PLAVIX Clinical Trials
CAPRIE (Clopidogrel versus Asprin in Patients at Risk of Ischemic Events) Trial

CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) was a randomized, blinded clinical trial of 19,185 patients from 384 centers in 16 countries to assess the potential benefit of clopidogrel (75 mg) compared with aspirin (325 mg) in reducing the risk of ischemic stroke, myocardial infarction (MI), or vascular death in patients with recent ischemic stroke, recent MI, or peripheral arterial disease (PAD). 11

Inclusion Criteria 13

  • Recent MI [ ≤ 35 days] with chest pain ≥ 20 minutes, increased cardiac enzymes or ECG changes.
  • Recent ischemic stroke (≥1 week and ≤6 months) with neurologic deficit of atherosclerotic origin, neurologic signs persisting for ≥1 week, and CT or MRI to rule out hemorrhage.
  • Established PAD, defined as either intermittent claudication of presumed atherosclerotic origin and ankle brachial index ≤0.85, or history of intermittent claudication with previous leg amputation, reconstructive surgery, or angioplasty.

Efficacy

The results of the CAPRIE trial established PLAVIX (clopidogrel bisulfate) as more effective than aspirin in reducing the combined risk of MI, ischemic stroke, and vascular death in patients with atherosclerotic vascular disease. 1 In the CAPRIE trial, PLAVIX demonstrated an 8.7% (P=0.045) relative risk reduction compared to aspirin in the combined end points of MI, ischemic stroke, and vascular death. 18

Although the statistical significance favoring clopidogrel bisulfate (PLAVIX®) over aspirin was marginal (P=0.045, based on overall incidence of primary outcome events: 9.78% for clopidogrel vs 10.64% for aspirin), and represents the result of a single trial that has not been replicated, the comparator drug, aspirin, is itself effective (vs placebo) in reducing cardiovascular events in patients with recent MI or recent stroke. Thus, the difference between clopidogrel and placebo, although not measured directly, is substantial. 13

Efficacy of PLAVIX vs. Aspirin in Reducing the combined risk of Myocardial Infarction (MI), Ischemic Stroke, and Vascular Death in patients with recent stroke, recent MI, or established PAD (CAPRIE chart)

The primary outcome analysis in CAPRIE was based on the composite end point of MI, ischemic stroke, or vascular death among all randomized patients (intent-to-treat analysis). Only the first occurrence of these outcomes was counted. The total number of patients randomized was 9,599 for clopidogrel bisulfate and 9,586 for aspirin. 13

Results from the CAPRIE trial demonstrated that clopidogrel had a lower event rate per year compared with aspirin, 5.32% vs 5.83%, respectively, which resulted in an overall risk reduction of 8.7% 17 (P=0.045) 13 vs aspirin.

The cumulative risk curves separated early and continued to diverge during the 3-year follow-up period. 13

Safety

CAPRIE Safety of PLAVIX vs. Aspirin for Selected Adverse Events (table)

Clopidogrel was associated with a 2.0% incidence of GI hemorrhage and 0.7% incidence of related hospitalizations. The percentage of patients experiencing peptic, gastric, or duodenal ulcers was 0.7% in the clopidogrel group. Clopidogrel also was associated with a 0.4% incidence of intracranial hemorrhage. 13

Differences noted above for GI hemorrhage and ulcers occurred despite the fact that patients who were unable to tolerate aspirin were excluded from the CAPRIE population. 17

Patients in CAPRIE were intensively monitored for neutropenia. The observed frequency of severe neutropenia (<450 neutrophils/microliter) was 0.04% (4 patients) with clopidogrel and 0.02% (2 patients) with aspirin. One of the four clopidogrel patients was receiving cytotoxic chemotherapy; another recovered and returned to the trial after temporary interruption of treatment with clopidogrel. Although the risk of myelotoxicity with clopidogrel thus appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other sign of infection. 12

CAPRIE Selected Tolerability Profile of PLAVIX vs. Aspirin (table)

Compared with aspirin, the incidence of GI disturbances including abdominal pain, dyspepsia, and gastritis was lower in the clopidogrel group. 17

Compared with aspirin, clopidogrel was associated with a higher incidence of diarrhea, rash, pruritus, and purpura (most often described as "bruising"). 11

The discontinuation rate due to adverse GI events was 3.2% with clopidogrel and 4.0% with aspirin. 13

Indications
–
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.

–
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.

–
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
–
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.*)

–
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.*)

–
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.*)

–
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.*)

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

–
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.*)