New Approaches to, and Indications for, Antiplatelet Therapy

1 New Approaches to, andIndications for, Antiplatelet TherapyKenneth A. Bauer, MDProfessor of Medicine, Harvard medical SchoolChief, Hematology Section, VA Boston Healthcare SystemDirector, Thrombosis Clinical Research,Beth Israel Deaconess medical CenterDisclosuresConsultantBayer HealthcareJanssen PharmaceuticalsBristol Myers SquibbPfizerBoehringer IngelheimInstrumentation LaboratoryAcknowledgementDeepak Bhatt, MDAtherothrombosis:Clinical ManifestationsStroke/TIAC arotid artery diseaseRenal artery stenosisPeripheral arterial diseaseAcute limb ischemiaClaudicationEndovascular stentingPeripheral bypassAcute coronary syndromes STEMI NSTEMI Unstable anginaStable CADA ngioplastyBare metal stentDrug eluting stentCABGA bdominal aortic aneurysm (AAA)Meadows TA, Bhatt Res. 2007;100 TA, Bhatt DL. Circ Res. 2007;100:1261 Platelet and Thrombus Formation:Vascular InjuryDesai NR, Bhatt DL.

2 JACC Intervention 2010 Antiplatelet Agents Mechanism Of Aspirin In Reducing Risks Of Cardiovascular DiseaseAspirin irreversibly acetylates the active site of cyclooxygenase (COX-1 and COX-2), which is required for the production of thromboxane A2 by platelets, which promotes platelet of Aspirin at Various Doses in Reducing Vascular Events in High-Risk PatientsVascular events included nonfatal MI, nonfatalstroke, and death from vascular causes. Antithrombotic Trialists 2002;324 <75313 Any aspirin6523 Antiplatelet BetterAntiplatelet WorseAspirin (mg daily)Odds Ratio0No. of Trials% Odds ReductionTreatment effect P<.0001 Effect of Antiplatelet Therapy in Reducing Vascular Events in Diabetic Patients Antiplatelet Trialists Collaboration BMJ 1994 Benefit/1000 pts (SD):36 (3)38 (12)2P: < < DiabetesDiabetesAdjusted (%) of pts (+1 SD)with vascular events 0102030 ControlAntiplatelet therapyADP ReceptorsReceptorsubtypeMolecularstructu reIntrinsicion channelGPCRGqGPCRGiSecondarymessengersys tem [Na+/Ca2+]i PLC/IP3 [Ca2+]i AC [cAMP]FunctionalresponseShape changeaggregationShape change transient aggregationSustained aggregation secretionG proteinG proteinP2Y1 ClopidogrelP2Y12 ActivemetaboliteBhatt DL et al.

3 Nat Rev Drug Discov. 2003;2 derivative: converted to active metabolites by liver cytochrome P450 isozymesIrreversible P2Y12receptor inhibitorLabeled indication: To reduce the risk of recurrent stroke in patients who have had a stroke or a TIAD osage: 250 mg bidIn combination with aspirin, demonstrated to be more effective than anticoagulation (heparin/warfarin) in the prevention of stent thrombosisReplaced by clopidogrel due to hematologic side effects:Neutropenia (2%)Thrombotic thrombocytopenic purpura (TTP)CAPRIE: Superior Efficacy of Clopidogrel versus ASA*MI, ischemic stroke or vascular death Intent-to-treat analysis (n=19,185)CAPRIE Steering Committee. Lancet1996; 348: 1329 15 18 21 24 27 30 33 36 Months of follow-upCumulative event rate* (%) RRR (p= )20 Patients with recent ischemic stroke, recent MI or symptomatic PADCAPRIE: Clopidogrel Provided Amplified Benefit in Patients with DiabetesBhatt DL et al.

4 Am J Cardiol2002; 90: 625 628. *MI, stroke, vascular death or rehospitalization for ischemic events/bleeding Number of events prevented per 1000 patients per year compared with without diabetes (n=15,233)Patients with diabetes (n=3866)Patients treated with insulin (n=1134)Event rate*/year (%)9 21 38 p= Antiplatelet TherapyClopidogrel adds to the benefit of aspirin in some circumstances (coronary artery disease).Benefits and risks:Aspirin + ClopidogrelIssues with ClopidogrelClopidogrel versus PrasugrelClopidogrel versus TicagrelorCangrelor (investigational) P2Y12receptor antagonist Aspirin + Dipyrimadole (Aggrenox) sustained releaseASA (25 mg bid)/dipyrimadole (200 mg bid)Approved indication: ischemic stroke or TIA Issues with ClopidogrelIrreversible P2Y12receptor: dosage 75 mg qdPharmacokinetics: Oral absorption 1 h, t1/2 8 hOnset: 4-6 hours (after loading dose)Offset: 5-7 daysVariable response: 25-30% of patients achieve less than 25% inhibition of platelet activityUndergoes 2 step metabolism (CYP3A4/2C19 mediated) to active agent (genetic variability)Potential drug interaction ( , PPIs)CURE: Primary Efficacy Results(MI/Stroke/CV Death) Randomized trial in acute MIYusuf S et Engl J Med2001; 345: 494 502.

