# Abstract

 

## Background Limited information has been published regarding how specific processes for event adjudication can affect event rates in trials. We reviewed nonfatal myocardial infarctions (MIs) reported by site investigators in the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and those adjudicated by a central clinical events committee (CEC) to determine the reasons for differences in event rates. 

## Methods The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. The primary end-point was death or post-enrolment MI at 30 days as assessed by the CEC; this end-point was also constructed using site-reported events. The CEC identified suspected MIs by systematic review of clinical, cardiac enzyme, and electrocardiographic data. 

## Results The CEC identified 5005 (46%) suspected events, of which 1415 (28%) were adjudicated as MI. The site investigator and CEC assessments of whether a MI had occurred disagreed in 983 (20%) of the 5005 patients with suspected MI, mostly reflecting site misclassification of post-enrolment MIs (as enrolment MIs) or underreported periprocedural MIs. Patients for whom the CEC and site investigator agreed that no end-point MI had occurred had the lowest mortality at 30 days and between 30 days and 6 months, and those with agreement that a MI had occurred had the highest mortality. 

## Conclusion CEC adjudication provides a standard, systematic, independent, and unbiased assessment of end-points, particularly for trials that span geographic regions and clinical practice settings. Understanding the review process and reasons for disagreement between CEC and site investigator assessments of MI is important to design future trials and interpret event rates between trials. # Results 

## Incidence of disagreement Overall, 5005 (46%) patients with possible or suspected MI were identified and adjudicated by the CEC. The CEC identified more patients with end-point events than did the site investigators (13.6% versus 7.7% for placebo, 12.6% versus 6.2% for eptifibatide). The CEC and site investigator assessments of MI disagreed for 9% of all patients enrolled in the PURSUIT trial. The CEC identified MIs in 1415 of the 5005 patients with suspected MI. The site investigator and the CEC assessments disagreed in 983 (20%) of the 5005 patients. Of these 983 patients with disagreements, 816 patients had a MI identified by the CEC but not the site investigator, and 167 patients had a MI identified by site investigator but not the CEC. The proportion of patients with disagreement was similar among regions. 

## Reasons for disagreement Most often, when the site investigator had identified a MI and the CEC had not, the investigator had misclassified a MI at enrolment as an end-point MI, although by protocol these were not end-point events (Table [1](#)). Recurrent ischemic events without elevated cardiac enzymes or ECG evidence of MI were also incorrectly identified by site investigators as MIs (Table [1](#)). In cases where the CEC had identified a MI and the site investigators had not, one-third of those identified were MIs defined by enzyme elevations without clinical or ECG evidence of ischemia or infarction (Table [2](#)). Enzyme elevations after bypass surgery accounted for 25% of these cases. Patients with clinically evident ischemia reported by the site investigator and associated with cardiac enzyme elevations were not reported as MIs by investigators in 27% of the cases of disagreement (Table [2](#)). Few infarctions based on new Q waves without clinical evidence of reinfarction were identified by the CEC and not by site investigators. ::::table-wrap

::: caption
Myocardial infarctions identified by site investigators but not
confirmed by the clinical events committee
:::

```
                                           Eastern Europe   Latin America   North America   Western Europe   Overall
```

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Clinical scenario (*n* = 24) (*n* = 8) (*n* = 57) (*n* = 78) (*n* = 167)
Enrolment myocardial infarction^\*^ 8 (33) 4 (50) 24 (42) 28 (36) 64 (38)
Ischemic event without infarction^†^ 7 (29) 0 (0) 8 (14) 19 (24) 34 (20)
Peri-death infarction^‡^ 6 (25) 2 (25) 13 (23) 8 (10) 29 (17)
Percutaneous coronary intervention related 0 (0) 1 (12.5) 6 (11) 10 (13) 17 (10)
Coronary artery bypass surgery related 2 (8) 1 (12.5) 5 (9) 7 (9) 15 (9)
Miscellaneous 1 (4) 0 (0) 1 (2) 6 (8) 8 (5)

Data presented as *n* (%). ^\*^ Not an end-point event per protocol. ^†^
Clinical evidence of ischemia without electrocardiography (ECG) or
cardiac enzyme evidence of infarction. ^‡^ Infarction suspected at the
time of death without supporting clinical, ECG, or cardiac enzyme data.:::: ::::table-wrap
::: caption
Myocardial infarctions identified by the clinical events committee but
not the site investigator
:::

```
                                        Eastern Europe   Latin America   North America   Western Europe   Overall
```

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Clinical scenario (*n* = 182) (*n* = 44) (*n* = 299) (*n* = 291) (*n* = 816)
Asymptomatic CK-MB elevation^\*^ 83 (46) 23 (52) 37 (12) 128 (44) 271 (33)
Ischemic event^†^ 89 (49) 12 (27) 48 (16) 68 (23) 217 (27)
Coronary artery bypass graft-related 6 (3) 6 (14) 138 (46) 52 (18) 202 (25)
PCI-related 2 (1) 1 (2) 62 (21) 22 (8) 87 (11)
Early myocardial infarction^‡^ 1 (1) 0 (0.0) 3 (1) 3 (1) 7 (1)
Isolated electrocardiogram (Q waves)^§^ 1 (1) 1 (2) 5 (2) 4 (1) 11 (1)
Peri-death^¶^ 0 (0) 1 (2) 1 (0.3) 4 (1) 6 (1)
Miscellaneous 0 (0) 0 (0) 5 (2) 10 (3) 15 (2)

