Sunday, August 30, 2009

HPV Vaccine: Debate Over Benefits, Marketing, and New Adverse Event Data

From Medscape Medical News
Zosia Chustecka

August 18, 2009 — The benefit of vaccinating against human papilloma virus (HPV) to prevent cervical cancer is questioned in an editorial in the Journal of the American Medical Association.

"The theory behind the vaccine is sound: if HPV infection can be prevented, cancer will not occur," writes editorialist Charlotte Haug, MD, PhD, from the Journal of the Norwegian Medical Association. "But in practice, the issue is more complex."

HPV is the most prevalent sexually transmitted infection, "but the virus does not appear to be very harmful because almost all HPV infections are cleared by the immune system," she explains. In a few women, the HPV infection persists, and some women may develop precancerous cervical lesions and eventually cancer, Dr. Haug writes, "but it is currently impossible to predict in which women this will occur."

The net benefit of the HPV vaccine to a woman is uncertain.
"The net benefit of the HPV vaccine to a woman is uncertain," Dr. Haug comments. "Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened [with cervical smear tests]."

Dr. Haug has spoken out against HPV vaccination previously. Last year, she urged caution over widespread vaccination programs in an editorial in the New England Journal of Medicine (2008;359:861–862), as reported by Medscape Oncology at the time.

This latest editorial accompanies 2 articles published in the same issue of JAMA. One of the articles is critical of the marketing of the HPV vaccine Gardasil (Merck & Co) in the United States, and the other details adverse events that have been reported with the vaccine since it was launched there in 2006.

Dr. Haug comments that, in view of the uncertain benefit from the HPV vaccine, "only a small risk of harmful effects from the vaccine" is acceptable.

The balance between the risks and benefits of HPV vaccination should rest only on medical and scientific evidence, Dr. Haug states.

However, she warns that this balance is "easily skewed" if other matters weigh in; for example, profit for a company or gains for physicians — issues that are explored in the article on marketing.

"The balance will also tilt if adverse events are not calculated correctly," Dr. Haug comments, and her editorial points out limitations of the system used for collecting adverse event reports, detailed in the other article.

Criticism of Gardasil Marketing

The article discussing the marketing of Gardasil in the United States was authored by Sheila Rothman, PhD, from sociomedical sciences and David Rothman, PhD, from social medicine, both at the Columbia College of Physicians and Surgeons, New York City.

Merck & Co promoted Gardasil primarily to "guard" against cervical cancer, rather than promoting it as a vaccine against HPV viruses or sexually transmitted diseases, the authors note. (The vaccine is active against 4 virus subtypes: HPV-6, HPV-11, HPV-16, and HPV-18; HPV-16 and HPV-18 are responsible for about 70% of cervical cancers worldwide and can also cause other anogenital cancers, whereas HPV-6 and HPV-11 are the most common causes of genital warts).

The marketing was so successful that in its first year, Gardasil was named in the industry journal Pharmaceutical Executive as the "brand of the year" for building a "market out of thin air," the authors point out.

"By making this vaccine's target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to all adolescents maximized, and the subpopulations most at risk practically ignored," they write.

"Rather than concentrating on populations in geographical areas with excess cervical cancer mortality, including African Americans in the South, Latinos along the Texas-Mexico border, and whites in Appalachia, the marketing campaign posited that every girl was at equal risk," Dr. Rothman and Dr. Rothman write.

"That these arguments were delivered by professional medical associations (PMAs) is cause for concern," they add. Merck & Co funded activities at the American College of Obstetricians and Gynecologists, the American Society for Colposcopy and Cervical Pathology, the Society for Gynecologic Oncologists, and the American College Health Association.

Among the company-funded activities were speaker lecture kits and education resource panels, with sample answers to patient questions, as well sample press releases and sample letters to parents and students explaining why they should have the vaccine. The authors detail specific instances in which the message being promulgated by PMAs was influenced by Merck & Co.

