ADP P2Y12 Receptor Blockade

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1 Is there a need to tailor antiplatelet therapy in diabetes? ADP P2Y12 Receptor Blockade Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI Director of Cardiovascular Research Associate Professor of Medicine

2 Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. 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, Abbott Vascular 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

Mechanisms Involved in Platelet Dysfunction in Diabetes Mellitus Hyperglycemia Increased P-selectin expression

Action Impaired response to NO and PGI 2 IRS-dependent factors: Increased intracellular Ca++ Degranulation

Dysfunction Increased platelet turnover Increased intracellular Ca++ Upregulation of P2Y 12 signaling H 2 O

Endothelial Cells ACP=adenosine disphosphate; GP=glycoprotein; IRS-1=insulin receptor substrate-1; NO=nitric oxide;

3 Mechanisms Involved in Platelet Dysfunction in Diabetes Mellitus Hyperglycemia Increased P-selectin expression Osmotic effect Activation of PKC Decreased membrane fluidity by glycation of surface proteins Deficient Insulin Action Impaired response to NO and PGI 2 IRS-dependent factors: Increased intracellular Ca++ Degranulation Associated Metabolic Conditions Obesity Dyslipidemia Inflammation Platelet Other Cellular Abnormalities Endothelial Dysfunction Increased platelet turnover Increased intracellular Ca++ Upregulation of P2Y 12 signaling H 2 O Oxidative stress Increased P-selectin and GP expression Increased production of TF Decreased NO and PGI 2 production Endothelial Cells ACP=adenosine disphosphate; GP=glycoprotein; IRS-1=insulin receptor substrate-1; NO=nitric oxide; PGI 2 =prostacyclin; PKC= protein kinase C; TF=tissue factor. Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation :

Meta-Analysis of GP IIb/IIIa Inhibitors: Diabetic Patients With Non-ST-Segment Elevation ACS OR with 95% CIs and corresponding P values for treatment effect on 3-day mortality among

N Odds Ratio and 95% Cl Placebo (%) IIb/IIIa (%) In diabetic patients (n=1279) undergoing PCI during index PURSUIT 2163 P=.33 6.1 5.

4 Meta-Analysis of GP IIb/IIIa Inhibitors: Diabetic Patients With Non-ST-Segment Elevation ACS OR with 95% CIs and corresponding P values for treatment effect on 3-day mortality among diabetic patients with ACS (n=6548) Trial Roffi M et al. Circulation. 21;14: N Odds Ratio and 95% Cl Placebo (%) IIb/IIIa (%) In diabetic patients (n=1279) undergoing PCI during index PURSUIT 2163 P= PRISM hospitalization, 687 the GPI use was associated P=.7 with 4.2 a mortality 1.8 PRISM-PLUS reduction at days from 4.% to 1.2% P=.17 (OR.3; % 3.6 CI GUSTO IV 1677 P= to.69; P=.2; NNT=36) PARAGON A 412 P= PARAGON B Pooled P=.93 P= IIb/IIIa Better Placebo Better Breslow-Day: P=.5

5 CURE: Outcomes With Clopidogrel in Various Subgroups Characteristic Percentage of Patients with Event No. of Patients Clopidogrel + ASA Placebo + ASA Overall Associated MI No associated MI Male sex Female sex yr old > 65 yr old ST-segment deviation No ST-segment deviation Enzymes elevated at entry Enzymes not elevated at entry Diabetes No diabetes Low risk Intermediate risk High risk History of revascularization No history of revascularization Revascularization after randomization No revascularization after randomization Yusf S et al. N Engl J Med. 21;345: Relative Risk (95% CI) Clopidogrel Better Placebo Better

6 Odds/hazard ratio Diabetes as Predictor of Stent Thrombosis at 1 Year in the Era of DES 5 4 OR=2. (.8-4.9) OR=2.8 ( ) HR=3.7 ( ) HR=2.3 ( ) IDDM IDDM Diabetes Diabetes Kuchulakanti et al. Circulation 26 Urban et al. Circulation 26 Iakovou et al. JAMA 25 Daemen et al. Lancet 27

