Podcast- Deepak L. Bhatt, MD, MPH, is the Executive Director of Brigham and Women's Hospital's Interventional Cardiovascular Programs and a Professor of Medicine at Harvard Medical School. Dr. Bhatt speaks about the Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT.
Link to Abstract-
The REDUCE-IT trial (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) assigned statin-treated patients with high triglycerides to IPE or placebo. With IPE, the primary outcome (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina necessitating hospitalization) and major secondary endpoints (CV death, MI, stroke) were both significantly reduced.
The goal of this research was to see how IPE affected investigator-reported incidents.
Blinded site investigators gathered potential endpoints, which were then judged by a blinded Clinical Endpoint Committee (CEC) according to a predetermined charter. For concordance, investigator-reported events were compared to adjudicated occurrences.
The concordance between investigator-reported and adjudicated endpoints was quite high. For the major outcome, the simple Kappa statistic between CEC-adjudicated vs site-reported incidents was 0.89, and for the critical secondary endpoint, it was 0.90. IPE significantly reduced the rate of the primary endpoint (19.1 percent vs 24.6 percent; HR: 0.74 [95 percent CI: 0.67-0.81]; P 0.0001) and the key secondary endpoint (10.5 percent vs 13.6 percent; HR: 0.75 [95 percent CI: 0.66-0.85]; P 0.0001) in 8,179 randomized patients, according to investigator-reported events. IPE reduced the rate of the primary and key secondary endpoints in adjudicated events in a comparable way.
As determined by independent, blinded CEC adjudication as well as blinded investigator-reported assessment, IPE resulted with consistent, significant reductions in CV events, including MI and coronary revascularization. These findings underline the strong evidence for IPE's significant CV advantages found in REDUCE-IT, and also raise the question of whether CV outcome trial endpoint adjudication is necessary in blinded, placebo-controlled studies. (REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361; Evaluating the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease
Central adjudication in clinical trials has been questioned because to its high cost, time-consuming nature, and disputed efficacy, particularly in double-blind, placebo-controlled trials (1-5). There was no significant difference between investigator-reported major bleeding and centrally adjudicated major bleeding as defined by either the TIMI (Thrombolysis In Myocardial Infarction) or GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions in a 2016 analysis of the CHAMPION PHOENIX (Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events) trial (5). More recently, a subanalysis of the SHIFT (Ivabradine and Outcomes in Chronic Heart Failure) trial, which looked at rates of cardiovascular (CV) death and heart failure hospitalizations among patients treated with ivabradine, found that investigator-reported and centrally adjudicated events had a high level of agreement (6). Because of cost constraints imposed by the COVID-19 pandemic, the SCORED (Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease) and SOLOIST-WHF (Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure) trials evaluating the effects of the sodium-glucose cotransporter-2 inhibitor sotagliflozin on CV outcomes abandoned adjudication entirely, with no discernible loss of statistical power (7-9).
The REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) found that icosapent ethyl (IPE) significantly reduced adjudicated events, including the primary endpoint and each of its components (CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization) (10-17). It was previously unknown whether the CV benefits of IPE demonstrated in REDUCE-IT required central adjudication. The purpose of this REDUCE-IT trial analysis was to see how IPE compared to placebo affected CV events as reported by site investigators and to see how closely investigator-reported and centrally adjudicated clinical events matched.
Design of the research
REDUCE-IT was a phase 3b, double-blind, placebo-controlled trial in which 8,179 statin-treated individuals with reduced LDL-C and moderately high triglycerides were assigned to 4 g daily of either IPE or a matched placebo (2 capsules twice daily with food). Each participating center's institutional review board or ethical committee gave their approval to the study. Blinded site investigators collected and reported potential endpoints, which were then judged by a blinded Clinical Endpoint Committee (CEC) according to a predetermined charter. All potential major adverse CV events were to be reported as adverse events or serious adverse events in the case report form, according to investigators and site staff. A blinded evaluation of adverse event reports was conducted to identify potential clinical endpoint occurrences that were not reported by trained investigators and were then adjudicated by the CEC.
CEC cardiologists examined all electrocardiograms (ECGs) for silent MIs in all patients. The presence of new Q waves on a patient's ECG was used to identify silent MIs. Through an adjudication database, an endpoint management team created and electronically delivered event packets to the CEC. Each conceivable endpoint was allocated to two principal adjudicators. If the principal adjudicators were unable to reach an agreement, the CEC chair made the final decision. Additional details about REDUCE-design IT's have previously been made public (18).
CV mortality, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, or unstable angina necessitating hospitalization were the primary endpoints. A composite of CV mortality, nonfatal MI, and nonfatal stroke was the primary secondary objective. Individual components of the primary and secondary composite endpoints, such as CV death, MI, stroke, coronary revascularization, and hospitalization for unstable angina, were also included as outcomes. The American College of Cardiology/American Heart Association standardized definitions for endpoint events in cardiovascular studies were previously published with details on the collected endpoints (19-21). Type 1 and Type 2 MIs were both included.
Investigator-reported endpoint events were compared to favorably adjudicated endpoint events in this study. The chi-square or Fisher exact test was used to compare categorical variables defined by frequency and percentage. The Student's t-test was used to compare continuous variables that were provided as mean SD. The intention-to-treat concept was applied to all of the analyses. Kaplan-Meier analyses were used to estimate time-to-event outcomes, which were then compared using the log-rank test. HRs and 95 percent CIs were calculated using a Cox proportional hazards model to analyze the relationship between clinical outcomes and the use of IPE vs placebo. The Cohen's technique was used to examine concordance, and the results were presented as simple kappa statistics with 95 percent confidence intervals. All tests were two-sided, and for the primary endpoint, a P value of 0.0437 was judged statistically significant (after accounting for two pre-specified interim analyses using O'Brien-Fleming bounds). SAS version 9.4 was used to conduct statistical analysis (SAS Institute).
Population and baseline features of the study
The baseline characteristics of REDUCE-IT patients have already been published (10). In summary, the median age was 64 years, 28.8% of patients were women, and the majority (70.7 percent) of patients had established CV disease when they were included. The median LDL-C concentration was 75.0 mg/dL, the median HDL-C concentration was 40.0 mg/dL, and the median triglyceride concentration was 216.0 mg/dL.