Analysis does not overturn positive findings from prior evidence reviews; negative conclusions stem from inclusion of a flawed trial in angina patients
Headline-hunting editors at news outlets worldwide have done their readers a major disservice.
You’d think—based on the irresponsibly credulous media reports—that a new review of the available clinical evidence suggests that fish oil does little to prevent heart attacks, stroke, and cancer.
If you’re thinking, in frustration, “say it ain’t so”, please rest easy, because it simply isn’t so.
US and UK health authorities, and expert observers, agree that this misleading review changes almost nothing: the vast preponderance of evidence still favors omega-3s for heart attack and stroke protection.
The authors’ negative conclusions stem entirely from inclusion of the almost uniquely negative results of a widely criticized trial in male angina patients: a study graded “poor quality” by a recent US government review.
The new evidence review does not challenge the uniformly positive findings of prior evidence reviews with regard to prevention of first or second heart attacks.
The new review ignored the vast majority of pertinent evidence, including all of the many large population studies, and studies that measured body levels of omega-3s (the most accurate gauge of preventive power).
The review did not find that omega-3s cannot help prevent cancer; it only found insufficient clinical evidence from which to draw a positive or negative conclusion. (There is ample laboratory evidence—such as the new study covered in this issue—that omega-3s inhibit cancer.)
The new review (Hooper L 2006), reported last week by a team of British researchers, does not overturn the extensive record of positive research.
In fact, its authors’ explicitly excluded the reams of clinical, epidemiological, and laboratory research showing that the long-chain “marine” omega-3 fatty acids in fish help prevent heart attacks, stroke, and cancer.
In fact, the new UK review merely highlights two things.
The authors of a recent clinical trial (Burr MI 2003)—one of the studies included in this evidence review—reported inexplicably negative results. Their odd findings skewed the results of the new evidence review, which otherwise would have echoed the unambiguously positive findings of other recent evidence reviews (e.g., Bucher 2002, Wang 2004). As we’ll show (see “Weakness # 2”, below), expert commentators are criticizing this seriously flawed study and deploring the reviewer’s decision to include it (it violated their own inclusion criteria) and give it the weight they did.
We need more large, well-controlled clinical trials designed to pinpoint the precise cardio-prevention effects of varying dietary intake and tissue levels of omega-3s, over varying periods of time.
Unfortunately, the competitive pressures that lead media outlets to report counterintuitive, attention-grabbing, news—no matter how misleading or likely to make harmful mischief—appear to trump journalists’ responsibility to deliver nuanced, carefully researched reports.
As a result, people keep getting misled by news articles that oversimplify the underlying facts and ignore the complexities that characterize many science-and-health stories, including this one.
What the new review reported
Researchers based at several British universities collaborated on the new study (Hooper L 2006), which was published online March 23 by the British Medical Journal.
We obtained a copy of the full report and subjected it to careful scrutiny by ourselves and our world-renowned science advisor, Professor William E. Lands, Ph.D.
The UK team analyzed 89 human studies—48 randomized controlled trials (RCTs) and 41 “cohort” studies—to assess the evidence regarding likely health effects of omega-3 fatty acids on the risk of heart attacks, cancer, and strokes, and overall death rates.
(See our “Untangling Study Terms” sidebar describing the various types of scientific studies.)
Most of them involved a treatment (omega-3) group and a control (placebo) group and all of the studies followed participants for at least six months. Differences in study design were taken into account when the reviewers weighted the significance of each one.
The authors concluded that the studies they selected, when analyzed as a group, did not show clear evidence of that omega-3s protect against cancer, strokes, or heart attacks.
As they said, “It is not clear that dietary or supplemental omega 3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population. There is no evidence we should advise people to stop taking rich sources of omega 3 fats, but further high quality trials are needed to confirm suggestions of a protective effect of omega 3 fats on cardiovascular health.”
But, when we analyzed the new review we quickly discovered several big elephants in the room.
Unfortunately most media reports missed or ignored these perfectly conspicuous, highly problematic pachyderms, to the probable detriment of public health.
