LAUSR

Overall, patients with heart failure (HF) and preserved left ventricular ejection fraction (HFpEF) assigned to spironolactone in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)1 trial did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for HF) compared with patients receiving placebo. However, in a post hoc analysis, an approximately fourfold difference was identified in this composite event rate between the patients randomized from Russia and Georgia compared with the patients enrolled in the Americas. This post hoc analysis demonstrated greater potassium and creatinine changes, together with possible clinical benefits with spironolactone in patients from the Americas.2 In addition, spironolactone, as compared with placebo, reduced the composite outcome of hospitalization for HF or cardiovascular mortality among the strata of patients with HFpEF randomized on the basis of an elevated baseline natriuretic peptide level.3 In contrast, the strata of patients enrolled only on the basis of history of HF did not appear to benefit from the intervention. It is likely that patients enrolled in Russia and Georgia (mostly based on history of HF only) did not have the disease and may also have had a poor adherence to the study drug, thus diluting a genuine benefit of spironolactone. Therefore, in the absence of alternative evidence-based treatment in patients with HFpEF, and given that this disease is often a disabling and life-shortening condition, it appears reasonable to treat patients with HFpEF, similarly to those enrolled in North and South America, with spironolactone to improve outcomes.4 In this issue of the journal, Bristow et al.5 describe how, in TOPCAT, routine monthly safety screens and data at regularly scheduled Data and Safety Monitoring Committee/Board (DSMB) meetings triggered an extensive investigation of a renal adverse effect signal, how the data were mined, what the reviewing process was, and