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In the subgroup of participants with detectable canrenone concentrations, the relationship between the doses of spironolactone that the participants reported taking and canrenone concentrations was consistent in the two regions ( Fig. In an analysis of all the participants who reported taking the assigned doses of spironolactone, a significant correlation between the doses of spironolactone that the participants reported taking and canrenone concentrations was found among the participants from the United States and Canada, but not among the participants from Russia ( Fig. Among the participants who were assigned to receive spironolactone and reported at the 12-month visit that they were taking the study drug (76 of 101 patients from the United States and Canada and 66 of 70 patients from Russia), canrenone concentrations were undetectable in a higher percentage of participants from Russia than from the United States and Canada (30% vs. 1A, and Table S2 in the Supplementary Appendix).

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As was the case in the overall trial population, regional disparities in reported study drug use and dosing were observed ( Fig. The clinical characteristics of the repository participants were generally representative of the overall TOPCAT trial population, although there were some differences in baseline characteristics ( Table S1 in the Supplementary Appendix).

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To further explore potential regional disparities in medication use, 3 we measured concentrations of canrenone (an active metabolite of spironolactone 4, 5) in 366 patients in the TOPCAT trial (206 patients from the United States and Canada and 160 patients from Russia) who provided consent to participate in the TOPCAT biorepository and had sufficient serum samples available from the 12-month study visit (see the Supplementary Appendix, available with the full text of this letter at ). 1 However, significant differences in the clinical profiles, event rates, and responses to spironolactone were identified between the patients who were enrolled in the trial in the Americas (United States, Canada, Brazil, and Argentina) and the patients who were enrolled in Russia and Georgia, and these differences have aroused concerns about study conduct at the Russian and Georgian sites.

The investigators found that the incidence of the primary composite end point of death from cardiovascular causes, hospitalization for heart failure, or resuscitated cardiac arrest was not significantly lower in the spironolactone group than in the placebo group, but the incidence of hospitalization for heart failure was significantly lower in the spironolactone group. In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, patients with heart failure and preserved ejection fraction were randomly assigned to receive either spironolactone or placebo.

Topcat profiles