Plavix (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg.

Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).

Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).

14 CLINICAL STUDIES

14.1 Acute Coronary Syndrome

CURE

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) 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-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 once daily) 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 (9.3%) in the Plavix-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%–28%; p < 0.001) for the Plavix-treated group (see Table 4).

Table 4: Outcome Events in the CURE Primary Analysis
OutcomePlavix (+ aspirin)*Placebo (+ aspirin)*Relative Risk Reduction (%) (95% CI)
(n=6259)(n=6303)
*
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.
Primary outcome (Cardiovascular death, MI, stroke)582 (9.3%)719 (11.4%)20% (10.3, 27.9) p < 0.001
All Individual Outcome Events:
CV death 318 (5.1%)345 (5.5%)7% (-7.7, 20.6)
MI324 (5.2%)419 (6.6%)23% (11.0, 33.4)
Stroke75 (1.2%)87 (1.4%)14% (-17.7, 36.6)

Most of the benefit of Plavix occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 2).

Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study
Figure
(click image for full-size original)

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, intravenous 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 antiplatelet 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
Figure
(click image for full-size original)

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%), 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%). The use of Plavix in CURE did not affect 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%).

COMMIT

In patients with STEMI, the safety and efficacy of Plavix were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e. , ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive Plavix (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.

The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.

The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.

As shown in Table 5 and Figure 4 and Figure 5 below, Plavix significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002).

Table 5: Outcome Events in the COMMIT Analysis
EventPlavix (+ aspirin)(N=22961)Placebo (+ aspirin)(N=22891)Odds ratio(95% CI)p-value
*
The difference between the composite endpoint and the sum of death+non-fatal MI+non-fatal stroke indicates that 9 patients (2 clopidogrel and 7 placebo) suffered both a non-fatal stroke and a non-fatal MI.
Non-fatal MI and non-fatal stroke exclude patients who died (of any cause).
Composite endpoint: Death, MI, or Stroke *2121 (9.2%)2310 (10.1%)0.91 (0.86, 0.97)0.002
Death 1726 (7.5%)1845 (8.1%)0.93 (0.87, 0.99)0.029
Non-fatal MI 270 (1.2%)330 (1.4%)0.81 (0.69, 0.95)0.011
Non-fatal Stroke 127 (0.6%)142 (0.6%)0.89 (0.70, 1.13)0.33
*
All treated patients received aspirin.
Figure 4: Cumulative Event Rates for Death in the COMMIT Study *
Figure
(click image for full-size original)
*
All treated patients received aspirin.
Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT Study *
Figure
(click image for full-size original)

The effect of Plavix did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history (see Figure 7). Such subgroup analyses should be interpreted cautiously.

Figure 6: Effects of Adding Plavix to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study
Figure
(click image for full-size original)
* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.
Figure 7: Effects of Adding Plavix to Aspirin in the Non-Prespecified Subgroups in the COMMIT Study
Figure
(click image for full-size original)

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