title: Trends in Utilization of Surrogate Endpoints in Contemporary Cardiovascular Clinical Trials.
abstract: Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p = 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p = 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p = 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p = 0.27) and intermediate endpoints (74.4% to 71.4%, p = 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes.
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ravi B
authors.initials: RB
authors.lastname: Patel
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Vaduganathan
authors.affiliation: Division of Cardiology, Emory University, Atlanta, Georgia.
authors.forename: Ayman
authors.initials: A
authors.lastname: Samman-Tahhan
authors.affiliation: Division of Cardiology, Emory University, Atlanta, Georgia.
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Kalogeropoulos
authors.affiliation: Division of Cardiology, Emory University, Atlanta, Georgia.
authors.forename: Vasiliki V
authors.initials: VV
authors.lastname: Georgiopoulou
authors.affiliation: Division of Cardiology, University of California Los Angeles, Los Angeles, California.
authors.forename: Gregg C
authors.initials: GC
authors.lastname: Fonarow
authors.affiliation: Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.affiliation: Division of Cardiology, Stony Brook University, Stony Brook, New York. Electronic address: javed.butler@stonybrookmedicine.edu.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism*; D002986:Clinical Trials as Topic; D023381:Endpoint Determination / Q000379:methods*; D006801:Humans; D055811:Journal Impact Factor
chemical_list: D015415:Biomarkers