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A fish tale with merit: Omega-3 PUFAs underrated for heart failure; for prevention
 
 
  October 14, 2009 | Steve Stiles, http://www.theheart.org
 
Boston, MA - More than one speaker at the Heart Failure Society of America 2009 Scientific Meeting last month plaintively commented on the shortage of new heart-failure agents to show a solid clinical benefit when given on top of beta blockers, ACE inhibitors, and other "standard medications." Was at least part of the answer residing a couple miles away in Boston Harbor, awaiting a Poisson distribution?
 
In one room on the last day of the conference, four invited faculty members meticulously made the case for an already-available substance as an example of the kind of agent the others were looking for. Their message: omega-3 polyunsaturated fatty acids (PUFAs), usually derived from fish oil, garner far less attention as a heart-failure therapy than they deserve, given the wealth of laboratory and clinical evidence supporting a treatment effect.
 
That applies to prevention of heart failure, with observational studies suggesting a benefit especially in some high-risk groups, as well as to treatment of existing heart failure based on a large randomized, placebo-controlled trial.
 
Dr Mihai Gheorghiade (Northwestern University Feinberg School of Medicine, Chicago, IL) touted omega-3 PUFAs potentially as a part of treatment strategy aimed at optimizing myocardial energy metabolism for the majority of heart-failure patients who have "viable but dysfunctional" myocardium.
 
"We've been concentrating on patients with end-stage heart failure; we're focusing on inotropes and vasodilators but paying no attention to what happens within the heart muscle," he said. "I think with having study after study [of potential heart-failure drugs] being negative, we have to study nontraditional ways to improve the terrible postdischarge outcomes."
 
Omega-3 supplementation "is just one example, and a very good one, but we don't talk about it," Gheorghiade said. "The bulk of evidence suggests that this intervention is relatively simple, well accepted by the patient, with no side effects, and has an effect-although modest-on cardiovascular mortality and heart failure."
 
Supporting omega-3s as a heart-failure therapy are dozens of clinical and laboratory studies defining their many physiologic effects that could potentially play a role in preventing or treating the disorder. As outlined at the meeting by Gheorghiade and the others, they include vasodilator effects with blood-pressure and heart-rate reduction, reduced oxygen consumption, neurohormone modulation, antiapoptotic and myocardial sodium- and calcium-channel effects, and prevention or slowing of myocardial fibrosis. There are very few drugs that you can put on top of beta blockers, ACE inhibitors, and spironolactone and actually reduce cardiovascular death by 10% in heart failure. That's a very profound benefit.
 
The most solid randomized-trial evidence for such a role comes from the recent Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico Heart Failure (GISSI-HF) trial [1], in which nearly 7000 patients with chronic NYHA class 2-4 heart failure received either omega-3 PUFAs from fish oil at 1 g/day or placebo.
 
As reported by heartwire when the study results were reported last year, the group getting omega-3s showed a 9% drop in all-cause mortality and an 8% decline in the composite of death or cardiovascular hospitalization over a mean of about four years. Both co-primary-end-point outcomes were significant. (In a separate randomization of the patients to either 10-mg rosuvastatin [Crestor, AstraZeneca] or placebo, the statin had no significant effect on either end point [2].)
 
An exceptionally large proportion of GISSI-HF patients had been on ACE inhibitors or angiotensin-receptor blockers, beta blockers, and spironolactone, and still there was a significant omega-3 effect. "It's tough to get incremental benefit for hard end points in maximally treated patients," observed Dr Dariush Mozaffarian (Harvard University, Boston, MA). He pointed out that for the prespecified secondary end point of cardiovascular death, the difference associated with omega-3 therapy reached 10% (p=0.045).
 
"There are very few drugs that you can put on top of beta blockers, ACE inhibitors, and spironolactone and actually reduce cardiovascular death by 10% in heart failure. That's a very profound benefit," Mozaffarian said, adding that it's similar to the CV-death reduction seen with implantable defibrillator therapy.
 
"Tickling the bottom of the curve . . . "
 
Both Dr William C Stanley (University of Maryland, Baltimore) and Dr David R Van Wagoner (Cleveland Clinic, OH) proposed that fish oil might pack more punch as a heart-failure therapy at higher omega-3 PUFA dosage levels.
 
"If there were this level of data for a prescription medication that still had a lot of time on its patent life, you would see a very large investment in looking to fully define the benefits in a variety of clinical settings."
 
At least one observational study of dietary fish and heart-failure prevention showed a dose-response effect (p=0.009) when consumption levels of various types of fish were converted to omega-3 PUFA intake [3]. A number of potential omega-3 physiologic effects require multigram doses, according to Stanley. "A gram a day is low, I think. With that I'd say you're tickling the bottom of the curve for most effects of fish oil that you'd want for [treating] heart failure. You probably need three or four times that dose for an optimal benefit," he said to heartwire.
 
