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Effects of the end point adjudication process on the results of the Perindopril Protection Against Recurrent Stroke
Toshiharu Ninomiya1, Geoff Donnan, Neil Anderson
1The George Institute for International Health, University of Sydney, Sydney, Australia.
Insights
End point adjudication committees (EPAC) in large clinical trials provide reassurance but do not significantly alter conclusions on treatment effects, as seen in the PROGRESS trial for blood pressure lowering. This ensures diagnostic robustness.
Area of Science:
- Clinical Trials Methodology
- Cardiovascular Research
- Neurology
Background:
- End point adjudication committees (EPAC) are standard in large clinical trials to verify diagnoses.
- Ensuring diagnostic accuracy is crucial for the reliability of trial outcomes.
Purpose of the Study:
- To evaluate the impact of EPAC on treatment effect estimates in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).
- To assess whether EPAC review alters conclusions drawn from clinical trial data.
Main Methods:
- The PROGRESS trial involved 6105 participants with cerebrovascular disease, randomized to blood pressure lowering treatments.
- Cox regression models were used to compare treatment effects based on investigator-reported events versus EPAC-adjudicated events.
Main Results:
- 90% of initial stroke diagnoses were confirmed by EPAC.
- Hazard ratios for stroke treatment effects were similar whether based on investigator (0.74) or EPAC (0.72) diagnoses.
- EPAC review did not significantly impact effect estimates for stroke subtypes, myocardial infarction, or mortality.
Conclusions:
- The EPAC process in the PROGRESS trial did not discernibly alter the study's conclusions.
- While EPAC may offer scientific gain in very large trials focused on subtypes, its primary value in PROGRESS was providing reassurance.
- The findings support the role of EPAC in enhancing confidence in clinical trial results.
Background And Purpose:
End point adjudication committees (EPAC) are widely used in large-scale clinical trials to ensure the robustness of diagnosis for end points.
Methods:
The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a double-blind randomized trial of blood pressure lowering in 6105 participants with pre-existing cerebrovascular disease. Separate estimates of the effects of randomized treatment were determined using Cox regression models that were based on the unadjudicated events initially reported by the investigator and on the final events assigned by the EPAC.
Results:
There were 992 strokes initially reported by the investigators and 894 (90%) retained these diagnoses after adjudication by the EPAC. The hazard ratios (95% CIs) for the effect of randomized treatment on stroke were 0.74 (0.64 to 0.85) based on the investigator diagnoses and 0.72 (0.62 to 0.83) based on the EPAC diagnoses (P homogeneity=0.7). For each stroke subtype reported, the corresponding numbers of diagnoses (investigators/EPAC) were ischemic (593/565), hemorrhagic (124/111), and unknown (124/93) with no impact of the EPAC review on the estimates of treatment effects (all P homogeneity >0.3). There was likewise no detectable effect of reclassification of diagnoses for the effect estimates calculated for myocardial infarction or the main causes of death (all P homogeneity >0.5).
Conclusions:
The EPAC process had no discernible impact on the trial conclusions. Very large trials powered to detect effects on stroke subtypes might obtain real scientific gain from an EPAC, but in the case of PROGRESS, the value of the EPAC was in the reassurance it provided.
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