Weighting Components of Composite End Points in Clinical Trials

Abstract

Background and Purpose— Conventional analysis of vascular prevention trials assigns equal weight to disparate vascular events in a composite end point at variance with the public's perception of their differential impact on health outcome. This study sought to apply the disability-adjusted life-year (DALY) metric to differential weighting individual vascular end points in trial analyses. Methods— DALY values for the most common major end points in vascular prevention trials (nonfatal myocardial infarction, nonfatal stroke, and vascular death), were derived by using World Health Organization Global Burden of Disease Project methodology. The standardized DALYs for each event were applied to recent major primary and secondary vascular prevention trials and to hypothetical model trials. Results— Standardized DALYs lost were 7.63 for nonfatal stroke, 5.14 for nonfatal myocardial infarction, and 11.59 for vascular death. In the published trials analyses, the direction of treatment effects was consistent between DALY and standard event analysis, but the rank order of treatment effect changed for 10 of 18 trials. The DALY analysis also permitted derivation of number-needed-to-treat values to gain 1 DALY: 2.1 for anticoagulation in atrial fibrillation, 2.7 for carotid endarterectomy in symptomatic stenosis, and 4.7 for clopidogrel added to aspirin in acute coronary syndrome. Hypothetical trial analyses demonstrated that the DALY metric more finely discriminates treatment effects. Conclusions— Compared with a nonfatal myocardial infarction, a nonfatal stroke causes a 1.48-fold greater loss and vascular death a 2.25-fold greater loss of DALY. DALY analysis integrates these valuations in a summary metric reflecting the net impact of therapy on patient and societal health, complementing conventional end point analyses.