#CardsJC: STRENGTH Trial Journal Club

  • Post author:

CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information check out the Cardionerds Journal Club Page.

Table of Contents: Visual abstractSummaryReferencesCredits


November 15, 2020 

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 

Stephen J. Nicholls, MBBS, PhD; A. Michael Lincoff, MD; Michelle Garcia, RN, BSN, CCRC; Dianna Bash, BSN; Christie M. Ballantyne, MD; Philip J. Barter, MBBS, PhD; Michael H. Davidson, MD; John J. P. Kastelein, MD, PhD; Wolfgang Koenig, MD; Darren K. McGuire, MD, MHSc; Dariush Mozaffarian, MD, DrPH; Paul M Ridker, MD; Kausik K. Ray, MBChB, MD, MPhil; Brian G. Katona, PharmD; Anders Himmelmann, MD, PhD; Larrye E. Loss, PharmD, MBA; Martin Rensfeldt; Torbjörn Lundström, MD, PhD; Rahul Agrawal, MD; Venu Menon, MD; Kathy Wolski, MPH; Steven E. Nissen, MD 

JAMA. 2020;324(22):2268-2280. doi:10.1001/jama.2020.22258 

➡ Elevated triglyceride (TG) levels have been associated with increased atherosclerotic cardiovascular (CV) disease (ASCVD) risk.1 Omega-3 fatty acids (2-4 g/d) TG levels. 

➡ Omega-3 supplements generally contain a combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), fatty acids naturally found in marine oils. 

RELEVANT GUIDELINES PRE-STRENGTH TRIAL 1,2

➡ Prescription of omega-3 (EPA+DHA or EPA-only) at a dose of 4 g/day is an effective and safe option for reducing TG as monotherapy or as an adjunct to lipid-lowering agents. 

➡ For patients with existing coronary artery disease (CAD), 1g/day EPA+DHA is recommended, preferably from oily fish. Supplements can also be considered under guidance of physician.  

➡ Treatment with omega-3 is reasonable for secondary prevention of CAD and sudden cardiac death among patients with prevalent CAD. 

➡ Treatment with omega-3 is reasonable for secondary prevention of outcomes in patients with heart failure. 

➡ AHA does not recommend omega-3 supplements for patients who do not have high CV disease risk. 

RELEVANT LITERATURE

STUDY RATIONALE

Two trials revealed a reduction in MACE with high-dose EPA alone (JELIS, REDUCE-IT). 

Unclear if combined omega-3 fatty acids EPA and DHA reduce CV risk, and if they are useful in secondary or primary CV disease prevention. 

OBJECTIVE

Determine effects of carboxylic acid formulation of EPA and DHA (omega-3 CA) on CV outcomes in patients with atherogenic dyslipidemia and high CV risk. 

TRIAL: Randomized, double-blind, placebo-controlled, parallel, multicenter 

INTERVENTION: In addition to usual guideline-directed therapies (including statins), patients were randomized to receive: 

• 4 g/d of omega-3 

OR 

• Corn oil (served as inert comparator) 

INCLUSION CRITERIA: 

EXCLUSION CRITERIA: 

  • Prior ischemic CV event within preceding 30 days 
  • Consumed > 1 capsule (1g) per day of omega-3 dietary supplements or any prescription medication containing EPA or DHA. 
  • Use of fibrates or weight loss drugs 

OUTCOMES 

Primary Endpoint –composite measure of: 

  • CV death 
  • nonfatal MI 
  • nonfatal stroke 
  • coronary revascularization 
  • unstable angina requiring hospitalization 

Secondary Endpoints – composite measure of: 

  • MACE 
  • CV events 
  • Coronary events 
  • CV death 
  • All-cause death 

Tertiary Endpoints

  • New onset Heart failure 
  • New onset Atrial fibrillation 
  • Stent thrombosis 
  • Venous/pulmonary thromboembolism 

STATISTICAL ANALYSIS 

  • Intention-to-treat analysis 
  • Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals 

TRIAL ENDED PREMATURELY  BASED ON INTERIM ANALYSIS THAT INDICATED LOW PROBABILITY OF CLINICAL BENEFIT OF OMEGA-3  COMPARED TO CORN OIL, ALONG WITH EVIDENCE OF RISK/ADVERSE EVENTS ASSOCIATED WITH OMEGA-3. 

