Clopidogrel in ACS: Overview Investigator, TIMI Study Group Associate Physician, Cardiovascular Division, BWH Assistant Professor of Medicine, Harvard Medical School Marc S. Sabatine, MD, MPH
Clopidogrel: Mechanism ADP = adenosine diphosphate, TXA 2 = thromboxane A 2, COX = cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101: Collagen Thrombin TXA 2 ADP Receptor (P2Y 12 ) TXA 2 ADP ADP GP IIb/IIIa receptor Activation COX Clopidogrel Ticlopidine Fibrinogen
Clopidogrel in NSTE ACS: CURE CURE. NEJM 2001;345: ,563 Pts, GP IIb/IIIa & early invasive approach discouraged RR 0.80, p<0.001 Clopidogrel (9.3%) Placebo (11.4%) CV Death, MI, Stroke Months of follow-up
Yusuf S et al. Circulation 2003;107: CURE: Very Early Efficacy of Clopidogrel in NSTE ACS Hours After Randomization P=.003 Placebo + Aspirin (n=6303) Clopidogrel + Aspirin (n=6259) 34% Relative Risk Reduction CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours Cumulative Hazard Rate
Fox et al. Circulation. 2004;110: Medical Rx Group Placebo Clopidogrel RR: 0.80 ( ) Clopidogrel PCI Group Placebo RR: 0.72 ( ) CABG Group Placebo Clopidogrel RR: 0.89 ( ) CURE: Benefit by Revascularization CVD/MI/Stroke
CURE Safety Results RR 1.38 (95% CI ) P=0.001 NEJM 2001;345:
Clopidogrel in STEMI Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups
Clopidogrel in STEMI PlaceboClopidogrel 36% P< % P< Sabatine MS et al. NEJM 2005; 352: 1179 days CV Death, MI, or Urg Revasc (%) Placebo Clopidogrel Odds Ratio 0.80 (95% CI ) P= %20%
Bleeding Outcome Clopidogrel (%) Placebo (%) P value Through angiography TIMI major (Hgb >5 g/dL or ICH) NS TIMI minor (Hgb 3-5 g/dL) NS Intracranial hemorrhage NS Through 30 days TIMI major NS In those undergoing CABG NS CABG w/in 5 d of study med NS TIMI minor NS Sabatine MS et al. NEJM 2005; 352: 1179
COMMIT: Clopidogrel (75 mg qd) in STEMI 9% relative risk reduction (P=.002) Placebo (10.1%) Clopidogrel (9.3%) Days Death, MI, Stroke (%) Mortality (%) Days Placebo (8.1%) Clopidogrel (7.5%) 7% relative risk reduction (P=.03) COMMIT Collaborative Group. Lancet. 2005;366: ,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)
Type Clopidogrel Placebo (n=22,958) (n=22,891) Cerebral Fatal3940 Non-fatal1615 Non-cerebral Fatal3637 Non-fatal4636 Any major bleed (0.58%) (0.54%) COMMIT: Major bleed in hospital Chen Z et al. Lancet 2005;366:
PCI – Rx following PCI Following percutaneous coronary intervention (PCI), treatment with ADP receptor blockers such as ticlopidine or clopidogrel reduces thrombotic & ischemic complications. Aspirin Aspirin + warfarin Aspirin + ticlopidine P=0.001 CREDO Steinhubl et al. JAMA. 2002; 288: STARS Leon et al. NEJM 1998; 339: Months after PCI 11.5% 8.5% Placebo + ASA Clopidogrel + ASA 27% RRR P = 0.02 Death/MI/stroke
PCI – PCI-CLARITY Design 30-day clinical follow-up 933 underwent PCI during index hosp. 930 underwent PCI during index hosp Patients Randomized into CLARITY-TIMI assigned clopidogrel 300 mg 75 mg/d 1739assigned placebo Open-label clopidogrel w/ loading dose recommended (CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT) A n g i o g r a p h y
PCI – CV Death, MI, or Stroke following PCI Days post PCI Percentage with outcome (%) No Pretreatment – 6.2% Clopidogrel – 3.6% Pretreatment 46%46% Odds Ratio 0.54 (95% CI ) P=0.008 Odds Ratio 0.54 (95% CI ) P=0.008 Sabatine MS et al. JAMA 2005;294:
Clopidogrel No TrialPretreatmentPretreatment PCI-CURE CREDOn/an/a PCI-CLARITY Overall ClopidogrelNo TrialPretreatmentPretreatment PCI-CURE CREDO PCI-CLARITY Overall Meta-Analysis of Clopidogrel Pretreatment OR (95% CI) CV Death or MI after PCI (%) MI before PCI (%) OR 0.67 P=0.005 P=0.005 Favors Pretreatment Favors No Pretreatment OR 0.71 P=0.004 P=0.004 Sabatine MS et al. JAMA 2005;294:
TrialClopi PreRxNo PreRx PCI-CURE27/1039 (2.6)39/988 (3.9) CREDO26/473 (5.5)34/519 (6.6) PCI-CLARITY22/639 (3.4)30/615 (4.9) OVERALL75/2151 (3.5)103/2122 (4.9) TrialClopi PreRxNo PreRx PCI-CURE14/274 (5.1)23/357 (6.4) CREDO29/427 (6.8)32/396 (8.1) PCI-CLARITY12/288 (4.2)28/310 (9.0) OVERALL55/989 (5.6)83/1063 (7.8) Efficacy of Clopidogrel PreRx by GPI Use OR (95% CI) OR 0.72 ( )P=0.03 ( )P=0.03 Favors PreRx Favors No PreRx OR 0.69 ( )P=0.05 ( )P=0.05 Without GPI P=0.85 for heterogeneity by GPI use With GPI Sabatine MS et al. AHJ in press.
