Clopidogrel Use in ACS and PCI: Clinical Trial Update

Transcription

1 Clopidogrel Use in ACS and PCI: Clinical Trial Update Matthew J. Price MD Director, Cardiac Catheterization Laboratory, Scripps Clinic, La Jolla, CA Assistant Professor, Scripps Translational Science Institute La Jolla, CA

2 PCI-CURE: Clopidogrel vs placebo + aspirin in patients with ACS undergoing PCI Cumulative Hazard Rate Composite of MI or cardiovascular death from randomization to end of follow-up Placebo + ASA Days of follow-up Clopidogrel + ASA 12.6% 8.8% 31% RRR P = N = 2658 Mehta SR et al, Lancet. August 2001.

3 OASIS 7- CURRENT Randomizing patients to low vs. high-dose clop + ASA 25,807 ACS patients Intended PCI < 24 hrs No restriction on GP IIb/IIIa inhibitors Clopidogrel 600 mg 150 mg from Day 2 to Day 7 75mg from Day 8 to 30 Clopidogrel 300 mg 75 mg from Day 2 to 30 ASA 300 mg Day mg from Day 2 to 30 ASA 300 mg Day mg 325 mg from Day 2 to 30 ASA 300 mg Day mg from Day 2 to 30 ASA 300 mg Day mg 325 mg from Day 2 to 30 1 o Outcome: Death / MI /stroke, 30 Days; 2 o outcome: CURRENT bleeding ClinicalTrials.gov Identifier: NCT

4 CV Death/MI/Stroke MI Clopidogrel: Double vs Standard Dose Primary Outcome and Components Standard Double HR 95% CI P Intn P PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) CV Death PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087)

5 Clopidogrel Double vs Standard Dose Bleeding Overall Population Clopidogrel Standard Double N=12579 N=12508 Hazard Ratio 95% CI P TIMI Major CURRENT Major CURRENT Severe Fatal ICH RBC transfusion 2U CABG-related Major ICH, Hb drop 5 g/dl (each unit of RBC transfusion counts as 1 g/dl drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or Hb 5 g/dl, sig hypotension + inotropes/surgery, ICH or txn of 4 units

6 PRINCIPLE TIMI-44: Comparative Pharmacodynamics of Prasugrel and High-Dose Clopidogrel SDW1 IPA (20 mm ADP) IPA (20 mm ADP) 100 N = 201 P< for each 100 P< Prasugrel 60 mg Clopidogrel 600 mg Hours 0 Clopidogrel 150 mg Prasugrel 10 mg Wiviott SD et al. Circulation. 2007;116: SCRIPPS Days CLINIC

7 Slide 6 SDW1 Could just move this up to before TRITON RESULTS,

8 TRITON-TIMI 38: Balance of Efficacy and Safety 15 Endpoint (%) 10 5 CV Death/MI/Stroke TIMI Major Non-CABG Bleeds Clopidogrel 12.1 Prasugrel* Prasugrel Clopidogrel Days After Randomization HR 0.81 (95% CI, ) P<0.001) NNT=46 HR 1.32 (95% CI, ) P=0.03 NNH=167 Wiviott SD et al. N Engl J Med. 2007;357(20):

9 ADP-induced Platelet Reactivity on Clopidogrel Therapy Varies Widely Among Individuals Maximal Aggregation 5 µmol/l ADP (%) n = Time from Loading Dose to Catheterization (hr) Hochholzer W et al. Circulation. 2005;111:

10 The Generation of Clopidogrel s Active Metabolite is Inefficient and CYP450-Dependent S O N C Cl O Clopidogrel 85% Inactive Metabolites O C O CH 3 CH 3 Pro-drug Hydrolysis (Esterases) S N Cl O C O CH 3 2-Step Oxidation (Cytochrome P450) O OCH 3 CYP1A2, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2B6 O S N Cl HOOC N * HS Active Metabolite Cl Herbert JM, Savi P. Semin Vasc Med 2003;3(2):

11 429 Healthy Amish after Clopidogrel 75 mg X 7d P=1.5 X 10-13

12 Influence of CYP2C19*2 In Cloidogrel-Treated Patients TRITON Results According to Carriage of Reduced Function CYP2C19 Allele Carriers 12.1% P= 0.01 Non-carriers 8.0% Reduced function allele present in 30% of population Mega JL et al, NEJM 2009;360:354-62

