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Table of Contents: Visual abstract • Summary • References • Credits • Published Archive
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.
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.
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
• Corn oil (served as inert comparator)
- 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
Primary Endpoint –composite measure of:
- CV death
- nonfatal MI
- nonfatal stroke
- coronary revascularization
- unstable angina requiring hospitalization
Secondary Endpoints – composite measure of:
- CV events
- Coronary events
- CV death
- All-cause death
- New onset Heart failure
- New onset Atrial fibrillation
- Stent thrombosis
- Venous/pulmonary thromboembolism
- 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 CA group (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.
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.
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.
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
The published archive features curated twitter highlights from the journal club event.
Pamela Morris (@PamelaBMorris): In high-risk patients with persistent HTG, it’s important to start with lifestyle intervention before considering prescription omega-3 FA. Never forget the impact of a powerfully healthy diet! #CardsJC
Neil Stone (@nstonedoc): I hope someone in comparing Strength to Reduce It, will compare the % who were primary prevention in both trials. REDUCE IT had only 30%. Much more in STRENGTH. Look at how REDUCE it did in primary prevention. #CARDSJC
Salim Virani (@virini_md): Fully agree @nstonedoc #CardsJC ~70% secondary prevention patients in REDUCE-IT versus 56% secondary prevention patients in STRENGTH. Event rates much lower in STRENGTH than REDUCE-IT
Viet Le (@VietHeartPA): What’s your experience with Omega-3 supplements in clinical practice? #CardsJC I consider EPA often, i.e., In those with ASCVD and trigs >=150, DM +>=2RF and trigs >=150 OR trigs >=500. Cost is an issue = don’t Rx often. I don’t consider mixed EPA/DHA formulations.
Martha Gulati (@DrMarthaGulati): I think we will get to this with @DLBHATTMD here. The studies are different and need to be compared for certain! #CardsJC Some other trials listed below @CardioNerdsJC
Neil Stone (@nstonedoc): Useful for cardiologists to go to their local pharmacy and see what’s in the fish oil section. NLA has recommended pharmacy grade if you prescribe fish oil #CardsJC
Neil Stone (@nstonedoc): When comparing trials, JELIS and others, useful to consider background diet. High fish intake background in JELIS – note lower dose in this trial with Japanese participants. #CARDSJC
Deepak Bhatt (@DLBHATTMD): JELIS was 80% primary prevention and that trial of icosapent ethyl (pure EPA) – the same active ingredient as in REDUCE-IT – was also positive. Primary vs secondary prevention of course affects absolute benefits, but the reason STRENGTH failed was the specific drug. #CardsJC
Viet Le (VietHeartPA): Notably, the JELIS population background plasma EPA: 90’s mcg/dL. In the US Reduce-it, 26 mcg/dL #CardsJC
Deepak Bhatt (@DLBHATTMD): True, the Japanese patients in JELIS started with higher EPA levels than the mostly Western patients in REDUCE-IT. Both groups ended with similar, high levels of EPA. Two separate trials, one open-label, one with placebo, both positive, w/ effects independent of trigs. #CardsJC
Neil Stone (@nstonedoc): Great point and agree its likely the drug, but risk counts in explaining the data. Would be interesting to have RCT for icosapent ethyl in primary prevention without DM with CAC>100 versus placebo. Without CAC, rates in primary prevention may be too low #CARDSJC
Deepak Bhatt (@DLBHATTMD): I am with you and a big believer in CAC for future primary prevention trials:
Martha Gulati (@DrMarthaGulati): From the presentation of #STREGTH at #AHA20 the authors suggested the placebo used in #REDUCEIT vs STRENGTH was one issue in the different results. But I think it is the EPA effect vs DHA #CardsJC @cardionerds @DLBHATTMD @nstonedoc
