Abstract 19637: Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints

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Background: Surrogate endpoint trials can test strategies more efficiently, but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We sought to determine recent trends in the publication of cardiovascular trials with surrogate outcomes.

Methods: We identified cardiovascular trials with primary surrogate endpoints published in NEJM, Lancet, and JAMA from January 1990 to December 2011. Trends in publication of surrogate endpoint trials, and the success of the trials in meeting their primary endpoint were evaluated. We also tracked the above three journals for publication of clinical outcome trials on the interventions tested in surrogate trials.

Results: We screened 3016 articles and identified 848 primary hypothesis cardiovascular trials, which included 220 surrogate endpoint trials. There was an increase over time in the number of surrogate endpoint trials (P=0.01). From the total of 220 surrogate trials, 157 (71.4 %) were positive for their primary endpoint. Sixty (27.5%) surrogate trials were followed by at least one clinical outcome trial. Among these 60 surrogate trials, in 24 cases the outcomes trial results validated the positive surrogates; whereas in 21 subsequent outcome trials were negative following positive results on a surrogate. However, we identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit (Figure).

Conclusions: Cardiovascular surrogate outcomes trials are common, frequently show superiority of the tested intervention and are infrequently followed by a prominent outcomes trial. However, when there was a high profile clinical outcomes study, half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.

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