PLAVIX Clinical Trials
CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) Trial

The CURE trial (Clopidogrel in Unstable angina to prevent Recurrent Events) was a randomized, double-blind, placebo-controlled, multicenter study of 12,562 men and women from 482 centers in 28 countries presenting within 24 hours of acute chest pain or symptoms consistent with ischemia. Patients diagnosed with acute coronary syndrome (ACS) were randomized to a 300 mg PLAVIX oral loading dose followed by 75 mg PLAVIX once daily or to placebo for up to 1 year (mean: 9 months). All patients received aspirin (75 mg-325 mg). 18

Inclusion Criteria 17

  • ACS without ST-segment elevation (unstable angina or non-Q-wave MI)
  • Presentation within 24 hours of symptom onset
  • ECG changes compatible with new ischemia, or elevation of cardiac enzymes or troponin I or T to at least twice upper limit of normal
  • No history of coronary revascularization within 3 months prior to study
  • No intravenous IIb/IIIa receptor inhibitors within 3 days prior to study

Efficacy

Clopidogrel, in addition to ASA and other standard therapy, provided a 20% RRR in the combined co-primary end point of MI, stroke, or cardiovascular death (95% CI, 0.72–0.90, P=0.00009). 14, 17 Overall, there were 719 (11.4%) first events in the placebo plus ASA group and 582 (9.3%) in the clopidogrel plus ASA group. The hazard rate curves began to separate within the first few hours after therapy initiation and remained separated over the course of the trial. 17

Efficacy of PLAVIX + Aspirin vs. Aspirin + Placebo in Reducing the combined risk of MI, Ischemic Stroke, and Vascular Death in UA/NSTEMI (CURE chart)

The addition of clopidogrel to ASA and other standard therapy significantly reduced the rate of the co-primary end point of MI, stroke, cardiovascular death, or refractory ischemia (16.5% vs 18.8%, RRR 14%, 95% CI, 6.2–20.6, P=0.0005). 14

Safety

CURE Safety of PLAVIX + Aspirin vs. Aspirin + Placebo for Selected Adverse Events (table)


PLAVIX + Aspirin vs. Placebo + Aspirin for Major Bleeding by Aspirin Dose (CURE table)

Definition of major bleeding:
Life–threatening bleeding, which was defined as fatal or leading to one of the following: intracranial hemorrhage, drop in hemoglobin of ≥5 g/dL, substantial hypotension requiring inotropic therapy, surgical intervention, or transfusion of four or more units of blood. 17

Other major bleeding was defined as substantially disabling bleeding, intraocular bleeding leading to the loss of vision, or bleeding necessitating the transfusion of two to three units of blood.

Major bleeding episodes were primarily gastrointestinal hemorrhages or bleeding at site of arterial puncture. 14 The incidence of major bleeding increased with aspirin (ASA) dose in both treatment groups, with the highest incidence among patients receiving more than 200 mg of ASA. 17

The risk of major or minor bleeding was increased for the clopidogrel and aspirin (ASA) group compared with the placebo plus ASA group (major bleeding: 3.7% vs 2.7%, respectively, P=0.001; minor bleeding 5.1% vs 2.4%, respectively, P<0.001).

Major bleeds were increased both early (<30 days) and late (>30 days). The principal sites for major bleeding included gastrointestinal and at arterial-puncture sites. 14

The percentage of patients receiving transfusions of two or more units of blood was higher in the clopidogrel plus ASA group (2.8% vs 2.2%, P=0.02). 14

Indications
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Use PLAVIX plus aspirin for patients with non–ST–segment elevation acute coronary syndrome (UA/non–Q–wave MI), including patients to be managed medically and those to be managed with percutaneous coronary intervention (with or without stent) or CABG, to decrease the rate of a combined end point of CV death, MI, or stroke as well as the rate of a combined end point of CV death, MI, stroke, or refractory ischemia.

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Use PLAVIX plus aspirin for patients with ST–segment elevation acute myocardial infarction to reduce the rate of death from any cause and the rate of a combined end point of death, reinfarction, or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.

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Use PLAVIX alone for patients with a history of recent stroke, recent MI, or established PAD to reduce the rate of a combined end point of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
Important Risk Information 18
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PLAVIX is contraindicated in patients with active pathologic bleeding such as peptic ulcer or intracranial hemorrhage. PLAVIX should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or coadministration with NSAIDs or warfarin. (See CONTRAINDICATIONS and PRECAUTIONS.*)

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The rates of major and minor bleeding were higher in patients treated with PLAVIX plus aspirin compared with placebo
plus aspirin in clinical trials. (See ADVERSE REACTIONS.*)

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Due to an expected reduction in drug levels and clinical efficacy, concomitant use of drugs that inhibit CYP2C19 (eg, omeprazole) should be discouraged. (See PRECAUTIONS.*)

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As part of the worldwide post–marketing experience with PLAVIX, there have been cases of reported thrombotic thrombocytopenic purpura (TTP), some with fatal outcome. TTP has been reported rarely following use of PLAVIX, sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). (See WARNINGS.*)

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Based on literature, patients with genetically reduced CYP2C19 function have diminished responses and generally exhibit higher CV event rates following MI. (See PRECAUTIONS.*)

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In clinical trials, the most common clinically important side effects were pruritus, purpura, diarrhea, and rash; infrequent events included intracranial hemorrhage (0.4%) and severe neutropenia (0.05%). (See ADVERSE REACTIONS.*)