5 Of follow-upCumulative Hazard RatePlacebo*(n = 6,303)Clopidogrel*(n = 6,259)20% Relativerisk reductionp = ,562*On top of standard Therapy (including ASA)CURE: Clopidogrel in Patients with ACS and Diabetes*Number of events prevented/1,000 patients treated/9 months On top of standard Therapy (including ASA)Myocardial Infarction, Stroke, or Vascular DeathNo previous diabetesn = 9,721 Diabetesn = 2,84018 Cumulative event rate (%) Clopidogrel 24681012141620*25*Yusuf S et Engl J Med2001; 345: 494 randomized, double-blind placebo controlled trial of 15,603 patients (79% ) with established CVD and 21% with multiple risk factors designed to test whether clopidogrel should be continued beyond 1 year in addition to patients received daily aspirin (75-162 mg) and were randomized to daily clopidogrel (75 mg) or placebo Clopidogrel patients had an event rate of and placebo patients had an event rate of CHARISMA demonstrated no significant benefit long term when clopidogrel is added to aspirin.

6 Rates of severe bleeding were similar, but clopidogrel patients experienced significantly higher rates of moderate bleeding. Bhatt DL, et al; N Engl J Med. 2006. 54: 1706-1717 CHARISMA: Proportion of Diabetic Patients in SubgroupsDiabetics42%Diabetics31%Diabeti cs83%Non Diabetics58%Non Diabetics17%Non Diabetics69%Overall populationSecondary preventionPrimary preventionN=15,613N=12,153N=3,284 PopulationRR (95% CI)p value Qualifying CAD, CVD or PAD * ( , ) (n=12,153) Multiple Risk Factors * ( , ) (n=3,284)Overall Population ( , ) (n=15,603)Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry + ASA BetterPlacebo + * A statistical test for interaction showed marginally significant heterogeneity (p= ) in treatment response for these pre-specified subgroups of patients 166 patients did not meet any of the main inclusion criteriaBhatt DL, Fox KA, Hacke W, et al.

7 NEJM populationN=15,603 Secondary preventionN=12,152 Primary preventionN=3,284 Non DiabeticsN=9,047 DiabeticsN=6,556 Non DiabeticsN=8,380 DiabeticsN=3,773 Non DiabeticsN=569 DiabeticsN=2,715 Primary Efficacy Diabetics vs Non DiabeticsPlacebo + ASAC lopidogrel + ASA0%2%4%6%8%10% for interaction: for interaction: for interaction: of Action of PrasugrelBhatt DL. N Engl J Med 30 60 90180270360450HR ( )P= ClopidogrelHR Endpoint (%) (781) (643)Primary EndpointCV Death,MI,StrokeNNT= 46 ITT= 13,608 LTFU = 14 ( )Wiviott et al. NEJM Thrombosis(ARC Definite + Probable)01230 30 60 90180270360450HR < (142)NNT= (68)DaysEndpoint (%)Any Stent at Index PCIN= 12,844 Wiviott SD et al NEJM courtesy of Dr. Elliott MajorBleedsLifeThreateningNonfatalFatalI CHB leeding Events -Safety Cohort(N=13,457)% EventsARD ClopidogrelPrasugrelARD 0%P= in Pts w Prior Stroke/TIA (N=518)Clop 0 (0) %Pras 6 ( )%(P= )Slide courtesy of Dr.

8 Elliott AntmanDiabetic Subgroup0246810121416180 30 60 90180270360450HR < (%)CV Death / MI / StrokeTIMI Major NonCABG BleedsNNT = N= Prasugrel ClopidogrelPrasugrel et al. Circulation of Action of Ticagrelor(a cyclopentyl triazolopyrimidine) Bhatt DL. Nature Reviews Cardiology. 2009;6 Death, MI, or StrokeNo. at riskClopidogrelTicagrelor9,2919,3338,521 8,6288,3628,4608,124 Days after randomisation6,7436,7435,0965,1614,0474, 147060120180240300360121110987654321013 Cumulative incidence (%) ,219HR (95% CI ), p= L, et al. N Engl J Med. at riskClopidogrelTicagrelor9,2919,3338,560 8,6788,4058,5208,177 Days after randomisation6,7036,7965,1365,2104,1094, 19106012018024030036065432107 Cumulative incidence (%) ,279HR (95% CI ), p= (95% CI ), p= ,2919,3338,8658,2948,7808,8228,589 Days after randomisation707971195,4415,4824,3644,41 98,626 Myocardial infarctionCardiovascular deathCumulative incidence (%)Secondary Efficacy EndpointsWallentin L, et al.

9 N Engl J Med. in Patients with Diabetes Mellitus PLATO StudyJames S et al. EHJ 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 JL, Angiolillo DJ. Circulation 2011. 123 of New Drugs/ Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical TrialsTRITON-TIMI ( ) ( )CURRENT OASIS 7 ( )(PCI Cohort)Study% of EventsHazard Ratio (95% confidence interval)Standard New Drug/ApproachNew Drug/ApproachBetterStandard Antiplatelet Therapy AND INCREASED RISKS OF BLEEDINGIn a meta-analysis of 18 randomized trials which included 129,314 patientsThose assigned to dual Antiplatelet Therapy have about a 50% increase in risk of major bleeding compared with those given single agent therapyThe magnitude of this excess risk is about as high as the approximately 60% increase observed in the trials comparing single Antiplatelet agents to placebo These excess risks of major bleeding should be considered in relation to the benefits on occlusive CVD events in choosing the optimal Antiplatelet strategy, especially for long-term treatment of patients with prior events or those at high risk of developing Clin Pharm 2008.

10 22:315-321 Conclusions Increased platelet activation/aggregation in diabetic patient contributes to their increased rate of ischemic eventsClear role for aspirin in secondary prevention, ? primary preventionDual Antiplatelet Therapy indicated for at least 1 year after ACS or PCIMore potent P2Y12 receptor antagonists likely of greater benefit in diabetics, if bleeding risk not too high