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 â¥65 years of age.
Patients were randomized to receive clopidogrel bisulfate (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 to 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 clopidogrel bisulfate-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel bisulfate-treated group (see Table 4).
| Outcome | Clopidogrel Bisulfate (+ aspirin)* (n=6259) | Placebo (+ aspirin)* (n=6303) | Relative Risk Reduction (%) (95% CI) |
|---|---|---|---|
| * Other standard therapies were used as appropriate. â 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. | |||
| ÂÂÂPrimary outcome ÂÂÂÂÂÂ(Cardiovascular death, MI, stroke) | 582 (9.3%) | 719 (11.4%) | 20% (10.3, 27.9) p < 0.001 |
| ÂÂÂAll Individual Outcome Events:â | |||
| ÂÂÂÂÂÂCV death | 318 (5.1%) | 345 (5.5%) | 7% (-7.7, 20.6) |
| ÂÂÂÂÂÂMI | 324 (5.2%) | 419 (6.6%) | 23% (11, 33.4) |
| ÂÂÂÂÂÂStroke | 75 (1.2%) | 87 (1.4%) | 14% (-17.7, 36.6) |
Most of the benefit of clopidogrel bisulfate 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).
In CURE, the use of clopidogrel bisulfate 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 clopidogrel bisulfate 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 clopidogrel bisulfate was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.
The use of clopidogrel bisulfate in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel bisulfate group, 126 patients [2%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel bisulfate group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel bisulfate in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36%] in the clopidogrel bisulfate group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4%).
COMMIT
In patients with STEMI, the safety and efficacy of clopidogrel bisulfate 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 clopidogrel bisulfate (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 TableÂ5 and FigureÂ4 andÂFigureÂ5 below, clopidogrel bisulfate 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).ÂÂ
| Event | Clopidogrel Bisulfate (+ 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 Non-fatal MI** Non-fatal Stroke** | 1726 (7.5%) 270 (1.2%) 127 (0.6%) | 1845 (8.1%) 330 (1.4%) 142 (0.6%) | 0.93 (0.87, 0.99) 0.81 (0.69, 0.95) 0.89 (0.7, 1.13) | 0.029 0.011 0.33 |
* All treated patients received aspirin.
The effect of clopidogrel bisulfate 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.
* 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.
Â14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease
CAPRIE
The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing clopidogrel bisulfate (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).
The trialâs primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.
| Patients | Clopidogrel Bisulfate n=9599 | Aspirin n=9586 |
|---|---|---|
| ÂÂÂIschemic stroke (fatal or not) | 438 (4.6%) | 461 (4.8%) |
| ÂÂÂMI (fatal or not) | 275 (2.9%) | 333 (3.5%) |
| ÂÂÂOther vascular death | 226 (2.4%) | 226 (2.4%) |
| ÂÂÂTotal | 939 (9.8%) | 1020 (10.6%) |
As shown in Table 6, clopidogrel bisulfate was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel bisulfate group.
The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3-year follow-up period.
The statistical significance favoring clopidogrel bisulfate over aspirin was marginal (p=0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel bisulfate is substantial.
The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel bisulfate relative to aspirin was heterogeneous across these randomized subgroups (p=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel bisulfate over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel bisulfate was not numerically superior to aspirin.
14.3 Lack of Established Benefit of Clopidogrel Bisulfate plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease
CHARISMA
The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel bisulfate (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel bisulfate group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel bisulfate.
