STRENGTH trial fails to demonstrate cardioprotective effect of omega-3 fatty acids

Elevated levels of eicosapentaenoic acid (EPA) were not associated with a reduced risk of major adverse cardiac events (MACE) in a post-hoc analysis of the STRENGTH trial data [1]. Additionally, elevated levels of docosahexaenoic acid (DHA) were not associated with any harm.

Controversy has surrounded the putative ability of omega-3 fatty acids EPA and DHA to protect against MACE. The REDUCE-IT trial (NCT01492361) reported that participants (n=8,179) who took 2 g of icosapent ethyl twice daily had a lower risk of ischaemic events than those who took a placebo (HR 0.75; 95% CI 0.68–0.83; P<0.001) [2]. In contrast, the STRENGTH trial (NCT02104817) (n=13,078) reported that 4 g a day of omega-3 carboxylic acid (CA) did not reduce ischaemic events compared with a  corn oil comparator (HR 0.99; 95% CI 0.90–1.09; P=0.84) [3].

Dr Steven Nissen (Cleveland Clinic, OH, USA) presented the results of a secondary analysis of 10,382 participants in the STRENGTH trial fro whom EPA and DHA levels were available for 12 months following randomisation [1,4]. EPA levels were divided into tertiles. The primary endpoint was a 4-item MACE composite (i.e. cardiovascular death, non-fatal myocardial infarction or stroke, need for coronary revascularisation, or unstable angina requiring hospitalisation). The outcome measure was the HR for the top tertile of achieved EPA and DHA levels in the omega-3 CA group compared with the corn oil group.

At 12 months, median plasma EPA level in the corn oil group was 19 µg/mL. In the top tertile of the omega-3 CA group, EPA level was 151 µg/mL; a 443% increase. Comparing MACE in the top tertile of the EPA levels in the omega-3 CA group to the corn oil group yielded an HR of 1.03 (95% CI 0.88–1.21; P=0.69). Adjustment for baseline fatty acid levels, region, cardiovascular disease, age, sex, diabetes, creatinine, non-high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, antiplatelet agents, β-blockers, and renin-angiotensin inhibitors yielded a HR of 0.98 (95% CI 0.83–1.16; P=0.81).

At 12 months, median plasma DHA level in the corn oil group was 58 µg/mL. In the top tertile of the omega-3 CA group, the DHA level was 118 µg/mL; a 68% increase. Comparing MACE in the top tertile of DHA levels in the omega-3 CA group with placebo yielded an HR of 1.12 (95% CI 0.96–1.31; P=0.16). The adjusted HR was 1.02 (95% CI 0.86–1.20; P=0.85).

Dr Nissen noted that all the recent trials that administered high doses of omega-3 CA showed an increase in atrial fibrillation (AF); the STRENGTH trial showed a 69% increase in AF. The associated HR was 1.69 (95% CI 1.29–2.21) (see Figure). Thus, harms can be associated with high doses of omega-3 CA.

Figure: Time to onset of atrial fibrillation in the STRENGTH trial [1]



CA, carboxylic acid; CI, confidence interval; HR, hazard ratio.

Dr Nissen noted that analysis by tertiles reduces the statistical power but he also remarked that the 95% CIs were quite narrow.

Findings of this secondary analysis of the STRENGTH trial suggest that despite an increase in plasma levels of EPA and DHA, there was no apparent cardiovascular benefit. Furthermore, there is potential harm (AF) that can result from the use of high doses of omega-3 CA.

1. 
   
   1. Nissen S. Relationship Between Omega-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients with High Cardiovascular Risk (STRENGTH). ACC 2021 Scientific Session, 15–17 May.
   2. Bhatt DL, et al. N Engl J Med 2019;380:11–22.
   3. Nicholls SJ, et al. JAMA 2020;324(22):2268–2280.
   4. Nissen SE, et al. JAMA Cardiol. 21 May 16;e211157.

 

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Posted on 9 July, 202127 March, 2024