Effects of clopidogrel and aspirin combination versus aspirin alone on platelet aggregation and major receptor expression in patients with heart failure: The PLavix Use for Treatment of Congestive Heart Failure (PLUTO-CHF) trial

Background: Persistent platelet activation may contribute to thrombotic events in patients with congestive heart failure (CHF). Chronic use of mild platelet inhibitors could therefore represent an independent avenue to improve morbidity, mortality, and quality of life in this expanding population. Although clopidogre is widely used in patients with acute coronary syndromes and ischemic stroke, the ability of this nove ADP-receptor antagonist to inhibit platelet function in patients with CHF is unknown. We assessed antiplatelet properties of clopidogrel with aspirin (C+A) versus aspirin alone (A) in patients with CHF with heightened platelet activity. Methods: Patients with left ventricular ejection fraction <40%, or CHF symptoms in the setting of preserved systolic function and New York Heart Association class II-IV were screened. Patients were considered to have platelet activation when 4 of the following 5 parameters were met: ADP-induced platelet aggregation >60%; collagen-induced aggregation >70%; whole blood aggregation >18 ohms; expression of GP IIb/IIIa >220 log MFI; and P-selectin cell positivity >8%. All patients were treated with 325 mg of acetylsalycilic acid (ASA) for at least 1 month. Patients receiving an antithrombotic agent other than ASA were excluded. Patients meeting clinical and laboratory criteria were randomly assigned to C+A (n=25), A (n=25) groups, or represent screen failures (n=38). Platelet studies (conventional and whole blood aggregometry, shear-induced activation, expression of 10 major receptors and formation of platelet-leukocyte microparticles) were performed at baseline and after 30 days of therapy. Results: There were no deaths, hospitalizations, or serious adverse events. There were no changes in platelet parameters in the A group. In contrast, therapy with C+A resulted in a significant inhibition of platelet activity assessed by ADP-induced (P = .00001), and epinephrine-induced (P = .0016) aggregation, closure time (P = .04), expression of PECAM-1 (P = .009), GP Ib (P = .006), GP IIb/IIIa antigen (P = .0001), GP IIb/IIIa activity with PAC-1 (P = .0021), and CD151 (P = .0026) when compared with the A group. Therapy with C+A a so resulted in the reduced formation of platelet-leukocyte microparticles (P = .021). Collagen-induced aggregation in plasma and in whole blood, expression of vitronectin receptor, P-selectin, CD63, CD107a, and CD107b did not differ among groups. Conclusions: Treatment with C+A for 1 month provides significantly greater inhibition of platelet activity than ASA alone in patients with CHF. Patients with CHF with heightened platelet activity represent a potential target population in which addition of clopidogrel may decrease mortality rates by reducing the incidence of thrombotic vascular events.