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA): Study Design Double-blind treatment up to 1,040 primary efficacy events occur* Aspirin 75–162 mg once daily Clopidogrel 75 mg once daily (n=7600) Placebo 1 tab once daily (n=7600) Aspirin mg once daily Final study visit (fixed study end date) 1-month visit 3-month visit Patients 45 years or older who are at high risk of atherothrombotic events R = randomization. N=15,603 R Bhatt et al. Am Heart J. 2004;148:263 *Event-driven trial: primary efficacy outcome of vascular death, MI, stroke Visits every 6 months (12 m, 18 m…), and intermediate phone calls in between (15 m, 21m…) 6-month visit
Overall Population: Primary Efficacy Outcome (CV Death, MI, or Stroke) Bhatt DL et al. NEJM 2006;354: Cumulative event rate (%) Months since randomization Placebo + ASA 7.3% Clopidogrel + ASA 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22
Overall Population: Safety Results Clopidogrel Placebo + ASA+ ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI)p value GUSTO Severe Bleeding130 (1.7)104 (1.3)1.25 (0.97, 1.61)0.09 Fatal Bleeding26 (0.3)17 (0.2)1.53 (0.83, 2.82)0.17 Primary ICH26 (0.3)27 (0.3)0.96 (0.56, 1.65)0.89 GUSTO Moderate Bleeding164 (2.1)101 (1.3)1.62 (1.27, 2.08)<0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL et al. NEJM 2006;354:
CHARISMA Study: Primary Efficacy Results (CV Death, MI, or Stroke) by Prespecified Entry Category PopulationRR (95% CI)P value Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998)0.046 (n=12,153) Multiple Risk Factors 1.20 (0.91, 1.59)0.20 (n=3284) Overall Population0.93 (0.83, 1.05)0.22 (n=15,603) Clopidogrel BetterPlacebo Better (P interaction =0.045) Bhatt DL et al. NEJM 2006;354:
Primary Endpoint (CV Death, MI, or Stroke) in Patients with Previous MI, IS, or PAD “CAPRIE-like Cohort” RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01 Primary outcome event rate (%) Months since randomization Clopidogrel + ASA 7.3% Placebo + ASA 8.8% N=9,478 Bhatt DL et al. JACC 2007;49:1982
Conclusions Upstream clopidogrel given across the spectrum of ACS death and ischemic complications Treatment benefit emerges early and is comparable regardless of ultimate revasc. Treatment mandated in patients after stenting Clopidogrel pretreatment before PCI death or ischemic complications after PCI, regardless of GP IIb/IIIa use Long-term use not beneficial in 1° prevention; may be beneficial in 2° prevention
Clopidogrel in the Guidelines SettingSocietyRecommendationGrade UA/ NSTEMI ACC/AHA mg upstream in INV strategy 300 mg upstream + GPI in INV 300 mg ASAP in CONS strategy I IIa I ESC mg immediately in all patientsI STEMI (non 1 PCI) ACC/AHA mg in all patients 300 mg load if age <75 yrs I IIa PCI ACC/AHA/ SCAI mg 6 hrs before PCI I ESC mg 6 hrs before PCI I