Abstract 16911: Behind the Looking Glass: Comparing Time to First Event versus Multiple Events Analyses in a Post-myocardial Infarction Clinical Trial
Introduction: Standard analysis of clinical trials with composite endpoints compare time-to-first event. Subsequent events are not counted and therefore not taken into account in treatment comparisons. We compared standard analyses to analyses that take into account all the events a patient may have experienced.
Methods: The Trial to Assess Chelation Therapy (TACT) enrolled 1708 post-MI pts in a factorial trial comparing edetate disodium infusions versus placebo infusions and oral vitamins and minerals versus oral placebo. TACT had a composite primary endpoint: death, MI, stroke, coronary revascularization, and hospitalization for angina. Pre-specified primary analysis for TACT was based on the standard approach of considering time until the occurrence of the first event. Two different approaches for multiple events analyses were compared to the standard approach: 1] a generalization of the Cox model to handle recurrent events, developed by Andersen & Gill (AG), and 2] a marginal modeling approach developed by Wie, Lin, and Weissfeld (WLW). Each considers the correlation among multiple events occurring within a pt.
Results: There were 743 events in TACT. 483/1708 (28%) of the patients had at least 1 event. Time-to-first-event analysis did not use information on 260 (35%) events. The standard analysis for edetate disodium vs placebo produced a hazard ratio (HR) 0.82, 95% confidence intervals 0.69,0.99, p=0.035. Both multiple events analyses demonstrated narrower confidence intervals and lower P values. AG: HR 0.80 (0.66,0.96), p=0.017; and WLW: HR 0.79 (0.66, 0.95), p=0.010. In the comparison of the active edetate + active MVM vs placebo edetate + placebo MVM, there were 247/858 (29%) pts with at least 1 event, but there were 371 events. Therefore, 124 (33%) were not used. Results of the standard analysis for edetate + MVM showed HR 0.74 (0.57,0.95), p=0.016; for AG HR 0.66 (0.51,0.85),p=0.002, and for WLW HR 0.38 (0.30,0.49), p<0.001.
Conclusion: In this post-MI trial, a standard time to first event analysis did not make use of over 1/3 of events. Multiple events analysis can improve the precision of the estimate of benefit by producing narrower confidence intervals. These methods could be considered to reduce sample size and budgets in future clinical trials.
Author Disclosures: K.L. Lee: None. R.S. Roberts: None. D.B. Mark: None. H.R. Al-Khalidi: None. R. Boineau: None. Y. Rosenberg: None. M. Stylianou: None. G.A. Lamas: None.
- © 2015 by American Heart Association, Inc.