Macrovascular Residual Risk Studies

The primary outcome was first MACE, defined as a composite of myocardial infarction (MI), ischemic stroke, hospitalization for unstable angina warranting unplanned coronary revascularization, or death from cardiovascular causes. On March 18, 2020, this was subsequently modified after blinded review to include any coronary revascularization.

Prespecified secondary end points included:
• the original primary end point (see above)
• a composite of MI, ischemic stroke, or death from cardiovascular causes
• a composite of the primary end point or hospitalization for heart failure
• a composite of the primary end point or death from any cause
• individual components of the primary end point
• new or worsening peripheral artery disease.
Other prespecified endpoints included lipid biomarkers, and protocol-defined retinopathy and nephropathy.

This was an event-driven trial designed to have 90% power to detect an 18% relative reduction in the risk of an original primary endpoint with pemafibrate versus placebo. Randomization aimed for inclusion of about 10,000 patients, with at least 300 enrolled in Japan, at least 20% women, and no more than one-third in the primary prevention cohort. With modification of the primary endpoint, the target number of events was increased from 1092 to 1304, allowing for a 90% power to detect a 16.6% relative difference in this primary endpoint with pemafibrate versus placebo.

Data were reviewed by an independent data and safety monitoring board (DSMB) for safety throughout the trial, and for futility and efficacy at three prespecified interim time points. On March 18, 2022, on review of the interim data (after 75% of the target number of events had accrued), the DSMB unanimously recommended early termination of the trial as the prespecified futility boundaries had been crossed.

In the analysis, patients were evaluated according to their randomized group irrespective of adherence. Analysis of the time to a primary end-point event was performed using a likelihood-ratio test based on a proportional-hazards model stratified according to sex, history of cardiovascular disease, and baseline statin use.

The study randomized 10,538 patients, of whom 10,497 (5240 allocated pemafibrate and 5257 allocated placebo) were included in the intention-to-treat (ITT) efficacy population. Overall, median age was 64 years, 27.5% of patients were women, 19.4% identified as Hispanic or Latin, 33.1% were primary prevention and almost all (95.7%) were receiving a statin. Baseline characteristics of the two groups were balanced. At baseline, median fasting TG was 271 mg/dL (3.1 mmol/L), median HDL‑C was 33 mg/dL (0.9 mmol/L), and median LDL-C was 78 mg/dL (2.0 mmol/L).

Table 1. Change in key lipids at 4 months and treatment effect

* calculated, **measured, CI confidence interval

The median percentage change in fasting TG from baseline to 4 months was −31.1% in the pemafibrate group and −6.9% in the placebo group (between-group difference of −26.2%). Similar effects were reported for very low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol (remnant-C) and apolipoprotein (apo) CIII (Table 1). These treatment effects were durable over time. As LDL-C levels increased with pemafibrate (median increase of 14.0%) with no change in non-HDL-C or total cholesterol levels (mean treatment effect versus placebo -0.2% and 0.8%, respectively), there was a small increase in apoB (4.8% versus placebo).

Over the median follow-up of 3.4 years (maximum 5.0 years), 572 patients in the pemafibrate group and 560 patients in the placebo group experienced a first MACE (hazard ratio, 1.03; 95% CI 0.91 to 1.15, p=0.67). Effects were neutral for all composite secondary cardiovascular endpoints and the individual components of these endpoints.

With respect to safety, statistically significant differences were reported for renal adverse events, hepatic adverse events and thromboembolic events (Table 2). There were no differences between the two groups for serious adverse events, infections, musculoskeletal events or other adverse events.

Table 2. Statistically significant differences in adverse events.

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