Stents Are Not Enough: Recent Clopidogrel Data Rob Henderson Nottingham City Hospital Rob Henderson Nottingham City Hospital

Stent thrombosis - ‘Thrombus Horribilis’ In early 1990’s stent thrombosis occurred in ~4% of elective cases within 2d to 4 weeks Associated with high risk of MI (60-90%) and death (12-17%) In early 1990’s stent thrombosis occurred in ~4% of elective cases within 2d to 4 weeks Associated with high risk of MI (60-90%) and death (12-17%) Bittl JA, JACC 1996; 28: Hasdai D, JACC 1996;28:361-7 Mak KH, JACC 1996;27:

Eur Heart J 2000;21: OR95%CI ISAR, 1996 STARS, 1998 MATTIS, 1998 FANTASTIC, 1998 Total ISAR, 1996 STARS, 1998 MATTIS, 1998 FANTASTIC, 1998 Total Study p=0.002, test for heterogeneity p=0.51 Aspirin + ticlopidine vs aspirin + warfarin after coronary stenting Aspirin and ticlopidine better Aspirin and ticlopidine better Aspirin and warfarin better Aspirin and warfarin better Odds of death or MI

CLASSICS - clopidogrel versus ticlopidine after coronary stenting Circulation 2000;102:624 Safety (major bleed, neutropenia, thrombocytopenia, early drug discontinuation) Safety (major bleed, neutropenia, thrombocytopenia, early drug discontinuation) Efficacy (Cardiac death, MI, TVR) Efficacy (Cardiac death, MI, TVR) P=0.005 NS

Clopidogrel - thienopyridine of choice dose? pre-treatment? duration of treatment? role with IIbIIIa receptor antagonists? dose? pre-treatment? duration of treatment? role with IIbIIIa receptor antagonists?

CURE: trial design

NEJM 2001;345:494 CURE: primary endpoint - CV death/MI/stroke Clopidogrel + ASA Placebo + ASA Months of Follow-Up 11.4%11.4% 9.3%9.3% 20% RRR P < N = 12,562 20% RRR P < N = 12, Cumulative Hazard Rate Δ2.1% Excess of 1 life-threatening and 6 major bleeds per 1000 patients treated with clopidogrel

Effect of aspirin dose in CURE CV death, MI, stroke, refractory angina Major bleeding Aspirin dose P<0.001 Peters, Circulation 2003; 108: 1682

PCI-CURE: 30 day results Effect of pre-treatment with clopidogrel Days of follow-up % RRR P = 0.03 N = % RRR P = 0.03 N = 2658 Cumulative Hazard Rate * Includes open label thienopyridine 6.4% 4.5% Clopidogrel + ASA* Placebo + ASA* Composite of cardiovascular death, MI, or urgent revascularization Mehta, Lancet 2001; 21: 2033 Δ1.9%

PCI-CURE – long-term results Mehta Lancet 2001;358:527 Placebo + ASA Days of follow-up 12.6% 8.8% P = N = 2658 Cumulative Hazard Rate 31% RRR Composite of cardiovascular death or MI from randomization to end of follow-up Clopidogrel + ASA Caveat - PCI-CURE was not a randomised trial Δ2.8%

CREDO: Clopidogrel for the Reduction of Events During Observation Aspirin in all patients IIbIIIa antagonist in 45% Aspirin in all patients IIbIIIa antagonist in 45%

Combined Endpoint Occurrence (%) Combined Endpoint Occurrence (%) Days From Randomization *Plus ASA and other standard therapies Death, MI, UTVR - PP Population (N=1815) 18.5% RRR, 95%CI to 41.8, p= % 6.8% Steinhubl, JAMA 2002; 288: 2411 CREDO - Pre-treatment with clopidogrel Clopidogrel pre-treatment No pre-treatment Δ1.5%

* Plus ASA and other standard therapies CREDO: 12 month benefits of clopidogrel in PCI patients Steinhubl, JAMA 2002; 288: 2411 Δ2.0%