Specifically, scientific experts who’ve commented on the new review have identified five major areas of weakness that fatally undermine its largely negative findings:
Weakness #1: Gives undue weight to small studies
With the exception of one large study (Natvig 1968), all of the trials that the reviewers rated “low bias”—and therefore gave greater statistical weight—involved small numbers of subjects: a weakness that renders their findings of little statistical significance in the context of the much larger trials included in the review (e.g., GISSI-P 1999, Burr/DART 1989, Natvig 1968).
|Untangling Study Terms: Clinical, Cohort, Case-Control, or Population?
Today, consumers of health news need to understand the differences between types of studies scientists can conduct.
Randomized Controlled Trials (RCTs) are often referred to as the “gold standard” of human health research. Their exaggerated reputation for definitiveness stems in large part from the fact that researchers use RCTs to determine the safety and efficacy of synthetic drugs seeking FDA approval.
In fact, unlike many cohort and population studies, many RCTs do not last long enough or involve enough people (due to their high cost) to be considered definitive. Nor are RCTs particularly well-suited to detecting relationships between diet and disease.
Here’s our pocket primer on types of research studies:
Clinical Trial: Any investigation that studies people in a controlled setting.
Randomized Controlled Trial: Subjects are divided into an “active” group, who receive the drug or nutrient being tested for its therapeutic or preventive effects, and a “control” group, who receive an identical-looking/tasting placebo (inactive) drug or nutrient. The most reliable controlled trials are “double-blind”, which means that neither the researchers nor the subjects know which subjects are getting the treatment being tested. RCTS are best suited to determining the short-term effects of drugs or nutrients with strong, fast-impact health effects.
Cohort Study: Researchers follow a group of participants prospectively over a set period of time, collecting data on possible disease-promoting and -preventing factors (diet, lifestyle, etc.) within the group and the rates at which people in it develop the disease being studied. These can detect the likely long-term effects of drugs or nutrients with suspected health effects.
Case-Control Study: Researchers collect data on a group of patients and look for unusual diet or other lifestyle patterns, in comparison with a group of healthy but otherwise similar people. These can detect the possible relationships between various factors (diet, lifestyle, drugs) and specific diseases.
Population (Epidemiological) Study: Using questionnaires, researchers collect information on a large population group, looking for correlations between diet or other lifestyle factors and rates of one of more diseases.
Experimental (“in vivo”) Study: Studies involving animals.
Laboratory (“in vitro”) Study: Studies involving isolated cells (human or animal) in test tubes.
Indeed, the evidence-review’s authors admitted that the lowest-bias-risk studies were too small to reveal much of anything:
“The largest studies reviewed had greater potential for bias than some of the smaller ones. We hoped that pooling studies at low risk of bias might provide enough power to inform us of effects on health, but this was not the case (only 138 deaths and 570 cardiovascular events). Similarly, analysis of the effects of omega 3 on rarer outcomes such as stroke had insufficient power to detect clinically important effects.”
Weakness #2: Gives undue weight to one seriously flawed trial
As the authors of the new evidence review noted—in a sidebar titled ”What is already known on this topic”—“A systematic review of randomised controlled trials in coronary heart disease showed reduced mortality in patients taking supplemental long chain omega 3 fats.”
They were referring to a similar review of the clinical evidence, published by a Swiss team in 2002 (Bucher HC et al), which came to the opposite (i.e., positive) conclusion concerning the ability of omega-3s to reduce heart-related health risks.
The Swiss authors of the 2002 evidence review came to a positive conclusion: “This meta-analysis suggests that dietary and non-dietary intake of n-3 polyunsaturated fatty acids reduces overall mortality, mortality due to myocardial infarction, and sudden death in patients with coronary heart disease.”
Since this prior analysis of data from RCTs and cohort studies already existed, why did the authors of the new review bother to perform their meta-analysis?
The chief reason that they wanted to repeat the 2002 evidence review was that a large trial in male angina patients had been published after the Swiss review appeared.
However, the 2003 angina-patient trial—led by Michael Burr, M.D. of Britain’s Cardiff University—featured some very serious flaws.
Indeed, the only major difference between the 2002 evidence review from Switzerland and the new one from Britain is that the latter included the anomalous results of Dr. Burr’s 2003 study.
And, significantly, the inexplicably negative findings of Dr. Burr’s angina-patient trial account for unjustifiably negative conclusions of the authors of the new evidence review, with regard to the ability of fish and fish oil to reduce cardiac risks.
As we will demonstrate, this is not just our opinion. Scientists expert in the field are already criticizing the decision to include Dr. Burr’s angina-patient trial.
