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New trial data show mixed findings for omega-3s
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The growth in popularity of omega-3 supplementation — typically a combination of eicosapentaenoic acid and docosahexaenoic acid — follows years of research suggesting benefits for a range of conditions, from brain and eye health to reducing risk for CVD or cancer. Recently, several large-scale randomized controlled trials generated headlines for omega-3, in supplement and prescription form, based on findings from the large ASCEND, VITAL and REDUCE-IT trials.
Publication of these anticipated trials led to renewed scrutiny for omega-3s in the cardiology community and beyond, following data that demonstrated a prescription omega-3 formulation reduced risk for ischemic events (REDUCE-IT) and other data that demonstrated no CV impact with omega-3 supplements (VITAL and ASCEND).
“It has to do with the drug that was studied,” Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School, executive director of interventional cardiovascular programs in the Heart and Vascular Center at Brigham and Women’s Hospital, said in an interview. “We can’t lump all of the omega-3s together because it is clear that they don’t all have the same cardiovascular benefits. From a distance, it does confuse many people who see a series of negative trials and then all of a sudden a very positive trial like REDUCE-IT and wonder how and why that can be.”
“When we are talking about supplements, there is a difference between a supplement and a prescription agent,” Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, professor of medicine, chief of the section of cardiovascular research and director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine, told Cardiology Today.
Deep dive into new findings
In ASCEND, the longest-duration trial of omega-3 supplementation (mean follow-up time, 7.2 years), 1 g per day of omega-3 supplementation did not prevent vascular events in people with diabetes but no prior CVD when compared with olive oil placebo (see Table). The findings were presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine.
“In ASCEND, we captured a huge amount of safety information in terms of all hospitalizations for all the patients across a very long follow-up,” ASCEND investigator Louise Bowman, BA, MBBS, MD, FRCP, professor of medicine and clinical trials at the Clinical Trial Service Unit at University of Oxford, told Cardiology Today. “ASCEND had the longest duration of follow-up of any of the omega-3 fatty acid trials. ... The other trials haven’t suggested any hazard, so that’s good news.”
Thereafter came the large-scale VITAL trial, presented at the American Heart Association Scientific Sessions in November and published in NEJM, showing no reduction in major CV events or development of invasive cancers with 1 g per day of an omega-3 drug (Lovaza or Omacor, Pronova/BASF) for primary prevention compared with placebo over 5.3 years of follow-up (Table).
“The results of VITAL were complex, nuanced and had signals for heart health benefit with omega-3s,” said JoAnn E. Manson, MD, DrPH, FAHA, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School.
Some secondary endpoints of VITAL showed promising signals of benefit. In prespecified secondary analyses, MI risk was 28% lower (95% CI, 10-41) with omega-3 vs. placebo, with the greatest reductions observed in subgroups with low dietary fish intake (< 1.5 servings per week) and in black participants. The primary endpoint of major CVD events was also significantly reduced, by 19%, among those with low fish consumption. Manson, who presented the findings, also noted that non-prespecified analyses showed reductions in PCI, fatal MI and total CHD with omega-3 supplementation.
“This suggests that if you are already obtaining a moderate amount of omega-3s from the diet, from fish, there may not be an additional benefit,” Manson said. “But for those with low fish consumption, there did appear to be a benefit. We did not see a reduction in stroke or CV death, but prior evidence has pointed to a greater effect for coronary disease.” She also noted that the finding of lower MI risk in black participants “needs to be replicated,” as “there haven’t been previous trials that have included a large number of black participants. This could point to an important way to reduce health disparities.”
Despite these promising signals, results of recent trials have been generally disappointing. “By the time VITAL was published, we had a compendium of trials, with data from ASCEND published right before it, showing us that, over and over again, a low dose of omega-3, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combinations in both high-risk and less high-risk patients did not seem to show any benefit,” James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA, FASPC, clinical assistant professor in the department of medicine at NYU Langone Health, director of Bellevue Hospital Lipid Clinic in New York and past president of the National Lipid Association, told Cardiology Today. “When I saw the results of VITAL, which was a primary prevention trial, it was completely consistent with what I expected to see.”
However, data from the REDUCE-IT trial — which used a high-dose, purified EPA-only prescription omega-3 (Vascepa, Amarin Pharmaceuticals) 4 g per day in a high-risk population — suggested that omega-3 formulation, the dose and the risk profile of the patient matter.
“Treatment with icosapent ethyl significantly reduced cardiovascular events, including a 20% reduction in cardiovascular death, a 31% reduction in heart attack, a 28% reduction in stroke and a low rate of adverse events,” Bhatt said while presenting the REDUCE-IT data at the AHA Scientific Sessions. “There was a consistent benefit across all subgroups, including in the primary and secondary prevention cohorts.”
Treatment with icosapent ethyl increased the risk for hospitalizations related to atrial fibrillation. Although the absolute rate of these events was small, it reached statistical significance, Bhatt said.
Mechanisms, differences
Taken together, conversations after the release of these new data have focused on the differences in formulation of omega-3, dose, patient population and trial design among the three trials.
