Objective

To compare the cardiovascular outcomes associated with treatment with ω-3 carboxylic acid (CA) versus corn oil placebo in Asian and non-Asian patients at high cardiovascular risk in the STRENGTH trial.

Study design

The STRENGTH trial was a randomized, placebo-controlled, double-blind study in patients at high cardiovascular risk, either as secondary (≥50%) or primary prevention, who were on maximally tolerated statin therapy for at least 4 weeks or had low-density lipoprotein cholesterol (LDL-C) <100 mg/dL, together with high-density lipoprotein cholesterol (HDL-C) <42 mg/dL for men or <47 mg/dL for women, and triglycerides 180–500 mg/dL. Patients were randomized 1: 1 to treatment with 4 g/day of ω-3 CA or corn oil for a maximal duration of 5 years. The study was terminated on January 8, 2020 following independent data monitoring review because of low probability of demonstrating clinical benefit of ω-3 CA over corn oil (1384 primary endpoints adjudicated at this time point). The current report was an exploratory post hoc analysis.

Study population

13,078 high cardiovascular risk patients were enrolled. The current post hoc analysis was based on data for 1355 Asian patients and 11,723 non-Asian patients.

Main study variable

The primary end point was a 5-point composite of major adverse cardiovascular events (MACE), i.e., cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina hospitalization.

Other endpoints included a 3-component MACE (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), the individual components of the five-component MACE, and all-cause mortality.

Methods

Cox proportional hazards regression analysis was used to compare the effect of ω-3 CA versus corn oil on cardiovascular outcomes within the Asian and non-Asian subgroups. Kaplan-Meier survival curves were produced for the cumulative incidence of the 5-point composite MACE endpoint comparing ω-3 CA versus corn oil within the Asian and non-Asian subgroups. Treatment groups were compared within the subgroups using the log-rank test.

Key results

The two cohorts included 1355 patients in Asian countries [China (n =712, 52.5%), Japan (n =305, 22.5%), South Korea (n =133, 9.8%) and Taiwan (n =59, 4.4%)], and 11,723 non-Asian patients (91% white race).  Compared with non-Asian patients, Asian patients were more likely to be men, younger, with lower body mass index, a higher prevalence of coronary and cerebrovascular disease but lower prevalence of cardiovascular risk factors (including diabetes, hypertension, chronic smoking, and history of congestive heart failure). Baseline levels of atherogenic lipids were also lower in Asian than in non-Asian patients (Table 1).

Table 1. Baseline lipids and % change at 1 year

Data are given as mean ± standard deviation except for triglycerides (median, interquartile range).

In both cohorts, the percent change from baseline to 1-year in the ω-3 CA group showed a similar 19–20% reduction in triglycerides (Table 1). Compared with the non-Asian cohort, Asian patients showed a greater increase in LDL-C (19.0% versus 9.8%) (Table 1) and a smaller increase in HDL-C (3.7% versus 9.0%).

Over a mean follow-up of 3.6 ± 0.7 years, the primary endpoint of 5-point MACE occurred in 184 (17.5%) patients in the Asian cohort and 1396 (15.7%) patients in the non-Asian cohort. Among Asian patients, treatment with ω-3 CA was associated with a significantly lower incidence of the primary endpoint during follow-up: 14.8% versus 20.4% in the corn oil group (Hazard ratio 0.72, 95% confidence interval 0.54–0.96, p =0.026). In non-Asians, there was no significant difference in primary endpoint rates between the two treatment arms (Table 2). Significant interactions between Asian or non-Asian race and the randomized treatment allocation of ω-3 CA and corn oil were observed for the primary endpoint 5-point MACE (p =0.021) and the 3-component MACE (p =0.02). This significance persisted in a multivariable model (p=0.01).

Table 2. Impact of study treatment on key study endpoints

CI confidence interval

Author conclusions

In this exploratory analysis from the neutral STRENGTH trial, ω-3 CA was associated with significant reduction in the primary endpoint in Asians but not in non-Asian patients with high cardiovascular risk. Further, ideally randomized, research is necessary to assess these hypothesis-generating findings and elucidate potential mechanisms for beneficial effects of ω-3 CA in Asians.