7 Platelet aggregation (%) Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects Acute Phase of Treatment DM No-DM P=.4 8% 8 6 Long-term Phase of Treatment P=.2 P<.1 38% 14% 6% 56% 78% 4 24 hrs post 3 mg LD Non-responders (Platelet inhibition <1%) Low responders (Platelet inhibition 1-29%) Responders (Platelet inhibition >3%) Angiolillo DJ et al. Diabetes. 25;54: DM No DM DM No DM ADP 2 M ADP 6 M Angiolillo DJ et al. J Am Coll Cardiol. 26;48:

8 Platelet Function According to Hypoglyemic Treatment % Platelet aggregation (LTA) 8 7 ADP 2µM p< NDM NIDDM IDDM Angiolillo DJ et al. J Am Coll Cardiol 26; 48:

9 Plasma Concentration of Clopidogrel and Prasugrel Active Metabolite by Diabetic Status Clopidogrel Prasugrel Erlinge, D. et al. J Am Coll Cardiol 28;52:

Δ P2Y 12 PRI % Upregulation of P2Y12 signaling in DM Absolute differences in PRI before and after incubation of clopidogrel active metabolite 8 DM

10 Δ P2Y 12 PRI % Upregulation of P2Y12 signaling in DM Absolute differences in PRI before and after incubation of clopidogrel active metabolite 8 DM non-dm p=.2 6 p= p=.27 ANCOVA; p=.14 (adjusted for baseline PRI values and obesity) Concentrations (µm) Ueno M. et al. Thromb Haemost 211

11 Strategies to Enhance P2Y 12 Inhibition in Patients With Diabetes Increase clopidogrel dosing (eg, 15 mg maintenance dosing) Adding agents that modulate intraplatelet camp (eg, triple therapy: ASA + clopidogrel + cilostazol) Using more potent P2Y 12 inhibitors (eg, prasugrel, ticagrelor, cangrelor, elinogrel)

12 Strategies to Enhance P2Y 12 Inhibition in Patients With Diabetes Increase clopidogrel dosing (eg, 15 mg maintenance dosing) Adding agents that modulate intraplatelet camp (eg, triple therapy: ASA + clopidogrel + cilostazol) Using more potent P2Y 12 inhibitors (eg, prasugrel, ticagrelor, cangrelor, elinogrel)

13 Platelet inhibition (%) P2Y 12 Reactivity Units OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus) Impact of high clopidogrel maintenance dosing on platelet function in DM patients with suboptimal clopidogrel response VerifyNow P2Y 12 substudy %IPA PRU 8 p=.9 3 p= Only ~4% of patients reach therapeutic target! mg 15 mg 75 mg 15 mg Angiolillo DJ et al. Circulation. 27;115: Angiolillo DJ et al. Am J Cardiol. 28;11:44-5.

14 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 Twice daily clopidogrel dosing for DM patients? Capodanno D et al. Circ Cardiovasc Interv. 211;4:18-7.

15 Strategies to Enhance P2Y 12 Inhibition in Patients With Diabetes Increase clopidogrel dosing (eg, 15 mg maintenance dosing) Adding agents that modulate intraplatelet camp (eg, triple therapy: ASA + clopidogrel + cilostazol) Using more potent P2Y 12 inhibitors (eg, prasugrel, ticagrelor, cangrelor, elinogrel)

Upregulation of P2Y 12 receptor signaling in type 2 diabetes mellitus ATP ADP O OCH 3 Clopidogrel O O CH 3 C

Gastro-intestinal absorption IP3 + DAG Ca 2+ mobilization GP IIb/IIIa receptor activation PKC MLCK-P Granule

camp VASP-P camp PI3K PDE-III Hepatic CYP Biotransformation 85% inactive metabolites (Esterases in blood)