They were overtly exuberant in their hopefulness for vaccination.
Approached for comment, Diane Harper, MD, from the University of Missouri- Kansas City School of Medicine, Kansas City, Missouri, commented to Medscape Oncology that the PMAs "must confess to both their memberships and to the women whose health they serve that they were overtly exuberant in their hopefulness for vaccination and are guilty of presenting essentially only the information that Merck wanted presented."

She added, "In order to move on from this mistake, PMAs need to work with researcher clinicians to develop informed consents that include detailed risks and benefits of vaccination and screening." Dr. Harper also said that, now that serious adverse events have been documented, full disclosure of benefits and risks must be presented in all educational lectures.

Dr. Harper is professor and vice-chair, Obstetrics and Gynecology, Community and Family Medicine and Informatics and Personalized Medicine, and she conducted the phase 2 and phase 3 trials for Gardasil, authoring their publications. She has spoken out previously about the HPV vaccine and its marketing, and to Medscape Oncology, she expressed her concern over how the message about the need for regular cervical smears was overshadowed by "aggressive and inappropriate promotion of the vaccine."

Dr. Harper also commented that nowhere in any of the information about Gardasil has it been pointed out that in developed countries such as the United States, which have Papanicolaou (Pap) screening programs in place, the HPV vaccine will do little to decrease the already very small cancer rate but mostly will allow screening intervals to be extended safely.

Also approached by Medscape Oncology for comment, Maurie Markman, MD, professor of gynecologic medical oncology at the M.D. Anderson Cancer Center, Houston, Texas, questioned the credibility of the article on marketing, which is published as a "special communication." The authors are social scientists, he points out, and they "quote opinions from editorials as if they equate to facts." He emphasized the need to distinguish opinion from data and pointed out that there was no reference to any of the extensive peer-reviewed research articles on the HPV vaccine, which have accumulated data from thousands of patients.

Dr. Markman said he cannot comment directly about the claims made in the article, but added that he would be concerned if there were any truth to the idea that PMAs were not acting appropriately.

However, he strongly disagreed with one of the main points made in the article — the implied criticism of Merck & Co for promoting the vaccine for the prevention of cervical cancer. "I can't say how strongly I disagree with this — in fact, I am appalled," Dr. Markman told Medscape Oncology.

This vaccine does prevent cervical cancer, he emphasized, on the basis of all the data that are available, and "you cannot get better studies or a better strategy," he added. He acknowledges that there is no proof, as yet, but "it will take another 30 years or so to have that proof, and in the meantime, thousands of women will have died from cervical cancer."

This paper is opinion masquerading as data.
"This paper is opinion masquerading as data," Dr. Markman said, and he added that it was "potentially harmful, as it may make people who have already received the vaccine think that they made a mistake."

(In fact, Gardasil is licensed for the prevention of cancer and is only the second vaccine to have this indication, point out the authors from the other article, all of who are from either the Centers for Disease Control and Prevention [CDC] or the US Food and Drug Administration. The first was the hepatitis B vaccine against liver cancer, which is also marketed by Merck & Co. Dr. Rothman and Dr. Rothman suggest that the company learned valuable lessons in the marketing of this first vaccine, which helped it make the marketing of Gardasil so successful.)

Dr. Harper says that HPV vaccination has a role to play in the prevention of cervical cancer. However, she emphasizes the need for regular cervical smears and points out that even women who are vaccinated need to have regular smears, as otherwise they are still at risk for developing cancer. In addition, women who do not receive the vaccine can still protect themselves equally well by undergoing regular Pap tests.

HPV vaccination will prevent more cervical cancers in populations that do not have access to cervical cancer screening, she continued. Some developing countries without screening have an incidence of cervical cancer that is 5 to 12 times higher than that seen in the United States. Because the death rate from cervical cancer is so much higher in these populations, they may also tolerate a high rate of serious adverse events, including death, that have been associated with Gardasil, Dr. Harper commented.

However, in the United States, the usefulness of the vaccine is to increase the chance that a woman's next Pap test will be normal, Dr. Harper commented. Women must still have Pap tests after vaccination, and vaccination alone in the United States will only incrementally reduce the rate of cervical cancer, with its greatest benefit being to increase the screening interval between screens, and hence being a cost-saving device, she added. In fact, if women who are vaccinated stop going for Pap smears, the incidence rate for cervical cancer would increase, she said.

