Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and Eicosapentaenoic Acid (RESPECT-EPA)
Abstract
Background Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. Methods In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio ( Results Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P =0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P =0.017). Conclusions Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reac…
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RESPECT-EPA did not quite achieve a statistically significant reduction in its primary composite endpoint (HR 0.79 [95% CI 0.62-1.00]; P=0.055).
“Although RESPECT-EPA did not quite achieve a statistically significant reduction in its primary composite endpoint (hazard ratio, 0.79 [95% CI, 0.62–1.00];P= 0.055) event rates were lower in the EPA group, and prespecified on-treatment analyses suggested that higher achieved EPA levels were associated with fewer cardiovascular events.”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [92]
In RESPECT-EPA, event rates were lower in the EPA group.
“Although RESPECT-EPA did not quite achieve a statistically significant reduction in its primary composite endpoint (hazard ratio, 0.79 [95% CI, 0.62–1.00];P= 0.055) event rates were lower in the EPA group, and prespecified on-treatment analyses suggested that higher achieved EPA levels were associated with fewer cardiovascular events.”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [92]
The clinical benefit of EPA relates more to attained EPA concentrations than to triglyceride lowering per se.
“These findings reinforced the hypothesis that the clinical benefit of EPA relates more to attained EPA concentrations than to triglyceride lowering per se [92].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [92]
In RESPECT-EPA, prespecified on-treatment analyses suggested that higher achieved EPA levels were associated with fewer cardiovascular events.
“Although RESPECT-EPA did not quite achieve a statistically significant reduction in its primary composite endpoint (hazard ratio, 0.79 [95% CI, 0.62–1.00];P= 0.055) event rates were lower in the EPA group, and prespecified on-treatment analyses suggested that higher achieved EPA levels were associated with fewer cardiovascular events.”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [92]
In RESPECT-EPA, the secondary endpoint was significantly reduced (0.73 [95% CI 0.55-0.97]).
“Furthermore, the secondary endpoint was significantly reduced (0.73 [95% CI, 0.55–0.97]).”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [92]
The RESPECT-EPA trial, conducted in statin-treated Japanese patients with stable coronary artery disease and a low baseline EPA-to-arachidonic acid ratio, showed a numerically lower incidence of major cardiovascular events with icosapent ethyl that did not reach statistical significance for the primary end point, although a significant reduction was observed in the secondary composite of coronary
“Similarly, the RESPECT-EPA trial [107], conducted in statin-treated Japanese patients with stable coronary artery disease and a low baseline EPA-to–arachidonic acid ratio, showed a numerically lower incidence of major cardiovascular events with icosapent ethyl that did not reach statistical significance for the primary end point, although a significant reduction was observed in the secondary”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [107]
Across several major RCTs (REDUCE-IT, RESPECT-EPA, GISSI-HF, ASCEND), the magnitude of CV benefit equaled or exceeded the observed increase in AF risk.
“Across several major RCTs, such as REDUCE-IT69, 125, RESPECT-EPA76, GISSI-HF77 and ASCEND79, 105; the magnitude of CV benefit equaled or exceeded the observed increase in AF risk.”
From Effects of Omega-3 Fatty Acid Treatment on Risk for Atrial Fibrillation: An Updated Meta-Analysis of 35 Trials including 114 592 Individuals (2026) · cites this paper as [76]
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- Authors
- Miyauchi, K., Iwata, H., Nishizaki, Y., Inoue, T., Hirayama, A., Kimura, K., Ozaki, Y., Murohara, T., Ueshima, K., Kuwabara, Y., Tanaka-Mizuno, S., Yanagisawa, N., Sato, T., Daida, H., & RESPECT-EPA Investigators
- Affiliations
- Juntendo University (JP)
- Nasu Red Cross Hospital (JP)
- Fukujuji Hospital (JP)
- Yokohama City University Medical Center (JP)
- Fujita Health University (JP)
- Nagoya University (JP)
- Takeda Hospital (JP)
- Osaka International Cancer Institute (JP)
- Department of Digital Health and Epidemiology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan (S.T.-M.).
- Kyoto University (JP)
- ORCID
- Venue
- Circulation
- Published
- 2024-08-06
- Volume
- 150
- Issue
- 6
- Pages
- 425-434
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W4399681552
- Semantic Scholar
- 77cfe46c1c963e7361653f9ceaa2fece50969c0f
- Cited by
- 92
- References
- 31
- Citations by year
- 2026: 35 · 2025: 35 · 2024: 14 · 2023: 5 · 2022: 1 · 2021: 1 · 2020: 1
- FWCI
- 19.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Keywords
- icosapent ethyl, eicosapentaenoic acid, statin therapy, coronary artery disease, secondary prevention, cardiovascular events, coronary revascularization, myocardial infarction, ischemic stroke, sudden cardiac death, atrial fibrillation, omega-3 fatty acids, omega-6 fatty acids, n-6/n-3 ratio
- MeSH terms
- Aged, Coronary Artery Disease, Drug Therapy, Combination, Female, Humans, Japan, Male, Middle Aged, Prospective Studies, Eicosapentaenoic Acid, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Secondary Prevention
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