ticagrelor 6999 6507 6407 6252 5143 3955 3191 Clopidogrel 6952 6434 6318 6153 5044 3869 3097 No diabetes Ticagrelor 2326 2113 2045 1959 1593 1199 953 Clopidogrel 2336 2084 2041 1968 1604 1225 975 Days after randomization James, Angiolillo, Cornel, et al Eur Heart J. 2010;31:3006-16.

HbA1c N=15,050 Primary endpoint Diabetes 14.2% HbA1c >6 11.4% 9.0% HbA1c <6 8.2% Primary endpoint Number at risk HbA1c >6 Ticagrelor 3912 3597 3512 3393 2825 2205 1797 Clopidogrel 3978 3597 3523 3409 2828 2209 1750 HbA1c <6 Ticagrelor 3666 3424 3368 3291 2661 1990 1584 Clopidogrel 3594 3369 3312 3229 2614 1918 1552 Days after randomization James, Angiolillo, Cornel, et al Eur Heart J. 2010;31:3006-16.

Need for tailored antithrombotic drug regimens in diabetics? Platelet Stimuli Need for tailored antithrombotic drug regimens in diabetics? Collagen Shear rate P2Y12 ADP Thrombin Anti-II (gatrans) Anti X (xabans) Serotonin Thrombin Epinephrine PAR-1 antagonists Atopaxar Vorapaxar AA COX-1 TxA2 TxA2 TX inhibitors Ridogrel NCX-4016 S18886 EV-077 GP IIb/IIIa integrin Platelet Aggregation

ABCs of Treatment of Diabetic Patients and Impact on Thrombosis A1C (blood glucose): <7% B Blood pressure: <130/80 mm Hg Platelet Reactivity C Cholesterol-LDL: <70 mg/dl

Conclusions Platelets from patients with diabetes mellitus are dysfunctional: increased platelet reactivity reduced responsiveness to antiplatelet agents Increased platelet reactivity and reduced responsiveness to standard dual antiplatelet treatment regimens (aspirin plus clopidogrel) are associated with atherothrombotic risk. Control of “ABC” ameliorates platelet function profiles. Abnormalities intrinsic to the diabetic platelet suggest the need for specific (“tailored”) drug regimens. The introduction of novel and more potent antiplatelet agents will enable more efficient blockade of the diabetic platelet.