Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT
Prakriti Gaba1, Deepak L Bhatt1, Robert P Giugliano1
1Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Insights
Icosapent ethyl (IPE) significantly reduced cardiovascular events in patients with elevated triglycerides, aligning with both investigator-reported and adjudicated outcomes. This confirms the robust CV benefits of IPE in the REDUCE-IT trial.
Area of Science:
- Cardiology
- Clinical Trials
- Pharmacology
Background:
- The REDUCE-IT trial investigated the efficacy of icosapent ethyl (IPE) in statin-treated patients with high triglycerides.
- IPE demonstrated significant reductions in major cardiovascular (CV) events, including the primary and key secondary endpoints.
Purpose of the Study:
- To evaluate the impact of IPE on investigator-reported cardiovascular events.
- To compare investigator-reported event data with Clinical Endpoint Committee (CEC) adjudicated data.
Main Methods:
- Investigator-reported events were collected and compared with blinded CEC-adjudicated events for concordance.
- The Kappa statistic was used to assess agreement between reported and adjudicated endpoints.
Main Results:
- High concordance was observed between investigator-reported and adjudicated endpoints (Kappa: 0.89 for primary, 0.90 for key secondary).
- IPE significantly reduced the primary endpoint (19.1% vs 24.6%) and key secondary endpoint (10.5% vs 13.6%) based on investigator reports.
- Similar significant reductions were observed for both endpoints when using adjudicated data.
Conclusions:
- IPE consistently and significantly reduces cardiovascular events, including myocardial infarction and coronary revascularization.
- The findings support the robust CV benefits of IPE established in the REDUCE-IT trial.
- The study questions the routine necessity of endpoint adjudication in blinded, placebo-controlled CV outcome trials given high concordance with investigator reports.
Background:
REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE.
Objectives:
The purpose of this study was to determine the effects of IPE on investigator-reported events.
Methods:
Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance.
Results:
There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints.
Conclusions:
IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
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