By Rakesh Calton, MD
Associate Professor, Clinical Foundations, Ross University School of Medicine, Barbados, West Indies
Summary Points
- In this pooled analysis of four cohort studies, the authors studied mortality and major cardiovascular disease (CVD) events in 191,558 individuals to determine if there is a difference in the association of fish consumption with the risk of CVD or mortality between individuals with and individuals without CVD.
- The researchers found a lower risk of major CVD and total mortality associated with higher fish intake of at least 175 g weekly among high-risk individuals or patients with vascular disease. This association was not found in general population without CVD.
- Consumption of oily fish, rich in omega-3 fatty acid, was associated with greater benefits.
SYNOPSIS: This article argues whether there is enough scientific evidence to suggest that there are associations between fish consumption and risk of cardiovascular disease, or of mortality, among people who consume fish compared to those who do not consume fish.
SOURCE: Mohan D, Mente A, Dehghan M, et al. Associations of fish consumption with risk of cardiovascular disease and mortality among individuals with or without vascular disease from 58 countries. JAMA Intern Med 2021;181:631-649
High consumption of fish, a rich source of long-chain omega-3 fatty acids, has been shown to improve cardiovascular disease (CVD) risk.1-3 Various studies have shown a beneficial role of omega-3 fatty acids in managing CVD, hyperlipidemias, and hypertension.1-3 However, the literature does not provide conclusive evidence to these effects.4 While some studies have shown a positive correlation in omega-3 fatty acid consumption and improvement in cardiovascular events, coronary heart diseases, and cardiovascular event-related mortality, other studies did not show similar beneficial effects. The authors hypothesized that, since increased fish intake improves blood lipid levels, there should be significant differences in the association between fish intake and cardiovascular outcomes and mortality among those with CVD vs. those without CVD.
The authors conducted a pooled analysis between January 2020 and June 2020 of participant data obtained from 191,558 individuals from four cohort studies. (See Table 1.) The data taken from Prospective Urban Rural Epidemiology (PURE) in 21 countries included 147,645 individuals (mean age 54.1 ± 8 years), 139,827 of whom did not have CVD while 7,818 had preexisting CVD. All outcome events known until July 31, 2019, were included in the analysis. The other set of data was obtained from 43,413 participants published in three prospective studies from 40 countries:
- The Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ONTARGET), a randomized clinical trial of antihypertensive medication for 25,620 patients aged 55 years or older;
- Data from 5,926 participants of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND), a randomized controlled trial of telmisartan vs. placebo; and
- Data from 12,422 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial.
Table 1. Age and Gender Distribution of Participants | ||||
PURE Trial |
ONTARGET and TRANSCEND |
ORIGIN Trial |
Pooled | |
Total number of subjects |
147,645 |
31,491 |
12,422 |
191,558 |
Number of participants |
0.6 (95% CI, 0.4-0.8) |
0.4 (95% CI, 0.3-0.5) |
0.3 (95% CI, 0.3-0.4) |
43,887 |
Mean age (standard deviation) in years |
21.8 (95% CI, 20.6-22.9) |
18.1 (95% CI, 17.7-18.5) |
18.5 (95% CI, 18.3-18.6) |
54.1 (8.0) |
Number of males |
15,020 (40%) |
1,779 (63.5%) |
2,136 (59.8%) |
91,666 (47.9%) |
PURE: Prospective Urban Rural Epidemiology; ONTARGET: Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial; TRANSCEND: Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease; ORIGIN: Outcome Reduction with Initial Glargine Intervention; CI: confidence interval. | ||||
Variables collected from all of the studies included demographic factors, lifestyle, health history, and medication. Physical assessment included data on weight, height, waist, hip circumference, and blood pressure. In the PURE study, habitual food intake was recorded using country-specific validated food frequency questionnaires (FFQ). In ONTARGET and TRANSCEND, dietary information was obtained using a 19-question FFQ. The ORIGIN study used a 25-question, qualitative FFQ on individual foods. However, for fish consumption, it used a separate 28-question FFQ.
Statistical analysis involved a calculation of adjusted hazard ratio (HR) by multilevel Cox regression analysis within each of the above-mentioned studies and then pooling using random-effects metanalysis.
Median fish intake was calculated overall, as well as for the geographical regions, with adjustments made for age and gender. For each of these cohorts, participants were divided into groups based on their fish consumption: lower than 50 g per month, between 50 g and 175 g per month, between 175 g and 350 g per month, and more than 350 g per month.
