Plavix - Clinical Pharmacology

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The CURE study included 12,562 patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q-wave myocardial infarction) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST segment elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients >65 years of age.

Patients were randomized to receive PLAVIX (300 mg loading dose followed by 75 mg/day) or placebo, and were treated for up to one year. Patients also received aspirin (75-325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.30%) in the PLAVIX-treated group and 719 (11.41%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the PLAVIX-treated group (see Table 2).

At the end of 12 months, the number of patients experiencing the co-primary outcome (CV death, MI, stroke or refractory ischemia) was 1035 (16.54%) in the PLAVIX-treated group and 1187 (18.83%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the PLAVIX-treated group (see Table 2).

In the PLAVIX-treated group, each component of the two primary endpoints (CV death, MI, stroke, refractory ischemia) occurred less frequently than in the placebo-treated group.

Table 2: Outcome Events in the CURE Primary Analysis

Outcome PLAVIX

(+aspirin)*

(n=6259)

Placebo

(+aspirin)*

(n=6303)

Relative Risk

Reduction (%)

(95% CI)

Primary outcome

(Cardiovascular death, MI, Stroke) 582

(9.3%) 719

(11.4%) 20%

(10.3, 27.9)

P=0.00009

Co-primary outcome

(Cardiovascular death, MI, Stroke, Refractory Ischemia) 1035

(16.5%) 1187

(18.8%) 14%

(6.2, 20.6)

P=0.00052

All Individual Outcome Events: †

CV death 318

(5.1%) 345

(5.5%) 7%

(-7.7, 20.6)

MI 324

(5.2%) 419

(6.6%) 23%

(11.0, 33.4)

Stroke 75

(1.2%) 87

(1.4%) 14%

(-17.7, 36.6)

Refractory ischemia 544

(8.7%) 587

(9.3%) 7%

(-4.0, 18.0)

* Other standard therapies were used as appropriate.

† The individual components do not represent a breakdown of the primary and co-primary outcomes, but rather the total number of subjects experiencing an event during the course of the study.

The benefits of PLAVIX were maintained throughout the course of the trial (up to 12 months).

Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study

In CURE, the use of PLAVIX was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with PLAVIX were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH (low molecular weight heparin), IV glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of PLAVIX was observed independently of the dose of aspirin (75-325 mg once daily). The use of oral anticoagulants, non-study anti-platelet drugs and chronic NSAIDs was not allowed in CURE.

Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study

The use of PLAVIX in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the PLAVIX group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%, P=0.0001), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the PLAVIX group, 454 patients [7.2%] in the placebo group; relative risk reduction of 18%, P=0.003). The use of PLAVIX in CURE did not impact the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the PLAVIX group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%, P=0.1658).