CREDO – loading dose timing and 28d MACE (D/MI/urgent TVR) Steinhubl, TCT 2003

CREDO – clopidogrel loading dose timing and MACE at 28d in per protocol patients (n=1762) Hours prior to PCI of study drug loading dose Log odds of death, MI or urgent TVR at 28 days Placebo Clopidogrel P=0.020 for treatment / timing interaction P=0.020 for treatment / timing interaction Steinhubl, TCT 2003

Clopidogrel loading dose – bigger is better? Müller Heart 2001;85;92-3 Time after administration (hours) µmol ADP-induced platelet aggregation (%) 20µmol ADP-induced platelet aggregation (%) Ticlopidine 2x 500mg, then 250 bd (n=10) Clopidogrel 300mg, then 75mg od (n=10) Clopidogrel 600mg, then 75mg bd (n=10)

ISAR-REACT - trial design 2,159 low-risk patients undergoing elective stenting, excluding patients with: Acute coronary syndromeAcute MI with 14 days ST-segment depressionPositive biomarkers Insulin-dependent diabetesChronic total occlusions Lesions in bypass grafts Thrombus presence EF <=30% 2,159 low-risk patients undergoing elective stenting, excluding patients with: Acute coronary syndromeAcute MI with 14 days ST-segment depressionPositive biomarkers Insulin-dependent diabetesChronic total occlusions Lesions in bypass grafts Thrombus presence EF <=30% Endpoints: Primary – 30 day death / MI / urgent target vessel revascularization Secondary –30 day bleeding complications Endpoints: Primary – 30 day death / MI / urgent target vessel revascularization Secondary –30 day bleeding complications Abciximab (n = 1,079) Placebo (n = 1,080) Aspirin at least 100mg od and Clopidogrel (600 mg loading, 75 mg bd to discharge, 75 mg od for 4 weeks) Aspirin at least 100mg od and Clopidogrel (600 mg loading, 75 mg bd to discharge, 75 mg od for 4 weeks) Kastrati, NEJM 2004; 350: 232

ISAR-REACT: efficacy analysis at 30 days No significant differences Kastrati, NEJM 2004; 350: 232 All patients had clopidogrel 600mg loading, then maintenance Rx

ISAR-REACT: death, MI or urgent TVR at 30d Days after randomization Cumulative incidence (%) Abciximab Placebo Relative risk 1.05 (95%CI ; p=082) Underpowered for triple endpoint at 30d Relative risk 1.05 (95%CI ; p=082) Underpowered for triple endpoint at 30d Kastrati, NEJM 2004; 350: 232 All patients had clopidogrel 600mg loading, then maintenance Rx N=2159

ISAR-REACT: safety analysis p=0.002 Kastrati, NEJM 2004; 350: 232 p=0.007 All patients had clopidogrel 600mg loading, then maintenance Rx

Thienopyridine use in drug-eluting stent trials TrialStent Thienopyridine (mg) IIbIIIaFUN Stent thrombosis DESControl Ravel Sirolimus (Cordis) Clopidogrel 300 loading and 75 od, or Ticlopidine 250 bd for 2/12 9.8%23800 E-SIRIUS Sirolimus (Cordis) Clopidogrel 300 loading + 75 od, or Ticlopidine 250 bd for 2/ %3521.1%0 SIRIUS Sirolimus (Cordis) Clopidogrel loading, 75 od for 3/12 60% %0.8% ASPECT Paclitaxel (Cook) Ticlopidine loading, then 1 or 6/12 Clopidogrel loading, then 1 or 6/12 Cilostazol 1.1% %000 TAXUS2 Paclitaxel (Boston) Clopidogrel 300 loading, then 75 od for 6/12 NA4020.4% TAXUS4Paclitaxel(Boston) 57%12/ %0.8% TAXUS6Paclitaxel(Boston) NA446NANA

Randomised trial evidence for prolonged clopidogrel treatment after DES placement

