ABC | Volume 111, Nº2, August 2018

Viewpoint Correia & Rassi Junior ISCHEMIA Trial: the elephant in the room Arq Bras Cardiol. 2018; 111(2):213-214 1. ClinicalTrials.gov. International Study of Comparative Health Effectiveness withMedical and Invasive Approaches (ISCHEMIA) trial. [Accessed in 2018 March 4]. Available at https://clinicaltrials.gov/ct2/show/NCT01471522. 2. International Study of Comparative Health Effectiveness with Medical and InvasiveApproaches (ISCHEMIA)trial. [Accessed in2018March4].Available at https://www.ischemiatrial.org/ 3. Evans S. When and how can endpoints be changed after initiation of a randomized clinical trial? PLoS Clin Trials . 2007;2(4):e18. 4. Ramagopalan SV, Skingsley AP, Handunnetthi L, Magnus D, Klingel M, Pakpoor J, et al. Funding source and primary outcome changes in clinical trials registered on ClinicalTrials.gov are associated with the reporting of a statistically significant primary outcome: a cross-sectional study. F1000Res . 2015;4:80. 5. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al. American College of Cardiology; American Heart Association. 2014 ACC/ AHA Key Data Elements andDefinitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force onClinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Circulation . 2015;132(4):302–61. References This is an open-access article distributed under the terms of the Creative Commons Attribution License overall prognosis may reduce statistical power, but also makes futile the choice for an invasive procedure expected to protect patients from an unlikely outcome, at the expense of physical and mental stress, unintended consequences and monetary costs. In fact, the need for a higher than expected statistical power indicates the intention to detect an absolute risk reduction that may be clinically irrelevant. The new components added to the composite primary endpoint also have implications for the trial’s findings. The original outcomes of cardiovascular death or MI are unequivocal, whereas hospitalization for angina or heart failure is mediated by a physician’s reaction to a clinical scenario. In an open study such as ISCHEMIA, it is possible that the knowledge that the patient was not revascularized could lower the physician's threshold for admitting patients due to symptoms. Although unstable angina and MI belong to the same spectrum of pathophysiological processes collectively described as acute coronary syndromes, the diagnosis of unstable angina involves significant subjectivity on the part of the treating clinician, the investigator, and adjudication committees. 5 Additionally, the prognostic relevance of unstable angina is much lower than that of MI and, of course, cardiovascular death. Therefore, the inclusion of hospitalization for unstable angina in the composite primary endpoint is susceptible to ascertainment bias and may alter the results towards a benefit for the routine invasive strategy. Heart failure is a heterogeneous syndrome related not only to atherosclerosis but also to hypertension, renal disease, and other causes that are generally not discernible from the records available to the study adjudicators. It is also often difficult to distinguish heart failure from other causes of acute dyspnea. In conclusion, it is highly questionable whether improving statistical power at the cost of impairing validity and relevance justifies this protocol modification. Changing the primary endpoint of a trial often evokes cynicism from the medical community and a study that uses a less relevant end point may not provide answers to clinically important questions. Time will tell whether such a strategy was a wise decision. Author contributions Conception and design of the research, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Correia LCL, Rassi Junior A. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. Study Association This study is not associatedwith any thesis or dissertationwork. 214