ATLANTA—Results from a study branded by its principal investigator as underpowered to produce a meaningful result still sparked attention at a major cardiology meeting by fanning the controversy swirling around clopidogrel's role following percutaneous coronary interventions with drug-eluting stents.
The Korean study that tried to test the long-term role of clopidogrel for preventing adverse cardiovascular events following placement of drug-eluting stents (DES) in roughly 2,700 patients “had insufficient statistical power to allow a firm conclusion,” Dr. Seung-Jung Park said at the annual meeting of the American College of Cardiology. That fact mitigated what would have otherwise been a highly surprising and troubling finding: More than a year out from coronary stenting, patients treated with aspirin alone fared no worse than and even trended toward better outcomes compared with patients maintained on dual-antiplatelet therapy with aspirin and clopidogrel.
The underpowered study size might, in other circumstances, have caused the report to be dismissed and quickly forgotten. But two extenuating circumstances instead thrust the study into the spotlight: First, despite its problems, the study simultaneously ran in the New England Journal of Medicine (2010 March 15 [doi:10.1056/NEJMoa1001266]). Second, the report came just days after the Food and Drug Administration on March 12 roiled concerns about clopidogrel's efficacy in patients who recently received a coronary stent by adding a boxed warning to the label of clopidogrel (Plavix) alerting prescribers that certain patients do not metabolize clopidogrel effectively, thereby blunting the drug's efficacy in these people (see article below). Such “poor metabolizers,” the FDA said, comprise an estimated 2%-14% of the American public and perhaps as high as 50% of some Asian populations.
“We see tremendous variability of responsiveness to clopidogrel and aspirin” in patients attributable to genetic differences in features such as the metabolic activation of clopidogrel, said Dr. George D. Dangas, a cardiologist at the Center for Interventional Vascular Therapy at Columbia University in New York. “How can we have a question of [clopidogrel treatment] duration in patients who are not responding? I'm not sure that makes much sense. Perhaps patients in Dr. Park's study were hyporesponders [to clopidogrel] and that's behind what he sees.”
The Korean study enrolled 2,701 patients who had received at least one DES and had been event free while on combined antiplatelet therapy with aspirin and clopidogrel for at least 12 months. Their average age was 62, and 70% were men. A median of 13 months after stent placement, the researchers randomized the patients to continue on 75 mg clopidogrel and 100-200 mg aspirin daily or just aspirin alone. Follow-up continued for a median of 19 months, but the total number of end point events remained low, about a quarter of the expected number, probably because the study involved low-risk patients, said Dr. Park, professor of medicine in the Heart Institute at Asan Medical Center in Seoul, South Korea.
The primary end point, the combined rate of MI or cardiac death, occurred in 1.8% of patients treated with clopidogrel and aspirin and in 1.2% of those on aspirin only, a nonsignificant, 65% relative increased risk of events among patients on the dual-antiplatelet regimen compared with aspirin alone.
In two other outcome measures the worse performance by the combined regimen just missed statistical significance. The combined rate of MI, stroke, or death from any caused occurred in 3.2% of the combined-treatment patients and in 1.8% of the aspirin-alone controls, and the rate of MI, stroke, or cardiac death tallied in 2.7% of the aspirin plus clopidogrel patients compared with 1.3% of patients on aspirin only. Rates of all-cause death and stent thrombosis were nearly identical in both treatment groups.
Many experts who heard these potentially troubling findings that seemingly cast doubt on clopidogrel's efficacy and safety as well as on prolonged dual-antiplatelet therapy following coronary stenting uniformly dismissed the findings as unreliable.
“The answers are not definitive. The lack of power is the primary concern,” said Dr. Laura Mauri, chief scientific officer of the Harvard Clinical Research Institute in Boston.
“We won't know [how long to treat these patients with clopidogrel] until we have an adequately powered study,” said Dr. Dean J. Kereiakes, chief executive officer of the Ohio Heart Health Center in Cincinnati.
While Dr. Dangas agreed that the results were inconclusive, he suggested that they may offer some guidance “until definitive studies come out.” The results were “reassuring that perhaps in patients who did well over the first year [following placement of DES] it might be okay to consider taking them off clopidogrel,” he said.