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The investigators are commended for successfully conducting such a large study – with patients recruited from 270 centers across 6 countries – in a disease entity where patient recruitment is notoriously known to be difficult. 13 TOPCAT is the largest study conducted to date to test the effect of spironolactone on clinical outcomes in HFpEF, and is one of the largest studies performed in this patient population in general. 8–10 In HFpEF, a number of small studies have previously suggested a beneficial effect with spironolactone, 11,12 and more recently, the ALDO-DHF study showed that spironolactone improved left ventricular diastolic function and remodeling compared to placebo. 7 Aldosterone receptor blockers have previously been shown to significantly reduce mortality in a wide spectrum of patients with HFrEF. 71 (8.4%) in East Europe.Īldosterone has several deleterious effects in patients with heart failure including salt and water retention, endothelial dysfunction, ventricular hypertrophy, and myocardial fibrosis. An interesting post-hoc analysis showed a striking regional difference in the placebo event rates: 280/881 (31.8%) in the Americas vs. Amongst 22 pre-specified subgroups, only patients with elevated natriuretic peptides showed a significant interaction with treatment. However, the number of patients with creatinine levels ≥ 3 mg/dL and the number of patients who required dialysis did not differ between both groups. Patients in the spironolactone group were also almost 50% more likely to experience doubling of creatinine above the upper limit of normal. Hyperkalemia was more common in patients receiving spironolactone, but there were no deaths related to hyperkalemia. The two other components of the primary endpoint – cardiovascular mortality and aborted cardiac arrest – did not differ between both groups.
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Patients receiving spironolactone had significantly fewer hospitalizations for heart failure compared to placebo (245 (14.2%) vs.
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After a mean follow-up period of 3.3 years, the primary endpoint occurred in 320 (18.4%) and 351 (20.4%) of patients in the spironolactone and placebo groups respectively. The results were recently presented at the American Heart Association Meeting in Dallas and will be published in the next issue of Circulation Heart Failure. The study was funded by the National Heart, Lung, and Blood Institute (NHLBI). A total of 3445 subjects were recruited over a period of 4 years from 270 clinical centers in the United States (1151), Russia (1066), Georgia (612), Canada (326), Brazil (167) and Argentina (123), and were randomized on 1:1 basis to either spironolactone (target dose of 30 mg daily) or placebo. Patients with uncontrolled hypertension, those with infiltrative or hypertrophic cardiomyopathy and patients with elevated baseline serum potassium levels (>5.0 mmol/L) were excluded. Importantly, objective evidence of diastolic dysfunction was not required for enrolment in the study. HFpEF was determined by the presence of LVEF >45%, signs and symptoms of heart failure in conjunction with prior hospital admission for HF within the prior year or elevated natriuretic peptides (BNP >100 pg/ml or NT-proBNP >360 pg/ml) within the 60 days preceding randomization. Secondary endpoints included all-cause mortality, new onset of diabetes mellitus or atrial fibrillation, and quality of life. TOPCAT was a multicenter, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy of spironolactone relative to placebo on the cumulative incidence of a composite endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with HFpEF.