Deepak Bhatt (@DLBHATTMD): The benefits seen in JELIS were incremental to statin therapy. Granted LDL control was not as tight as recommended these days, but LDL reduction and EPA are complementary pathways of risk reduction, maybe even synergistic. #CardsJC
Amit Goyal (@AmitGoyalMD): The consistency b/w JELIS & REDUCE-IT despite differnt population, background therapy, diets does seem to advocate for pure high dose EPA. #CardsJC
Nishant Shah (@Nishant_ShahMD): Great table! The JELIS trial is also a good one to throw into the mix when comparing studies pre REDUCE IT and STRENGTH, also studied an EPA product #CardsJC
Danielle Belardo (@DBelardoMD): One of the advantages of Tele Health visits is that your patients can show you the bottles of the pills they are taking. Great if they bring them, but doesn’t always happen. #CardsJC
Martha Gulati (@DrMarthaGulati): Yes, no more “I didn’t bring my medications with me”. I just have them walk to where the meds are and show me! #CardsJC
Salim Virani (@virani_md): Difficult to explain 25%RRR and 4.8%ARR with just placebo differences and small increase in LDL-C/hs-CRP. Beneficial effect of IPE in REDUCE-IT not related to whether patients in the placebo arm had an increase, decrease or no change in LDL-C @CardioNerdsJC @cardionerds #cardsJC
Heather Johnson (@DrHeatherJohn): Given the primary outcomes, in STRENGTH, the study would require higher risk patients. I agree – need additional studies in lower risk populations. #CardsJC
Deepak Bhatt (@DLBHATTMD):I think it is a great study! Not easy to compare placebos, but we did the best we could and found no difference between pharmaceutical grade mineral oil placebo and cellulose placebo. #CardsJC @SuvasiniL@BudoffMd@cshekarMD
Salim Virani (@virani_md):Placebo arm event rates much higher in REDUCE-IT (22%) compared to STRENGTH (12%). ?Higher risk population in REDUCE-IT or just a measure of short f/u in STRENGTH @CardioNerdsJC @cardionerds #cardsjc
Stephen Nicholls (@ProfSNicholls): Agree, therapeutic changes in CAC are likely to be very different than “natural history” changes #cardsJC
Deepak Bhatt (@DLBHATTMD): Interesting point, but I would also be cautious about comparing between two randomized clinical trials of two totally different drugs and concluding that the positive trial was in fact negative! #CardsJC
Martha Gulati (@DrMarthaGulati): It’s important to remember that Both EPA & DHA lower TG and non-HDL but DHA increase LDL but EPA does not (& may decrease LDL by 6%- as much as doubling the dose of a statin!) #cardsJC
Mark Brady (@MarkBrady2014): #cardsJC the simplest explanation for the difference between REDUCE-IT and STRENGHT is that E series resolvins are cardioprotective and D series resolvins and protectins are not (and possibly harmful).
Stephen Nicholls (@ProfSNicholls): I think the simplest explanation is that there were less events in the icosapent arm compared with mineral oil and there was no difference between epanova and corn oil. Everything else becomes speculation #cardsJC
Danielle Belardo (@DBelardoMD): Evidence based medicine is knowing that scientific research is important, but is also meaningless if you’re not considering if it applies to the patient directly in front of you . Representation matters #WIC #CardsJC @cardionerds @DrMarthaGulati
Viet Le (@VietHeartPA): Much to unpack here. There is a level of #implicitbias that leads to unequal ratios, not reflective of disease prevalence in the community of trial enrollment in gender as well as race in trials. #CardsJC Would support mandating trials reflect the disease prevalence
Stephen Nicholls (@ProfSNicholls):Systematic use of comparators would be good so we can take that off the table once and for all. I suspect you then see the ultimate benefits of EPA #cardsJC
Karan Desai (@karanpdesai): My continued takeaway: growing # of hyper-TG pts w/ T2DM and metabolic syndrome whose lipid profile requires treatment beyond LDL-C lowering alone. Pure EPA an effective treatment and EPA/DHA not #cardsJC
Deepak Bhatt (@DLBHATTMD): Four positive trials of pure EPA: CHERRY, EVAPORATE, JELIS, REDUCE-IT. Time now for implementation science to use EPA for FDA approved indications, and time for RCTs for new indications. #CardsJC