Relationship Between Omega-3 Fatty Acid Levels And Major Adverse Cardiovascular Outcomes In Patients With High Cardiovascular Risk

KEY POINT:

• There is not enough evidence to state whether Omega-3 Fatty Acid levels are beneficial or harmful against major adverse cardiovascular events in patients with high cardiovascular risk.

Dr. Steven E. Nissen is the chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.  Prior to summarizing Dr. Nissen’s late breaking trial at presented May 16, Day 2 of ACC 2021 that is concurrently published in JAMA Cardiology .

REDUCE-IT was a multicenter, randomized controlled trial that compared statin treated patients with 4 grams of icosapent ethyl to mineral oil. Ultimately, the study found an absolute risk reduction in the primary outcome of cardiovascular events (hazard ratio 0.75).

STRENGTH was also a double-blind, randomized, multicenter trial that compared 4 grams of omega-3 fatty acids [carboxylic acid formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] to corn oil. This trial was stopped early due to low probably of clinical benefit (hazard ratio 0.99).

There have been three predominant theories in the lipid community explaining why two recent, high quality trials had such discordant outcomes:

1. The comparators were different. Corn oil, used in the STRENGTH trial, is considered a neutral placebo, whereas mineral oil, used in the REDUCE-IT trial, is thought to be more proinflammatory. Some speculated because there was a signal towards increased event rates in the mineral oil control group used in the REDUCE-IT, this translated to comparatively less event rates for the icosapent ethyl group, and thus a relative benefit of the medication.
2. The bioavailability of the omega-3 fatty acids was different. Purified EPA used in the REDUCE-IT trial may have have resulted in higher concentrations than the carboxylic acid formulation of EPA and DHA used in the STRENGTH trial. Higher plasma levels may lead to better outcomes.
3. DHA could have caused harm, outweighing the benefits of EPA. There could have been a negative effect of DHA in the STRENGTH trial, neutralizing any benefit from EPA.

With that in mind, there was great anticipation from the lipid community to hear about Dr Nissen’s late breaker on omega-3 fatty acids and major adverse events in high-risk patients. This late breaker focused on assessing the later 2 theories. In his secondary analysis of the STRENGTH trial, Dr Nissen and his colleagues examined the hazard ratio of the top tertile of achieved EPA and DHA levels compared to corn oil control group.  Ultimately, the trial was neutral. Despite data showing reduction in triglycerides, there was no significant reduction in major adverse cardiovascular events to taking omega-3 fatty acids when compared to corn oil (adjusted hazard ratio EPA and cardiovascular outcome was 0.98 for with confidence interval of 0.83-1.16, P=0.81). The level of EPA was monitored and achieved comparable to levels from the REDUCE-IT trial, invalidating theory #2. In addition, there was not an elevated adjusted hazard ratio for those patients with high levels of DHA (adjusted hazard ratio of 1.02 with confidence interval of 0.86-1.20, P=0.85), making theory #3 also an incorrect hypothesis.

In the end, after discussing the trial results directly with Dr Nissen, it seems that the first theory, different comparators, is the most promising to explain the differences in the REDUCE-IT and STRENGTH trial. According to Dr Nissen, “we will not know if fatty acids are beneficial or harmful until we see purified EPA studied directly against corn oil.” Given this would require a large trial and is unlikely to be funded by industry, it is unlikely to happen.

Limitations of the study included it’s tertile analysis, which translated to less statical power. It was a post hoc analysis and only studied patients at high cardiovascular risk making it non-generalizable to all patient populations. Moderate correlation (r² value-0.45-0.55) between EPA and DHA levels also demonstrates that these compounds were not truly assessed independently.

When asked if prescribing Vascepa for his patients, Dr Nissen replied that he has yet to prescribe it, as he does not find the evidence sufficient. He stated “In the world of clinical trials, reproducibility is important and we have to always worry about reliably in our field.” Interestingly, those in the fatty acid group demonstrated higher rate of atrial fibrillation than those in the corn oil placebo group. This was also demonstrated in the REDUCE-IT trial. While the mechanism for this relationship is unclear, Dr Nissen tells us that it gives him even more pause when considering the prescription of omega-3 fatty acids for his patients.

The STRENGTH trial was sponsored by the AstraZeneca. STRENGTH ClinicalTrials.gov number, NCT02104817.