OPEN ACCESS ORIGINAL RESEARCH

Regular use of fish oil supplements and course of cardiovascular

BMJ Medicine: first published as 10.1136/bmjmed-2022-000451 on 21 May 2024. Downloaded from https://bmjmedicine.bmj.com on 25 May 2025 by guest.
diseases: prospective cohort study
Ge Chen,1 Zhengmin (Min) Qian,2 Junguo Zhang,1 Shiyu Zhang,1 Zilong Zhang ‍ ‍,1
Michael G Vaughn,3 Hannah E Aaron,2 Chuangshi Wang,4 Gregory YH Lip,5,6 Hualiang Lin ‍ ‍1

► Additional supplemental ABSTRACT supplements had different roles in the transitions from
material is published online
only. To view, please visit the OBJECTIVE To examine the effects of fish oil healthy status to atrial fibrillation, to major adverse
journal online (https://​doi.​ supplements on the clinical course of cardiovascular cardiovascular events, and then to death. For people
org/​10.​1136/​bmjmed-​2022-​ disease, from a healthy state to atrial fibrillation, major without cardiovascular disease, hazard ratios were 1.13
000451).
adverse cardiovascular events, and subsequently (95% confidence interval 1.10 to 1.17) for the transition
from healthy status to atrial fibrillation and 1.05 (1.00

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For numbered affiliations see death.
end of article. DESIGN Prospective cohort study. to 1.11) from healthy status to stroke. For participants
Correspondence to: Dr
Hualiang Lin, Department SETTING UK Biobank study, 1 January 2006 to 31 with a diagnosis of a known cardiovascular disease,
of Epidemiology, Sun Yat-­ December 2010, with follow-­up to 31 March 2021 regular use of fish oil supplements was beneficial for
Sen University, Guangzhou, (median follow-­up 11.9 years). transitions from atrial fibrillation to major adverse
Guangdong 510080, China;
​linhualiang@​mail.​sysu.​edu.​cn PARTICIPANTS 415 737 participants, aged 40-­69 years, cardiovascular events (hazard ratio 0.92, 0.87 to 0.98),
Cite this as: BMJMED enrolled in the UK Biobank study. atrial fibrillation to myocardial infarction (0.85, 0.76 to
2024;3:e000451. doi:10.1136/ MAIN OUTCOME MEASURES Incident cases of atrial 0.96), and heart failure to death (0.91, 0.84 to 0.99).
bmjmed-2022-000451 fibrillation, major adverse cardiovascular events, and CONCLUSIONS Regular use of fish oil supplements
GYL and HL are joint senior death, identified by linkage to hospital inpatient records might be a risk factor for atrial fibrillation and stroke
authors. and death registries. Role of fish oil supplements in among the general population but could be beneficial
different progressive stages of cardiovascular diseases, for progression of cardiovascular disease from atrial
Received: 6 December 2022
Accepted: 3 April 2024 from healthy status (primary stage), to atrial fibrillation fibrillation to major adverse cardiovascular events,
(secondary stage), major adverse cardiovascular events and from atrial fibrillation to death. Further studies are
(tertiary stage), and death (end stage). needed to determine the precise mechanisms for the
RESULTS Among 415 737 participants free of development and prognosis of cardiovascular disease
cardiovascular diseases, 18 367 patients with events with regular use of fish oil supplements.
incident atrial fibrillation, 22 636 with major adverse
cardiovascular events, and 22 140 deaths during
follow-­up were identified. Regular use of fish oil
Introduction
WHAT IS ALREADY KNOWN ON THIS TOPIC Cardiovascular disease is the leading cause of death
worldwide, accounting for about one sixth of overall
⇒ Findings of the effects of omega 3 fatty acids or fish oil on the risk of cardiovascular
mortality in the UK.1 2 Fish oil, a rich source of omega 3
disease are controversial
fatty acids, containing eicosapentaenoic acid and doco-
⇒ Most previous studies focused on one health outcome and did not characterise
sahexaenoic acid, has been recommended as a dietary
specific cardiovascular disease outcomes (eg, atrial fibrillation, myocardial
measure to prevent cardiovascular disease.3 The UK
infarction, stroke, heart failure, and major adverse cardiovascular events)
National Institute for Health and Care Excellence recom-
⇒ Whether fish oil could differentially affect the dynamic course of cardiovascular mends that people with or at high risk of cardiovascular
diseases, from atrial fibrillation to major adverse cardiovascular events, to other disease consume at least one portion of oily fish a week,
specific cardiovascular disease outcomes, or even to death, is unclear and the use of fish oil supplements has become popular
WHAT THIS STUDY ADDS in the UK and other western countries in recent years.4 5
Although some epidemiological and clinical studies
⇒ In people with no known cardiovascular disease, regular use of fish oil
have assessed the effect of omega 3 fatty acids or fish
supplements was associated with an increased relative risk of atrial fibrillation and
oil on cardiovascular disease and its risk factors, the
stroke
findings are controversial. The Agency for Healthcare
⇒ In people with known cardiovascular disease, the beneficial effects of fish oil
Research and Quality systematically reviewed 37 obser-
supplements were seen on transitions from atrial fibrillation to major adverse
vational studies and 61 randomised controlled trials,
cardiovascular events, atrial fibrillation to myocardial infarction, and heart failure
and found evidence indicating the beneficial effects of
to death
higher consumption of fish oil supplements on ischaemic
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY stroke, whereas no beneficial effect was found for
⇒ Regular use of fish oil supplements might have different roles in the progression of atrial fibrillation, major adverse cardiovascular events,
cardiovascular disease myocardial infarction, total stroke, or all cause death.6
In contrast, the Reduction of Cardiovascular Events with
⇒ Further studies are needed to determine the precise mechanisms for the
Icosapent Ethyl-­Intervention Trial (REDUCE-­IT) reported
development and prognosis of cardiovascular disease events with regular use of
a decreased risk of major adverse cardiovascular events
fish oil supplements
with icosapent ethyl in patients with raised levels of