16 Upregulation of P2Y 12 receptor signaling in type 2 diabetes mellitus ATP ADP O OCH 3 Clopidogrel O O CH 3 C HOOC N N P2X 1 * HS Cl 15% active metabolite S Cl Ca 2+ flux Shape change PLCβ G q G 12 PIP2 Rho Shape change Gastro-intestinal absorption IP3 + DAG Ca 2+ mobilization GP IIb/IIIa receptor activation PKC MLCK-P Granule secretion Initiation of Platelet Aggregation VASP α i β γ AC PKB/Akt Rap1b GP IIb/IIIa receptor activation camp VASP-P camp PI3K PDE-III Hepatic CYP Biotransformation 85% inactive metabolites (Esterases in blood) Cilostazol Stabilization of Platelet Aggregation PGE 1 GP IIb/IIIa receptor activation Angiolillo DJ et al JACC 27

OPTIMUS-2: Impact of adjunctive treatment with cilostazol in Diabetes Mellitus patients on aspirin and clopidogrel 1 9 8 7 6 5 4 3 2 1 P2Y 12 inhibtion PRU

17 OPTIMUS-2: Impact of adjunctive treatment with cilostazol in Diabetes Mellitus patients on aspirin and clopidogrel P2Y 12 inhibtion PRU p=.1 CILOSTAZOL PLACEBO VerifyNow P2Y12 assay p=.2 CILOSTAZOL PLACEBO Angiolillo DJ et al. Eur Heart Journal 28; 29:222-11

18 Impact of adjunctive treatment with cilostazol according to Diabetes Mellitus status in patients on aspirin and clopidogrel P2Y12 Reactivity Index (PRI) * p between =.39 p<.1 p<.1 = 23.1* = 15.* Angiolillo DJ et al. Thromb Haemost. 211 May 26;16(2). [Epub ahead of print]

19 Strategies to Enhance P2Y 12 Inhibition in Patients With Diabetes Increase clopidogrel dosing (eg, 15 mg maintenance dosing) Adding agents that modulate intraplatelet camp (eg, triple therapy: ASA + clopidogrel + cilostazol) Using more potent P2Y 12 inhibitors (eg, prasugrel, ticagrelor, cangrelor, elinogrel)

20 OPTIMUS-3: Optimizing Antiplatelet Therapy in Diabetes Mellitus Prasugrel (standard dose) vs Clopidogrel (high dose) in DM patients VN-P2Y 12 % PRU Inhibition B A Verify Now -P2Y 12 % Inhibition *** *** *** LD MD Washout LD MD Washout *** *** *** *** *** ***p<.1 Mean±SE days No study drug 4 Hours post LD 24 7 days No (7 study days) drug Hours post LD (7 days) prasugrel 6 mg LD/1 mg MD clopidogrel 6 mg LD/15 mg MD Similar findings obtained with MPA to 5 and 2 µm ADP, VASP PRI, and Verify Now PRU Angiolillo DJ et al. European Heart Journal 211; 32:

21 OPTIMUS-3: Optimizing Antiplatelet Therapy in Diabetes Mellitus /34 22/35 1/32 24/34 /32 12/34 /34 29/35 /34 22/35 1/32 24/34 /32 12/34 /34 29/35 PRU > 235 MPA>5% IPA 2% PRI>5% PRU > 235 MPA>5% IPA 2% PRI>5% C Poor Responder Rate at 4 Hours post LD (%) Poor Responder Rate at 24 Hours Post LD (%) te A 1 C p< p< Poor R at 4 Ho Poor Responder Rate at 24 Hours Post LD (%) p<.1 p<.1 B p< p< p=.6 p=.3 /34 22/35 1/32 24/34 /32 12/34 /3429/35 /34 19/35 / /33 /3 17/33 /33 25/35 PRU > 235 MPA>5% IPA 2% PRI>5% /34 19/35 /3 26/33 /3 17/33 /33 25/35 PRU > 235 MPA>5% 21.2 IPA 2% PRI>5% PRU > 235 MPA>5% IPA 2% PRI>5% Po at 4 1 Poor Responder Rate at 24 Hours Post LD (%) Poor Responder Rate at 7 Days (%) p<.1 Poor Responder Rate at 7 Days (%) 8 p< p< B p< p< p<.1 B C C p< p< p<.1 8 p<.1 p= MPA>5% p=.1 p< p< p=.6 p=.3 4 p= p= /34 19/35 /3 26/33 /3 17/33 / / /35 1/34 7/33 18/34 1/33 8/34 3/34 16/34 PRU > 235 MPA>5% IPA 2% PRI>5% 1/35 1/34 7/33 18/34 1/33 8/34 3/34 16/34 PRU > 235 MPA>5% IPA 2% PRI>5% PRU > 235 MPA>5% IPA 2% PRI>5% prasugrel 6 mg LD/1 mg MD clopidogrel 6 mg LD/15 mg MD Poor Responder Rate at 7 Days (%) 51.5 prasugrel 6 mg LD/1 mg MD clopidogrel 6 mg LD/15 mg MD PRU > 235 MPA>5% IPA 2% Poor responder analyses at: A) 4 hrs post LD ; B) 24 hrs post LD; and C) 7 days post MD Angiolillo DJ et al. European Heart Journal 211; 32: p= PRU > 235 IPA 2% prasugrel 6 mg LD/1 mg MD clopidogrel 6 mg LD/15 mg MD PRI>5 p< /35 1/34 7/33 18/34 1/33 8/34 3/34 16/ PRI>5

