An Exercise in Critical Thinking: Fish Oil and Cardiovascular Disease


Over the past four decades there has been evidence to suggest that people who regularly eat fish have lower rates of heart disease, and many have postulated that this is due to the fact that fats/oils in some fish are enriched with long-chain, polyunsaturated n-3 (omega-3) fatty acids. Nevertheless, there is currently controversy about whether increased dietary intake of n-3 fatty acids by eating fish or taking fish oil capsules is beneficial.

To practice the critical review strategies presented earlier in this module, we have selected four articles that provide different view-points on the issue of fish oil and cardiovascular disease. Each article is accompanied by a set of questions. All articles are available via Pub Med.

The Question:

Fish oil supplements are solid with marketing that often suggests that fish oil consumption reduces the risk of cardiovascular disease.

Should you or your parents should be encouraged to eat more fish and/or take dietary supplements containing fish oil? Your goal is to make an evidence-based recommendation. For the purpose of this discussion, please disregard the potential adverse effects of mercury in pregnant woman. 

Paper #1

Kromhout D, Bosschieter EB, et al.: The inversion relation between fish consumption and 20-year mortality from coronary heart disease. N. Engl. J. Med. 1985;312:1205-9. Link to PDF for this article: http://www.nejm.org/doi/pdf/10.1056/NEJM198505093121901

What type of study is this? Who were the participants?

What were the primary exposures and outcomes (endpoints) of interest? How were they ascertained? Did the investigators adequately define and precisely assess these? Is it likely that misclassification of the primary exposures and outcomes affected the results of the study?

How were the subjects selected into the study? Is it possible that selection bias affected the results of the study?

How did the investigators evaluate random error? Was the statistical analysis adequate?

How did the investigators deal with potential confounding? Was this adequate?

What does Table 1 show? How would you interpret these findings? Can a risk ratio be = 0? How would you interpret the confidence intervals in the last row of the table?

What does Table 4 show? How would you interpret these findings?

What is your overall assessment of the quality of this study? Do you believe the results are internally valid? Are the results externally valid? If so, to whom?

Paper #2

Albert CM, Campos H, et al.: Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N.   Engl. J. Med. 2002;346:1113-8. Link to PDF for this article: http://www.nejm.org/doi/pdf/10.1056/NEJMoa012918

What type of study is this? Who were the participants?

What were the primary exposures and outcomes (endpoints) of interest? How were they ascertained? Did the investigators adequately define and precisely assess these?

How were the subjects selected into the study? Is it possible that selection bias affected the results of the study?

How did the investigators evaluate random error? Was the statistical analysis adequate?

How did the investigators control for confounding?

What is the purpose of Table 1? What conclusions can you draw from this table?

On page 1115 the authors state, " ...significantly lower levels of long-chain n-

3 fatty acids were found among current smokers than among former smokers or those who had never smoked ...." Is this important? Why or why not?

On page 1115 the authors also state, "In addition, the base-line blood level of long-chain n-3 fatty acids was significantly correlated with fish intake at 12 months (R2=0.24, P=0.001). What can one conclude from this?

What does Table 2 show? What conclusions would you draw from this table?

What does Table 3 show? What conclusions would you draw from this table?

What is your overall assessment of the quality of this study? Do you believe the results are internally valid? Are the results externally valid? If so, to whom?

Paper #3

Kromhout D, Giltay EJ: n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl. J. Med. 2010;363:2015-26. Link to PDF for this article: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1003603

What type of study was this?

Who comprised the study population? What were the inclusion and exclusion criteria for participation in the study?

What groups were compared?

Were the methods adequately described?

Is it likely that random error had a major effect on the conclusions drawn by the authors?

How did the investigators assess adherence to the protocol? Is it likely that misclassification of exposure affected the results?

Is it likely that selection bias affected the results?

Is it likely that misclassification of outcome affected the results?

What are your conclusions based on Table 1?

The authors state, " The two groups that received EPA-DHA were combined and compared with the two groups that did not receive EPA-DHA. Similarly, the two groups that received ALA were combined and compared with the two groups that did not receive ALA." Why did they do this?

What do the results in Table 2 indicate?

What do the findings in Table 3 suggest?

What is your overall assessment of the quality of this study? Do you believe the results are internally valid? Are the results externally valid? If so, to whom?

Paper #4

The Risk and Prevention Study Collaborative Group: n−3 fatty acids in patients with multiple cardiovascular risk factors. N Engl. J. Med. 2013;368:1800-8. Link to PDF for this article: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1205409

(Note: In the study the authors computed a "hazard ratio," which is something that we haven't talked about in EP713. For our purposes in this exercise, you can regard the hazard ratio as a rate or risk ratio that compares risk over time.)

What type of study was this?

What were the inclusion and exclusion criteria for participation in the study?

What groups were being compared?

Were the methods adequately described?

Is it likely that random error had a major effect on the conclusions drawn by the authors?

What is the purpose of Table 1? What conclusions can you draw from Table 1?

In the section entitled " CARDIOVASCULAR RISK FACTORS AND MEDICATIONS" the authors note that, " By the end of the trial, the overall cardiovascular risk profile had improved in both groups...." Exactly what was the improvement? Why is it that the "placebo" group improved? What is the significance of this in terms of the validity of the study? In the same section the authors stated (page 1803), " Prescriptions of recommended cardiovascular drugs increased during follow-up to a similar degree in the two study groups." What is the potential importance of this, if any?

Is it likely that bias had a significant impact on the conclusions? If so, which type of bias?

Is it likely that confounding had a significant impact on the conclusions?

The authors indicate that there was no evidence of interaction of treatment with n−3 fatty acids in relation to aspirin use and statin use at baseline showed no evidence of interaction with these drugs (P = 0.34 and P = 0.28 for interaction, respectively).

What does Figure 2 show? Pay particular attention to gender effects and effects in those who had > cardiovascular risk factors vs. those who had fewer.

What were the rates of non-compliance? How did the authors deal with non-compliance? What effect would this have on the results/outcome?

What is your overall assessment of the quality of this study? Do you believe the results are internally valid? Are the results externally valid? If so, to whom?