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The Landscape of Oral Antiplatelet Agents 2009

The Landscape of Oral Antiplatelet Agents 2009. George D. Dangas, MD, PhD, FSCAI, FACC Associate Professor of Medicine Columbia University Medical Center. Disclosures. Advisory Board: Accumetrics, Astra-Zeneca Consultant: Lilly, Daichi-Sankyo Speaker honoraria: Sanofi-Aventis, BMS. 33% 

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The Landscape of Oral Antiplatelet Agents 2009

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  1. The Landscape of Oral Antiplatelet Agents 2009 George D. Dangas, MD, PhD, FSCAI, FACC Associate Professor of Medicine Columbia University Medical Center

  2. Disclosures • Advisory Board: Accumetrics, Astra-Zeneca • Consultant: Lilly, Daichi-Sankyo • Speaker honoraria: Sanofi-Aventis, BMS

  3. 33%  P=0.033 38%  P=0.028 13.4 % MACE (Death, MI, Urgent Revasc) 8.9 5.5 5.2 Placebo/ No PreRx N=343 Placebo/ PreRxN=466 Abciximab/ No PreRx N=328 Abciximab/ PreRx N=466 EPISTENT: IV vs po Anti-Platelet Rx IV placebo/abciximab & po ticlopidine preRx/no-preRx Currently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBC Steinhubl SR, Circulation 1998;98:I-573

  4. CURE ACS pts Benefit of Clopidogrel Therapy at Early and Late Time Intervals MI, stroke, CV Death: 0–30 days MI, stroke, CV Death: 31 d - 1 y 1.00 1.00 Clopidogrel + ASA Clopidogrel + ASA 0.98 0.98 0.96 0.96 Proportion Event-Free Proportion Event-Free Placebo + ASA 0.94 0.94 Placebo + ASA 0.92 0.92 RRR 21% 95% CI 0.67–0.92 P=0.003 RRR 18% 95% CI 0.70–0.95 P=0.009 0.90 0.90 1 4 6 8 10 12 0 1 2 3 4 Weeks Months Yusuf S et al for the CURE Trial Investigators. Circulation. 2003;107:966-972.

  5. CLARITY trial of APT in STEMI:Occluded Artery (or D/MI thru Angio/HD) Odds Ratio 0.64(95% CI 0.53-0.76) 36% Odds Reduction P=0.00000036 0.4 0.6 0.8 1.0 1.2 1.6 n=1752 n=1739 Clopidogrel better Placebo better Clopidogrel Placebo

  6. N=12,563 1 year FU CURE major bleed N=2,116 1 year FU TIMI major bleed NEJM 2001;345;494-502 JAMA 2002;288:2411-20 Safety of Long-Term Clopidogrel 3 Placebo Controlled Trials P=0.07 P<0.001 P=0.001 N=15,603 2.5 year FU GUSTO major + moderate bleed NEJM 2006;354:1706-17

  7. <100 mg 2.6% 2.0% 100–200 mg 3.5% 2.3% >200 mg 4.9% 4.0% CURE Major Bleeding by ASA Dose Clopidogrel + ASA* Placebo + ASA* ASA Dose

  8. Step-wise reloading increased % Inhibition and % responders After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target. Log rank p =0.007 MACE: CV death, MI, revascularization Bonello et al. J Am Coll Cardiol 2008

  9. Study Design, Flow and Compliance • 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) • Planned Early (<24 h) Invasive Management with intended PCI • Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose(600 mg then150 mg/d x 7d then 75 mg/d) vsStandard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vsLow dose(75-100 mg/d) Angio 24,769 (99%) PCI 17,232 (70%) No PCI 7,855 (30%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Compliance: Clop in 1st 7d (median) 7d 7 d 2 d 7d Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup:PCI v No PCI Complete Followup 99.8%

  10. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or Stroke Clopidogrel Standard 15% RRR 0.04 Clopidogrel Double 0.03 Cumulative Hazard 0.02 HR 0.85 95% CI 0.74-0.99 P=0.036 0.01 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  11. Clopidogrel Double vs Standard DoseBleeding PCI Population 1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

  12. Definite Stent Thrombosis in 4 Groups (Angiographically Proven) C Standard, A Low 0.012 C Standard, A High C Double, A Low 0.008 Cumulative Hazard C Double, A High 0.004 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  13. PRINCIPLE-TIMI 44: Comparison of Prasugrel with Higher Dose Clopidogrel IPA (%; 20 mM ADP) IPA (%; 20 mM ADP) P<0.0001 P<0.0001 for each N=201 Prasugrel 60 mg Clopidogrel 600 mg Clopidogrel 150 mg Prasugrel 10 mg 14 Days Hours Wiviott et al Circ 2007

