Geographic Disparities: Lessons Learned From TOPCAT Trial
What are the reasons for heterogeneity of results in a clinical trial?
TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) was a multinational clinical trial of 3,445 patients with heart failure with preserved ejection fraction, enrolled in 233 sites in six countries in North America, Eastern Europe, and South America. TOPCAT primary results showed no significant spironolactone treatment effect overall (primary endpoint hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.77-1.04), with a significant HR in North and South America (HR, 0.82; 95% CI, 0.69-0.98; p = 0.026), but not in Russia and Georgia (HR, 1.10; 95% CI, 0.79-1.51; interaction p = 0.12). The geographic heterogeneity of results prompted the review of this clinical trial. The authors of this article reviewed reports provided to the open and closed sessions of the various Data Safety and Monitoring Board (DSMB) meetings, the meeting minutes, monthly safety reports viewed by the DSMB chair, correspondence of the chair with the National Heart, Lung, and Blood Institute, and published data from the entire TOPCAT cohort. The study authors performed extensive “data freeze” analysis of the data available to them.
- The authors stated that complete lack of treatment effect in Russia and Georgia compared with the other regions strongly suggests that more than the play of chance occurred.
- TOPCAT started behind schedule, and once begun, there was brisk enrollment from two countries where data ultimately proved to be qualitatively problematic. By the time it was appreciated that there were serious issues with patient characteristics and event rates in patients from Russia and Georgia, both countries had enrolled substantial numbers of subjects. The study authors opined that the “lesson learned here is that during the early as well as the later phases of trial enrollment, recruitment from 1 or 2 regions or sites should not dominate, and patient characteristics should be monitored carefully to identify potential regional irregularities in study subpopulations.”
- The discrepant patterns of patient characteristics and event rates in Russia or Georgia were present from the first opportunity to observe them, and persisted throughout the trial. The study authors concluded that “it would seem prudent to place considerable weight on early observations that remain consistent, particularly if they could threaten trial integrity.”
- Country-specific event rates were not specifically disclosed by the DSMB to the Steering Committee, and the authors believed it is possible that such information would have triggered earlier or more definitive corrective actions. The authors opined that “continuing to enroll in a region where the event rate is inadequate to assess the tested treatment effect is questionable and, at a minimum, should be brought to a steering committee’s attention.”
- The study authors concluded that “for various reasons that include regulatory compliance and site burden, investigators are understandably reluctant to make substantive changes in clinical protocols during a trial.” They opined that “in a large multicenter clinical trial, change is difficult, but not changing may be fatal.”
- The study authors concluded that “adaptive increases in trial sample size can be prospectively designed and may increase the probability of success,” particularly when information was available at the 75% of total events interim analysis.
- The study authors recommended a detailed plan for surveillance.
- They also recommended rigorous criteria for enrollment, particularly when the diagnosis of a condition is challenging.
The authors concluded that “unanticipated developments are to be expected in a large multicenter clinical trial, and provisions can and should be built into trial design to facilitate identifying and managing them.”
This is an important overview of the TOPCAT trial. The study authors need to be congratulated for a thorough review of the pitfalls of what one can expect in a multicenter trial. Their recommendations should minimize duplication of such methodologies in future trials.
Keywords: Clinical Protocols, Clinical Trials as Topic, Diuretics, Geographic Locations, Heart Failure, Mineralocorticoid Receptor Antagonists, Spironolactone
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