Higher DHA levels adjusted for EPA increase risk of MACE

Higher Docosahexanoic Acid (DHA) levels lower the protective impact of eicosapentaenoic acid (EPA) on long-term MACE in those with and without angiographic CAD

News - May 27, 2021

Presented at ACC.21 by Viet Le (Salt Lake City, UT, USA)

Introduction and methods

Several large omega-3 polyunsaturated fatty acids (OM3-PUFA) trials have been performed during the last 2 decades, including VITAL, ASCEND, STRENGTH, OMEMI, JELIS and REDUCE-IT. There are differences in the cohorts that were enrolled (primary or secondary prevention, or mixed) and differences in the dose of capsules and treatment regimes. Moreover, in the first 4 mentioned trials a combination of EPA and DHA was used. And in JELIS and REDUCE-IT only EPA was used. With regard to outcomes, the VITAL, ASCEND, STRENGTH and OMEMI trials were neutral and in the JELIS and REDUCE-IT trials, MACE was reduced (19% RRR in JELIS with P=0.01 and 25% RRR in REDUCE-IT, P<0.001).

In this study using data from the INSPIRE registry at Intermountain Healthcare (start at 1993), 987 patients were enrolled. These patients were randomly selected among those undergoing a first coronary angiographic study between 1994 and 2012. Primary endpoint was 10-year MACE, comprised of all-cause death, MI, stroke and HF hospitalization.


Main results

  • Patients in the highest quartile of EPA had lower MACE (HR 0.48 for Q4 vs. Q1, P<0.0001 and HR 0.71 for Q2/Q3 vs. Q1, P=0.02), this appeared to be driven by reduction in 10-year death.
  • Adjusting EPA for DHA resulted in similar findings, as did adjustment for DHA and comorbidities. When adjusted, the dose-dependent relationship became more apparent.
  • DHA levels were not associated with MACE.
  • When DHA levels were adjusted for EPA, higher quartiles of DHA were associated with increased MACE risk. A similar finding was observed when DHA was adjusted for EPA and comorbidities. These results suggest when EPA is combined with DHA, the net impact of higher EPA is blunted by the negative effect of DHA.
  • Looking at EPA/DHA ratio, 444 patients had EPA/DHA ≤1 and 543 patients had EPA/DHA >1. Those with EPA/DHA ≤1 had a 10-year MACE of 37% and those with EPA/DHA >1 had 10-year MACE of 27% (adjusted HR 0.69, 95%CI: 0.55-0.86, P=0.0012).


In a study using data from the INSPIRE registry, higher levels of unadjusted and adjusted EPA were associated with lower 10-year MACE. In contrast, higher levels of DHA adjusted for EPA (and comorbidities) increased the risk of MACE. These findings suggest that when combining EPA and DHA, higher DHA blunts the benefit of EPA.

Viet Le said that concerns are raised about the use of combination EPA-DHA preparations to reduce CV risk.

- Our coverage of ACC.21 is based on the information provided during the congress –

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