title: 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.
authors.affiliation: Cardiovascular Institute, University of Colorado, Boulder and Aurora, CO.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
authors.affiliation: UC San Diego Medical Center, La Jolla, CA.
authors.forename: Jorge Silva
authors.initials: JS
authors.lastname: Enciso
authors.affiliation: Mayo Clinic, Rochester, MN.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Gersh
authors.affiliation: Department of Bioethics, National Institutes of Health Clinical Center, Bethesda, MD.
authors.forename: Christine
authors.initials: C
authors.lastname: Grady
authors.affiliation: George Washington University Biostatistics Center, Washington, DC.
authors.forename: Madeline Murguia
authors.initials: MM
authors.lastname: Rice
authors.affiliation: Washington VA Medical Center, Washington, DC.
authors.forename: Steven
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD.
authors.forename: George
authors.initials: G
authors.lastname: Sopko
authors.affiliation: Office of Clinical and Regulatory Affairs, National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD.
authors.forename: Robin
authors.initials: R
authors.lastname: Boineau
authors.affiliation: Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD.
authors.forename: Yves
authors.initials: Y
authors.lastname: Rosenberg
authors.affiliation: UC San Diego Medical Center, La Jolla, CA.
authors.forename: Barry H
authors.initials: BH
authors.lastname: Greenberg