With the exception of Dr. Burr’s 2003 trial—which is the only one ever conducted in men with angina (chest pain caused by clogged arteries)—all of the larger trials included in the review demonstrated that omega-3s reduce the risk of death from cardiovascular causes.
But US researchers who wrote a 2004 evidence review for the federal government rated both the Burr angina trial and another one conducted by the same research team (Burr ML 1989) as “poor quality studies”.
While Dr. Burr’s anomalous 2003 study indicates that high intake of omega-3s might present risks to substantially heart-sick men suffering from angina, it is not credible to find—as the authors of the deplorably flawed new evidence review did—that its unusual, inexplicable findings outweigh the predominantly positive findings of all other studies on omega-3s and heart health.
In Dr. Burr’s 2003 British angina trial, 3,114 men under 70 with angina were randomly assigned to four groups: (1) advised to eat two portions of oily fish each week, or to take three fish oil capsules daily; (2) advised to eat more fruit, vegetables and oats; (3) given both the above types of advice; and (4) given no specific dietary advice. Rates of death among each group were ascertained after 3-9 years of the study.
Risk of death was not reduced in any of the groups, while the risk of cardiac death was significantly higher among subjects in the fish-or-fish-oil group, with the excess risk occurring predominantly among the subgroup who took fish oil capsules instead of eating fish.
As Dr. Burr’s team concluded, “Men advised to eat oily fish, and particularly those supplied with fish oil capsules, had a higher risk of cardiac death. This result is unexplained; it may arise from risk compensation or some other effect on patients' or doctors' behaviour.”
When they said “The result is unexplained …” they were referring to the fact that an overwhelming preponderance of prior clinical evidence indicates that consuming substantial amounts of fish or fish oil supplements can reduce the risk of cardiac death.
And by “risk compensation” the authors meant the well-known phenomena in which people on heart medication(s) continue or resume eating and behaving in unhealthy ways, believing that the drug(s)—or in this case, fish oil—frees them from the need to lead a heart-smart life.
Actually, we can think of another explanation for the uniquely negative results of this trial, which is that these were relatively sick men. After all, angina—the chest pain or discomfort that occurs when your heart muscle does not get enough blood—is a sign of advanced cardiovascular disease.
We cannot be sure how sick they were, because the authors did not say how many participants had each of three classifications of “angina”, which range from cautionary to serious or very critical.
If, for example, a substantial number suffered from “unstable angina”, it would mean that they were at high risk of dying from a heart attack, and that no amount of fish or fish oil would be likely reduce their risk of early death.
In their discussion, the authors of Dr. Burr’s 2003 angina-patient trial acknowledged that they could not explain why the men who took supplemental fish oil suffered a very substantial increase in risk of sudden cardiac death, despite the large body of prior research showing that omega-3s reduce sudden cardiac death rates.
They also made an unwarranted assertion—“There was no evidence that it was due to interactions with medication”—that has no apparent scientific basis. The authors of Dr. Burr’s trial did not autopsy the men who died, and even if they had, it is medically unlikely that they would have found physical evidence of fatal drug-nutrient interactions.
Several scientists have already written to the British Medical Journal, which published the new evidence review, to criticize its authors’ decision to include Dr. Burr’s angina patient trial and give it such undue weight. (To read all of the “rapid responses” posted at the BMJ Web site, click here.)
These are two of the letters that critiqued Dr. Burr’s angina patient trial and the reviewer’s inexplicable decision to give it such great, unwarranted weight:
Eiliv Lund, Professor of epidemiology at the University of Tromsø, Norway:
“Dear Editor, in their paper Hooper et al. describe the method for selecting papers for the systematic review of risk and benefits of omega 3 fats given mainly as dietary supplements. They conclude in the review that omega 3 fats have no effect on total mortality, cancer or cardiovascular events. The findings of no effect are mainly due to the inclusion of the study by Burr et al , and differ from most previous reviews which have concluded with an positive effect on cardiovascular conditions. However, the inclusion of the clinical trial by Burr et al. violates their own inclusion criteria twice. First, the Burr article was published one year after the date of the last systematic search of relevant articles (February 2002). Secondly, they stated that all studies with multifactorial interventions were excluded. The Burr trial was in fact multifactorial having a 2X2 design including both fish or fish oil and fruit. In addition, it was stopped and then restarted with another design.