Chen G, et al. BMJMED 2024;3:e000451. doi:10.1136/bmjmed-2022-000451 1

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detailed progression of cardiovascular diseases would

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502 461
Baseline participants provide substantial insights into the prevention or
treatment of future disease at critical stages. Whether
1299
Withdrew from study fish oil could differentially affect the dynamic course
of cardiovascular disease (ie, from atrial fibrillation to
501 162 major adverse cardiovascular events, to other specific
Participants
cardiovascular disease outcomes, or even to death) is
71 694 unclear.
Diagnoses at baseline To deal with this evidence gap, we conducted a
8326 Atrial fibrillation
2748 Heart failure longitudinal cohort study to estimate the associations
7943 Stroke
11 949 Myocardial infarction
between fish oil supplements and specific clinical cardi-
48 624 Cancer ovascular disease outcomes, including atrial fibrilla-
tion, major adverse cardiovascular events, and all cause

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429 468
Participants
death in people with no known cardiovascular disease
or at high risk of cardiovascular disease for the purpose
11 748 of primary prevention. We also assessed the modifying
Incomplete or outlier data
Fish oil supplements, age, sex, effects of fish oil supplements on the disease process,
ethnic group, consumption of from atrial fibrillation to other outcomes, in people
oily fish, consumption of
non-oily fish, smoking status, with known cardiovascular disease for the purpose of
consumption of alcohol,
Townsend deprivation index
secondary prevention.

417 720
Participants Methods
The UK Biobank is a community based cohort study
1983 with more than half a million UK inhabitants aged
Other transition patterns
40-­69 years at recruitment.11–13 Participants were
415 737 invited to participate in this study if they were regis-
Participants tered with the NHS and lived within 35 km of one of 22
Figure 1 | Flowchart of selection of participants in study. Biobank assessment centres. Between 1 March 2006
The count of diagnosed diseases does not equate to the and 31 July 2010, a baseline survey was conducted,
total number of individuals, because each person could based on a touch screen questionnaire and face-­to-­
have multiple diagnoses face interviews, to collect detailed personal, socioeco-
nomic, and lifestyle characteristics, and information on
diseases.11–13
triglycerides, regardless of the use of statins.7 Most of We excluded patients who had a diagnosis of atrial
these findings, however, tended to assess the role of fibrillation (n=8326), heart failure (n=2748), myocar-
fish oil at a certain stage of cardiovascular disease. For dial infarction (n=11 949), stroke (n=7943), or cancer
example, some studies restricted the study population to (n=48 624) at baseline; who withdrew from the study
people with a specific cardiovascular disease or at a high during follow-­ up (n=1299); or who had incomplete
risk of cardiovascular disease,8 9 whereas others evalu- or outlier data for the main information (n=11 748).
ated databases of generally healthy populations.10 All Because we focused only on a specific sequence of
of these factors might preclude direct comparison of the progression of cardiovascular disease (ie, from healthy
effects of omega 3 fatty acids on atrial fibrillation events status to atrial fibrillation, to major adverse cardi-
or on further deterioration of cardiovascular disease. ovascular events, and then to death), we excluded
Few studies have fully characterised specific cardio- 1983 participants with other transition patterns. The
vascular disease outcomes or accounted for differential remaining 415 737 participants were included in this
effects based on the complex disease characteristics of analysis (figure 1).
participants. Hence, in this study, we hypothesised that
fish oil supplements might have harmful, beneficial, or
no effect on different cardiovascular disease events in Determining use of fish oil supplements
patients with varying health conditions. Information on regular use of fish oil supplements was
Most previous studies on the association between collected from a self-­reported touchscreen questionnaire
fish oil and cardiovascular diseases generally focused during the baseline survey.14 15 Each participant was
on one health outcome. Also, no study highlighted asked whether they regularly used any fish oil supple-
the dynamic progressive course of cardiovascular ment. Trained staff conducted a verbal interview with
diseases, from healthy status (primary stage), to atrial participants, asking if they were currently receiving
fibrillation (secondary stage), major adverse cardio- treatments or taking any medicines, including omega 3
vascular events (tertiary stage), and death (end stage). or fish oil supplements. Based on this information, we
Clarifying this complex pathway in relation to the classified participants as regular users of fish oil supple-
ments and non-­users.

2 Chen G, et al. BMJMED 2024;3:e000451. doi:10.1136/bmjmed-2022-000451

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Follow-up and outcomes Transition B

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(n=17 826)
Participants were followed up from the time of
recruitment to death, loss to follow-­up, or the Transition A Transition D
415 737 (n=18 367) 18 367 (n=4810) 22 636
end date of follow-­u p (31 March 2021), which- Baseline Atrial fibrillation Major adverse
ever came first. Incident cases of interest, cardiovascular
Transition E events
including atrial fibrillation, heart failure, stroke, (n=1653)
and myocardial infarction, were identified by Transition C Transition F
linkage to death registries, primary care records, (n=14 902) 22 140 (n=5583)
and hospital inpatient records.11 Information Death

on deaths was obtained from death registries of

Figure 2 | Numbers of participants in transition pattern
the NHS Information Centre, for participants in I, from baseline to atrial fibrillation, major adverse
England and Wales, and from the NHS Central cardiovascular events, and death
Register Scotland, for participants in Scotland.11

