The data monitoring experience in the Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) program.

BACKGROUND: The CHARM program was designed as 3 separate randomized trials comparing candesartan with placebo in patients with chronic heart failure (CHF) who (1) were intolerant to angiotensin-converting enzyme inhibitor and had left ventricular ejection fraction (LVEF) < or =0.40; (2) were on angiotensin-converting enzyme inhibitor and had LVEF < or =0.40; or (3) had LVEF >0.40. CHARM provides an interesting example of the challenges faced by a Data and Safety Monitoring Committee (DSMC). METHODS: Although the primary efficacy end point for each component trial was cardiovascular (CV) death or hospitalization for CHF, the primary outcome for the overall program was all-cause mortality. The DSMC received monthly safety reports and also met every 6 months (7 times in all) to review interim reports. Statistical stopping guidelines were predefined for all-cause mortality in the overall program. The overarching principle of the DSMC was proof beyond a reasonable doubt that would be likely to influence clinical practice. RESULTS: There were significant treatment differences in all-cause mortality for the overall program at several interim analyses, and the statistical stopping guideline was reached on one occasion. However, even a conventional level of statistical significance (P < .050) was achieved in only 1 of the 3 component trials. The DSMC consistently recommended that the program continue as planned. The final published result for all-cause death over a median of 3.1 years was a 9% reduction in hazard (95% CI 0%-17%, P = .055), whereas for CV death or hospitalization for CHF, there was a 16% reduction in hazard (95% CI 9%-23%, P < .0001). Subsequent exploratory analyses suggest that the hazard reduction in CV death was more marked in the first year after randomization and that, if real, this apparent treatment-time interaction offers a plausible explanation for why the interim mortality data showed statistically more extreme findings than the overall final results. CONCLUSION: The DSMC experience in the CHARM program illustrates the importance of continuing a trial to its scheduled completion unless there is proof beyond a reasonable doubt that would influence clinical practice rather than strict reliance on a statistical stopping guideline.