  14. Balance of Efficacy and Safety 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days

  15. TIMI-38 STENT ANALYSISDefinite/Probable ST: DES Only (N=5743) EARLY ST LATE ST HR 0.29 [0.15-0.56] P=0.0001 HR 0.46 [0.22-0.97] P=0.04 CLOPIDOGREL PRASUGREL 1.44% % of Subjects 0.91% 71% 54% 0.42% 0.42% DAYS Wiviott et al, SCAI-ACCi2 2008

  16. TIMI-38 STENT ANALYSISDefinite/Probable ST: BMS Only (N=6461) EARLY ST LATE ST HR 0.45 [0.28-0.73] P=0.0009 HR 0.68 [0.35-1.31] P=0.24 CLOPIDOGREL 1.66% PRASUGREL % of Subjects 55% 0.78% 32% 0.75% 0.53% DAYS Wiviott et al, SCAI-ACCi2 2008

  17. AZD6140:Inhibition of Platelet aggregation Compared With Clopidogrel in NSTEMI ACS Patients (DISPERSE-2) Inhibition of platelet aggregation after initial doses *P<0.05 Mean % inhibition of platelet aggregation derived from maximum aggregation response after addition of ADP 20 mol/l (optical aggregometry). Storey, RF et al. J Am Coll Cardiol.2007;50:1852-6

  18. PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

  19. K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 13 12 11.7 Clopidogrel 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 3 2 HR 0.84 (95% CI 0.77–0.92), p=0.0003 1 0 0 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

  20. Secondary efficacy endpoints over time Cardiovascular death Myocardial infarction 7 7 6.9 Clopidogrel 6 6 5.8 Clopidogrel 5.1 5 5 Ticagrelor 4.0 4 4 Ticagrelor Cumulative incidence (%) Cumulative incidence (%) 3 3 2 2 1 1 HR 0.84 (95% CI 0.75–0.95), p=0.005 HR 0.79 (95% CI 0.69–0.91), p=0.001 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomisation Days after randomisation No. at risk 9,333 8,294 8,822 8,626 7119 5,482 4,419 Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,291 8,865 8,780 8,589 7079 5,441 4,364 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109

  21. Non-CABG and CABG-related major bleeding 9 Ticagrelor Clopidogrel NS 7.9 8 7.4 7 NS 5.8 6 5.3 p=0.026 5 K-M estimated rate (% per year) 4.5 3.8 4 p=0.025 2.8 3 2.2 2 1 0 Non-CABGPLATO majorbleeding Non-CABGTIMI major bleeding CABGPLATO major bleeding CABG TIMI major bleeding

  22. TIMI major+minor bleed N=13,608 15-month FU TIMI major+minor bleed N=18,864 12-month FU PLATO Major bleed N=25,087 1-month FU CURRENT major bleed PLATO Major bleed NEJM 2009 NEJM 2009 NEJM 2007 NEJM 2007 NEJM 2009 Safety of New DAPT Regimens 3 Active Controlled Trials (vs Standard Clop) P=0.32 P<0.001 Non-CABG related bleeding P=0.03 P=0.002 P=0.001

  23. Efficacy of New DAPT Rx in ACS N=13,608 15-month FU D/MI/CVA N=18,864 1- Year FU D/MI/CVA Def/Prob N=25,087 1-month FU D/MI/CVA Def/Prob Def/Prob NEJM 2007 NEJM 2009 NEJM 2009 NEJM 2007 ESC 2009 ESC 2009 3 Active Controlled Trials (vs Standard Clop) P<0.001 P=0.0003 P=0.37 P<0.001 P=0.02 P=0.002

  24. Efficacy of New DAPT Rx: ACS+PCI N=11,289 1-year FU D/MI/CVA N=13,608 15-month FU D/MI/CVA Def/Prob N=17,232 1-month FU D/MI/CVA Def/Prob Def/Prob NEJM 2007 TCT 2009 NEJM 2007 ESC 2009 ESC 2009 NEJM 2009 3 Active Controlled Trials (vs Standard Clop) P<0.001 P=0.0 P=0.04 P=0.02 P<0.001 P=0.002

  25. In patients in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating left main, or last patent coronary vessel), platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated. I IIa IIb III ACC/AHA/SCAI Guideline Update for PCIOral Antiplatelet Adjunctive Therapies C

  26. Antiplatelet Therapy Summary • Major recent advances in clinical research have established the value of early + sustained therapy with combination oral antiplatelet agents for CAD • More complex combination regimens are under investigations that address the different clinical situations • Prasugrel: newest addition as an FDA approved agent. Improved efficacy. Drawback bleeding. Need for risk stratification • Ticagrelor: newest clinical results with improved efficacy. Reversibility likely related to less CABG bleeding. • Cilostazol • 3ple combination therapy investigational

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