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Outcomes were defined by a three character
ICD-­1 0 (international classification of diseases,
10th revision) code. In this study, atrial fibrilla- alcohol consumption and binge drinking in the
tion was defined by ICD-­1 0 code I48, and major UK Biobank was reported previously.16
adverse cardiovascular events was determined by
a combination of heart failure (I50, I11.0, I13.0, Statistical analysis
and I13.2), stroke (I60-­ I64), and myocardial Characteristics of participants are summarised
infarction (I21, I22, I23, I24.1, and I25.2) codes. as number (percentages) for categorical variables
and mean (standard deviation (SD)) for contin-
uous variables. Comparisons between regular
Covariates users of fish oil supplements and non-­users were
We collected baseline data on age (<65 years and made with the χ2 test or Student's t test.
≥65 years), sex (men and women), ethnic group We used a multi-­ state regression model to
(white and non-­ white), Townsend deprivation assess the role of regular use of fish oil supple-
index (with a higher score indicating higher levels ments in the temporal disease progression from
of deprivation), smoking status (never, previous, healthy status to atrial fibrillation, to major
and current smokers), and alcohol consumption adverse cardiovascular events, and subsequently
(never, previous, and current drinkers). Data for to death. The multi-­state model is an extension
sex were taken from information in UK Biobank of competing risks survival analysis. 17–19 The
rather than from patient reported gender. Baseline model allows simultaneous estimation of the role
dietary data were obtained from a dietary ques- of risk factors in transitions from a healthy state
tionnaire completed by the patient or by an inter- to atrial fibrillation (transition A), healthy state
viewer. The questionnaire was established for to major adverse cardiovascular events (tran-
each nation (ie, England, Scotland, and Wales) to sition B), healthy state to death (transition C),
assess an individual's usual food intake (oily fish, atrial fibrillation to major adverse cardiovascular
non-­oily fish, vegetables, fruit, and red meat). events (transition D), atrial fibrillation to death
Diabetes mellitus was defined by ICD-­10 codes (transition E), and major adverse cardiovascular
E10-­ E14, self-­reported physician's diagnosis, events to death (transition F) (transition pattern I,
self-­reported use of antidiabetic drugs, or haemo- figure 2). The focus on these six transitions rather
globin A1c level ≥6.5% at baseline. Hypertension than on all possible health state transitions was
was defined by ICD-­ 1 0 code I10 or I15, self-­ preplanned and evidence based. If participants
reported physician's diagnosis, self-­reported use entered different states on the same date, we used
of antihypertensive drugs, or measured systolic the date of the theoretically previous state as the
and diastolic blood pressure ≥130/85 mm Hg at entry date of the latter state minus 0.5 days.
baseline. Information on other comorbidities We further examined the effects of regular
(obesity (ICD-­1 0 code E66), chronic obstructive use of fish oil supplements on other pathways.
pulmonary disease (J44), and chronic renal failure For example, we divided major adverse cardio-
(N18)) was extracted from the first occurrence vascular events into three individual diseases
(UKB category ID 1712). Information on the use of (heart failure, stroke, and myocardial infarction),
drugs, including antihypertensive drugs, antidia- resulting in three independent pathways (transi-
betic drug, and statins, was extracted from treat- tion patterns II, III, and IV, online supplemental
ment and drug use records. Biochemistry markers figures S1–S3). All models were adjusted for age,
were measured immediately at the central labo- sex, ethnic group, Townsend deprivation index,
ratory from serum samples collected at baseline. consumption of oily fish, consumption of non-­
Binge drinking was defined as consumption of ≥6 oily fish, smoking status, alcohol consumption,
standard drinks/day for women or ≥8 standard obesity, hypertension, diabetes mellitus, chronic
drinks/day for men. Detailed information on

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Table 1 | Baseline characteristics of study participants grouped by use of fish oil supplements
All participants Non-­users of supplements Users of supplements
Characteristics (n=415 737) (n=285 372) (n=130 365)
Age (years)
 <65 346 524 (83.4) 245 679 (86.1) 100 845 (77.4)
 ≥65 69 213 (16.6) 39 693 (13.9) 29 520 (22.6)
Sex
 Women 228 758 (55.0) 153 715 (53.9) 75 043 (57.6)
 Men 186 979 (45.0) 131 657 (46.1) 55 322 (42.4)
Ethnic group
 White 392 851 (94.5) 268 845 (94.2) 124 006 (95.1)
 Non-­white 22 886 (5.5) 16 527 (5.8) 6359 (4.9)