22 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 (.58.85) PLATO ( ) CURRENT OASIS ( ) (PCI Cohort) 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 :

23 Diabetes and Coronary Artery Disease: Do all patients carry the same risk?

24 % Event-Free Survival High platelet reactivity and MACE in T2DM ROC defined cut-off value 1% MACE (CV death, STEMI, UA/NSTEMI, stroke) Log Rank, p = %? 62.2% >62% HPR (n=45) <62% non-hpr (n=128) 2 HR: 3.35; 95% CI, ; p= Months Angiolillo DJ et al. J Am Coll Cardiol 27; 5:1541-7

25 % HPPR According to Renal Function in DM Patients on Aspirin + Clopidogrel Therapy unadj. OR 2.1, p =.7 adj.* OR 3.8, p =.1 unadj. OR 1.8, p =.43 adj.* OR 2.4, p =.29 unadj. OR, 2.6, p =.4 adj.* OR 3.3; p =.1 moderate/severe CKD normal/mild CKD 35,7 2,8 33,3 22,1 23,8 1,8 HPPR-ADP HPPR-COLL HPPR-ADP+COLL Yes No p Yes No p Yes No p Antifibrinogen 37±2 27±19 <.1 37±2 28±2.1 4±19 28±2 <.1 PAC-1 49±19 34±2 <.1 44±19 36± ±19 36±2 <.1 P-selectin 44±18 31±18 <.1 37±19 33± ±19 33±19.1 * Adjusted for age, gender, insulin-dependent diabetes, obesity, smoking, dyslipidemia, and hypertension, calcium antagonists, ACEI, beta-blockers, nitrates, lipophilic statins, and PPI Angiolillo DJ, et al. J Am Coll Cardiol. 21;55:

26 Genetic determinants of HPR in diabetes mellitus Genetic profiling for the insulin receptor substrate (IRS-1) 97% of genetic variance rs rs rs rs rs rs rs (%) 1 9 Max ADP 2 μm aggregation > 64% Carriers Non Carriers 3.6% vs 11.4%; HR: 2.88; 95% CI, P= % % Log rank=.4 GG GC + CC Angiolillo DJ et al. J Am Coll Cardiol : 3-39.

27 Platelet Stimuli Need for tailored antithrombotic drug regimens in diabetics!! Collagen Serotonin Epinephrine Shear rate AA GP IIb/IIIa integrin P2Y 12 ADP COX-1 TxA 2 TxA 2 TxA 2 Platelet Aggregation Thrombin Thrombin Thrombin Thrombin Anti-II (gatrans) Anti X (xabans) PAR-1 antagonists E5555 SCH TX inhibitors Ridogrel NCX-416 S18886

28 ABCs of Treatment of Diabetic Patients and Impact on Thrombosis A A1C (blood glucose): <7% B Blood pressure: <13/8 mm Hg Platelet Reactivity C Cholesterol-LDL: <7 mg/dl

29 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 warrant specific ( tailored ) drug regimens. The introduction of novel and more potent antiplatelet agents will enable more efficient blockade of the diabetic platelet.

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