The grey zone of truth.

Registration of new drugs and devices, and our guidelines for management of cardiovascular disease, are mostly based on the results of clinical trials. Trial results are reported in great detail, with primary and secondary endpoints, event rates in the relevant treatment groups, relative risks or odds ratios with confidence intervals, and the corresponding statistical analyses. However, the busy clinician may remember only whether the trial was ‘significant’ (P , 0.05) or ‘non-significant’, white or black. Some trial endpoints are clear and straightforward, such as total mortality. Other endpoints, however, require interpretation of clinical data in order to decide whether death was from cardiovascular disease, whether a myocardial infarction or ischaemic stroke occurred, whether hospital admission was for heart failure, or whether bleeding was ‘minor’ or ‘major’. This judgement can be made by the physician who treated the patient in a trial (investigator), or it may be made by an independent central ‘Clinical Event Committee’ (CEC). At first glance, it might be expected that such judgement should be consistent, since both the investigator and the CEC interpret the same data. However, the investigatormay not beawareof the precisedefinitions of the events specified in the trial protocol. For example, in recent years the definition of myocardial infarction has evolved, with three reports by the European Society of Cardiology (ESC) together with several other organizations. 3 In particular, different arbitrary choices have been made for the definition of procedure-relatedmyocardial infarction. In the first international report, any elevation of markers of myocardial necrosis above the upper reference limit after a percutaneous coronary intervention (PCI) procedure was labelled ‘infarction’, while in the secondand third reports an elevation exceeding three times and five times the upper reference limit, respectively, was arbitrarily chosen as a threshold to define procedurerelated infarctions (Figure 1). This reflects differences in opinion and new evidence about the clinical implications of procedure-related myocardial necrosis. Similarly it requires an expert to distinguish the different definitions for ‘major bleeding’ according to the International Society for Thrombosis and Hemostasis (ISTH), TIMI, GUSTO, and those in specific study protocols (Figure 2). The membersofaCECare trained toclassifypossibleevents suchasamyocardial infarction, bleeding, stroke, or hospital admission according to the specific criteria specified in the study protocol, while the local investigator is likely to apply ‘clinical’ judgement. Because the interpretation of clinical data may differ between the investigator and the CEC, the outcome of a trial may vary when different criteria (investigator call or CEC evaluation) are applied (Table 1). For example, the EPIC study, the first study to document the value of glycoprotein (GP) IIb/IIIa receptor blockers in patients undergoing PCI, was stopped upon recommendation of the Data Safety Monitoring Committee because of a major reduction in the primary endpoint, which was driven by a reduction in PCI procedure-related infarcts after CEC adjudication. However, if the investigator reports had been used, the treatment effect would have been smaller, and not statistically significant. In contrast, the results of IMPACT-II, with another GP IIb/IIIa receptor blocker, were statistically significant based on the investigator-reported infarcts, but not according to the CEC. Also the events in the CHARM-preserved study were not statistically significant according to the CEC-reported primary endpoint, while the investigatorreported events were significantly reduced. In PURSUIT, the difference between the new treatment and placebo was similarly reduced by the CEC evaluation of events, although both the CEC-reported