Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.
BACKGROUND
Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes.


RESULTS
We identified cardiovascular trials with primary surrogate endpoints published in theNew England Journal of Medicine,Lancet, andJAMA: Journal of the American Medical Associationfrom 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high-impact journals.


CONCLUSIONS
Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high-profile clinical outcomes study, nearly 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.
Center for Outcomes Research and Evaluation, Yale New Haven Health, New Haven, CT.|Division of Cardiology, Columbia University Medical Center New York-Presbyterian Hospital, New York, NY.
Behnood
B
Bikdeli
University at Buffalo, NY.
Natdanai
N
Punnanithinont
Saint Vincent Hospital, Worcester, MA.
Yasir
Y
Akram
Yale School of Medicine, New Haven, CT.
Ike
I
Lee
Center for Outcomes Research and Evaluation, Yale New Haven Health, New Haven, CT.|Section of Cardiovascular Medicine Yale School of Medicine, New Haven, CT.
Nihar R
NR
Desai
Center for Outcomes Research and Evaluation, Yale New Haven Health, New Haven, CT.|Section of General Internal Medicine Yale School of Medicine, New Haven, CT.|Robert Wood Johnson Foundation Clnical Scholars Program Yale School of Medicine, New Haven, CT.|Department of Internal Medicine Yale School of Medicine, New Haven, CT.|Department of Health Policy and Management, Yale School of Public Health, New Haven, CT.
Joseph S
JS
Ross
Center for Outcomes Research and Evaluation, Yale New Haven Health, New Haven, CT harlan.krumholz@yale.edu.|Section of Cardiovascular Medicine Yale School of Medicine, New Haven, CT.|Robert Wood Johnson Foundation Clnical Scholars Program Yale School of Medicine, New Haven, CT.|Department of Health Policy and Management, Yale School of Public Health, New Haven, CT.
Harlan M
HM
Krumholz
D015415:Biomarkers; D002318:Cardiovascular Diseases / Q000628:therapy*; D002986:Clinical Trials as Topic; D023381:Endpoint Determination / Q000379:methods*; D006801:Humans
D015415:Biomarkers
clinical trial; outcome; surrogate endpoints