Experts who spoke with Cardiology Today cautioned that the different types of omega-3 fatty acids should not be grouped together.
“What we proved in REDUCE-IT is that a high dose of purified EPA has cardiovascular benefits, but it is not clear whether other preparations at higher doses would or wouldn’t,” Bhatt said.
Bhatt added that part of REDUCE-IT’s success may have been due to the triglyceride reduction or cell membrane stabilization from the EPA in icosapent ethyl, which led to reductions in sudden cardiac death and cardiac arrest. This CV benefit has been proved for EPA, but has yet to be determined for DHA and other omega-3 fatty acids, experts said.
Some heart health benefits seen in the REDUCE-IT trial, which studied a 4-g dose of icosapent ethyl, were also seen in patients assigned 1 g of omega-3 fatty acids in the VITAL trial. These benefits with the lower dose included a modest amount of triglyceride lowering and a reduction in both nonfatal and fatal MI, which may have been due to a decrease in ventricular arrhythmias, stabilizing of heart rhythm and a decline in inflammation, Manson said.
“For many years, there has been discussion as to whether there might be some membrane-stabilizing effect and maybe the effects are through acting on arrhythmias, but it’s not clear what the overall mechanism may be,” Bowman told Cardiology Today. “The triglycerides aspect is likely to be important, but that may not be the whole answer. Given the reduction in triglyceride levels that was seen in REDUCE-IT, the clinical benefit was very substantial. It would be surprising if that was all due to the triglyceride-lowering effect.”
Regardless of which dose a patient takes, some experts said they believe that it should be titrated to potentially prevent any hazards.
Moreover, some patient populations may yield a greater benefit from omega-3 fatty acids compared with others. One example is the population assessed in REDUCE-IT: patients with established CVD or with diabetes and other risk factors who were already treated with statin therapy. Patients enrolled in this trial had a fasting triglyceride level of 135 mg/dL to 499 mg/dL and LDL of 41 mg/dL to 100 mg/dL.
“It is the full gamut of secondary prevention as well as at least high-risk primary prevention we found benefited from icosapent ethyl,” Bhatt said in an interview.
Previously, patients with increased triglycerides and LDL were treated with omega-3 fatty acids for other risks beyond those related to CV events.
“In the past, we already had approval to treat people with triglycerides above 500 mg/dL with fish oil, not always because of the cardiac risk, but because they were at high risk of pancreatitis,” Martha Gulati, MD, MS, FACC, FAHA, FASPC, cardiologist and chief of the division of cardiology at the University of Arizona in Phoenix, told Cardiology Today. “Now we have a new group that we can use it in and actually have benefits in outcomes.”
“If you are already at the high-risk end of the CV-risk spectrum, then anything that can reduce your risk is likely to have a bigger effect in absolute terms,” Bowman said.
Others have commented that the assumption that trials like ASCEND and VITAL were negative is not correct based on the trial outcomes.
“As the omega-3 research has evolved since VITAL and ASCEND were designed, it’s become clear that composite endpoints are not an optimal choice,” William S. Harris, PhD, FAHA, FNLA, professor of medicine at University of South Dakota Sanford School of Medicine in Vermillion and president and CEO of OmegaQuant Analytics, told Cardiology Today. “If in VITAL the primary endpoint had been fatal heart attacks or total coronary events, and in ASCEND vascular death, these trials would have shown statistically significant benefits.”
Further research
Investigation continues, with several trials and more analyses from REDUCE-IT and VITAL currently underway.
Manson said more than 20 other health outcomes from VITAL will be assessed, including HF, cardiac function and structure determined by 2D echocardiography, sudden cardiac death and AF. Results are expected within the next 6 months, Manson added.
Researchers for REDUCE-IT will assess biomarkers to learn more about the mechanisms behind the benefits of icosapent ethyl. Genetic and cost-effectiveness analyses will also be performed, Bhatt said.
Other studies are being conducted in this area, such as the EVAPORATE trial, which will assess the effect of icosapent ethyl on low attenuation plaque in patients with elevated triglycerides. The ongoing STRENGTH trial will assess omega-3-carboxylic acids (Epanova, AstraZeneca) in addition to statin therapy in patients with hypertriglyceridemia, low HDL and high CVD risk. According to Bhatt, STRENGTH “will provide important information about whether what we saw in REDUCE-IT is a class effect for different high-dose omega-3s or whether it’s a drug-specific effect.”
More research on whether EPA or DHA contributes to the benefit of omega-3 fatty acids is also warranted. Potentially repeating the REDUCE-IT trial but with a combined preparation of omega-3 fatty acids could be insightful. However, conducting trials such as those are often expensive and cumbersome, Bowman said.
A closer look at some of the secondary outcomes in VITAL is also warranted, such as a trial of patients with reduced or no fish intake, similar to what was studied in VITAL, to determine a patient population that would greatly benefit from omega-3 fatty acids.
Until other studies are completed, it should be assumed that the benefits from omega-3s were from the drug itself (icosapent ethyl/EPA) and not a class benefit, experts told Cardiology Today.
