Adherence and legacy effects of high dose eicosapentaenoic acid in hypertriglyceridemia and high CV risk – REDUCE-IT Legacy

Introduction

In long-term cardiovascular (CV) outcome trials, non-adherence to study drug can lead to underestimation of treatment effect. Analysis of initially adherent subjects who stop study drug can reveal possible persisting benefits of treatment.

Purpose

This analysis of REDUCE-IT evaluated the effect of icosapent ethyl (IPE) in subjects with good adherence. We expected the full benefit of IPE to be apparent after a period of adherence, and evidence of a potential ‘legacy’ effect to emerge thereafter if drug intake ceased.

Methods

REDUCE-IT randomised 8179 statin-treated participants with high triglycerides and high CV risk to IPE 4g/day or placebo. Adherence was assessed based on duration of study drug consumption. Hazard ratios (HR), 95% confidence intervals and log-rank P-values for the primary endpoint were determined for participants who took study drug per protocol for ≥1.5, ≥2, ≥2.5 and ≥3 years. We evaluated maximum risk reduction in the whole cohort and in 5785 secondary prevention subjects. To test for a legacy effect, we constructed Kaplan-Meier (KM) curves for time to first event from randomisation for adherers in the secondary prevention group who stopped study drug before study end. KM curves were also derived restarting the ‘clock’ on the day each subject stopped taking study drug.

Results

The HR for the whole cohort regardless of whether they adhered to the drug protocol (Intention-To-Treat (ITT) analysis) was 0.75 (Table). ‘Good adherers’ were defined as participants who took IPE for ≥1.5 years (n=6921), and they experienced a risk reduction of 29-30%. The secondary prevention group exhibited a similar pattern. Baseline risk factors in good adherers were comparable with the whole cohort.

In the whole trial cohort, 2042 participants stopped study drug prematurely (mean years on study drug 2.3, mean years off study drug 2.1). For these subjects, the KM curves showed a trend towards maintained separation over time with a HR of 0.83 (95% CI:0.70, 1.00), P=0.05. In the secondary prevention group, 1318 participants stopped study drug prematurely (mean years on study drug 2.3, mean years off study drug 2.1). For these subjects, separation of the KM curves was maintained over the entire trial follow up, HR 0.73 (Figure A). Separation of curves was also apparent for CV events occurring after stopping study drug, HR 0.73 (Figure B). These findings are consistent with IPE generating a persisting ‘legacy’ risk reduction.

Conclusion

Good adherers who took IPE for ≥1.5 years achieved about a 30% risk reduction. Secondary prevention participants who stopped IPE prematurely after a mean of 2.3 years on treatment exhibited a ‘legacy’ effect with no apparent diminution in the HR difference over the next 1 to 4 years. This therapeutic response (analogous to statins) suggests that IPE altered the trajectory of disease.