Perspectives The Fragility of Cardiovascular Clinical Trial Results LEMUEL A. MOYÉ,MD,PhD,* ANITA DESWAL, MD † Houston, Texas ABSTRACT Background: Clinical trials that have their prospective analysis plan altered are difficult to interpret. Methods and Results: After providing 4 examples of problematic trial results that have had their findings reversed, the necessity of a fixed research protocol is developed. Investigators generally wish to extend the results from their research sample to the larger population; however, thisdelicate extension is complicated by the presence of sampling error. No computational or statistical tools can remove sampling error—the most that researchers can do is to provide to the medical and regulatory communities a measure of the distorting effect that sampling error can produce. Investigators accomplish this by providing an estimate of how likely it is that the population produced a misleading sample for them to study. However, studies in which the data determine the analysis plan damage these estimators. When they are damaged, these estimators produce untrustworthy assessments of the degree to which the study results reflect the population findings. Conclusions: The way to avoid these complications is to design the experiment carefully, then carefully execute the experiment as it was designed. Key Words: Statistics, estimators, epidemiology, prospective design, clinical trials. The prospectively designed, randomized, double-blind clinical trial is held as the most advanced research tool to assess an intervention’s effect in clinical medicine. Often meticulously planned, requiring hundreds of researchers, thousands of patients, and millionsof dollars,these research enterprises can provide important new informa- tion abouthe safety and efficacy of medicaland or surgical management of patients. Pharmaceutical com- panies, regulatory agencies, managed care organizations, and private physicians look to these research devices as the conduit through which this critical, new information for treating patients is transmitted. However, there has been a curioustrend in recent clinicaltrialreports studying congestive heart failure (CHF). Although cir- cumstances in which two clinical trials have been carried outto assess the same intervention are rare, the results from these trial pairs,when available, have notbeen consistent. This has been the case with the evaluations of vesnarinone, losartan, and amlodipine. In each of these three circumstances a pair of clinical trials was carried outsequentially. In each circumstance, the first clinical trialsuggested abenefit, followed by asecond clinical trialthatreversed or nullified the result of the first experiment. In these circumstances, the nonstatistical From the *University of Texas School of Public Health, Houston, Texas, and † Winters Center for Heart Failure Research and Houston Center for Quality of Care and Utilization Studies, Veterans Adminis- tration Medical Centerand BaylorCollege ofMedicine, Houston, Texas. Manuscript received February 15, 2002; revised manuscript received May 15, 2002; revised manuscript accepted May 30, 2002. Reprint requests: Lemuel A. Moyé,MD,PhD,University of Texas School of Public Health, RAS Building E815, 1200 Herman Pressler, Houston, TX 77030. Dr. Deswal’seffortwassupported by V.A. Cooperative Studies Program Clinical ResearchCareerDevelopment Award(CRCD #712B). Copyright 2002, Elsevier Science (USA). All rights reserved. 1071-9164/02/0804-0010$35.00/0 doi:10.1054/jcaf.2002.126917 Journalof Cardiac Failure Vol. 8 No. 4 2002 247