Clopidogrel vs New Antiplatelet Therapy (Prasugrel) Adnan Kastrati, MD Deutsches Herzzentrum, Technische Universität München, Germany

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1 Clopidogrel vs New Antiplatelet Therapy () Adnan Kastrati, MD Deutsches Herzzentrum, Technische Universität München, Germany Seoul, April 3, 21

2 Dual Antiplatelet Therapy for Stenting MACE, % In addition, drastic reduction in bleeding!!! ISAR FANTASTIC STARS MATTIS Dual Antiplatelet Therapy ISAR, NEJM 1996 FANTASTIC, Circ 1998 Oral Anticoagul. Therapy STARS, NEJM 1998 MATTIS, Circ 1998

3 A Patient with Stent Thrombosis and Clopidogrel Resistance

4 A Patient with Stent Thrombosis and Clopidogrel Resistance A B baseline 6 h after 16 h after 2 6 mg Clopidogrel 6 h after h after 6 6 Light Transmission (%) Time (s) Stent Thrombosis Patient Light Transmission (%) Light Transmiss 8 1 baseline Time (s) Control Individual Beckerath et al, Thromb Haemost 25

5 A Patient with Stent Thrombosis and Failed Metabolization of Clopidogrel A B ST patient Control 3 ST patient Control Clopidogrel (ng/ Time (hours) Active Metab Time (hours) Clopidogrel Active Metabolite Beckerath et al, Thromb Haemost 25

6 A New Alternative to Clopidogrel Cardiovascular Death, MI, or Ischemic Stroke by CYP2C19 Genotype Stent Thrombosis by CYP2C19 Genotype Mega et al, AHA 29

7 A New Alternative to Clopidogrel Schomig A. NEJM 29

8 vs. Clopidogrel Platelet Inhibition PRINCIPLE-TIMI 44, Circ 27

9 vs. Clopidogrel TRITON-TIMI 38 ACS (STEMI or UA/NSTEMI) & Planned PCI 13,68 patients ASA Double-blind CLOPIDOGREL 3 mg LD/ 75 mg MD PRASUGREL 6 mg LD/ 1 mg MD Median duration of therapy - 12 months 1 o endpoint: CV death, MI, Stroke 2 o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic

10 Primary Endpoint 15 Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke TRITON-TIMI 38, NEJM 27 Primary Endpoint (%) 1 5 HR.77 ( ) p <.1 HR.8 ( ) p <.1 Clopidogrel 12.1 (781) 9.9 (643) HR.81 ( ) p <.1 NNT = 46 Intent To Treat = 13,68; Lost to Follow-Up = 14 (.1%) Days After Randomization TRITON-TIMI 38, NEJM 27

11 Primary Endpoint Primary Endpoint (%) Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke Clopidogrel HR.82 ( ) p = Days after Randomization Clopidogrel Days after Randomization HR.8 ( ) p =.3

12 Periprocedural and Spontaneous MI Morrow et al, Circ 29

13 Early and Late MI 6 Clopidogrel 5.2 Clopidogrel MI (%) HR=.81 (.7-.95) P= Loading Dose Days HR=.69 ( ) P< Maintenance Dose Morrow et al, Circ 29

14 Stent Thrombosis 2.5 HR.48 ( ); P<.1 Clopidogrel 2.35 % of Subjects year: 1.6 vs. 2.15% HR.48 ( ); P< Days Wiviott et al, Lancet 28

15 Early and Late Stent Thrombosis 2. Stent thr HR=.49 ( ) P=.6 Clopidogrel Loading Dose Days Clopidogrel HR=.45 ( ) P< Maintenance Dose Wiviott et al, Lancet 28

16 Safety Endpoint % TIMI Major Bleeding (%) Clopidogrel 1.8% HR 1.32 ( ) P= Days TRITON-TIMI 38, NEJM 27

17 Safety Endpoint

18 Net Clinical Benefit 15 ITT= 13,68 Clopidogrel 13.9 Endpoint (%) Events per 1 pts + 19 events HR.87 CI 95% P= MI Major Bleed (non CABG) Days

19 Net Clinical Benefit TRITON-TIMI 38, NEJM 27

20 STEMI Subset All ACS/PCI patients N=13.68 UA/NSTEMI patients N=1.74 STEMI patients N= Primary PCI 3 N=2.438 (69%) Secondary PCI 4 N=1.94 (31%) Clopidogrel Clopidogrel N=1.235 N=1.23 N=53 N=564 Montalescot et al, Lancet 29

21 STEMI Subset Primary endpoint: CV death, nonfatal MI, nonfatal stroke 15 Clopidogrel 12.4% Percent (%) 1 9.5% 6.5% 1.% HR.79 ( ) P=.2 5 HR.68 ( ) P=.2 RRR 21% NNT Age adjusted HR.81 ( ) Days From Randomization Montalescot et al, Lancet 29

22 3 TRITON-TIMI 38 STEMI Subset Stent thrombosis ALL STEMI patients Clopidogrel 2.8% % RRR 42% 2 NNT = 83 Percent (%) % HR.49 ( ) P=.8 1.6% HR.58 ( ) P=.8 P=.2.5 Age adjusted HR =.59, CI 95% Days from Randomization Montalescot et al, Lancet 29

23 2.5 TRITON-TIMI 38 STEMI Subset Main safety endpoint (TIMI major non-cabg bleedings) All STEMI patients 2.4% 2 2.1% Percent (%) Clopidogrel HR 1.11 ( ) P= Days from Randomization Montalescot et al, Lancet 29

24 Diabetic Subset Primary endpoint: CV death, nonfatal MI, nonfatal stroke Wiviott et al, Circ 28

25 Diabetic Subset Stent Thrombosis Wiviott et al, Circ 28

26 Diabetic Subset TIMI Major Bleeding Wiviott et al, Circ 28

27 vs Clopidogrel In the majority of patients with ACS undergoing PCI, prasugrel is a superior alternative to clopidogrel The role of prasugrel in patients with stable CAD undergoing PCI waits for evaluation

28 Platelet Function Testing After Clopidogrel Hyporesponsivenes and Thrombosis n=168 pts Cumulative incidence of definite ST (%) P<.1 Low responders Days after randomization Normal responders Cumulative incidence of death or definite ST (%) P<.1 Low responders 2 1 Normal responders Days after randomization Sibbing et al, JACC 29

29 Flow-chart TRIGGER-PCI Study Successful PCI with DES without major complication and NO GPIIb/IIIa use N ~68 Post-PCI VerifyNow P2Y12 Assay (PRU) Non-Responder Yes PRU > 28 No Responder A N = 175 arm 6 mg LD 1 mg MD + Clopidogrel placebo B N = 175 Clopidogrel arm Placebo LD Clopidogrel 75 mg MD + placebo C N = 465 Standard Therapy Clopidogrel 75 mg N = 2,15 33% Non-interventional study (Registry) Clinical Follow-up and blinded VerifyNow Assessment at 9 days, 18 days Primary Endpoint: 6 month CV Death and MI