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Setting*
 Rural 57 474 (14.0) 38 731 (13.7) 18 743 (14.5)
 Urban 354 186 (86.0) 243 654 (86.3) 110 532 (85.5)
Body mass index*
 Underweight 2149 (0.5) 1565 (0.6) 584 (0.4)
 Normal weight 137 806 (33.3) 92 895 (32.7) 44 911 (34.6)
 Overweight 176 041 (42.6) 119 539 (42.1) 56 502 (43.5)
 Obese 97 774 (23.6) 69 950 (24.6) 27 824 (21.4)
Consumption of oily fish (times/week)
 <2 343 096 (82.5) 241 491 (84.6) 101 605 (77.9)
 ≥2 72 641 (17.5) 43 881 (15.4) 28 760 (22.1)
Consumption of non-­oily fish (times/week)
 <2 348 253 (83.8) 241 331 (84.6) 106 922 (82.0)
 ≥2 67 484 (16.2) 44 041 (15.4) 23 443 (18.0)
Consumption of vegetables* (times/week)
 <2 28 365 (6.8) 21 963 (7.7) 6402 (4.9)
 2-­3 119 066 (28.7) 84 866 (29.8) 34 200 (26.3)
 ≥4 267 926 (64.5) 178 254 (62.5) 89 672 (68.3)
Consumption of fruit* (times/week)
 <2 115 111 (27.7) 88 845 (31.2) 26 266 (20.2)
 2-­3 169 869 (40.9) 116 655 (40.9) 53 214 (40.8)
 ≥4 130 467 (31.4) 79 657 (27.9) 50 810 (39.0)
Consumption of red meat* (times/week)
 <2 61 945 (14.9) 42 846 (15.0) 19 099 (14.7)
 2-­3 183 952 (44.3) 122 621 (43.0) 61 331 (47.1)
 ≥4 169 588 (40.8) 119 712 (42.0) 49 876 (38.9)
Smoking status
 Never 233 367 (56.1) 161 564 (56.6) 71 803 (55.1)
 Ever 139 168 (33.5) 91 189 (32.0) 47 979 (36.8)
 Current 43 202 (10.4) 32 619 (11.4) 10 583 (8.1)
Consumption of alcohol
 Never 17 911 (4.3) 12 982 (4.5) 4929 (3.8)
 Ever 13 836 (3.3) 9762 (3.4) 4074 (3.1)
 Current 383 990 (92.4) 262 628 (92.0) 121 362 (93.1)
Physical activity* (%)
 Low 62 892 (18.5) 46 526 (20.0) 16 366 (15.4)
 Moderate 138 203 (40.8) 95 958 (41.2) 42 245 (39.8)
 High 137 878 (40.7) 90 241 (38.8) 47 637 (44.8)
Townsend deprivation index (mean, SD) −1.4 (3.1) −1.3 (3.0) −1.5 (3.0)
Data are number (%) unless stated otherwise.
*These variables included missing values.

obstructive pulmonary disease, chronic renal additionally adjusting for setting (urban and rural),
failure, and use of statins, antidiabetic drugs, and body mass index (underweight, normal, overweight,
antihypertensive drugs. and obese), and physical activity (low, moderate,
We conducted several sensitivity analyses for and high) in the model; adjusting for binge drinking
the multi-­state analyses of transition pattern A: rather than alcohol consumption; additionally

4 Chen G, et al. BMJMED 2024;3:e000451. doi:10.1136/bmjmed-2022-000451

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adjusting for other variables of dietary intake A) and 17 826 participants had major adverse cardi-

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(consumption of vegetables, fruit, and red meat); ovascular events (transition B); 14 902 participants
calculating participants' entry date into the previous died without having atrial fibrillation or major
state with different time intervals (0.5 years, one adverse cardiovascular events (transition C). Among
year, and two years); excluding participants who patients with incident atrial fibrillation, 4810 devel-
entered different states on the same date; excluding oped major adverse cardiovascular events (transition
events occurring in the first two years of follow-­up; D) and 1653 died (transition E). Among patients
restricting the follow-­up date to 31 March 2020 to with incident major adverse cardiovascular events,
evaluate the influence of the covid-­19 pandemic; and 5585 died during follow-­up (transition F, figure 2).
the use of the inverse probability weighted method to In separate analyses for individual diseases (tran-
deal with biases between the regular users and non-­ sition patterns II, III, and IV, online supplemental
users of fish oil supplements. Also, we conducted figures S1–S3), in patients with atrial fibrillation,
grouped analyses for sex, age group, ethnic group, 3085 developed heart failure, 1180 had a stroke, and

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smoking status, consumption of oily fish, consump- 1415 had a myocardial infarction. During follow-­up,
tion of non-­oily fish, hypertension, and drug use, to 2436, 2088, and 2098 deaths occurred in patients
examine effect modification. The interactions were with heart failure, stroke, and myocardial infarction,
tested with the likelihood ratio test. All analyses were respectively.
carried out with R software (version 4.0.3), and the
multi-­model analysis was performed with the mstate
package. A two tailed P value <0.05 was considered Multi-state regression results
significant. Table 2 shows the different roles of regular use of fish
oil supplements in transitions from healthy status to
atrial fibrillation, to major adverse cardiovascular
Patient and public involvement events, and then to death. For individuals in the
Patients and/or the public were not involved in the primary stage (healthy status), we found that the use
design, or conduct, or reporting, or dissemination of fish oil supplements had a harmful effect on the
plans of this research. Participants were involved in transition from health to atrial fibrillation, with an
developing the ethics and governance framework for adjusted hazard ratio of 1.13 (95% CI 1.10 to 1.17,
UK Biobank and have been engaged in the progress transition A). The hazard ratio for transition B (from
of UK Biobank through follow-­ up questionnaires health to major adverse cardiovascular events) was
and additional assessment visits. UK Biobank keeps 1.00 (95% CI 0.97 to 1.04) and for transition C (from
participants informed of all research output through health to death) was 0.98 (0.95 to 1.02).
the study website (https://www.ukbiobank.ac.uk/​ For individuals in the secondary stage (atrial
explore-your-participation), participant events, and fibrillation) at the beginning of the study, regular
newsletters. use of fish oil supplements decreased the risk of
major adverse cardiovascular events (transition D,
Results hazard ratio 0.92, 95% CI 0.87 to 0.98), and had a
A total of 415 737 participants (mean age 55.9 borderline protective effect on the transition from
(SD 8.1) years; 55% women), aged 40-­ 69 years, atrial fibrillation to death (transition E, 0.91, 0.82 to
were analysed, and 31.4% (n=1 30 365) of partici- 1.01). For transition F, from major adverse cardiovas-
pants reported regular use of fish oil supplements cular events to death, after adjusting for covariates,
at baseline (figure 1). Table 1 shows the character- the hazard ratio was 0.99 (0.94 to 1.06, transition
istics of regular users (n=130 365) and non-­users pattern I, table 2).
(n=285 372) of fish oil supplements. In the group We divided major adverse cardiovascular events
of regular users of fish oil supplements, we found into three individual diseases (ie, heart failure,
higher proportions of elderly people (22.6% v stroke, and myocardial infarction) and found that
13.9%), white people (95.1% v 94.2%), and women regular use of fish oil supplements was margin-
(57.6% v 53.9%), and higher consumption of alcohol ally associated with an increased risk of stroke in
(93.1% v 92.0%), oily fish (22.1% v 15.4%), and people with a healthy cardiovascular state (hazard
non-­oily fish (18.0% v 15.4%) than non-­users. The ratio 1.05, 95% CI 1.00 to 1.11), whereas a protec-
Townsend deprivation index (mean −1.5 (SD 3.0) v tive effect was found in transitions from healthy
−1.3 (3.0)) and the proportion of current smokers cardiovascular states to heart failure (0.92, 0.86
(8.1% v 11.4%) were lower in regular users of fish oil to 0.98). For patients with atrial fibrillation, we
supplements. Online supplemental table S1 provides found that the beneficial effects of regular use
more details on patient characteristics and online of fish oil supplements were for transitions from
supplemental table S2 compares the basic character- atrial fibrillation to myocardial infarction (0.85,
istics of included and excluded people. 0.76 to 0.96), and from atrial fibrillation to death
Over a median follow-­up time of of 11.9 years, (0.88, 0.81 to 0.95) for transition pattern IV. For
18 367 participants had atrial fibrillation (transition patients with heart failure, we found a protective

