'Faith Healing' and 'Subtraction Anxiety' in Unblinded Trials of Procedures: Lessons from DEFER and FAME-2 for End Points in the ISCHEMIA Trial

At its conception, a randomized controlled trial is carefully designed to detect a significant effect of an intervention on a prespecified primary end point. Each aspect of a trial is deliberately constructed to allow it to answer this principal question. From the moment the first patient is recruited, the primary end point is fixed, and all other outcomes are considered secondary. The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial was designed around a clear primary end point: cardiovascular death and nonfatal myocardial infarction (MI).1 Eighty-four million dollars of United States National Heart, Lung, and Blood Institute (US NHLBI) funding was awarded, and >5000 patients signed informed consent to participate. However, on January 17, 2018, over 99% of the way through the recruitment period,2 an amendment was made to the clinicaltrials.gov website.3 This amendment indicated that the primary endpoint for ISCHEMIA had been altered to cardiovascular death, nonfatal MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. The ISCHEMIA investigators have now detailed the steps involved in the change, which began in June 2017 after a recommendation from an NHLBI-appointed Independent Advisory Panel. This Perspective discusses the implications of this in light of what other trials teach us, and why readers should retain their focus on the primary end point of cardiovascular death or nonfatal MI.3 Cardiovascular death and nonfatal MI are largely objective, dichotomous events. Their measurement is resistant to bias, and they are therefore often called hard clinical end points. Although both commonly occur in clinical practice, they may be less frequent in trial populations. Patients enrolled in trials tend to be younger, have fewer comorbidities, and are closely supported by trial clinicians. However, more important than this is the powerful influence of motivation and interest …