- Dr. Johanna M Geleijnse and colleagues at Holland’s Wageningen University:
“As Hooper et al [the authors of the new evidence review] stated in their discussion, the trial by Burr et al in patients with angina pectoris had a major impact on the pooled risk estimate for overall and cardiovascular mortality. “Data from many epidemiological studies and the GISSI-P trial suggest that omega 3 fats from fish protect against heart disease. Although the trial by Burr et al in angina patients should not be ignored, it is hard to interpret these adverse findings in light of previous studies. “A different conclusion would be derived from the review by Hooper et al if these data are omitted, favoring a cardioprotective effect of omega 3 fats from fish. The pooled relative risk … [a 27 percent reduction in risk] … that would then be obtained is in line with the meta-analysis of Bucher et al. “In conclusion, the majority of epidemiological studies and randomized controlled trials indicate a protective effect of omega 3 fatty acids from fish against fatal cardiovascular events. The advice for healthy people and myocardial infarction patients to consume oily fish on a regular basis does not confer adverse risks to health and is fully justified on the basis of current scientific evidence.”
Note: Last year, Dr. Geleijnse and a group of Harvard University researchers published a meta-analysis (Mozaffarian D 2005) of randomized controlled trials testing the ability of fish oil to moderate heart rate in ways that reduce the risk of heart attacks. Their review came to an unambiguously positive conclusion
Weakness #3: Excluded the vast majority of relevant evidence
The authors chose not to consider any evidence from three major sources:
Epidemiological evidence: Dozens of large epidemiological (population) studies demonstrate a strong correlation between higher consumption of fish or marine omega-3s and lower risk of heart attacks and stroke.
Tissue-level trials: The new review did not include studies that actually measured levels of omega-3s in people’s blood or adipose (fatty) tissue, in addition to asking people how much fish they ate, which is a notoriously unreliable way to judge the effect of any nutrient. As we heard Drs. William Lands and Joseph Hibbeln of the National Institutes of Health say many times at last year’s Seafood & Health conference—“The tissue is the issue”. Almost without exception, whenever researchers have compared blood or tissue levels of omega-3s with rates of heart attack, they’ve found that higher body levels of omega-3s correlate with a reduced risk of heart attack (e.g., Lemaitre RN 2003, Guallar E 2003, Albert CM 2002, Siscovick DS 1995, Simon JA 1995).
Laboratory evidence: Hundreds of laboratory experiments demonstrate that omega-3s exert physiological effects known to help prevent heart attacks, stroke, and cancer.
Why did the authors of the new evidence review decide to ignore the many epidemiological (population) studies, when these provide the biggest body of evidence indicating that fish and fish oil help prevent heart attacks and strokes?
Presumably, the reason was that randomized controlled trials (RCTs) and cohort studies—if they include enough people, last long enough, and are sufficiently well-controlled—permit conclusions firmer than those possible from population studies.
Their potential for scientific superiority stems in part from the fact that RCTs and cohort studies can, hypothetically, allow researchers to eliminate or adjust for diet and lifestyle factors that could muddy the waters.
But, as with all scientific studies, the devil is in the details. An RCT or cohort study whose design is deficient, or whose size or duration is insufficient, will be no better able to deliver definitive results than would a series of well-designed, carefully conducted population studies backed by solid case-control and laboratory studies.
Vital Choice science advisor William Lands, Ph.D. told us that it was a serious scientific mistake for the authors to exclude evidence from population and laboratory studies, and to lend excessive weight to Dr. Burr’s angina-patient trial and a few trials whose design parameters were somewhat superior to the larger trials included in the review, but whose small size could not permit statistically powerful conclusions.
As a result, Dr. Lands found the authors’ sweeping, negative conclusions insupportable.
Weakness #4: Negative studies included in the review did not consider omega-6 intake
Dr. Lands emphasizes that researchers should not consider dietary omega-3 intake alone when attempting to evaluate their impact on heart health or cancer risk. This is because omega-3s have to compete with dietary omega-6 fats for a place in cell membranes. If your omega-6 intake is high, it will blunt the benefits of your omega-3 intake.