"It's possible that a gram a day just isn't sufficient," agreed Van Wagoner. "The dose levels that are used for lowering triglycerides may also be more appropriate for [achieving] antiarrhythmic and anti-heart-failure effects," he said.
 
Still, the data are the data. "GISSI-HF did show a benefit, but it was a very modest benefit that required adjustment of the p values," Dr Gregg C Fonarow (University of California, Los Angeles) told heartwire. "And because of that, and because there isn't another large confirmatory trial, there's still an opening for further trials for confirmation."
 
"Based on the data we have so far, I personally do not prescribe fish-oil supplementation for prevention of heart failure-the data are mixed."
 
In his editorial on the occasion of the publication of the GISSI-HF results [4], Fonarow wrote that omega-3 PUFAs "should join the short list of evidence-based life-prolonging therapies for heart failure."
 
To heartwire he said, "This is a therapy that deserves consideration as a treatment for patients with chronic heart failure, but there certainly aren't enough data for a mandate, or a performance measure, or a class 1 indication in the guidelines." A second large, confirmatory trial could potentially change that, according to Fonarow.
 
Indeed, another large randomized test of whether omega-3 PUFA therapy can improve clinical outcomes in patients with heart failure is noteworthy by its absence.
 
"If there were this level of data for a prescription medication that still had a lot of time on its patent life, you would see a very large investment in looking to fully define the benefits in a variety of clinical settings, for both prevention and treatment of heart failure, as well as prevention and treatment of atherosclerotic cardiovascular disease," Fonarow said.
 
"Further data may not be forthcoming." But based on what's known now, given the GISSI-HF data and "a drug that was safe, well tolerated, and incremental to other standard-of-care therapies, it may be reasonable to utilize omega-3 fatty-acid supplementation, with a GISSI-like regimen and dosing, for patients with heart failure."
 
Prevention of heart failure and other events
 
Actually, the evidence base for omega-3 PUFAs is less solid for the prevention of heart failure than for treating heart failure. "We just have observational data for prevention of heart failure, but for prevention of cardiovascular events in individuals who've had them, we have the GISSI Prevenzione trial," Fonarow said [5]. "There have been other trials where the results have been less impressive. Still, when you pool all that data together, there is some suggestion that, overall, cardiovascular events are modestly reduced."
 
"To our knowledge, this would be the first true primary-prevention trial of the omega-3s for which participants are selected on the basis of age alone and not risk factors."
 
In the 1999 placebo-controlled GISSI-Prevenzione trial, more than 11 000 post-MI patients were randomized to receive 1 g/day omega-3 PUFAs, vitamin E, both, or neither on top of standard medical therapy and lifestyle-modification "advice," for three and a half years. The omega-3s on their own were associated with a significant 15% drop in the primary end point of death, nonfatal MI, and stroke, a 20% decrease in all-cause mortality, and a 30% decline in cardiovascular mortality driven by a steep reduction in sudden cardiac death.
 
For more strictly defined primary prevention of heart failure, there is the 2005 study from Mozaffarian et al [3] that followed more than 4000 adults at least 65 years old and initially free of heart failure for their intake of "tuna or other broiled or baked fish, but not fried fish" as documented on food-frequency questionnaires. Over the 12 years of follow-up, that kind of fish consumption was inversely associated with adjusted hazard ratios for incident heart failure. The risk reduction climbed significantly from 20% with up to two servings per week to 31% with twice that intake and 32% with at least five servings per week (estimated omega-3 PUFA levels with five servings, >1000 mg/day), compared with less than one serving per month.
 
In contrast, a similar analysis from the population-based Rotterdam Study published this month found no evidence that fish intake can prevent new heart failure [6]. About 5300 people initially without heart failure were followed for an average of 11.4 years. Fish consumption as documented on questionnaires by type of fish, method of cooking, and other parameters was converted to estimated daily intake of omega-3 PUFAs.
 
As reported by Dr S Coosje Dijkstra (Wageningen University, the Netherlands) and colleagues in the October 2009 European Journal of Heart Failure, none of the hazard ratios for incident heart failure for intake quintiles 2 (omega-3 PUFA at 28 mg/day to 61 mg/day) through 5 (>212 mg/day) showed a significant decrease in risk relative to the first intake quintile even after adjustment for age, sex, total dietary fat intake, total caloric intake, smoking, body-mass index, education, and other factors.
 
"There still are important questions that remain about optimal dosing and formulation. . . . Would a 2000-mg/day dose be more effective? A different ratio of EPA to DHA?"
 
The Rotterdam analysis appears to conflict with the 2005 report's findings, but "I think it's a nonresult," Van Wagoner, who is not a coauthor on either study, said to heartwire. In Rotterdam, "the fish consumption was not high enough to test the idea that eating fish is going to have a beneficial effect." The median omega-3 PUFA intake among persons in the highest intake quintile was 313 mg/day, far below the gram-a-day level of the GISSI trials.
 