This is a sobering reality.
In the United States, the death rate from cervical cancer (3/100,000 women by statistics from the CDC) is at present similar to the rate of reported serious adverse events from Gardasil (3.4/100,000 doses distributed), Dr. Harper pointed out. "This is a sobering reality," she commented. "Would a parent accept such a rate of serious adverse events if the same cancer prevention can occur with continued Pap screening? Is there any acceptable level of risk of serious adverse events, including death, to prevent genital warts?" she asked, referring to one of the vaccine's other benefits.

Latest Adverse Event Data

The latest data on adverse events with Gardasil, published in the same issue of the journal, comes from the US Vaccine Adverse Event Reporting System (VAERS). In total, 12,424 adverse events after immunization were reported to in United States between June 2006 and December 2008, during which an estimated 23 million doses had been distributed (with a course of 3 doses per person recommended). This represents a reporting rate of 53.9 reports per 100,000 doses distributed.

Of these, 772 reports (6.2% of the total) were described as serious, including 32 reports of death.

The authors, headed by Barbara Slade, MD, from the CDC, comment that most of the rates of adverse events after immunization were "not greater than the background rates compared with other vaccines," with the exception of syncope and venous thromboembolic events, which were higher for the HPV vaccine.

These 2 events, syncope and thromboembolic events, were also reported for the HPV vaccine at a higher rate during this postlicensure period than they had been in clinical trials before marketing, the authors note.

Syncope or syncope vasovagal was mentioned in 1896 reports, and dizziness was mentioned in 1572 and nausea in 1164 reports. The reporting rate was 8.2 cases per 100,000 doses distributed. The majority (>90% – 95%) of these reports were classified as nonserious, the authors note. However, some of the reports mentioned falls, and some of these led to fractures, concussions, hemorrhages, and lacerations.

Venous thromboembolic events were mentioned in 56 reports, giving a reporting rate of 0.2 cases per 100,000 doses distributed. Of these, 19 cases involved pulmonary embolism, and 4 of these resulted in death.

Other adverse events included local site reactions (reporting rate, 7.5 cases per 100,000 doses distributed), headache (4.1 cases per 100,000 doses distributed), hypersensitivity reactions (3.1 cases per 100,000 doses distributed), urticaria (2.6 cases per 100,000 doses distributed), autoimmune reactions (0.2 cases per 100,000 doses distributed), Guillain-Barré syndrome (0.2 cases per 100,000 doses distributed), anaphylaxis (0.1 cases per 100,000 doses distributed), death (0.1 cases per 100,000 doses distributed), transverse myelitis (0.04 cases per 100,000 doses distributed), pancreatitis (0.04 cases per 100,000 doses distributed), and motor neuron disease (0.009).

Dr. Markman commented to Medscape Oncology that he saw nothing very new or surprising in this article and said that the surveillance shows that the vaccine is "generally quite safe."

Dr. Harper agreed that "HPV vaccination is generally safe for most girls or women," but she also commented that the adverse events reported are "quite significant."

However, Dr. Harper was critical of the system in which the reports were collected. "VAERS, by all accounts, is an inadequate reporting system whose function in this form is biased towards not showing causality," she said. The definition of the denominator (those exposed to the vaccine) is very broad — if this figure was divided by 3 for women who received all 3 doses, then the reporting rate would be increased, she added.

One cannot conclude that there is no association.
"If a statistical association is shown with this level of inaccuracy, then it is truly there," Dr. Harper commented. "But conversely, if no statistical association is seen, one cannot conclude that there is no association."

This point is also made by Dr. Haug in her editorial. She points out limitations of the VAERS reporting system, which the authors themselves emphasize by saying that the "data must be interpreted cautiously and cannot generally be used to infer causal association." Dr. Haug, however, adds that "these limitations work both ways: it is also difficult to conclude that a serious event is not caused by the vaccine."

