CURE CURE (OASIS-4) Clopidogrel in Unstable Angina to prevent Recurrent ischemic Events

CURE Atherothrombosis: a Generalized and Progressive Process Normal Fatty streak Fibrous plaque Athero- sclerotic plaque Plaque rupture/ fissure & thrombosis MI Ischemicstroke/TIA Critical leg ischemia Clinically silent Cardiovascular death Increasing age Stable angina Intermittent claudication Unstableangina } ACS ACS, acute coronary syndrome; TIA, transient ischemic attack

CURE Based on data from the Atherosclerotic Risk in Communities study (ARIC) of the National Heart, Lung, and Blood Institute, 1987–94. Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs. American Heart Association, 2001, Heart and Stroke Statistical Update Epidemiology of MI and Angina in the USA Single largest cause of death – deaths in the USA in 1998 –1 in every 5 deaths Incidence – Americans will have a new or recurrent coronary attack each year. Over 40% of people who experience a coronary attack in a given year will die of it in the same year – new cases of stable angina and about new cases of unstable angina per year Prevalence – with a history of MI, angina, or both

CURE Hospitalizations in the USA Due to ACS Acute Coronary Syndromes 1.5 million hospital admissions per year Unstable angina Myocardial infarction (Q-wave and non-Q-wave) Cairns J et al Can J Cardiol 1996;12:1279– admissions

CURE Théroux P et al Circulation 1998; 97:1195–1206 The Role of Antiplatelet Therapy in Unstable Angina and Non-Q-wave MI Atherothrombosis is a generalized disease affecting the coronary, cerebral and peripheral circulations Unstable angina/non-Q-wave MI is one of the classic examples of the progression of atherothrombotic disease Platelets play a key role in thrombus formation associated with rupture of an unstable atherosclerotic plaque Angioscopic findings show that unstable angina is due to the formation of a platelet-rich thrombus Consequently, antiplatelet therapy is recognized as the foundation of long-term management

CURE Efficacy of Antiplatelet Therapy: Antiplatelet Trialists’ Collaboration Antiplatelet Trialists’ Collaboration BMJ 1994;308:81–106 Prior MI111331/ /991425% (4) Acute MI9992/ /938529% (4) Prior stroke/181076/ /587022% (4) TIA Unstable angina 7182/ /2027 Category of trial No. of trials with data Anti- platelet Adjusted controls Odds ratio and confidence interval (Antiplatelet: control) % odds reduction (SD) MI, stroke, or vascular death Antiplatelet therapy better Antiplatelet therapy worse TIA, transient ischemic attack

CURE UA: CV Death or MI - ASA vs Placebo % of Patients with Event Cairns et al NEJM 1985;313: Efficacy: Cardiac Death or Non-Fatal MI At Risk ASA (263) No ASA (274) (174) (180) (137) (144) (107) (115) (73) (80) Time

CURE The Role of an ADP Receptor Antagonist Clopidogrel is an advanced ADP receptor antagonist and inhibits platelet aggregation by antagonizing the effects of ADP Clopidogrel is indicated for the reduction of atherothrombotic events in patients with a history of stroke, MI or peripheral arterial disease. Clopidogrel is at least as safe as ASA Combining clopidogrel with ASA may potentially lead to greater benefit Jarvis B et al Drugs 2000;60:347–377 Antiplatelet Trialists’ Collaboration BMJ 1999;308:81–106 CAPRIE Steering Committee Lancet 1996:348:1329–1339

CURE Complementary Mode of Action between Clopidogrel and ASA COX, cyclooxygenase; ADP, adenosine diphosphate; TxA 2, thromboxane A 2 Schafer AI Am J Med 1996;101:199–209

CURE Trials of ADP-receptor Antagonists vs Placebo in Patients with Atherosclerosis Trial, YearSettingPrimary OutcomeOdds Ratio95% CI DefinitionThieno- pyridine (n/N) Comparator (n/N) Thienopyridine versus Placebo or Control CATS 1989 (Ticlopidine vs Placebo Recent Stroke Death, MI, Stroke 106/525134/ Balsano 1990 (Ticlopidine vs Control) Unstable Angina Death, MI23/31446/ STIMS 1990 (Ticlopidine vs Placebo) Intermittent Claudication Death, MI, Stroke 89/34699/ TOTAL218/ / CURE Study Investigators Eur Heart J 2000; 21:

CURE Trials of ADP-receptor Antagonists vs ASA in Patients with Atherosclerosis Trial, YearSettingPrimary OutcomeOdds Ratio95% CI DefinitionThieno- pyridine (n/N) Comparator (n/N) Thienopyridine versus ASA TASS, 1989 (Ticlopidine vs ASA) Cerebral Ischemia Death, Stroke 306/ / CAPRIE, 1996 (Clopidogrel vs ASA) Recent Stroke, Previous MI or PVD Death, MI, Stroke 939/ / TOTAL1245/ / CURE Study Investigators Eur Heart J 2000; 21:

