PARIS – Clopidogrel nonresponsiveness is a modifiable cardiovascular risk factor in patients undergoing percutaneous coronary intervention, according to the results of the third Responsiveness to Clopidogrel and Stent-Related Events (RECLOSE-3) study.
High residual platelet activity following a loading dose of clopidogrel in patients undergoing PCI was shown in the earlier RECLOSE-2 study to be a potent predictor of an increased 2-year cardiovascular event rate (JAMA 2011;306:1215-23). This left open the question of whether switching to a different antiplatelet drug would reduce that elevated 2-year risk.
The new RECLOSE-3 study shows that this clopidogrel nonresponsiveness is indeed a modifiable risk factor. All that’s necessary is to identify affected patients via a commercially available in vitro assay, switch them to prasugrel, and their long-term cardiac outcomes become markedly better than if they stayed on clopidogrel, Dr. David Antoniucci reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.
The prospective RECLOSE-3 study included 302 consecutive patients undergoing PCI who were determined to be clopidogrel nonresponders based upon residual platelet activity of 70% or more as measured by light transmittance aggregometry. All were switched to prasugrel and underwent repeat platelet activity measurement. The control group consisted of 248 clopidogrel nonresponders who stayed on the antiplatelet agent in RECLOSE-2.
It was necessary to rely on historical controls for ethical reasons; based upon the RECLOSE-2 results, it’s no longer appropriate to randomize clopidogrel nonresponders to continued use of clopidogrel, according to Dr. Antoniucci, head of the division of cardiology at Careggi Hospital in Florence, Italy.
Mean residual platelet reactivity improved from 78% in RECLOSE-3 participants on clopidogrel to 47% on prasugrel. All but 6% of clopidogrel nonresponders demonstrated acceptable suppression of platelet activity on prasugrel.
The primary study endpoint was 2-year cardiac mortality. With a follow-up rate of 99%, the rate was 4% in clopidogrel nonresponders switched to prasugrel, significantly better than the 9.7% in controls. Moreover, the rate of definite stent thrombosis – a key secondary endpoint – was 0.7% in the group switched to prasugrel, fourfold lower than in controls. Probable stent thrombosis was diagnosed in 1.6% of controls and none of the prasugrel group.
All patients in the control group from RECLOSE-2 had been admitted with an acute coronary syndrome. Restricting the analysis to the 126 RECLOSE-3 participants switched to prasugrel who had an acute coronary syndrome upon hospitalization, the 2-year cardiac death rate was 3.2%, still significantly lower than the 9.7% in controls.
In a multivariate analysis that controlled for potential confounders – including the more frequent use of drug-eluting stents and lower prevalence of a left ventricular ejection fraction of 40% or less in the RECLOSE-3 patients – switching clopidogrel nonresponders to prasugrel was associated with a highly significant 50% reduction in the risk of cardiac death at 2 years’ follow-up. The only other significant predictors were a baseline serum creatinine greater than 1.5 mg/dL and advanced age, both of which were associated with increased risk.
The RECLOSE-3 study was sponsored by the Italian Department of Health. Dr. Antoniucci reported having no financial conflicts.