Marine-derived n-3 fatty acids therapy for stroke (Review-Intervention)

Celia Gabriela Alvarez Campano, Mary Joan Macleod, Lorna Aucott, Frank Thies

Research output: Contribution to journalReview articlepeer-review

3 Citations (Scopus)


BACKGROUND: Currently, with stroke burden increasing, there is a need to explore therapeutic options that ameliorate the acute insult. There is substantial evidence of a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs) in animal models of stroke, leading to a better functional outcome.

OBJECTIVES: To assess the effects of administration of marine-derived n-3 PUFAs on functional outcomes and dependence in people with stroke.

SEARCH METHODS: We searched the Cochrane Stroke Trials Register (last searched 31 May 2021), the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 5), MEDLINE Ovid (from 1948 to 31 May 2021), Embase Ovid (from 1980 to 31 May 2021), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 31 May 2021), Science Citation Index Expanded ‒ Web of Science (SCI-EXPANDED), Conference Proceedings Citation Index-Science - Web of Science (CPCI-S), and BIOSIS Citation Index. We also searched ongoing trial registers, reference lists, relevant systematic reviews, and used the Science Citation Index Reference Search.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing marine-derived n-3 PUFAs to placebo or open control (no placebo) in people with a history of stroke or transient ischaemic attack (TIA), or both.

DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials for inclusion, extracted data, assessed risk of bias, and used the GRADE approach to assess the certainty of the body of evidence. We contacted study authors for clarification and additional information on stroke/TIA participants. We conducted random-effects meta-analysis or narrative synthesis, as appropriate. The primary outcome was efficacy (functional outcome) assessed using a validated scale, for example, the Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, the Barthel Index (higher score is better; scale from 0 to 100), or the Rivermead Mobility Index (higher score is better; scale from 0 to 15). Our secondary outcomes were vascular-related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood.

MAIN RESULTS: We included 30 RCTs; nine of them provided outcome data (3339 participants). Only one study included participants in the acute phase of stroke (haemorrhagic). Doses of marine-derived n-3 PUFAs ranged from 400 mg/day to 3300 mg/day. Risk of bias was generally low or unclear in most trials, with a higher risk of bias in smaller studies. We assessed results separately for short (up to three months) and longer (more than three months) follow-up studies. Short follow-up (up to three months) Functional outcome was reported in only one pilot study as poor clinical outcome assessed with the GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68, P = 0.52; 40 participants; very low-certainty evidence). Mood (assessed with the GHQ-30, lower score better) was reported by only one study and favoured control (mean difference (MD) 1.41, 95% CI 0.07 to 2.75, P = 0.04; 102 participants; low-certainty evidence). We found no evidence of an effect of the intervention for the remainder of the secondary outcomes: vascular-related death (two studies, not pooled due to differences in population, RR 0.33, 95% CI 0.01 to 8.00, P = 0.50, and RR 0.33, 95% CI 0.01 to 7.72, P = 0.49; 142 participants; low-certainty evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84, P = 0.57; 18 participants; very low-certainty evidence); incidence of other type of stroke (two studies, not pooled due to different type of index stroke, RR 6.11, 95% CI 0.33 to 111.71, P = 0.22, and RR 0.63, 95% CI 0.25 to 1.58, P = 0.32; 58 participants; very low-certainty evidence); and quality of life (physical component, MD -2.31, 95% CI -4.81 to 0.19, P = 0.07, and mental component, MD -2.16, 95% CI -5.91 to 1.59, P = 0.26; 1 study; 102 participants; low-certainty evidence). Adverse events were reported by two studies (57 participants; very low-certainty evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73, P = 0.16) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35, P = 0.47). Longer follow-up (more than three months) One small trial assessed functional outcome with both the Barthel Index for activities of daily living (MD 7.09, 95% CI -5.16 to 19.34, P = 0.26), and the Rivermead Mobility Index for mobility (MD 1.30, 95% CI -1.31 to 3.91, P = 0.33) (52 participants; very low-certainty evidence). We carried out meta-analysis for vascular-related death (RR 1.02, 95% CI 0.78 to 1.35, P = 0.86; 5 studies; 2237 participants; low-certainty evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55, P = 0.37; 3 studies; 1819 participants; low-certainty evidence). We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI -2.07 to 4.07, P = 0.61; 1 study; 14 participants; low-certainty evidence). Incidence of other type of stroke and quality of life were not reported. Adverse events (all combined) were reported by only one study (RR 0.94, 95% CI 0.56 to 1.58, P = 0.82; 1455 participants; low-certainty evidence).