CUREStudy HALL, 1996 STARS, 1998* TOTAL Odds Ratio 95% CI P= Test for heterogeneity P=0.66 ASA + Ticlopidine versus ASA after Coronary Artery Stenting Page 30 of 30 Death or MI CURE Study Investigators Eur Heart J 2000; 21: Combination Better ASA Alone Better

Study ISAR, 1996 MATTIS, 1998 TOTAL Odds Ratio 95% CI P=0.002 Test for heterogeneity P=0.51 ASA + Ticlopidine vs ASA + Oral Anticoagulation after Stenting FANTASTIC, STARS, Death or MI Combination Better ASA Alone Better CURE Study Investigators Eur Heart J 2000; 21: CURE

CURE Effect of Clopidogrel Alone or in Combination with ASA on Thrombus Formation: Animal Model Time (min) Clopidogrel + ASA ( mg/kg) Clopidogrel (10 mg/kg) ASA (10 mg/kg) Placebo Herbert JM et al Thromb Haemost 1998;80:512–518 Blood flow (% decrease)

CURE Rapid and Synergistic Effect of Clopidogrel on top of ASA (Healthy Volunteers) Mean reduction of platelet deposition compared with ASA alone Cadroy Y et al Circulation 2000;101:2823–2828 C75+ASA vs ASA alone C300+ASA vs ASA alone Day hrs Day 1 6 hrs Day 10 6 hrs Mean reduction (%) p=0.03 vs ASA p<0.001 vs ASA p=0.04 vs ASA p<0.001 vs ASA p=0.03 p=0.01 p=NS n=18 for all comparisons

CURE Randomized, double-blind, parallel group, clinical trial of clopidogrel vs placebo in patients with ACS All patients receive ASA ( mg) International trial (28 countries) 12,562 patients (482 Hospitals) Central randomization 3-12 month Rx and follow-up Main outcomes: -CV death/MI, stroke -Above + refractory ischemia Study Design

CURE Study Objectives To evaluate if clopidogrel is superior to placebo in preventing a)CV death, MI, stroke (Primary at  0.045) b)Above and refractory ischemia (Co-primary at  0.01)

CURE Inclusion Criteria Ischemic symptoms, suspected to represent UA or MI without ST segment elevation Randomized within 24 hours of onset of CP and ECG evidence of ischemia at inclusion or already elevated cardiac enzymes or Troponin I or T to at least 2 x ULN* *Prior to June 1999, pts > 60 yrs with normal ECG allowed Revised July, 1999

CURE Outcome Definitions (1/2) CV Death: Excludes clear non-CV deaths MI: Two of three usual criteria (CP, ECG or enzyme changes) Stroke: Neurological deficit  24 hrs (CT/MRI encouraged) Refractory Ischemia: Inhosp*: recurrent ischemia on max med Rx + ECG changes + intervention  1 day After discharge: Rehosp for UA with ECG changes Severe Ischemia*: Changes similar to in hospital Refractory Ischema, but no intervention Recurrent Angina*: All other ischemic CP in hospital

CURE Outcome Definitions (2/2) Major Bleeds: Significantly disabling, intraocular (vision loss), or transfusion of  2 units Classified as Life Threatening if: Hb  > 5g/dl, hypotension needing IV inotropes, surgery to stop bleeding, symptomatic ICH or transfusion or  4 units of blood

CURE Patient Schedule 3 months  double-blind treatment  12 months Aspirin mg Clopidogrel (~6,250 patients) Placebo 1 tab o.d. (~6,250 patients) Aspirin mg Day 1 6 m. Visit9 m. Visit 12 m. or Final Visit 3 m. Visit Discharge Visit 1 m. Visit Patients with Acute Coronary Syndrome (UA or MI Without ST elevation) R loading dose 300 mg loading + 75 mg o.d. dose

CURE Sample Size (12,500) and Power Calculations Main EndpointsControl Event Rate 80% Power 90% Power CV Death/MI/Stroke10%14.7%16.9%  =0.045 (two-sided) 12%13.3%15.3% Above + Refractory ischemia 14%14.6%16.4%  =0.01 (two-sided) 16%13.6%15.3%

CURE: 12,562 from 482 centres in 28 countries

CURE Baseline Characteristics (1) PlaceboClopidogrel N=6303 % N=6259 % Male Female Unstable Angina74.9 MI w/o ST Elevation25.1 Abnormal ECG Elevated enzymes/marker25.3

CURE Baseline Characteristics (2) PlaceboClopidogrel N=6303 Mean (SD) N=6259 Mean (SD) Age64.2 (11.3) Heart rate73.0 (14.6)73.2 (14.8) Systolic BP134.1 (22.0)134.4 (22.5) Symptom onset to randomization (hrs) 14.1 (7.1)14.2 (7.2)