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Table 2 | Hazard ratios (95% confidence intervals) for each transition, for different transition patterns for progressive
cardiovascular disease by regular use of fish oil supplements
Transition pattern No of events Hazard ratio (95% CI) P value
Transition pattern I    
 Baseline→atrial fibrillation 18 367 1.13 (1.10 to 1.17) <0.001
 Baseline→major adverse cardiovascular events 17 826 1.00 (0.97 to 1.04) 0.819
 Baseline→death 14 902 0.98 (0.95 to 1.02) 0.280
 Atrial fibrillation→major adverse cardiovascular events 4810 0.92 (0.87 to 0.98) 0.008
 Atrial fibrillation→death 1653 0.91 (0.82 to 1.01) 0.680
 Major adverse cardiovascular events→death 5585 0.99 (0.94 to 1.06) 0.937
Transition pattern II    
 Baseline→atrial fibrillation 18 367 1.13 (1.10 to 1.17) <0.001

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 Baseline→heart failure 4552 0.92 (0.86 to 0.98) 0.011
 Baseline→death 17 580 0.99 (0.96 to 1.02) 0.655
 Atrial fibrillation→heart failure 3085 0.95 (0.88 to 1.02) 0.162
 Atrial fibrillation→death 2124 0.89 (0.82 to 0.98) 0.016
 Heart failure→death 2436 0.91 (0.84 to 0.99) 0.040
Transition pattern III    
 Baseline→atrial fibrillation 18 367 1.13 (1.10 to 1.17) <0.001
 Baseline→stroke 6098 1.05 (1.00 to 1.11) 0.050
 Baseline→death 17 400 0.97 (0.94 to 1.01) 0.131
 Atrial fibrillation→stroke 1180 1.00 (0.89 to 1.13) 0.983
 Atrial fibrillation→death 2652 0.91 (0.84 to 0.99) 0.021
 Stroke→death 2088 1.04 (0.95 to 1.14) 0.347
Transition pattern IV    
 Baseline→atrial fibrillation 18 367 1.13 (1.10 to 1.17) <0.001
 Baseline→myocardial infarction 9300 1.01 (0.96 to 1.05) 0.711
 Baseline→death 17 378 0.98 (0.95 to 1.01) 0.235
 Atrial fibrillation→myocardial infarction 1415 0.85 (0.76 to 0.96) 0.006
 Atrial fibrillation→death 2664 0.88 (0.81 to 0.95) 0.002
 Myocardial infarction→death 2098 1.03 (0.94 to 1.13) 0.510
Model adjusted for age, sex, ethnic group, Townsend deprivation index, consumption of oily fish, consumption of non-­oily fish, smoking status, consumption
of alcohol, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic renal failure, and use of statins, antidiabetic drugs, and
antihypertensive drugs.
CI, confidence interval.

effect of regular use of fish oil supplements on the interaction=0.002) (online supplemental figures S5
risk of mortality (0.91, 0.84 to 0.99) (transition and S6). The results were not substantially changed
patterns II, III, and IV, table 2). in the sensitivity analyses (online supplemental
table S3).
Stratified and sensitivity analyses
We found that age, sex, smoking, consumption of Discussion
non-­ oily fish, prevalent hypertension, and use of Principal findings
statins and antihypertensive drugs modified the Our study characterised the regular use of fish oil
associations between regular use of fish oil supple- supplements on the progressive course of cardiovas-
ments and the transition from healthy states to cular disease, from a healthy state (primary stage),
atrial fibrillation (online supplemental figure S4). to atrial fibrillation (secondary stage), major adverse
We found that the association between regular use cardiovascular events (tertiary stage), and death
of fish oil supplements and risk of transition from (end stage). In this prospective analysis of more
healthy states to major adverse cardiovascular events than 400 000 UK adults, we found that regular use
was greater in women (hazard ratio 1.06, 95% CI of fish oil supplements could have a differential role
1.00 to 1.11, P value for interaction=0.005) and non-­ in the progression of cardiovascular disease. For
smoking participants (1.06, 1.06 to 1.11, P value people with a healthy cardiovascular profile, regular
for interaction=0.001) (online supplemental figure use of fish oil supplements, a choice of primary
S4). The protective effect of regular use of fish oil prevention, was associated with an increased risk
supplements on the transition from healthy states to of atrial fibrillation. For participants with a diag-
death was greater in men (hazard ratio 0.93, 95% CI nosis of atrial fibrillation, however, regular use of
0.89 to 0.98, P value for interaction=0.003) and fish oil supplements, as secondary prevention, had a
older participants (0.91, 0.86 to o 0.96, P value for protective effect or no effect on transitions from atrial

