Detection and Management of Geographic Disparities in the TOPCAT Trial: Lessons Learned and Derivative Recommendations

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. 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. 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. 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. Although final enrollment reflected the increased contribution from North America, a plurality of the final cohort came from Russia and Georgia (49% vs. 43% in North America). 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. The primary results showed no significant spironolactone treatment effect overall (primary endpoint hazard ratio [HR]: 0.89; 95% confidence interval [CI]: 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). 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. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial [TOPCAT]; NCT00094302)