Marine‐derived n‐3 fatty acids therapy for stroke



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 experimental stroke, leading to a better functional outcome.


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

Our secondary outcomes were vascular‐related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood.

Search methods

We searched the Cochrane Stroke Group trials register (6 August 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, January 2019), MEDLINE Ovid (from 1948 to 6 August 2018), Embase Ovid (from 1980 to 6 August 2018), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 6 August 2018), 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 quality 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 e.g. Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, Barthel Index (higher score is better; scale from 0 to 100) or Rivermead Mobility Index (higher score is better; scale from 0 to 15).

Main results

We included 29 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 GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68; 40 participants; very low quality evidence). Mood (assessed with 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; 102 participants; low‐quality 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, and RR 0.33, 95% CI 0.01 to 7.72; 142 participants; low‐quality evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84; 18 participants; very low quality 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, and RR 0.63, 95% CI 0.25 to 1.58; 58 participants; very low quality evidence); and quality of life (physical component mean difference (MD) −2.31, 95% CI −4.81 to 0.19, and mental component MD −2.16, 95% CI −5.91 to 1.59; one study; 102 participants; low‐quality evidence).

Adverse events were reported by two studies (57 participants; very low quality evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35).

Longer follow‐up (more than three months)

One small trial assessed functional outcome with both Barthel Index (MD 7.09, 95% CI −5.16 to 19.34) for activities of daily living, and Rivermead Mobility Index (MD 1.30, 95% CI −1.31 to 3.91) for mobility (52 participants; very low quality evidence). We carried out meta‐analysis for vascular‐related death (RR 1.02, 95% CI 0.78 to 1.35; five studies; 2237 participants; low‐quality evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55; three studies; 1819 participants; low‐quality evidence).

We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI −2.07 to 4.07; one study; 14 participants; low‐quality 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; 1455 participants; low‐quality 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‐quality evidence. More well‐designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention.

Studies assessing functionality 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.

Plain language summary

Marine‐derived fatty acid therapy for stroke

Review question
To assess the effect of marine‐derived omega‐3 fatty acids for stroke after a short (up to three months) and a longer (more than three months) follow‐up.

The term stroke refers to a group of diseases of blood vessels in the brain. Stroke can be caused by either bleeding or blockage in these vessels that leads to a loss of function of brain cells. Transient ischaemic attack (TIA), also called a ‘mini‐stroke’, is a temporary disruption of blood supply to the brain. Stroke is a disabling disease that usually requires prolonged specialised care and currently there are few treatment options for stroke patients. Omega‐3 fatty acids — eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) — present in oily fish have important functions in the brain. In animal research, they appear to protect the brain cells after stroke particularly if they are administered very early. However, the effects of EPA and DHA as a treatment for stroke in humans are unclear.

Study characteristics
We identified 29 studies that included participants with stroke or TIA and we found relevant information in nine of them (3339 participants in total). Three had a short follow‐up (up to three months) and six had a longer follow‐up. Three studies compared marine‐derived omega‐3 fatty acids to normal care and the remainder used a placebo (dummy). Not all the studies assessed all outcomes.

Key results
Effects of marine‐derived omega‐3 fatty acids are unclear for stroke recovery. Only two very small studies reported it, without finding significant differences. One study found less improvement in mood with marine‐derived omega‐3 fatty acids but the evidence was of low quality. The effect of marine‐derived omega‐3 fatty acids on vascular‐related death, recurrence of stroke, adverse events, and quality of life after having a stroke or TIA is unclear, due to the small number of studies that have assessed them.

Quality of the evidence
In the short follow‐up, we considered the quality of the evidence very low for recovery, recurrence, frequency of other type of stroke (bleeding or blockage), and adverse events, and low for vascular‐related death, quality of life, and mood. For the longer follow‐up, the evidence was of very low quality for recovery from stroke, and low quality for vascular‐related death, recurrence, adverse events, and mood. Frequency of other type of stroke and quality of life were not reported in the long follow‐up.

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