CURE Medications After Randomization in Hospital PlaceboClopidogrel % IV Heparin LMW Heparin Beta-blocker Any CCB36.0 ACE-I Lipid-lowering

CURE Temporary Interruptions by Procedure Any Procedure (PTCA + CABG + Other Surgery) PlacClop With procedure No. pts % interruptions(84%) Without procedure No. pts % interruptions(21%)(23%)

CURE ASA at Each Visit Placebo N = 6303 Clopidogrel N = 6259 % on ASAMedian Dose% on ASAMedian Dose Pre-Rand Since-Rand Month Month Month Month

CURE Outcomes 1 /2 PlacClop %RRCIp # Patients st Co-Primary < CV Death MI Stroke Non CV death

CURE Cumulative Hazard Rates for CV Death/MI/Stroke P < Clopidogrel Placebo Cumulative Hazard Rates Months of Follow-up Plac Clop No of Pts

CURE Cumulative Hazard Rates for CV Death/MI/Stroke up to 30 Days P = Clopidogrel Placebo Cumulative Hazard Rates Days of Follow-up No. Plac No. Clop

CURE Outcomes 2/2 PlacClop %RRCIp # Patients nd Co-Primary < Refract.Ischemia In hospital After Discharge Severe Ischemia < 0.001

CURE Cumulative Hazard Rates for CV Death/MI/Stroke/RFA P < Clopidogrel Placebo Cumulative Hazard Rates Months of Follow-up Plac Clop No of Pts

CURE Events During Initial Hospitalization PlacClopRR (95% CI)P % Refract Isch ( )< Other Severe Ischemia ( )< Other Recurrent Angina ( )< 0.01 Heart Failure ( )< 0.027

CURE CV Death/MI/Stroke in Subgroups: (1) Subgroup 2NPlacebo % Clopidogrel % RRCI Major ST Dev Others With Enzyme Elevation Without Enzyme Elevation

CURE CV Death/MI/Stroke by Revascularization : (2) Subgroup 2NPlac % Clop % RRCI H/O Revasc Others Post Rand Revasc Post Rand Revasc

CURE Thrombolytic & GP IIb/IIIa Inhib use after Randomization Plac N=6303 Clop N=6259 RRCIp (%) Thrombolytics <0.001 IV GP IIb/IIIa Inhib

CURE Bleeding Complications PlaceboClopidogrelRR95% CIp # Patients Major2.7%3.7% Life Threatening 1.8%2.2% Other Major0.9%1.5% < Minor2.4%5.1% < Transfusion (2+Units) 2.2%2.8%

CURE TIMI Major Bleeding / GUSTO Severe- Life-Threatening Bleeding Criteria PlacClopRR (95% CI) P # Patients TIMI Criteria73 (1.2%) 68 (1.1%) GUSTO Criteria70 (1.1%) 78 (1.2%)

CURE Major/Life-Threatening Bleeds within 7 Days of CABG Surgery PlacClopRRp Stopped < 5 days prior to CABG N = 476N = 436 Pts with Maj/LT Bleeds6.3%9.6% Stopped > 5 days prior to CABG N = 454N = 456 Pts with Maj/LT Bleeds5.3%4.4%

CURE Thrombocytopenia and Neutropenia PlacClop # Rand Thrombocytopenia28 (0.44%)26 (0.42%) Neutropenia5 (0.1%)8 (0.13%)

CURE Conclusions Clopidogrel significantly reduces the risk of: a)CV Death, MI, Stroke by about one-fifth (p < 0.001) b)CV Death, MI, Stroke, and Refractory Ischemia by about one-sixth (p < 0.001) c)Early revascularization, severe and recurrent ischemia and heart failure by about one-fifth to one- quarter in hospital There is a small (absolute 1%) significant excess of major, but not life threatening, bleeds

CURE Clinical Implications Clopidogrel is beneficial both early and long term in patients with ACS, with a small excess in bleeds. The benefits are consistently observed in various subgroups examined and in addition to other established therapies. Treating 1000 patients for 9 months prevents about 27 major events in 23 patients at a cost of 4 life threatening bleeds (+ 2 other transfusions).

CURE Public Health Implications USA: 1.5 million MI per year  0.5 mill non-fatal non-Q MI 1.5 million UA pts per year Potential eligible for clopidogrel is about 2 million Major vascular events (CV death/MI/Stroke) reduced from about 250,000 to 200,000 (i.e. 12.5% to 10%) at one year. If patients are treated longer (e.g. 3 yrs) 500,000 reduced to 400,000 (i.e. 25% to 20%) Therefore 50,000 to 100,000 individuals will avoid a major vascular event in the USA per year Global impact: if one-fifth of eligible pts receive clopidogrel, 250,000–500,000 individuals could benefit