Dr. Harper also highlighted another concern about the VAERS data. The majority of the reports (68%) were submitted by the manufacturer (Merck & Co), which the authors say compares with a rate of 40% from manufacturers of other vaccines. But for nearly 90% of these reports, Merck & Co would not provide the CDC with any follow-up information to investigate possible statistical causality link. As the authors pointed out in the article, this is unusual behavior for a pharmaceutical company, Dr. Harper comments. During the same reporting period, manufacturers reported only 14.5% of the adverse events associated with Menactra (a meningitis vaccine from sanofi pasteur) and only 7.5% of the adverse events associated with Adacel (a tetanus, diphtheria, and acellular pertussis booster vaccine from sanofi pasteur), she points out.

"Why would Merck make a concentrated effort at reporting nearly 70% of the adverse events for Gardasil if they did not want to control the information?" Dr. Harper comments. "Legislation needs to be enacted to require adverse events reported to pharma to include medical and contact information for potential follow-up by the CDC."

The editorialist and the authors of both articles have disclosed no relevant financial relationships. Dr. Harper reports having received honoraria from Merck & Co and GlaxoSmithKline, and institutions at which she has worked have received funding from both companies to support clinical trials on HPV vaccines. Dr. Markman reports having received grants for educational activities from Eli Lilly and serving as an advisor or consultant for Genentech, Celgene Corporation, Tibotec, and Boehringer Ingelheim.

JAMA. 2009;302:750–757, 795–796, 781–786.

Zosia Chustecka is news editor for Medscape Hematology-Oncology and prior news editor of, a Web site acquired by WebMD. A veteran medical journalist based in London, UK, she has won a prize from the British Medical Journalists Association and is a pharmacology graduate. She has written for a wide variety of publications aimed at the medical and related health professions. She can be contacted at

Zosia Chustecka has disclosed no relevant financial relationships.

Friday, August 14, 2009

Insufficient Nightly Sleep May Raise Risk of Diabetes

From Reuters Health Information

NEW YORK (Reuters Health) Aug 11 - An inadequate amount of nightly shut-eye, coupled with physical inactivity and overeating, may fuel the development of insulin resistance and reduced glucose tolerance, results of a new study indicate.

"Our findings suggest that combining the unhealthy aspects of the Westernized lifestyle with insufficient sleep may add to the risk of overweight and sedentary individuals to develop diabetes," Dr. Plamen Penev of the University of Chicago, Illinois, and a senior author of the study, told Reuters Health.

The findings stem from a randomized controlled crossover study involving 11 healthy but sedentary middle-aged men and women (mean BMI, 26.5) who reported sleeping 7.6 hours daily.

The study subjects participated in two controlled 2-week periods of sedentary living with ad libitum food intake and 5.5 or 8.5 hours in bed per night. As nightly time in bed changed from 8.5 to 5.5 hours, subjects went to bed later and got out of bed earlier and, as a result, mean sleep duration was reduced by 122 minutes a day. At the end of each intervention, the study subjects took oral and intravenous glucose challenge tests.

According to the report in the September issue of the Journal of Clinical Endocrinology and Metabolism, recurrent sleep restriction (5.5 hours) led to reduced oral glucose tolerance (p < 0.01) and insulin sensitivity (p < 0.03), and increased glucose effectiveness (p < 0.04).

Both sleep times (5.5 hours and 8.5 hours) led to comparable weight gain in these sedentary overeating adults.

Sleep restriction also led to a modest increase in 24-hour epinephrine and nighttime norepinephrine levels, whereas 24-hour cortisol and growth hormone concentrations remained unchanged.

"This is the first controlled experiment to document that recurrent bedtime restriction, which approximates short sleep times experienced by many people in everyday life, can result in decreased oral glucose tolerance," the researchers note in their report.

Additional studies, they say, are needed to study the impact of habitual sleep curtailment on glucose metabolism under normal "free-living" conditions.

"If confirmed by future larger studies, these results would indicate that a healthy lifestyle should include not only healthy eating habits and adequate amounts of physical activity, but also obtaining a sufficient amount of sleep," Dr. Penev said.

J Clin Endocrinol Metab 2009.

