Variation in Placebo Effect on Health-Related Quality of Life in Heart Failure (from the TOPCAT Trial)

Globalization of clinical trials has prompted significant interest in assessing regional variation in patient characteristics and treatment effects. Although the placebo effect overall has been well described, it is not known whether differences in placebo effect exist in countries. The objective of this study was to assess the country-level differences in placebo effect. We undertook an exploratory post-hoc analysis of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial. The main outcomes were changes in the overall summary score (OSS) and clinical summary score (CSS) of the Kansas City Cardiomyopathy Questionnaire at 4, 12, 24, 36, 48, and 60 months. Of 1,723 subjects who were randomized to the placebo arm, 33.6% were enrolled from United States, 9.3% from Canada, 31.2% from Russia, 4.7% from Brazil, 3.5% from Argentina, and 17.7% from Georgia. Although patients from Georgia had the lowest (p <0.001) OSS and CSS at baseline, they had the highest improvement (>10 points) in CSS at all time points compared with other countries (p <0.001). Patients enrolled in Georgia had more than 3 times the improvement in OSS compared with patients in United States and Canada. Patients enrolled in Argentina had significantly (p <0.001) higher improvement in OSS and CSS at all time points compared with other countries, except Georgia. Greater than 10 points improvement in OSS was observed in patients from Argentina at all time points, which was more than 2-fold improvement seen in patients from United States and Canada. In conclusion, there were significant variations in longitudinal changes in Kansas City Cardiomyopathy Questionnaire scores in countries in patients receiving placebo.