6 Chen G, et al. BMJMED 2024;3:e000451. doi:10.1136/bmjmed-2022-000451

 OPEN ACCESS

fibrillation to major adverse cardiovascular events, In terms of composition of omega 3 fatty acids, a

BMJ Medicine: first published as 10.1136/bmjmed-2022-000451 on 21 May 2024. Downloaded from https://bmjmedicine.bmj.com on 25 May 2025 by guest.
atrial fibrillation to death, and major adverse cardi- recent meta-­analysis showed that eicosapentaenoic
ovascular events to death. When we divided major acid alone can be more effective at reducing the risk
adverse cardiovascular events into three individual of cardiovascular disease than the combined effect of
diseases (ie, heart failure, stroke, and myocardial eicosapentaenoic acid and docosahexaenoic acid.25
infarction), we found associations that could suggest Similar outcomes were reported in the INSPIRE study,
a mildly harmful effect between regular use of fish oil which showed that higher levels of docosahexaenoic
supplements and transitions from a healthy cardio- acid reduced the cardiovascular benefits of eicos-
vascular state to stroke, whereas potential beneficial apentaenoic acid when given as a combination.26
associations were found between regular use of fish Another possible explanation is that age, sex, ethnic
oil supplements and transitions from atrial fibrilla- group, smoking status, dietary patterns, and use of
tion to myocardial infarction, atrial fibrillation to statins and antidiabetic drugs by participants might
death, and heart failure to death. modify the effects of regular use of fish oil supple-

Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies.
ments on cardiovascular disease events. Despite
these differences in risk estimates, our findings do
Comparison with other studies
not support the use of fish oil or omega 3 fatty acid
Primary prevention
supplements for the primary prevention of incident
The cardiovascular benefits of regular use of fish oil
atrial fibrillation or other specific clinical cardiovas-
supplements have been examined in numerous studies
cular disease events in generally healthy individuals.
but the results are controversial. Extending previous
Caution might be warranted when fish oil supple-
reports, our study estimated the associations between
ments are used for primary prevention because of the
regular use of fish oil supplements and specific clin-
uncertain cardiovascular benefits.
ical cardiovascular disease outcomes in people with
no known cardiovascular disease. Our findings are
in agreement with the results of several previous Secondary prevention
randomised controlled trials and meta-­analyses. The Our large scale cohort study assessed the role of
Long-­Term Outcomes Study to Assess Statin Residual regular use of fish oil supplements on the disease
Risk with Epanova in High Cardiovascular Risk process, from atrial fibrillation to more serious
Patients with Hypertriglyceridaemia (STRENGTH) cardiovascular disease stages, to death, in people
reported that consumption of 4 g/day of marine omega with known cardiovascular disease. Contrary to the
3 fatty acids was associated with a 69% higher risk observations for primary prevention, we found asso-
of new onset atrial fibrillation in people at high risk ciations that could suggest beneficial effects between
of cardiovascular disease.20 A meta-­analysis of seven regular use of fish oil supplements and most cardi-
randomised controlled trials showed that users of ovascular disease transitions. No associations were
marine omega 3 fatty acids supplements had a higher found between regular use of fish oil supplements
risk of atrial fibrillation events, with a hazard ratio of and transitions from atrial fibrillation to death, or
1.25 (95% CI 1.07 to 1.46, P=0.013).21 The Vitamin from major adverse cardiovascular events to death.
D and Omega-­3 Trial (VITAL Rhythm study), a large Consistent with our hypothesis, the Gruppo
trial of omega 3 fatty acids for the primary prevention Italiano per lo Studio della Sopravvivenza nell'In-
of cardiovascular disease in adults aged ≥50 years, farto Miocardico (GISSI) Prevenzione study reported
however, found no effects on incident atrial fibrilla- an association between administration of low dose
tion, major adverse cardiovascular events, or cardio- prescriptions of n-­ 3 polyunsaturated fatty acids
vascular disease mortality among those treated with and reduced cardiovascular events in patients with
840 mg/day of marine omega 3 fatty acids compared recent myocardial infarction.27 A meta-­analysis of 16
with placebo.10 22 randomised controlled trials also reported a tendency
One possible explanation for the inconsistent towards a greater beneficial effect for secondary
results in these studies is that adverse effects might prevention in patients with cardiovascular disease.28
be related to dose and composition. Higher doses of Why patients with previous atrial fibrillation benefit
omega 3 fatty acids used in previous studies might is unclear. These findings indicate that triglyceride
have had an important role in causing an adverse independent effects of omega 3 fatty acids might in
effect on atrial fibrillation.21 One study found that part be responsible for the benefits in cardiovascular
high concentrations of fish oil altered cell membrane disease seen in previous trials.29–31 No proven biolog-
properties and inhibited Na-­K-­ATPase pump activity, ical mechanism for this explanation exists, however,
whereas a low concentration of fish oil minimised and the dose and formulation of omega 3 fatty acids
peroxidation potential and optimised activity.23 In used in clinical practice are not known.
another study, individuals with atrial fibrillation For the disease process, from cardiovascular
or flutter had higher percentages of total polyun- disease to death, our findings are consistent with
saturated fatty acids, and n-­3 and n-­6 polyunsatu- the results of secondary prevention trials of omega
rated fatty acids, on red blood cell membranes than 3 fatty acids, which have mostly shown a weak
healthy controls.24 or neutral preventive effect in all cause mortality