13 CYP2C19 and MACE: A Collaborative Meta-analysis Carriers vs Non-Carriers Risk Ratio (95% CI) 1.61 ( ) P Value <0.001 Heterozygotes vs Wildtype 1.50 ( ) Homozygotes vs Wildtype 1.81 ( ) N=9,684 Risk Lower with CYP2C19 Variant Risk Higher with CYP2C19 Variant Mega JL et al, AHA 2009

14 CYP2C19 and Stent Thrombosis: A Collaborative Meta-analysis Risk Ratio (95% CI) P Value Carriers vs Non-Carriers 2.76 ( ) <0.001 Heterozygotes vs Wildtype 2.51 ( ) <0.001 Homozygotes vs Wildtype 4.78 ( ) < N=5,772 Risk Lower with CYP2C19 Variant Risk Higher with CYP2C19 Variant Mega JL et al, AHA 2009

15 Out-of-hospital 6-Month Outcomes Post-PCI Stratified by Reactivity in Patients on Consistent Clopidogrel Therapy at 6 Months PRU < 235 PRU > 235 P = Patients (%) P = 0.04 P = % 1.8% P = % 6.5% 1.0% 1.0% 0.0% 0.0% CV Death Non-fatal MI ST CV Death/MI/ST *On clopidogrel at 30 day & 6-month FU or reached an endpoint on clopidogrel by 6-month FU Price MJ et al. Eur Heart J 2008; 29(8):

16 G R A V T A S Successful PCI with DES without major complication or GPIIb/IIIa use VerifyNow P2Y12 Assay hours post-pci Yes PRU 230? No Normal On-treatment Reactivity High On-treatment Reactivity R A B C N = 1100 N = 1100 N = 583 Tailored Therapy clopidogrel 600-mg*, then clopidogrel 150-mg/day ACS Standard Therapy placebo loading dose, then clopidogrel 75mg +placebo/day Random Selection Standard Therapy placebo loading dose clopidogrel 75mg +placebo/day Clinical Follow-up And Platelet Function Assessment at 30 days, 6M Primary Endpoint: 6 month CV Death, Non-Fatal MI, ARC definite/prob ST Safety Endpoint: GUSTO Moderate or Severe Bleeding *total first day dose Price MJ et al, Am Heart J 2009

17 The Degree of CYP2C19 Inhibition Differs Among The Proton Pump Inhibitors Ki (μm) Ki = concentration required to decrease metabolic activity by 50% Li XQ et al, Drug Metab Dispos 2004;32(8):821-7

18 Omeprazole CLopidogrel Aspirin (OCLA) Study: A randomized, placebo controlled trial of the influence of omeprazole on the PD effect of clopidogrel N=120 (60 each group) VASP PRI (%) day 1 VASP PRI (%) day 7 Lower PRI means greater platelet inhibitory effect Gilard M et al, J Am Coll Cardiol. 2008;51(3):

19 Influence of PPI Therapy on Outcome After ACS in Clopidogrel Treated Patients A Retrospective Analysis N= CLOP + PPI + CLOP - PPI Ho et al, JAMA. 2009;301(9):

20 TRITON: Primary endpoint stratified by use of a PPI PPI use at randomization (n= 4529) 14% 12% No PPI PPI Clopidogrel CV death, MI or stroke 10% 8% 6% 4% 2% PPI Prasugrel No PPI CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI % Days O Donoghue et al, Lancet. 2009;374(9694):989-97

21 COGENT Bhatt et al, TCT 2009

22 COGENT No PPI-clopidogrel interaction, or a net null effect? Interference with clop effect balanced by Prevention of events that precipitate DAPT d/c? Bhatt et al, TCT 2009

23 FAMOUS: Famotidine 20-mg Bid for the Prevention of Esophagitis in Patients Taking Low-Dose Aspirin Incidence of peptic ulcers Grades of erosive esophagitis P< p= p= Taha et al, Lancet 2009;374:119-25

24 Summary CURRENT-OASIS 7: no ischemic benefit of short course of high-dose clopidogrel in ACS patients undergoing an invasive management strategy, with higher rates of major bleeding. Sub-group analysis of the PCI population appears to show ischemic benefit with high-dose therapy. Carriage of a CYP2C19 loss-of-function allele, which decreases clopidogrel AM generation and reduces its antiplatelet effect, has been associated with MACE in TRITON and in other trials. Homozygosity (poor metabolizers substantially higher risk)

25 Summary (2) CYP2C19 genotype explains only a portion of the variability of clopidogrel s antiplatelet effect. Randomized trials of tailored antiplatelet therapy based on platelet function testing (phenotype), such as GRAVITAS, are ongoing. The PPI story is still not finished. If GI treatment is necessary, consider pantoprazole, rabeprazole, or, famotidine.