This analysis of the adjudication process of nonfatal MI by a central CEC in the PURSUIT trial has five key findings. First, post-enrolment MI rates were higher than those reported in prior trials of acute coronary syndromes. Second, the site investigator and CEC assessments of end-point MI disagreed for nearly 10% of all patients enrolled. Third, the site investigators underreported protocol-defined end-point MIs. Fourth, the observed treatment effect was smaller using the CEC-adjudicated MI rates versus site investigator-identified event rates. Finally, in a retrospective analysis that excluded patients with post-enrolment MI who had conflicting clinical, ECG, and cardiac enzyme data (although they met prespecified endpoint criteria), the treatment effect was larger than that seen when such patients were included. These findings, in aggregate, suggest the use of a CEC is important for systematic ascertainment of nonfatal end-points. The definition of MI and its application in CEC event adjudication in the PURSUIT trial may, however, have been too inclusive of MIs defined by low-level enzyme elevations, which either represented 'noise' or clinically unimportant events.
The MI rates adjudicated by the CEC in the PURSUIT trial were higher than those reported in trials of similar patient populations [6
]. The reasons for these higher rates have been detailed previously [16
], and include the review of nearly 50% of patients by physicians to identify suspected events, more liberal MI criteria, and rigorous measurement of cardiac enzymes in all patients. Studies that have used only investigator-reported events probably underestimate the true MI rate.
Lack of concordance between site investigator and CEC event rates
Site investigators underreported MIs. A similar lack of concordance between events adjudicated by a CEC and those identified by clinical investigators has been observed in trials in which a similar CEC group adjudicated MIs [1
] and in other trials [7
The MI definitions in the PURSUIT trial were formulated by the International Steering Committee based on experience and clinical expertise. Because of the broad geographic enrolment planned for the PURSUIT trial, definitions were designed to be applicable in an array of clinical practice situations. The definitions were detailed in the study protocol, in study newsletters, and in study materials so the CEC and site investigators had the same set of criteria to classify MIs.
The reasons for disagreements in MI assessment between the site investigators and the CEC in the PURSUIT trial (Tables and ) are similar to those seen in the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) and the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT-II) trials (unpublished personal data). Many of the disagreements reflect physician reluctance to diagnose MI in patients they are treating, particularly when the definition of MI includes events with low-level cardiac enzyme elevations (often called 'enzyme leaks' in clinical practice). This reluctance by physicians to diagnose MI is also apparent for patients undergoing PCI, in which the clinical significance of postprocedural enzyme elevations is controversial, even though such elevations correlate with worse outcome [5
The disagreements also may partly reflect the definitions (see Appendix) of MI themselves. These definitions were designed to be applied to a broad set of clinical scenarios, including events after PCI or bypass surgery, and to events occurring early after enrolment, which needed to be differentiated from pre-enrolment or enrolment MIs. Site investigators may have had difficulty applying these criteria, particularly with conflicting cardiac enzyme, ECG, and clinical information. In addition, the enzyme criteria in the PURSUIT trial required only one cardiac enzyme value above normal to provide supportive evidence of MI. Substantial clinical uncertainty exists regarding the need for more than one elevated enzyme value and whether the CK-MB criteria should specify elevations greater than 1 × ULN or 2 × ULN.
The strategy used by a CEC to adjudicate MIs can dramatically influence event rates and the proportion of events with disagreements between site investigators and a CEC. Some trials have confirmed only events reported by the investigators [9
], while other trials have adjudicated all suspected events identified by systematic screening of patient data [1
]. When only events reported by investigators are reviewed by a CEC, the reported event rates will be identical to or lower than the site investigator rates. When events are identified independently by the CEC, the CEC event rates may be higher, lower, or the same as the site investigator-reported rates.
Difference in treatment effect
The absolute difference in the MI rates was 1.6% (6.2% for eptifibatide versus 7.8% for placebo) as assessed by the site investigators, and 1.0% (12.6% versus 13.6%) as adjudicated by the CEC. The higher event rates in both treatment arms using the CEC data, despite the similar absolute difference, reduced the relative treatment effect (7.4% versus 20.5% reduction) as expected. A similar decrease in relative treatment effect has been noted in some trials [1
] but not others [17
The MIs determined by cardiac enzyme elevations without clinical symptoms or ECG changes accounted for 33% of the disagreements in which the CEC identified a MI and the site investigators did not. The median CK-MB elevation in these events was 1.6 × ULN. About 50% of these events were thus defined by CK-MB values between 1 × ULN and 1.5 × ULN, with normal median CK values (0.9 × ULN) (Table ).
A retrospective but blinded review of MIs identified by the CEC but not the site investigator found that 18% (98/540) of these patients were assigned a low level of clinical certainty. This was because, although the CK or CK-MB elevations met the end-point criteria, the cardiac enzyme data were considered inconsistent or unreliable, or were associated with conflicting clinical and ECG data.
We noted regional differences in the proportion of patients with low clinical certainty. The highest proportions were in Eastern Europe and Latin America, where the observed treatment effect using the CEC definition was negligible. Furthermore, the magnitude of the enzyme elevations (Table ) parallels discrepancies in the assigned level of certainty. The highest enzyme elevations were observed in North America (median CK-MB elevation, 2.9 × ULN; median CK elevation, 1.6 × ULN), where the treatment effect was mostpronounced. CK-MB elevations in other regions were less striking (median CK-MB elevation, 1.4 × ULN–2.0 × ULN). The regional differences in treatment effect are, however, complex and include differences in patient demographics, the use of cardiac procedures, medications and revascularisation, and the reliability of laboratory data [23
]. These findings support the hypothesis that including MI end-points defined by low-level cardiac enzyme elevations or events associated with conflicting clinical and ECG data may dilute the actual treatment effect.
Predictive value of CEC-identified events
The 30-day treatment effect was reduced using CEC-adjudicated end-points versus site investigator assessments, but patients with events adjudicated by the CEC (but not identified by the site investigators) had greater mortality between 30 days and 6 months than did patients with MI reported only by the site investigators (Table ). In addition, MIs identified by a similar CEC process have been associated with worse long-term outcomes at 3-year follow-up [24
]. These data suggest that events identified by the CEC alone are of prognostic importance.