Chen G, et al. BMJMED 2024;3:e000451. doi:10.1136/bmjmed-2022-000451 7

OPEN ACCESS

with oil fish supplements. The GISSI heart failure for multiple covariates, residual confounding could

BMJ Medicine: first published as 10.1136/bmjmed-2022-000451 on 21 May 2024. Downloaded from https://bmjmedicine.bmj.com on 25 May 2025 by guest.
trial (GISSI-­HF), conducted in 6975 patients with still exist. Thirdly, information on dose and formu-
chronic heart failure, reported that supplemental lation of the fish oil supplements was not available
omega 3 fatty acids reduced the risk of all cause in this study, so we could not evaluate potential
mortality by 9% (hazard ratio 0.91, 95% CI 0.833 dose dependent effects or differentiate between the
to 0.998, P=0.041).32 Zelniker et al showed that effects of different fish oil formulations. Fourthly, the
omega 3 fatty acids were inversely associated with a use of hospital inpatient data for determining atrial
lower incidence of sudden cardiac death in patients fibrillation events could have excluded some events
with non-­ ST segment elevation acute coronary triggered by acute episodes, such as surgery, trauma,
syndrome.33 A meta-­analysis found that use of omega and similar conditions, resulting in underestimation
3 supplements of ≤1 capsule/day was not associated of the true risk because undiagnosed atrial fibrilla-
with all cause mortality, but among participants with tion is a common occurrence.43 Fifthly, most of the
a risk of cardiovascular disease, taking a higher dose participants in this study were from the white ethnic

Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies.
was associated with a reduction in cardiac death and group and whether the findings can be generalised to
sudden death.28 Individuals who might benefit the other ethnic groups is not known. Finally, our study
most from fish oil or omega 3 fatty acid supplements did not consider behavioural changes in popula-
are possibly more vulnerable individuals, such as tions with different cardiovascular profiles because
those with previous cardiovascular diseases and of limited information, and variations in outcomes
those who can no longer live in the community. How for different cardiovascular states merits further
fish oil supplements stop further deterioration of exploration.
cardiovascular disease is unclear, but the theory that
supplemental omega 3 fatty acids might protect the Conclusions
coronary artery is biologically plausible, suggesting This large scale prospective study of a UK cohort
that omega 3 fatty acids have anti-­ inflammatory suggested that regular use of fish oil supplements
and anti-­hypertriglyceridaemia effects, contributing might have differential roles in the course of cardi-
to a reduction in thrombosis and improvement in ovascular diseases. Regular use of fish oil supple-
endothelial function.34–41 Nevertheless, the effects of ments might be a risk factor for atrial fibrillation and
omega 3 fatty acids vary according to an individual's stroke among the general population but could be
previous use of statins, which might partly explain beneficial for disease progression, from atrial fibril-
the different effects of fish oil supplements in people lation to major adverse cardiovascular events, and
with and without cardiovascular disease. from atrial fibrillation to death. Further studies are
Many studies of omega 3 fatty acids, including needed to determine whether potential confounders
large scale clinical trials and meta-­analyses, have not modify the effects of oil fish supplements and the
produced entirely consistent results.21 25 42 Our study precise mechanisms for the development and prog-
mainly explored the varied potential effects of regular nosis of cardiovascular disease events.
use of fish oil supplements on progression of cardio-
vascular disease, offering an initial overview of this AUTHOR AFFILIATIONS
ongoing discussion. Our findings suggest caution in 1
Department of Epidemiology, Sun Yat-­Sen University, Guangzhou,
the use of fish oil supplements for primary preven- China
2
tion because of the uncertain cardiovascular benefits Department of Epidemiology and Biostatistics, College for Public
Health and Social Justice, Saint Louis University, Saint Louis,
and adverse effects. Further studies are needed to Missouri, USA
determine whether potential confounders modify the 3
School of Social Work, College for Public Health and Social Justice,
effects of oil fish supplements and the precise mech- Saint Louis University, Saint Louis, Missouri, USA
4
Medical Research and Biometrics Centre, Fuwai Hospital, National
anisms related to the development and prognosis of Centre for Cardiovascular Diseases, Peking Union Medical College,
cardiovascular disease events. Beijing, China
5
Liverpool Centre for Cardiovascular Science, University of Liverpool
and Liverpool Heart and Chest Hospital, Liverpool, UK
6
Department of Clinical Medicine, Aalborg University, Aalborg,
Strengths and limitations of this study Denmark
The strengths of our study were the large sample size,
long follow-­up period, which allowed us to analyse Acknowledgements This study was conducted with UK Biobank
clinically diagnosed incident diseases, and complete Resource (application No: 69550). We appreciate all participants and
professionals contributing to UK Biobank.
data on health outcomes. Another strength was our
Contributors HL supervised the whole project and designed the
analytical strategy. The multi-­state model gives less
work. GC and HL directly accessed and verified the underlying data
biased estimates than the conventional Cox model, reported in the manuscript. GC contributed to data interpretation
and distinguished the effect of regular use of fish and writing of the report. ZQ, SZ, JZ, ZZ, MGV, HEA, CW, and GYHL
contributed to the discussion and data interpretation, and revised
oil supplements on each transition in the course of the manuscript. All authors had full access to all of the data in the
cardiovascular disease. study and had final responsibility for the decision to submit for
Our study had some limitations. Firstly, as an publication. The corresponding author attests that all listed authors
meet authorship criteria and that no others meeting the criteria have
observational study, no causal relations can be drawn been omitted. HL is the guarantor. Transparency: The lead author
from our findings. Secondly, although we adjusted (guarantor) affirms that the manuscript is an honest, accurate, and

8 Chen G, et al. BMJMED 2024;3:e000451. doi:10.1136/bmjmed-2022-000451

 OPEN ACCESS

transparent account of the study being reported; that no important 6 Djuricic I, Calder PC. Beneficial outcomes of omega-­6 and omega-­3

