The Data Monitoring Experience in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Program

Abstract

The Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) program was designed as three separate randomized trials comparing candesartan with placebo in patients with chronic heart failure (CHF) who (1) were intolerant to angiotensin converting enzyme (ACE)-inhibitor and had left ventricular ejection fraction (LVEF) ≤ 40%, (2)) were on ACE-inhibitor and had LVEF ≤ 40% or (3)) had LVEF > 40%. CHARM provides an interesting example of the challenges faced by a Data and Safety Monitoring Committee (DSMC).

While the primary efficacy endpoint 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 six months (seven 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.

There were significant treatment differences in all-cause mortality at several interim analyses, and the statistical stopping guideline was reached on one occasion. The DSMC consistently recommended that the program continue as planned. The final published results for all-cause death over a median 3.1 years were a 9%; reduction in hazard (95%; CI 0%; to 17%;, p = 0.055), whereas for CV death or hospitalization for CHF there was a 16%; reduction in hazard (95%; CI 9%; to 23%; p < 0.0001). 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.

The DSMC experience in the CHARM program illustrates the importance of continuing a trial to its scheduled completion unless there is proof beyond reasonable doubt that would influence clinical practice rather than strict reliance on a statistical stopping guideline.

This paper first published in the Am Heart J 2005; 149:939–943.