Sunday, August 9, 2009

Role of Alcohol in Liver Carcinogenesis

From Seminars in Liver Disease
Iain H. McKillop, Ph.D.; Laura W. Schrum, Ph.D.


Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and contributes significantly to cancer-related morbidity and mortality. Chronic alcohol consumption has long been associated with progressive liver disease toward the development of hepatic cirrhosis and the subsequent increased risk for developing HCC. In assessing the role of alcohol during hepatic disease, and as a carcinogen, many of the deleterious effects of alcohol can be attributed to alcohol metabolism in hepatocytes. In addition to the direct effects of alcohol/alcohol metabolism on hepatocyte transformation, increasing evidence indicates that other intrahepatic and systemic effects of alcohol are likely to play an equally significant role in the process of hepatic tumorigenesis.


Primary tumors of the liver represent the fifth most common type of cancer in the world and the third leading cause of cancer-related death.[1-3] Current estimates indicate that 500,000 to 1,000,000 new cases are diagnosed each year.[2-5] Of all primary tumors arising in the liver, ~80% are hepatocellular carcinomas (HCCs) that occur following transformation of cells of the hepatic parenchyma (hepatocytes).[1,6-8] Unlike many other common malignancies, HCC is unusual in that common familial patterns of development rarely exist. Rather, the incidence of HCC strongly correlates with exposure to one or more known risk factors, of which viral hepatitis infection, aflatoxin ingestion, and/or prolonged heavy alcohol consumption are the most common.[1,7,9-11] Each of these factors is considered significant for the development of underlying hepatic disease and progression to HCC, and in combination the effects are synergistic.[8,12-16]

The nature of these risk factors is such that distinct geographical patterns of HCC incidence exist.[2,3,6,16] The majority of HCC occur in countries located in Eastern Asia or sub-Saharan Africa. These countries exhibit the highest incidence of hepatitis B (HBV) and C (HCV) virus infection and risk of exposure to aflatoxins (naturally occurring mycotoxins from the Aspergillus species of fungi that typically colonize poorly stored grain, especially in regions of high humidity[16]). In these regions, the incidence of HCC is typically 20 to 50/100,000 and has been reported as high as 95.7/100,000 in regions of China.[3,4] In North America and Northern Europe, HCC has traditionally been considered a relatively rare cancer with an incidence rate of 1 to 2.5/100,000. Despite increases in HCC in the United States over the past two decades (due to increased HCV infection) alcohol-associated risk for HCC development is still considered the major risk factor.[9,17-20] In addition to the correlation with exposure to risk factors, demographic factors, such as age, sex, and ethnicity, have also been reported to influence susceptibility to HCC development.[2-4,7]

Regardless of the underlying etiology of HCC, the prognosis for those diagnosed is uniformly bleak; the annual number of estimated HCC-related deaths only marginally lagging behind that of new cases diagnosed.[4,7,21,22] At present, the best available treatments for HCC remain resection or ablation of the tumor mass or complete hepatic transplant.[22-28] However, the insidious nature of HCC coupled with the absence of reliable, early disease markers often leads to late detection, which, coupled with the underlying pathophysiology, limits the therapeutic options available.[15,22,24,29-31] Similarly, although complete liver transplant represents an alternative to resection, a lack of transplantable organs, underlying pathophysiology, and the incidence of metastases often limits this option.[27,30,32]

Saturday, August 8, 2009

Physical Activity May Benefit Patients With Nonalcoholic Fatty Liver Disease

Laurie Barclay, MD

July 21, 2009 — Physical activity may benefit patients with nonalcoholic fatty liver disease (NAFLD) independent of weight changes, according to the results of a study reported in the July issue of Hepatology.

"Nonalcoholic fatty liver disease, characterized by elevated liver enzymes, central obesity, and insulin resistance, is becoming increasingly prevalent," write Alexis St. George, PhD, from the University of Sydney and Westmead Hospital in Sydney, Australia. "The effects of changes in physical activity on the metabolic profile of this group have not been reported."

