The review of the clinical-events classification process in the current study raises some important issues for clinical investigators. First, the rates of end-point infarction or re-infarction were higher than those reported in prior trials of patients with acute coronary syndromes. Second, the CEC identified more events than the site investigators. Third, the site investigator and the CEC assessments of MI disagreed for 20% of the patients reviewed by the CEC.
CECs have become an integral aspect of clinical trials of new therapies for patients with acute coronary syndromes. The primary function of these committees has been to systematically adjudicate nonfatal end-points such as MI. The first large trials in these patients used mortality as the primary end-point; thus, standardised assessment of patient outcome was not required [25
]. More recent trials, however, have included nonfatal end-points such as MI, congestive heart failure, stroke, or safety measures as part of composite clinical end-points. Myocardial infarction has been considered a 'hard' end-point, but its assessment can be as difficult in clinical trials as it is in clinical practice, because clinical, laboratory, and ECG data may conflict and physicians often disagree whether a patient has suffered a MI. An example of this difficulty is the evaluation of small enzyme elevations in patients undergoing percutaneous coronary intervention [28
]. Although these low-level enzyme elevations are defined as MIs in many trial protocols, physicians do not consistently consider them to be infarctions in daily clinical practice and therefore may be reluctant to report them as such.
The rates of infarction as adjudicated by the CEC in the PURSUIT trial were higher than reported in previous trials of patients with acute coronary syndromes, for several reasons [1
]. First, the PURSUIT trial CEC effort was more liberal in its identification of possible events. Committee physicians reviewed events for almost 50% of the patients in the trial, which is nearly double the percentage that underwent adjudication by the same CEC group in two other trials: Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT-II) [9
], and Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) [1
]. Second, the definition of MI is evolving and has varied among clinical trials in this patient population. For example, criteria for MI after bypass surgery in the GUSTO-IIb trial were more stringent than those in the PURSUIT trial, requiring two of three criteria to be met (CK or CK-MB fraction ≥ 5 times the upper limit of normal, two new Q waves, or new regional wall-motion abnormalities). Finally, more cardiac enzyme samples were collected per patient in the PURSUIT trial than in GUSTO-IIb (median [25th
] 4.5 [3
] versus 3 [1
]) (RAHarrington, unpublished data). These factors, particularly the systematic collection of cardiac enzymes (missing for only 0.2% of the patients), contributed to a higher ascertainment of MI in the PURSUIT trial. Trials that rely on investigator-reported MI probably underestimate the true event rate.
Before implementation of the CEC process, the International Steering Committee agreed on the definitions for MI, which were based on experience and clinical expertise. Because of the global nature of the PURSUIT investigation, attempts were made to model definitions after everyday clinical practice. The study protocol provided the end-point definitions, so that the CEC and site investigators had the same set of criteria to classify MI. Nevertheless, the site investigators underreported infarctions. Similar findings have been noted in prior trials [1
The strategy used to identify suspected infarctions can affect the proportion of events with disagreements. Some trials have confirmed events reported only by the investigators [5
], whereas other trials have adjudicated all suspected events identified by systematic screening of patient data [1
]. In the first strategy, the CEC event rates will be the same as or lower than the site investigator-reported rates. In the second, the CEC event rates may be higher, lower, or the same as the site investigator-reported rates.
The impact of adjudication of cases from other regions of the world by physicians based in North America is unknown. In the current study, however, medical records were translated to English, physicians fluent in other languages were used when needed, and the criteria for re-infarction were based, for the most part, on objective data such as enzyme and ECG data.
There are several key implications of these findings. The strategy used to identify and adjudicate end-point events is one of many factors to be considered when comparing event rates between clinical studies. During trial planning, the events classification strategy being considered may also have an important impact on estimation of event rates and the calculations of sample size and power. Education and training of clinical investigators regarding end-point definitions and ascertainment may help in minimising differences between CEC and site investigator assessments of end-points. Finally, the strategy and rigor of the clinical event adjudication process used may influence the interpretation of trial results by the clinical and regulatory communities. We believe that CEC adjudication of suspected nonfatal MI end-point events is important to provide independent, unbiased, standard, systematic assessments, particularly in trials that include broad geographic regions and different clinical practice settings.