  • 1384 primary end-points had been recorded 
  • 1580 patients had an adjudicated first primary end point event by the completion of the study 
  • Trial ended on January 8, 2020  
  • Median follow-up 42 months, median treatment time 38.2 months 
  • Patient baseline characteristics comparable in both treatment arms 

The primary endpoint occurred in 785 patients (12.0%) treated with omega-3 vs 795 (12.2%) treated with corn oil (p = 0.84). 

Secondary endpoint – All-cause mortality occurred in 373 patients (5.7%) in the omega-3 CA group and 333 (5.1%) in the corn oil group (p = 0.11). 

Tertiary endpoints – There was a significantly increased rate of new-onset atrial fibrillation within the omega-3 CAgroup (2.2%) compared to the corn oil group (1.3%) (p < 0.001). There were no statistically significant differences in new-onset heart failure, stent thrombosis, or venous thromboembolic events. 

Biochemical endpoints –  There were greater reductions in TG, non-HDL cholesterol, and hs-CRP in the omega-3 group, compared to the corn oil group. Both LDL and HDL cholesterol levels were higher in the omega-3 CA group. 

ADVERSE EVENTS 

There were more drug-related adverse events, more treatment discontinuations, dose reductions, and more GI side effects seen with omega-3 than compared to the group treated with corn oil. 

In statin-treated patients with high CV risk, the addition of omega-3 CA (EPA+DHA), compared to corn oil, on top of usual background therapies, resulted in no significant difference in a composite outcome of MACE. 

These findings do not support the use of this omega-3 fatty acid formulation to reduce MACE in high-risk patients. 

Omega-3 CA administration is associated with a higher risk of GI adverse events and with a higher incidence of investigator-reported atrial fibrillation. 

LIMITATIONS AND CONSIDERATIONS 

  • It is unclear if a lower-risk primary prevention population could benefit from omega-3 supplements. 
  • This trial evaluated the effect of administration of 4 g/day of a combination of EPA and DHA in fixed proportion, thus different doses and proportions were not evaluated. 
  • The role of purified DHA on cardiovascular outcomes has not yet been studied in large clinical trials.
  • Corn oil could be a confounder as well, even though it was not shown to have a significant impact on the lipid profile in STRENGTH. Corn oil seems to have less systemic effects than mineral oil had in REDUCE it.

References

1. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation. 2019;140(12):e673-e691. 

2. Siscovick DS, Barringer TA, Fretts AM, et al. Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the American Heart Association. Circulation. 2017;135(15):e867-e884. 

3. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090-1098. 

4. Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309-318. 

5. Bowman L, Mafham M, Stevens W, et al. ASCEND: A Study of Cardiovascular Events iN Diabetes: Characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144. 

6. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33(1):159-171. 

7. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. 

SUMMARY BY: 

Dr. Teodora Donisan, @TDonisan, PGY2 Internal Medicine Resident, Beaumont, Royal Oak, MI

Dr. Patrick Zakka, @PatrickZakka, PGY4 Internal Medicine Chief Resident, Emory University, Atlanta, GA.

VISUAL ABSTRACT BY: 

Dr. Luis Calderon, @LMCalderonMD, Hospitalist at MedStar Washington Hospital Center, Washington DC

JOURNAL CLUB PROMO GRAPHIC BY: 

Dr. Madiha Khan, @madhattans, internal medicine resident at Houston Methodist Hospital, Houston, TX

HOUSE TAUSSIG CHIEF FELLOWS

Dr. Rick Ferraro, @RichardAFerraro, internal medicine resident at the Johns Hopkins Hospital, Baltimore MD

Dr. Eunice Dugan, @EuniceDuganMD, internal medicine resident at the Johns Hopkins Hospital, Baltimore MD

ASSOCIATE SCIENCE PROGRAM DIRECTOR

Dr. Carine Hamo, @CarineHamo, cardiology fellow at the Johns Hopkins Hospital, Baltimore, MD

#CardsJC: STRENGTH Trial Journal Club