The investigators studied the effect at 3 months of a behavior change–based lifestyle intervention on physical activity and on the metabolic profile of 141 patients with NAFLD who were prospectively enrolled into either a low-intensity or moderate-intensity lifestyle intervention or to a control group. A validated reporting tool was used to measure physical activity, and the YMCA protocol on a cycle ergometer was used to determine physical fitness. All participants in the intervention groups received individualized counseling to increase physical activity.

Follow-up rate for the 3-month evaluation was 96%. Compared with participants in the control group, those in the moderate-intensity and low-intensity intervention groups were 9 times more likely to increase physical activity by at least 1 hour per week.

Compared with patients who were least active, those who improved or maintained their reported physical activity to more than 150 minutes per week and those who improved their objective levels of fitness had the greatest improvements in liver enzymes and other metabolic markers.

These benefits were independent of weight loss and were corroborated by an objective measure of fitness. With incremental increases in physical activity of more than 60 minutes per week, there was no dose-response effect on liver enzymes.

"Lifestyle counseling interventions are effective in improving physical activity behavior," the study authors write. "Maintaining or increasing physical activity provides health benefits for patients with fatty liver, independent of changes in weight."

Limitations of this study include lack of objective measures of change in physical activity.

"Improvements in physical activity can have positive effects on liver enzymes, insulin resistance, and other metabolic parameters in people with NAFLD," the study authors conclude. "This is a particularly important outcome, as liver fat has been shown to correlate independently with all risk factors of the metabolic syndrome....This study highlights the risk of remaining or becoming physically inactive (irrespective of whether weight loss is achieved) on metabolic parameters in patients with liver disease, and demonstrates the importance of physical activity for patients with NAFLD."

•Individual lifestyle counseling interventions are effective in improving physical activity behavior in patients with NAFLD. Participants in the moderate-intensity and low-intensity intervention groups were 9 times more likely than those in the control group to increase physical activity by at least 1 hour per week.
•Independent of weight changes, maintaining or increasing physical activity provides health benefits for patients with NAFLD, with improvements in liver enzymes and other metabolic markers. The underlying mechanism may be improved insulin resistance through positive changes in fatty acid metabolism in muscle.

Hepatology. 2009;50:68-76.

New Review Endorses CV Benefits of Fish Oil

From Heartwire
Lisa Nainggolan

August 3, 2009 (New Orleans, Louisiana) — A new review concludes that there is extensive evidence from three decades of research that fish oils, or more specifically the omega-3 polyunsaturated fatty acids (PUFAs) contained in them, are beneficial for everyone [1].

This includes healthy people as well as those with heart disease--including post-MI patients and those with heart failure, atherosclerosis, or atrial fibrillation--say Dr Carl J Lavie (Ochsner Medical Center, New Orleans, LA) and colleagues in their paper published online August 3, 2009 in the Journal of the American College of Cardiology.

"We reviewed everything that was published on omega-3 that was clinically important, and the major finding is that there are a tremendous amount of data to support the benefits of omega-3, not just as a nutritional supplement--people have known that for years--but evidence that it prevents and treats many aspects of cardiovascular disease," Lavie told heartwire .

The omega-3 data may not be as impressive or as plentiful as [statin data] but it should be 'promoted' to clinicians.
Lavie said he believes physicians are not as familiar with the omega-3 studies as they should be: "Clinicians know the findings of many statin trials even if they do not know all the details--they know that there are a ton of statin data. The omega-3 data may not be as impressive or as plentiful as this, but it should be 'promoted' to clinicians."

Omega-3 PUFA, says Lavie, "is a therapy that clinicians should be considering prescribing to their patients. Not just as something healthy but as something that may actually prevent the next event. In HF, it may prevent death or hospitalization and the same thing post-MI." He and his colleagues reiterate the advice of the AHA: that those with known CHD or HF eat four or five oily-fish meals per week or take the equivalent in omega-3 supplements; healthy people should consume around two fatty-fish meals per week or the same in supplements.

Most Data on EPA and DHA

In their review, Lavie and colleagues explain that most of the data on omega-3 have been obtained in trials using docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the long-chain fatty acids in this family. The most compelling evidence for cardiovascular benefits comes from four controlled trials of almost 40 000 participants randomized to receive EPA with or without DHA in studies of primary prevention, after MI, and most recently with HF, they note.