"Based on the data we have so far, I personally do not prescribe fish-oil supplementation for prevention of heart failure-the data are mixed," Fonarow said. "However, in patients with coronary artery disease, for those at high risk, for prevention of cardiovascular events, the data are also suggestive and integrated into the secondary-prevention guidelines with a recommendation to consider supplementation."
 
Further insights may be in the offing from an upcoming primary-prevention trial that will randomize a planned 20 000 people to receive vitamin-D supplements at 2000 IU/day (with omega-3 placebo), 1 g/day of omega-3 PUFA (with vitamin D placebo), both supplements, or neither (double placebo) [7]. The Vitamin D and Omega-3 Trial (VITAL) will enroll women older than 65 and men older than 60 and follow them for five years, starting in early 2010. Plans are for at least 25% of the population to be African American, according to the study's cochair Dr JoAnn E Manson (Brigham and Women's Hospital, Boston, MA).
 
"To our knowledge, this would be the first true primary-prevention trial of the omega-3s for which participants are selected on the basis of age alone and not risk factors," Manson told heartwire. Its cardiovascular primary end point (the study is also exploring possible cancer-prevention effects) is a composite of nonfatal MI, nonfatal stroke, or vascular death.
 
Even if we had that second trial, we'd still be likely to see a very slow uptake.
 
Manson points out that the Japan EPA Lipid Intervention Study (JELIS) [8] wasn't actually a primary-prevention trial. As previously reported by heartwire, JELIS saw a 19% risk reduction in a composite of fatal or nonfatal MI, unstable angina, sudden death, or need for revascularization over 4.6 years in >18 000 patients on low-dose statins who were randomized to omega-3 PUFA or placebo. It was a mixed primary- and secondary-prevention population. The benefit for the primary end point was driven by a 25% drop in risk for unstable angina.
 
VITAL ancillary studies are in the works to look at any changes in ventricular function over time in a 1000-person echocardiographic subcohort and at heart-failure end points in the full population, Manson said. "We're hoping that by the end of five full years of treatment and follow-up that we'll have some indication of the effects on clinical heart-failure events."
 
Other planned ancillary studies will track development of hypertension, diabetes, infections, autoimmune diseases, and other disorders, she said.
 
"Even if we had that second trial . . . "
 
Fonarow said he's been prescribing omega-3s at 1000 mg/day for patients with established heart failure. "If the patient has prescription drug access, then we'll use the version that is available as a branded prescription medication, but if not, we'll consider supplements."
 
The GISSI trials used the fish-oil-based product Lovaza (GlaxoSmithKline), which, in the US at least, is labeled for lowering high triglycerides at a dosage of 4 g/day of mixed omega-3 PUFAs. It, like most fish-oil-derived capsules, is primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in about a 5-to-4 ratio, plus smaller amounts of other fatty acids. Alone among the major omega-3 PUFA trials in cardiovascular disease, JELIS used a highly purified EPA-only formulation at 1800 mg/day that was aimed at dyslipidemia.
 
But for heart failure, "there still are important questions that remain about optimal dosing and formulation," observed Fonarow. "Would a 2000-mg/day dose be more effective? A different ratio of EPA to DHA?"
 
Even if another heart-failure trial of omega-3 therapy were conducted, "even if we had that second trial, we'd still be likely to see a very slow uptake," he said, pointing to experience with the hydralazine and isosorbide dinitrate combination (BiDil, formerly owned and marketed by NitroMed) that showed a profound effect in African Americans with heart failure in the A-HeFT trial. "We had a 43% reduction in all-cause mortality incremental to other standard-of-care therapies." But despite a class 1 recommendation for it in the guidelines, registry data show "less than one in 10 perfect candidates for treatment being treated," according to Fonarow. Aldosterone antagonists for moderate to severe heart failure are following a similar pattern.
 
"So there is very slow translation of even our strongest clinical-trial evidence into routine clinical practice."
 
Gheorghiade reports being a consultant for or receiving honoraria from Abbott, Astellas, Bayer, AstraZeneca, Corthera, Debiopharm, Errekappa, Terapeutici, EKR Therapeutics, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Nile, Novartis, Otsuka, PeriCor, PDL BioPharma, Scios/Johnson & Johnson, Solvay Pharmaceuticals, and Sigman-Tau. Mozaffarian reports receiving research grants or speaker fees from GlaxoSmithKline, Pronova, Searle, Sigma Tau, Aramark, the Institute of Food Technologists, and the International Life Sciences Institute. According to Stanley, "the University of Maryland has a patent pending for use of docosahexaenoic acid for the treatment of heart failure." Van Wagoner reports having been a consultant or an advisory board member for Boehringer-Ingelheim, Proctor & Gamble, and Wyeth. Fonarow reports receiving speaker fees or honoraria from or being a consultant or on an advisory board for Abbott, AstraZeneca, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, and Schering-Plough.
 
 
 
 
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