Shared decision-making
With the popularity of omega-3 dietary supplements and the availability of omega-3 prescription medications, shared decision-making is critical when patients discuss their interest in omega-3 fatty acids with their health care provider, since dietary supplements are different from prescription drugs in terms of the level of regulatory oversight and the body of scientific evidence. Discussion about adopting a healthy lifestyle with increased fish take is an important conversation.
“In a population that is more at usual risk, our recommendation is to have two or more servings of fish a week,” Manson said. She noted that there are some plant-based sources of omega-3 for patients who follow a vegetarian or vegan lifestyle.
As easy as it is to access omega-3 fatty acid dietary supplements, some experts advise against them due to their cost and lack of evidence on their effectiveness for CV prevention.
“If you take a supplement, you need to read the label and get a high concentration of EPA/DHA, as most supplements which are advertised as 1 gram of fish oil only contain 300 mg total of EPA/DHA, which is far below the dose used in VITAL, much less REDUCE-IT,” Ballantyne told Cardiology Today.
Looking ahead
The great attention on omega-3 fatty acids and the wave of new data to come in the near future have the potential to affect clinical practice.
“When we look back at REDUCE-IT and we ask the question if you compare EPA in REDUCE-IT and its benefit in statin-treated patients, and we look at other recent studies like the PCSK9 inhibitors, cholesterol-blocking inhibitors, [cholesteryl ester transfer protein] inhibitors or interleukin inhibitors, all of these drugs have been tried in the last 10 years to add to the benefit of statins. None of them has been as effective as EPA by a long shot,” Harris said in an interview.
The trajectory that omega-3 fatty acids are taking may be akin to that of statins a few decades ago, Bhatt said.
“The statin era started a couple of decades ago, with initial studies showing promise and subsequent studies expanding the patient population that would benefit,” Bhatt said. “My hope is we’ll do the same thing over time with icosapent ethyl and EPA.” – by Darlene Dobkowski, with additional reporting by Regina Schaffer
- References:
- Bhatt DL, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1812792.
- ClinicalTrials.gov. Outcomes Study to Assess Statin Residual Risk Reduction with Epanova in High CV Risk Patients with Hypertriglyceridemia. Available at: www.clinicaltrials.gov/ct2/show/NCT02104817. Accessed Feb. 4, 2019.
- ClinicalTrials.gov. Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy. Available at: www.clinicaltrials.gov/ct2/show/NCT02926027. Accessed Feb. 4, 2019.
- Manson JE, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1811403.
- The ASCEND Study Collaborative Group. N Engl J Med. 2018;doi:10.1056/NEJMoa1804989.
- von Schacky C, et al. J Cardiovasc Med. 2007;doi:10.2459/01.JCM.0000289273.87803.87.
- For more information:
- Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, can be reached at 6665 Travis St., Suite 320, Houston, TX 77030; email: cmb@bcm.edu.
- Deepak L. Bhatt, MD, MPH, can be reached at Brigham and Women’s Hospital, Director Interventional Cardio Prog, SH-5150, 75 Francis St., Boston, MA 02115; email: dlbhattmd@post.harvard.edu; Twitter: @dlbhattmd.
- Louise Bowman, BA, MBBS, MD, FRCP, can be reached at Medical Research Council, Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, United Kingdom; email: louise.bowman@ndph.ox.ac.uk.
- Martha Gulati, MD, MS, FACC, FAHA, FASPC, can be reached at University of Arizona College of Medicine, 550 E. Van Buren St., Phoenix, AZ 85004; email: marthagulati@email.arizona.edu; Twitter: @drmarthagulati.
- William S. Harris, PhD, FAHA, FNLA, can be reached at OmegaQuant Analytics LLC, 5009 W. 12th St., Suite 8, Sioux Falls, SD 57106; email: bill@omegaquant.com.
- JoAnn E. Manson, MD, DrPH, FAHA, can be reached at Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave., 3rd Floor, Boston, MA 02215; email: jmanson@rics.bwh.harvard.edu.
- James Underberg, MD, MS, FACPM, FACP, FASH, FNLA, FASPC, can be reached at Murray Hill Medical Group, 317 E. 34th St., 7th Floor, New York, NY 10016; email: james.underberg@nyumc.org; Twitter: @lipiddoc.
Disclosures: VITAL was supported by the NHLBI, the NIH, and the National Cancer Institute, and the study drugs were donated by industry. REDUCE-IT was funded by Amarin Pharmaceuticals. ASCEND was supported in part by Abbott, Bayer, Mylan and Solvay and funded by the British Heart Foundation. Ballantyne reports he received honoraria from Amarin. Bhatt reports he received research funding from Amarin to Brigham and Women’s Hospital and was the principal investigator and study chair of the REDUCE-IT trial. Bowman reports she received research grants from Merck and The Medicines Company. Gulati reports no relevant financial disclosures. Harris reports he co-owns and operates OmegaQuant Analytics, a laboratory that measures blood omega-3 levels. Underberg reports he is on the scientific advisory board for the FH Foundation, a consultant for Amgen and a member of the speakers bureau for Amarin, Amgen, Regeneron and Sanofi.