Clopidogrel fails to reduce mortality risk in most PCI patients

A meta-analysis of the results of 15 studies published between August, 2001 and September, 2012, has determined that patients scheduled for PCI who were pretreated with clopidogrel experienced fewer major cardiac events than patients who were not treated, but clopidogrel was not associated with a lower risk of death. The findings were published online Dec. 19 in the Journal of the American Medical Association.

Anne Bellemain-Appaix, MD, of La Fontonne Hospital in Antibes, France, and colleagues analyzed data from six randomized controlled trials (RTC), two observational analyses of RTCs and seven observational studies to determine whether treatment with clopidogrel prior to PCI had an impact on bleeding and mortality compared to no clopidogrel pre-treatment. The researchers limited their main analysis to data from the RCTs, then performed two confirmatory analyses using data from the observational analyses of RCTs and the observational studies.

The researchers established the following inclusion criteria for the RTCs they analyzed:

• Patients with coronary artery disease scheduled for PCI, catheterization or both;
• Controlled comparison between clopidogrel pretreatment and no treatment;
• Clopidogrel loading dose available;
• Data on mortality and bleeding available.

Ongoing studies were excluded from the meta-analysis, as were studies without a control group. The primary endpoint of the meta-analysis was mortality; the safety endpoint was major bleeding; and the secondary endpoints were a composite of major cardiac events and individual endpoints of MI, stroke or urgent revascularization.

For the main analysis, the researchers compared data of 4,283 patients in the pretreatment group to 4,325 who were not pretreated with clopidogrel. They found no association between clopidogrel pretreatment and reduction of mortality risk (absolute risk 1.54 percent in the pretreatment group vs 1.95 percent in the no treatment group), although when analyzing by subgroups, the researchers found that mortality risk declined in STEMI patients who received pretreatment (1.28 percent vs. 2.54 percent).

Nor was clopidogrel associated with increased risk of bleeding (absolute risk 3.57 percent in the pretreatment group vs. 3.08 percent in the no treatment group). Bellemain-Appaix et al identified an increased risk of minor bleeding with clopidogrel treatment in the RTC cohort (3.66 percent vs. 2.74 percent) but could not reproduce that finding through their confirmatory analyses.

The risk of major coronary events declined significantly with clopidogrel pretreatment (9.83 percent vs. 12.35 percent), as did the risk of MI (4.53 percent vs. 5.9 percent). Data on stroke and urgent revascularization were available for five of the seven RCTs studied; the researchers found that clopidogrel pretreatment was not associated with a significant reduction in risk for these endpoints.

In their subset analyses, the researchers found that clopidogrel pretreatment is most effective in reducing risk of mortality and major coronary events in patients with STEMI and non-ST elevation acute coronary syndrome. It had the least impact on low-risk patients who underwent elective PCI.

The researchers explained that the current guidelines recommending clopidogrel pretreatment were based on evidence from studies performed in the early 2000s. In those studies, some patients had their PCI postponed for a day or more, and so did not reflect contemporary practice of prompt revascularization. “Our meta-analysis includes the most recent studies … and may better reflect current real-world practice,” the authors wrote.

Further noting that although the recommendations for clopidogrel pretreatment are broad, their meta-analysis revealed the primary benefit was to the sickest patient; therefore, the authors suggested that their results should lead to “questioning the need of such a systematic [clopidogrel pretreatment] strategy at least in low-risk patients.”

The authors conceded that their analysis, like all systematic reviews of study data, may incorporate bias. They also acknowledged that the study may have had insufficient power to definitely exclude an effect on mortality, but pointed out that the confirmatory analyses supported their findings that clopidogrel pretreatment did not reduce mortality risk. They suggested that large prospective studies are needed to assess the value of pretreatment with clopidogrel and other, newer antiplatelet medications.