Another “rapid response” letter to the British Medical Journal echoed Dr. Lands’ viewpoint. It came from nutritionist Evelyn Tribole, R.D. a former nutrition expert for ABC's "Good Morning America” and national spokesperson for the American Dietetic Association, and we’ve excerpted her key points here:
“Conducting a meta-analysis study on the effectiveness of omega-3 fats for mortality, cardiovascular disease and cancer, without considering the impact of excess omega-6 fat in the diet, is akin to reviewing the efficacy of a healthy diet without factoring the effects of smoking.
“Excess omega-6 fats interfere with the health benefits of omega-3 fats because they compete for the same rate-limiting enzymes. A high proportion of omega-6 to omega-3 fat in the diet shifts the physiological state of the body toward the pathogenesis of many diseases: prothrombotic [clot-promoting], proinflammatory and proconstrictive [artery-narrowing].
“Chronic excessive production of omega-6 eicosanoids [metabolic products of dietary omega-6 fats] is associated with heart attacks, thrombotic stroke, arrhythmia, arthritis, osteoporosis, inflammation and cancer. Furthermore, coronary heart disease mortality has been demonstrated to be proportional to plasma [blood] levels of long chain omega-6 fat.
“Prior to industrialization, no population has been exposed to the current high levels of omega-6 polyunsaturated fats in westernized diets. Today we eat fat that did not exist 100 years ago, such as cottonseed oil. Humans evolved on a diet with a balanced ratio of omega-6 to omega-3 fats of about 1:1. Today, that ratio in westernized countries is near 17:1.”
Weakness #5: The new review included studies on omega-3 plant oils
This decision has been criticized by several commentators, both because long-chain omega-3s from fish (EPA and DHA) are far more important to bodily functions and cell structure, and because the body only converts two to ten percent of dietary short-chain omega-3s into long-chain omega-3s.
By including trials using plant-drreived omega-3s, the authors only muddied the picture further, to the detriment of marine omega-3s.
Dr. William E. Lands decries oversimplification of science
Vital Choice science advisor William E.M. Lands, Ph.D. deplores researchers’ all-too-frequent failure to see the forest for the trees: a tendency detectable in the decision of the authors of the new review to ignore 99.4 percent of the available, relevant studies (15,070 of the 15,159 available studies were excluded).
Dr. Lands served as Professor of Biochemistry at the University of Michigan (1955-1980) and the University of Illinois (1980-1991) and authored over 250 research papers and the book, Fish and Human Health (AOCS Press 2005).
After retiring from teaching, he directed the basic research program at the National Institute on Alcohol Abuse and Alcoholism (1990-1997) and served as Senior Scientific Advisor to the Director (1997-2002).
Dr. Lands spoke more with bemusement than annoyance concerning the misleading conclusions of the review’s authors, but expressed some concern that the researchers’ narrowly-based conclusions and the media’s oversimplified characterizations might discourage dietary decisions—that is, consuming more fish and fewer omega-6 fats—that are clearly good for peoples’ heart health.
And it sounds as if he'd foreseen the current flawed review when he composed these comments on the subjects of scientific myopia in a 2003 paper published in the journal Nutrition, Metabolism, and Cardiovascular Diseases (key points underlined for emphasis):
“Essential fatty acids in the foods we eat have a subtle but powerful influence on hundreds of different processes in the life and death of humans, understanding of which has been delayed by two attitudes in the biomedical community. One involves a bias towards expensive curative/treatment interventions that neglect prevention of initial nutritional causes of disease and death, and the other involves careless logic in interpreting evidence of causes of disease and death.
“Both attitudes interfere with translation of published science of essential fatty acids into effective prevention of cardiovascular deaths, a situation made worse by a widespread wish for simple descriptions of complex interactions in disease.
“Death from coronary heart disease comes from acute ischemia [drop in blood flow to the heart muscles] and arrhythmia [irregular heart beat], often following long-term chronic inflammatory vascular damage that predisposes to acute fatal thrombosis [artery-blocking blood clots] and arrhythmia.
“Readily corrected nutritional imbalances in … omega-3/omega-6 essential fatty acids are causal risk factors with plausible mechanisms contributing to fatal [coronary] events which can be prevented.”
In conclusion, the new evidence review does not even come close to overturning the vast body of evidence indicating that the omega-3 fats in fish and fish oil help prevent heart attacks and stroke, and are likely to inhibit growth of cancers.
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