BMJ Medicine: first published as 10.1136/bmjmed-2022-000451 on 21 May 2024. Downloaded from https://bmjmedicine.bmj.com on 25 May 2025 by guest.
aspects of the study have been omitted; and that any discrepancies polyunsaturated fatty acids on human health: an update for 2021.
from the study as planned (and, if relevant, registered) have been Nutrients 2021;13:2421. 10.3390/nu13072421
explained. 7 Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction
with icosapent ethyl for hypertriglyceridemia. N Engl J Med
Funding This work was supported by the Bill and Melinda Gates 2019;380:11–22. 10.1056/NEJMoa1812792
Foundation (grant No INV-­016826). Under the grant conditions of 8 Galan P, Kesse-­Guyot E, Czernichow S, et al. Effects of B vitamins
the foundation, a creative commons attribution 4.0 generic license and omega 3 fatty acids on cardiovascular diseases: a randomised
has already been assigned to the author accepted manuscript placebo controlled trial. BMJ 2010;341:c6273. 10.1136/bmj.c6273
version that might arise from this submission. The funder had no 9 Einvik G, Klemsdal TO, Sandvik L, et al. A randomized clinical trial
role in considering the study design or in the collection, analysis, on N-­3 polyunsaturated fatty acids supplementation and all-­cause
interpretation of data, writing of the report, or decision to submit the mortality in elderly men at high cardiovascular risk. Eur J Cardiovasc
article for publication. Prev Rehabil 2010;17:588–92. 10.1097/HJR.0b013e328339cc70
10 Manson JE, Cook NR, Lee I-­M, et al. Marine N-­3 fatty acids and
Competing interests All authors have completed the ICMJE uniform prevention of cardiovascular disease and cancer. N Engl J Med
disclosure form at www.icmje.org/disclosure-of-interest/ and declare: 2019;380:23–32. 10.1056/NEJMoa1811403
support from Bill and Melinda Gates Foundation for the submitted 11 Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access
work; no financial relationships with any organisations that might resource for identifying the causes of a wide range of complex

Protected by copyright, including for uses related to text and data mining, AI training, and similar technologies.
have an interest in the submitted work in the previous three years; no diseases of middle and old age. PLoS Med 2015;12:e1001779.
other relationships or activities that could appear to have influenced 10.1371/journal.pmed.1001779
the submitted work. 12 Fry A, Littlejohns TJ, Sudlow C, et al. Comparison of
sociodemographic and health-­related characteristics of UK biobank
Patient consent for publication Consent obtained directly from
participants with those of the general population. Am J Epidemiol
patients.
2017;186:1026–34. 10.1093/aje/kwx246
Ethics approval The UK Biobank study obtained ethical approval 13 Littlejohns TJ, Sudlow C, Allen NE, et al. UK biobank: opportunities
from the North West Multicentre Research ethics committee, for cardiovascular research. Eur Heart J 2019;40:1158–66. 10.1093/
Information Advisory Group, and the Community Health Index eurheartj/ehx254
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Participants gave informed consent to participate in the study before supplementation with cardiovascular outcomes and all cause
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Data availability statement Data are available upon reasonable
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request. UK Biobank is an open access resource. Bona fide
beverage-­specific alcohol consumption and incident atrial
researchers can apply to use the UK Biobank dataset by registering fibrillation. JACC Clin Electrophysiol 2021;7:1561–9. 10.1016/j.
and applying at http://ukbiobank.ac.uk/register-apply/. jacep.2021.05.013
Supplemental material This content has been supplied by the 17 Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing
author(s). It has not been vetted by BMJ Publishing Group Limited risks and multi-­state models. Stat Med 2007;26:2389–430. 10.1002/
(BMJ) and may not have been peer-­reviewed. Any opinions or sim.2712
recommendations discussed are solely those of the author(s) and 18 LCd W, Fiocco M. mstate: anrpackage for the analysis of competing
are not endorsed by BMJ. BMJ disclaims all liability and responsibility risks and multi-­state models. J Stat Softw 2011;38. 10.18637/jss.v038.
i07
arising from any reliance placed on the content. Where the content
19 Wu Y, Zhang S, Qian SE, et al. Ambient air pollution associated with
includes any translated material, BMJ does not warrant the accuracy
incidence and dynamic progression of type 2 diabetes: a trajectory
and reliability of the translations (including but not limited to local analysis of a population-­based cohort. BMC Med 2022;20:375.
regulations, clinical guidelines, terminology, drug names and drug 10.1186/s12916-022-02573-0
dosages), and is not responsible for any error and/or omissions 20 Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-­dose omega-­3
arising from translation and adaptation or otherwise. fatty acids vs corn oil on major adverse cardiovascular events in
Open access This is an open access article distributed in accordance patients at high cardiovascular risk: the STRENGTH randomized
with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) clinical trial. JAMA 2020;324:2268–80. 10.1001/jama.2020.22258
license, which permits others to copy, redistribute, remix, transform 21 Gencer B, Djousse L, Al-­Ramady OT, et al. Effect of long-­term marine
and build upon this work for any purpose, provided the original ɷ-3 fatty acids supplementation on the risk of atrial fibrillation
in randomized controlled trials of cardiovascular outcomes: a
work is properly cited, a link to the licence is given, and indication
systematic review and meta-­analysis. Circulation 2021;144:1981–90.
of whether changes were made. See: https://creativecommons.org/​
10.1161/CIRCULATIONAHA.121.055654
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Zilong Zhang http://orcid.org/0000-0002-7003-6565
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10 Chen G, et al. BMJMED 2024;3:e000451. doi:10.1136/bmjmed-2022-000451