[Omega-3 PUFA] is a therapy that clinicians should be considering prescribing to their patients, as something that may actually prevent the next event.

They discuss the results for each specific cardiovascular condition in turn. For CHF, three large randomized trials--the Diet and Reinfarction Trial (DART), the Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico (GISSI)-Prevenzione, and the Japan EPA Lipid Intervention Study (JELIS)--have indicated that omega-3 PUFAs lower CV risk in both the primary- and secondary-prevention settings, they note.

Lavie elaborated to heartwire : "The benefit is different in different studies but can be as much as 30%." The effects are seen on total mortality, sudden death, CHD mortality, and cardiovascular mortality.

But there are some studies that have not shown favorable results, although there are generally methodological reasons for this, they say. However, they do flag the most recent study of post-MI patients, OMEGA, which suggests there may not be additional short-term benefit of omega-3 PUFAs in low-risk patients already receiving optimal modern therapy.

There is also evidence of benefit in atherosclerosis and in a wide range of arrhythmias, with the most significant effect and potential benefit seen in "the current epidemic" of AF, note the researchers. But more studies are needed to explore the effects of various doses of omega-3 PUFAs on the primary and secondary reduction of AF and to determine whether the benefits are caused by antiarrhythmic effects, benefits on autonomic tone, or even anti-inflammatory effects, they observe.

Benefit of Fish Oils Also Extend to HF

Recently, the potential benefits of omega-3 PUFAs "have been extended to the prevention and treatment of HF," say Lavie et al. Although the reduction in events was "only 8% to 9% in the recent GISSI-HF trial, which is not huge," Lavie admits, "when you think of HF, it's a very serious disorder, and in GISSI-HF, those patients were treated vigorously for their HF, so they were on good therapy, and adding just one [omega-3 PUFA] pill a day reduced deaths by between 8% and 9%, which is a pretty nice additional benefit."

But he and his colleagues say further studies are needed to determine the optimal dosing of omega-3 PUFA for different stages of HF and to investigate the underlying mechanisms for the benefits. However, in the meantime, omega-3 PUFA supplements "should join the short list of evidence-based life-prolonging therapies for HF."

[Omega-3 PUFA supplements] should join the short list of evidence-based life-prolonging therapies for HF.
They also discuss the data on omega-3 PUFAs in hyperlipidemia, noting that the FDA has approved one such supplement for the treatment of very high triglyceride levels.

And they note that more studies are needed to determine the optimal mix of DHA relative to EPA in various populations.

Finally, they state that this review does not focus on the plant-based precursor of EPA, alpha-linolenic acid (ALA), which is found in abundance in flaxseed and to a lesser extent in other plants. But they observe "the overall evidence is much weaker for ALA than for EPA and DHA."

Recommendations for Omega-3 Consumption

Mirroring recommendations from the AHA, European Society of Cardiology, and WHO, Lavie and colleagues recommend that healthy people consume at least 500 mg per day of EPA/DHA--equal to around two fatty-fish meals per week--and that those with known CHD or HF get 800 to 1000 mg per day EPA/DHA.

Asked by heartwire whether people should try to consume more fish or alternatively take supplements, Lavie says: "If somebody really were eating salmon and tuna and mackerel and sardines, and they were doing that several times a week, then they wouldn't need to be taking a supplement. But in the US, at least, very few people are going to eat the therapeutic doses of fatty fish."

Other good reasons to take supplements include the fact that they have usually had impurities, such as mercury, removed, he notes.

If people are trying to improve their consumption of oily fish, they could take supplements only on the days they were not eating such fish or every other day to try to get up to the recommended amount of omega-3 PUFAs, Lavie says.

But he warns that regimens that are too complex might result in underconsumption: "I would tend to think that most people are getting very little omega-3 PUFAs in the diet. There's no harm in taking extra--the only negative of extra is the calories. I don't think anyone thinks now that fish oil is doing any harm."