AUTHORS' CONCLUSIONS: We are very uncertain of the effect of marine-derived n-3 PUFAs therapy on functional outcomes and dependence after stroke as there is insufficient high-certainty evidence. More well-designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention. Studies assessing functional outcome might consider starting the intervention as early as possible after the event, as well as using standardised, clinically relevant measures for functional outcomes, such as the modified Rankin Scale. Optimal doses remain to be determined; delivery forms (type of lipid carriers) and mode of administration (ingestion or injection) also need further consideration.

Original languageEnglish
Article numberCD012815
Number of pages110
JournalThe Cochrane database of systematic reviews
Issue number6
Early online date29 Jun 2022
Publication statusPublished - 29 Jun 2022

Bibliographical note

Prof Malcolm R Macleod was a co-author for the protocol of thisreview and he also assisted with the retrieval of some reports.

We thank Cochrane Stroke, and in particular Hazel Fraser(Managing Editor) for her guidance, and Joshua Cheyne(Information Specialist) for his support in the development of thesearch strategies and performing some of the searches, and for hisadvice throughout the review process. We are grateful to JennyBellorini for copy editing this update of the review.

We also thank all the authors of the original trials that replied to ourinformation requests. In particular, Prof Marianne Geleijnse (ALPHAOMEGA), Dr Aldo P Maggioni (GISSI HF), Prof Alan Dangour andProf Elizabeth Allen (OPAL), Dr Irene Marzona and Dr Maria CarlaRoncaglioni (Risk & Prevention Study), and Dr Rodrigo Zapata (Saito2017), for providing additional data from their studies.

Dr He Ni, Dr Teresa Grohmann, and Khairun N Sumali provided support with translation of study reports.

CG Alvarez Campano was funded by the Mexican Council for Scienceand Technology (CONACYT) and the Institute of Innovation andTechnology Transfer (IWTW) (grant number 457349).

Funding Information:
Chinese Nutrition Society (CNS) Nutrition Research Foundation—DSM Research Fund (grant number: 2014-003)

The National Health and Medical Research Council of Australia, Canberra, Australia; additionally, the National Heart Foundation of Australia (supporting Dr Sanders) and the National Health and Medical Research Council of Australia (supporting Dr Gibson)

The Danish Council for Strategic Research—(AF Study Group), The Arvid Nilsson Foundation, The Danish Kidney Association, The Danish Society of Nephrology, and Medical Specialist Heinrich Kopp’s Grant Supplement provided free of charge by Pharma Marine, Norway

The Danish Heart Foundation, The Danish Kidney Foundation, the Research Foundation of the County of Northern Jutland, and Pronova Biocare

Mexican Council for Science and Technology (CONACyT) and the Institute of Innovation and Technology Transfer (I2T2) (grant number 457349),Mexico

Heart and Stroke Foundation of Ontario and Rhône Poulenc Rorer

The Ministry of Science and Higher Education of Poland (N402 095 31/2947 to G.G.) and the Foundation "Helping the Heart" at the Department of Coronary Disease, Jagiellonian University School of Medicine (SKC1 to Dr Gajos)

Spar Nord Foundation, the Obelske Family Foundation and Heinrich Kopp's Grant. Capsules supplied by Napro Pharma, Brattvaag, Norway

Dietary information: individuals taking fish oil within 4 weeks of trial commencement were excluded. No further information provided Funding: National Health and Medical Research Council of Australia Project Grant (APP458652), Am-gen Australia Pty Ltd and Mylan EPD (at the time of funding was Abbott Products Operations AG). Study medication supplied by Mylan EPD (at the time of supply was Abbott Products Operations AG) (fish oil and placebo) and Bayer Healthcare (aspirin and placebo) free of charge

Dietary information: dietary data, including intake of different types of fish, collected by a FFQ. For the total population, median intake of fish was 14 g/day (IQR 5 to 18 g/day), and 12% of the participants never consumed fish. Participants were asked to avoid n-3 fatty acids supplements during the trial Funding: Netherlands Heart Foundation (grant no. 2000T401), US National Institutes of Health (NIH/ NHLBI and ODS, grant no. R01HL-076200) and Unilever R&D, Vlaardingen

Publisher Copyright:
Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


  • Fatty Acids
  • Fatty Acids, Omega-3/therapeutic use
  • Fatty Acids, Unsaturated
  • Humans
  • Ischemic Attack, Transient/epidemiology
  • Neuroprotective Agents/therapeutic use
  • Stroke/epidemiology


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