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

Abstract

TOPCAT was a multinational clinical trial of 3,445 heart failure with preserved ejection fraction (HFpEF) patients that enrolled in 233 sites in six 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 (BNP) were randomized to the mineralocorticoid receptor antagonist spironolactone vs. placebo. Sites in Russia and the Republic of Georgia provided the majority of early enrollment, primarily based on the hospitalization criterion since BNP 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 DSMB 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). BNP 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 0.89 (0.77, 1.04)), with a significant hazard ratio in North and South America (0.82 (0.69, 0.98), p =0.026) but not in Russia and Georgia (1.10 (0.79, 1.51), interaction p = 0.12). This report describes the DSMB'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.

Figure 1

DSMB Reviews and Recommendations in TOPCAT The Data and Safety Monitoring Board’s (DSMB) timeline, reviews, and recommendations (A) From December 2006 to October 1, 2010, and (B) October 27, 2010 to September 2013 for the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). BNP = B-type natriuretic peptide; CAD = coronary artery disease; CRA = Clinical Research Associate; CTCC = Clinical Trial Coordinating Center; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; NI = myocardial infarction; NA = North America; NHLBI = National Heart, Lung, and Blood Institute; NL = normal limits; NP = natriuretic peptide; NT-proBNP = N-terminal pro–B-type natriuretic peptide; SC = Steering Committee; Sx = symptoms; WNL = within normal limits.

Figure 2

TOPCAT Projected Versus Actual Enrollment by Country TOPCAT pre-trial projected (presented to DSMB on January 30, 2008) versus actual final enrollment as of January 31, 2012, percentage of total for each. Abbreviations as in Figure 1.

Figure 3

TOPCAT Actual Enrollment by Region TOPCAT actual enrollment by region, as percentage of enrollment at the sampling interval. Sampling interval dates on the x-axis are either from the review data freeze or updated numbers available immediately prior to the DSMB review. Abbreviations as in Figure 1.