Challenges of subgroup analyses in multinational clinical trials: Experiences from the MERIT-HF trial

Background International placebo-controlled survival trials (Metoprolol Con trolled-Release Randomised Intervention Trial in Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS-II], and Carvedilol Prospecti ve Randomized Cumulative Survival trial [COPERNICUS]) evaluating the effect s of P-blockade in patients with heart failure have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization. Also, the analysis of the US Carvedilol Pr ogram indicated an effect on these end points. Although none of these trial s are large enough to provide definitive results in any particular subgroup , it is natural for physicians to examine the consistency of results across various subgroups or risk groups. Our purpose was to examine both predefin ed and post hoc subgroups in the MERIT-HF trial to provide guidance as to w hether any subgroup is of increased risk, despite an overall strongly posit ive effect, and to discuss the difficulties and limitations in conducting s uch subgroup analyses. Methods The study was conducted at 313 clinical sites in 16 randomization r egions across 14 countries, with a total of 3991 patients. Total mortality (first primary end point) and total mortality plus all-cause hospitalizatio n (second primary end point) were analyzed on a time to first event. The fi rst secondary end point was total mortality plus hospitalization for heart failure. Results Overall, MERIT-HF demonstrated a hazard ratio of 0.66 for total mor tality and 0.81 for mortality plus all-cause hospitalization. The hazard ra tio of the first secondary end point of mortality plus hospitalization for heart failure was 0.69. The results were remarkably consistent for both pri mary outcomes and the first secondary outcome across all predefined subgrou ps as well as for nearly all post hoc subgroups. The results of the post ho c US subgroup showed a mortality hazard ratio of 1.05. However, the US resu lts regarding both the second primary combined outcome of total mortality p lus all-cause hospitalization and of the first secondary combined outcome o f total mortality plus heart failure hospitalization were in concordance wi th the overall results of MERIT-HF. Tests of country by treatment interacti on (14 countries) revealed a nonsignificant P value of .22 for total mortal ity. The mortality hazard ratio for US patients in New York Heart Associati on (NYHA) class III/IV was 0.80, and it was 2.24 for patients in NYHA class II, which is not consistent with causality by biologic gradient. We have n ot been able to identify any confounding factor in baseline characteristics , baseline treatment, or treatment during follow-up that could account for any treatment by country interaction. Thus we attribute the US subgroup mor tality hazard ratio to be due to chance. Conclusions Just as we must be extremely cautious in overinterpreting posit ive effects in subgroups, even those that are predefined, we must also be c autious in focusing on subgroups with an apparent neutral or negative trend . We should examine subgroups to obtain a general sense of consistency, whi ch is clearly the case in MERIT-HF. We should expect some variation of the treatment effect around the overall estimate as we examine a large number o f subgroups because of small sample size in subgroups and chance. Thus the best estimate of the treatment effect on total mortality for any subgroup i s the estimate of the hazard ratio for the overall trial.