BACKGROUND:Aspirin has been associated with adverse heart failure outcomes, probably because of a blunting interaction with angiotensin-converting enzyme (ACE) inhibitors. Therefore, we hypothesized that clopidogrel when compared with aspirin would be associated with a slower progression of heart failure as determined by levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS:In an open-label, randomized, 2-treatment, 2-period crossover study, 18 patients with ischemic heart failure (14 post-myocardial infarction, left ventricular ejection fraction 0.32 +/- 0.08), median age 73, New York Heart Association class II (11 patients) or III (7 patients), all taking ACE inhibitors were included. Patients were randomized to 8 weeks of aspirin 100 mg/day followed by 8 weeks of clopidogrel 75 mg/day, or the reversed sequence. Blood levels of NT-proBNP were measured using sandwich immunoassay. Patients on aspirin experienced an 8-times greater increase in log-transformed values of NT-proBNP compared with patients on clopidogrel (average change 4.757% versus 0.597%; P = .0395 for intervention, P = .4453 for period, P = .4046 for sequence). We observed no change in functional class, 6-minute walking test, creatinine levels, or electrolytes. CONCLUSION:Aspirin is associated with a greater increase in natriuretic peptides (log-transformed NT-proBNP levels), implying that aspirin therapy is associated with a more progressive course of heart failure.