Lukes, Boston Scientific Corporation, Teva Pharmaceutical, Janssen Scientific Affairs, St. Gersh has consulting relationships with Mount Sinai St. Gersh, Grady, Rice, Singh, and Greenberg are DSMB voting members. Bristow is the TOPCAT Data Safety and Monitoring Board (DSMB) chair and he is an officer and director of Arca Biopharma, and consultant to Miragen Therapeutics. This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health.
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The TOPCAT trial was supported by NHLBI contract HHSN268200425207C awarded to New England Research Institutes Clinical Trials Coordinating Center. The TOPCAT Trial was funded by the National Institutes of Health, National Heart, Lung, and Blood Institute (contract N01 HC45207). (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial NCT00094302) This report describes the Data Safety and Monitoring Board’s detection and management recommendations for regional differences in patient characteristics in TOPCAT and suggests methods of surveillance and corrective actions that may be useful for future trials. The primary results showed no significant spironolactone treatment effect overall (primary endpoint hazard ratio : 0.89 95% confidence interval : 0.77 to 1.04), with a significant hazard ratio in North and South America (HR: 0.82 95% CI: 0.69 to 0.98 p = 0.026) but not in Russia and Georgia (HR: 1.10 95% CI: 0.79 to 1.51 interaction p = 0.12). B-type natriuretic peptide measurements from Russia and Georgia, available later in the trial, suggested no or a mild level of heart failure consistent with low event rates.
Although final enrollment reflected the increased contribution from North America, a plurality of the final cohort came from Russia and Georgia (49% vs.
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With the emergence of country-specific aggregate event rate data indicating lower rates in Eastern Europe and differences in patient characteristics there, the Data Safety and Monitoring Board recommended relatively increasing enrollment in North America plus other corrective measures. Sites in Russia and the Republic of Georgia provided the majority of early enrollment, primarily based on the hospitalization criterion because B-type natriuretic peptide levels were initially unavailable there. Patients with a heart failure hospitalization in the last 12 months or an elevated B-type natriuretic peptide were randomized to the mineralocorticoid receptor antagonist spironolactone versus placebo. TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) was a multinational clinical trial of 3,445 heart failure with preserved ejection fraction patients that enrolled in 233 sites in 6 countries in North America, Eastern Europe, and South America.
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