Data presented as *n* (%). CK-MB, CK-MB = creatine kinase-myocardial
band; PCI, percutaneous coronary intervention. ^*^ No clinical symptoms
or electrocardiography (ECG) evidence of ischemia. ^†^ Clinical evidence
of ischemia and ECG/cardiac enzyme evidence of infarction. ^‡^ Cardiac
enzyme or ECG evidence of infarction < 24 hours after enrolment,
different from the enrolment event. ^§^ Identified by systematic review
of ECGs without clinical evidence of reinfarction. ^¶^ Myocardial
infarction at the time of death with clinical, ECG, or cardiac enzyme
evidence.:::: Table [3](#) presents the cardiac enzyme elevation for MIs that the CEC identified and the site investigators did not. These data exclude MIs associated with PCI or bypass surgery; by definition, those types of MI required enzyme elevations greater than three or five times the upper limit of normal (ULN), respectively. The ratio of creatine kinase-myocardial band (CK-MB) to its ULN was highest in North America (median [25^th^, 75^th^] 1.6 [1.2, 2.9]). Enzymes were similarly elevated between patients with MIs defined only by enzyme elevations (without symptoms or ECG changes) and patients with elevations associated with ECG or clinical evidence of ischemia. ::::table-wrap
::: caption
Enzyme elevations in patients with myocardial infarction identified by
the clinical events committee but not the site investigator^*^
:::

```
                     Median peak CK/ULN               Median peak CK-MB/ULN
```

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Region *n* (25th, 75th percentiles) *n* (25th, 75th percentiles)
Eastern Europe 172 0.6 (0.3, 1.2) 167 1.4 (1.2, 1.9)
Latin America 34 0.7 (0.4, 1.2) 34 2.0 (1.3, 2.6)
North America 112 1.6 (1.0, 3.1) 106 2.9 (1.5, 5.5)
Western Europe 202 0.7 (0.4, 2.0) 196 1.7 (1.2, 3.0)
Overall 520 0.9 (0.4, 1.9) 503 1.6 (1.2, 2.9):::: Table [4](#) presents the level of clinical certainty for MIs not associated with PCI or bypass surgery, as identified by the CEC but not the site investigators. Overall, 98 (18%) of these patients were assigned a low level of clinical certainty. The proportion of patients assigned a low level of clinical certainty varied among the regions, with the lowest in North America. ::::table-wrap
::: caption
Level of clinical certainty^\*^ for myocardial infarction identified by
the clinical events committee but not the site investigator
:::

```
               High certainty   Low certainty   Total
```

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Eastern Europe 133 (76) 42 (24) 175
Latin America 21 (58) 15 (42) 36
North America 111 (98) 2 (2) 113
Western Europe 177 (82) 39 (18) 216
Overall 442 (82) 98 (18) 540

Data presented as *n* (%). ^\*^ See Methods.:::: 

## Effect of disagreement on outcomes The 30-day CEC rates of MI and death or MI overall are presented in Table [5](#) by geographic region. The event rates are also shown for the analyses in which the 98 patients assigned a low level of certainty were reclassified as no infarction. ::::table-wrap
::: caption
Clinical events committee event rates (%) at 30 days
:::

```
                               All patients   With reclassification^*^                                    
```

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Event Eptifibatide Placebo *P* Eptifibatide Placebo *P*
Death or myocardial infarction\
Eastern Europe 21.0 19.7 18.0 17.9\
Latin America 16.1 15.7 14.1 13.2\
North America 11.7 15.0 11.7 15.0\
Western Europe 13.8 14.8 12.9 13.7\
Overall 14.2 15.7 0.042 13.3 14.9 0.021

Myocardial infarction\
Eastern Europe 18.8 17.3 15.8 15.3\
Latin America 11.6 11.7 9.6 9.1\
North America 10.1 12.9 10.1 12.9\
Western Europe 12.6 12.9 11.7 11.8\
Overall 12.6 13.6 0.137 11.6 12.7 0.08

^\*^See Methods; 98 patients with low clinical certainty reclassified as
having no infarction.:::: The lowest mortality rates were in patients for whom the CEC and site investigators agreed that no MI had occurred by 30 days (Table [6](#)). The highest rates were in patients for whom there was agreement that a MI had occurred. Mortality was high in the group with MI identified by the site investigators but not the CEC; however, many of these patients had suspected sudden cardiac death as the event identified as a MI by the investigator (Table [1](#)). The absolute increase in mortality between 30 days and 6 months was greater in patients with CEC-determined MIs not identified by the site investigators than in patients with MI identified by the site investigators but not the CEC. ::::table-wrap
::: caption
Mortality (30 days and 6 months) for cases of disagreement
:::

```
                          Mortality (%)                       
```

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```
                   *n*    30 days         30 days--6 months   6 months
```

CEC no / site no 9366 1.7 2.1 3.8
CEC yes / site yes 599 22.0 5.7 27.7
CEC yes / site no 816 7.2 5.4 12.6
CEC no / site yes 167 24.0 2.3 26.3

CEC, Clinical events committee.::::


Extracted trial result:
Outcome: Death or myocardial infarction (binary)
Intervention: eptifibatide
Comparator: placebo
Notes: Group sizes are not given so the events cannot calculate using the percentages.