Analysis of covariance was performed to determine mean lipid blood levels and blood pressure levels among fish intake groups, adjusted for covariates. A two-stage participant meta-analysis also was performed. In the first stage, association between fish intake and events in each cohort were determined separately. In the second stage cohort, specific HRs and 95% confidence intervals (CIs) were pooled in a random-effects meta-analysis.
Proportionality assumption was tested using a global goodness-of-fit test and Schoenfeld residuals in each cohort. A test of heterogenicity were conducted by employing the I2 statistic. Additionally, for the PURE study, Cox frailty models with random effects were used to correlate between fish intake and the outcomes.
Results included the following:
- A total of 191,558 participants with a mean age of 54.1 ± 8.0 years were included in the present analysis. Of these, 91,666 participants (47.9%) were males.
- In the PURE study, over a follow-up period of 9.1 years, intake of 350 g/week or more was not associated with risk of major CVD (HR, 0.95; 95% CI, 0.86-1.04) or total mortality (HR, 0.96; 0.88-1.05).
- In the other three cohorts, the HR for risk of major CVD (HR, 0.84; 95% CI, 0.73-0.96) and total mortality (HR, 0.82; 95% CI, 0.74-0.91) was lowest with intakes of at least 175 g/week.
- There was no further apparent decrease in HR with consumption of 350 g/week or higher.
- Consumption of fish with higher amounts of omega-3 fatty acids were strongly associated with a lower risk of CVD (HR, 0.94; 95% CI, 0.92-0.97 per 5-g increment of intake).
- A lower risk was found among patients with vascular disease. This benefit was not seen in general populations without CVD (for major CVD, I2 = 82.6 [P = .02]; for death, I2 = 90.8 [P = .001]).
COMMENTARY
This well-designed meta-analysis of pooled data from four studies found a strong correlation between consumption of fish with a higher amount of omega 3 fatty acids and lower risk of CVD among patients with vascular disease. This observation is in accordance with other studies. The 1989 DART trial reported a 29% reduction in all-cause mortality over a two-year follow-up period in male myocardial infarction survivors when advised to increase their intake of oily fish to 200 g/week to 400 g/week.5
Hu et al conducted a meta-analysis of data from 13 trials and found a positive correlation between consumption of marine omega-3 fatty acid supplementation and lowered risk for myocardial infarction, coronary heart disease (CHD) death, total CHD, CVD death, and total CVD.6 The authors in the present study recommend consumption of at least two servings of fish rich in omega-3 fatty acids per week in patients with preexisting CVD. This is consistent with the recommendations made by the American Heart Association.7
The study is well-designed and has appropriate statistical measures employed. The problem statement is well-articulated and is based on a sound hypothesis. The research topic is relevant to the complementary and alternate medicine approach while dealing with cardiovascular morbidity and mortality.
The conceptual framework is explicit and well-justified, and the constructs being investigated are clearly identified and presented. The authors have conducted a thorough and well-researched review of the literature. However, the gaps in the available literature could have been better highlighted.
The research is well-designed, and appropriate statistical tools are employed wherever warranted to ensure trustworthiness. The study conforms to external validity by taking in account participants, settings, and conditions. The internal validity is maintained by addressing potential confounding variables and biases. Given the information provided by the analysis, clinicians should feel confident prescribing 175 g (approximately two servings) of fish rich in omega-3 fatty acids for their patients with prior CVD.
REFERENCES
- Filion KB, El Khoury F, Bielinski M, et al. Omega-3 fatty acids in high-risk cardiovascular patients: A meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2010;10:24.
- Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: Effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011;58:2047-2067.
- Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: A systematic review and meta-analysis. JAMA 2012;308:1024-1033.
- Fialkow J. Omega-3 fatty acid formulations in cardiovascular disease: Dietary supplements are not substitutes for prescription products. Am J Cardiovasc Drugs 2016;16:229-239.
- Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and reinfarction trial (DART). Lancet 1989;2:757-761.
- Hu Y, Hu FB, Manson JE. Marine omega-3 supplementation and cardiovascular disease: An updated meta-analysis of 13 randomized controlled trials Involving 127,477 participants. J Am Heart Assoc 2019;8:e013543.
- Jain AP, Aggarwal KK, Zhang P-Y. Omega-3 fatty acids and cardiovascular disease. Eur Rev Med Pharmacol Sci 2015;19:441-445.
Is there enough scientific evidence to suggest there are associations between fish consumption and risk of cardiovascular disease, or of mortality, among people who consume fish compared to those who do not consume fish?
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