Prodrug clopidogrel is metabolised to active metabolite by cytochrome P450 (?isozymes 3A4 and 3A5) Atorvastatin (and other statins) also metabolised by CP450 3A4 Some ex-vivo evidence that co- administration of these drugs inhibits activation of clopidogrel Prodrug clopidogrel is metabolised to active metabolite by cytochrome P450 (?isozymes 3A4 and 3A5) Atorvastatin (and other statins) also metabolised by CP450 3A4 Some ex-vivo evidence that co- administration of these drugs inhibits activation of clopidogrel Does atorvastatin reduce the effect of clopidogrel on platelet aggregation? Clarke, Drug Metab Disp 2003; 31: 53 Lau, Circulation 2003;107:32 Clarke, Drug Metab Disp 2003; 31: 53 Lau, Circulation 2003;107:32

CREDO – no clinically important interaction between statins and clopidogrel Saw, Circulation 2003; 108: 921 No statistical evidence of a clinically important interaction between statin use and effect of clopidogrel

Clopidogrel resistance Several studies demonstrate marked inter- patient variability in response to clopidogrel No consistent definition of ‘resistance’ but reported incidence ranges from 4.8% to 31% Clinical significance of clopidogrel ‘resistance uncertain Aspirin resistance increases risk of death, MI or stroke 3-fold during 1-2 year follow-up Several studies demonstrate marked inter- patient variability in response to clopidogrel No consistent definition of ‘resistance’ but reported incidence ranges from 4.8% to 31% Clinical significance of clopidogrel ‘resistance uncertain Aspirin resistance increases risk of death, MI or stroke 3-fold during 1-2 year follow-up Müller, Thromb Haemost 2003; 89: 783 Gurbel, Circulation 2003; 107: 2908 Gum, JACC 2003;41: 961 Müller, Thromb Haemost 2003; 89: 783 Gurbel, Circulation 2003; 107: 2908 Gum, JACC 2003;41: 961

Hollopeter, Nature 2001;409:202 Fontana, Circulation 2003;108:989 Hollopeter, Nature 2001;409:202 Fontana, Circulation 2003;108:989 Normal platelet aggregation requires simultaneous activation of Gq and Gi pathways by ADP Normal platelet aggregation requires simultaneous activation of Gq and Gi pathways by ADP * Phosphoinositide 3-kinase pathway? P2Y12 ADP receptor is target of clopidogrel Transient  Ca 2+ Transient  Ca 2+ Platelet shape change and reversible aggregation GqGq GqGq GiGi GiGi Adenylate cyclase inhibition  cAMP P2Y 12 P2Y 1 Thienopyridine ADP Progressive and sustained platelet aggregation Progressive and sustained platelet aggregation GPIIbIIIa activation * *

Maximal platelet aggregation in response to 2µmol/L ADP for different P2Y 12 haplotype Mean maximal aggregation (%) H1/H1 H1/H2 H2/H2 n=74 n=21 n=3 34.7% 67.9% 82.4% P2Y 12 platelet receptor haplotype Fontana, Circulation 2003;108:989

Clopidogrel in PCI patients Pretreatment has a small but important beneficial effect on MACE rate Whenever possible start early (3-5 days) or give loading dose (600mg within 12-15h) Optimal duration of treatment uncertain –In ACS continue clopidogrel at least 3 months but cost efficacy of longer-term treatment uncertain –DES trials used 3-6 months Combine with low-dose aspirin (75mg) Pretreatment has a small but important beneficial effect on MACE rate Whenever possible start early (3-5 days) or give loading dose (600mg within 12-15h) Optimal duration of treatment uncertain –In ACS continue clopidogrel at least 3 months but cost efficacy of longer-term treatment uncertain –DES trials used 3-6 months Combine with low-dose aspirin (75mg)

Clopidogrel in PCI patients Combined use of clopidogrel and IIbIIIa antagonist may increase bleeding risk In low risk PCI abciximab may not add major benefit to clopidogrel 600mg loading at least 2h pre-procedure Currently no evidence of clinically important clopidogrel / statin interaction Clopidogrel ‘resistance’ occurs ex vivo but no data to support clinical relevance Combined use of clopidogrel and IIbIIIa antagonist may increase bleeding risk In low risk PCI abciximab may not add major benefit to clopidogrel 600mg loading at least 2h pre-procedure Currently no evidence of clinically important clopidogrel / statin interaction Clopidogrel ‘resistance’ occurs ex vivo but no data to support clinical relevance