Contrasting results of REDUCE-IT and STRENGTH trials of Omega 3

Contrasting results of REDUCE-IT and STRENGTH trials of Omega 3

Contrasting results of REDUCE-IT [1] and STRENGTH [2] trials of Omega 3 fatty acid preparations have caught the attention of scientific community. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester was evaluated in REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial). In STRENGTH trial carboxylic acid formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were used.

REDUCE-IT was a multicenter, randomized, double blind, placebo controlled trial. Patients enrolled had established cardiovascular disease or diabetes with other risk factors. They were receiving statin therapy and had fasting triglyceride level between 135 to 499 mg/dL and low density lipoprotein (LDL) cholesterol between 41 to 100 mg/dL.

Primary endpoint for the REDUCE-IT trial was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. Key secondary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Of the total 8179 patients enrolled, 70.7% were for secondary prevention of cardiovascular events and median follow up was 4.9 years. Primary endpoint occurred in 17.2% of the icosapent ethyl group compared to 22.0% in the placebo group. Key secondary endpoint occurred in 11.2% and 14.8% respectively.

A higher incidence of hospitalization for atrial fibrillation or flutter was noted in the icosapent ethyl group, 3.1% vs 2.1%, P=0.004. Serious bleeding events occurred in 2.7% of the icosapent ethyl group compared to 2.1% in the placebo group (P=0.06).

REDUCE-IT CABG was a subgroup analysis of 1837 patients from the trial with a history of coronary artery bypass grafting [3]. Icosapent ethyl group had significant reduction in the primary endpoint, key secondary endpoint and total ischemic events (first plus subsequent or recurrent ischemic events).

Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH) was a double blind, randomized, multicenter trial comparing omega 3 carboxylic acids with corn oil. Participants were statin treated patients with high cardiovascular risk, hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. 13,078 patients were randomized at 675 academic centers in 22 countries across 6 continents.

Primary efficacy measure in the STRENGTH trial was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The trial was halted prematurely as an interim analysis showed a low probability of clinical benefit. Primary endpoint occurred in 12% of patients in the study group and 12.2% of patients in the control group (P=0.84). Greater rate of gastrointestinal adverse events were noted in the omega 3 carboxylic acid group, 24.7% vs 14.7%.

There was a concern that docosahexaenoic acid could negate the beneficial effects of eicosapentaenoic acid as icosapent ethyl had shown benefit in the REDUCE-IT trial. A secondary analysis of STRENGTH trial checked this out [4]. It was concluded that the highest achieved levels of eicosapentaenoic acid and docosahexaenoic acid were associated with neither benefit nor harm in patients at high cardiovascular risk.

Another small study, the EVAPORATE trial, which enrolled 80 patients, checked the effect of icosapent ethyl on coronary plaque regression by serial multidetector computed tomography (MDCT). Icosapent ethyl demonstrated significant regression of low-attenuation plaque volume on MDCT compared with placebo over 18 months [5].

References

1. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10. PMID: 30415628.
2. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Ridker PM, Ray KK, Katona BG, Himmelmann A, Loss LE, Rensfeldt M, Lundström T, Agrawal R, Menon V, Wolski K, Nissen SE. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020 Dec 8;324(22):2268-2280. doi: 10.1001/jama.2020.22258. PMID: 33190147; PMCID: PMC7667577.
3. Verma S, Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Dhingra NK, Ketchum SB, Juliano RA, Jiao L, Doyle RT Jr, Granowitz C, Gibson CM, Pinto D, Giugliano RP, Budoff MJ, Mason RP, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Icosapent Ethyl Reduces Ischemic Events in Patients With a History of Previous Coronary Artery Bypass Grafting: REDUCE-IT CABG. Circulation. 2021 Dec 7;144(23):1845-1855. doi: 10.1161/CIRCULATIONAHA.121.056290. Epub 2021 Oct 28. PMID: 34710343.
4. Nissen SE, Lincoff AM, Wolski K, Ballantyne CM, Kastelein JJP, Ridker PM, Ray KK, McGuire DK, Mozaffarian D, Koenig W, Davidson MH, Garcia M, Katona BG, Himmelmann A, Loss LE, Poole M, Menon V, Nicholls SJ. Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial. JAMA Cardiol. 2021 May 16;6(8):1–8. doi: 10.1001/jamacardio.2021.1157. Epub ahead of print. PMID: 33993205; PMCID: PMC8126992.
5. Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, Muhlestein JB, Le VT, May HT, Shaikh K, Shekar C, Roy SK, Tayek J, Nelson JR. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J. 2020 Oct 21;41(40):3925-3932. doi: 10.1093/eurheartj/ehaa652. PMID: 32860032; PMCID: PMC7654934.