February 27, 2012 — New data from the Framingham Offspring Study cohort suggest that higher dietary intake of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may help protect the aging brain.
Dr. Zaldy S. Tan
Results showed that lower red blood cell (RBC) levels of DHA and EPA in late middle age were associated with smaller brain volumes and a "vascular" pattern of cognitive impairment, even in persons free of clinical dementia.
"People with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about 2 years of structural brain aging," study author Zaldy S. Tan, MD, MPH, from the Easton Center for Alzheimer's Disease Research and the Division of Geriatrics, University of California, Los Angeles, comments in a written statement.
This study, Dr. Tan told Medscape Medical News, "adds to the current body of evidence on the beneficial health effects of omega-3 fatty acids." However, he said, it is premature to make clinical recommendations solely based on this study. "It needs to be validated in other populations and extended to clinical trials, which may be able to provide more specific recommendations."
"With that said, people who are already consuming fish as part of a balanced diet can take stock in the promising findings of this study that omega-3 fatty acid may benefit not only their heart but their brain as well," Dr. Tan said.
The findings were published in the February 28 issue of Neurology.
Building on Prior Studies
Some previous population-based studies have suggested an association between higher intake of fatty fish and a lower risk of dementia, as well as other health outcomes. As previously reported by Medscape Medical News, in the original Framingham Study cohort, individuals with the highest DHA levels had a 47% reduction in all-cause dementia and a 39% lower risk of developing Alzheimer's disease.
"We wanted to see whether RBC omega-3 fatty acid levels (which is more reflective of actual tissue exposure to these nutrients) [have] an effect on structural and cognitive brain aging in the late–middle age, nondemented offspring of the original Framingham Study cohort," Dr. Tan said. "To our knowledge, this is the first study that utilized RBC omega-3 fatty acid levels to markers of brain aging," he added.
The researchers related RBC DHA and EPA levels in 1575 dementia-free men and women (mean age, 67 years) to performance on standard cognitive tests and to volumetric brain magnetic resonance imaging scans.
After adjusting for age, sex, and time interval, those patients with RBC DHA levels in the lowest quartile (Q1, <3.9%) had significantly lower total brain volume (P = .009) and significantly greater white matter hyperintensity volume (P = .049) compared with those patients with higher RBC DHA levels (Q2 - Q4, >3.9%). The association persisted for total brain volume in the fully adjusted multivariable analysis (P = .019).
Participants with lower DHA and DHA+EPA levels (Q1 vs Q2 - Q4) also scored lower on tests of visual memory (P = .008), executive function (P = .004), and abstract thinking (P = .004) in the model, adjusting for age, sex, and time interval. The results remained significant in multivariable analysis.
Results Supportive Not Definitive
"These findings add some favorable data to the question regarding whether polyunsaturated fatty acids (PUFAs), like DHA and omega-3 fatty acids, could be related to better brain health," Rachelle S. Doody, MD, PhD, who was not involved in the study, told Medscape Medical News. Dr. Doody is Effie Marie Cain Chair in Alzheimer's Disease Research and director, Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas.
She said the key strengths of the study are a well-defined population and careful measurements of the PUFAs. "Key limitations are that this study does not investigate causality; you would have to follow people longitudinally to determine whether their levels of these PUFA's influence their brain health or their likelihood of developing dementia over time," Dr. Doody said.
"These findings cannot support definitive actions on the part of prescribing physicians or patients; that is, they do not provide proof that eating fish or taking supplements is beneficial, and they did not address safety," Dr. Doody added.
The study was supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute contract and by the National Institute on Aging. Dr. Tan has received research support from the National Institutes of Health and the National Institute on Aging. A coinvestigator on the study is employed by Health Diagnostic Laboratory Inc, which offers blood omega-3 testing, and is the owner of OmegaQuant LLC, a company that offers blood fatty acid testing. A complete list of author disclosures can be found with the original article. Dr. Doody has disclosed no relevant financial relationships.
Missing Data Lead FDA Panel to Vote Against Rivaroxaban for ACS May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine. Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data. We Don't Know What We're Missing Based on the ATLAS ACS 2 results, FDA reviewer Dr Karen Hicks recommended approval of rivaroxaban for the requested indications except all-cause mortality. However, another FDA reviewer, Dr Thomas Marciniak, was adamant that the trial results are not interpretable because about 12% of the patients had incomplete follow-up, far higher than the 1% to 1.5% differences in the end-point rates between rivaroxaban and placebo. A total of 1294 subjects discontinued the trial prematurely, and the company was only able to contact 183, of which 177 were confirmed to be alive. Because of the patient dropouts, the company adopted a "modified intention-to-treat analysis," whereby patients were observed for 30 days after randomization or the global end date for the trial, instead of observing all the patients until the end of the trial as the FDA originally suggested. Marciniak criticized the sponsor's efforts to follow the patients and said that three patient deaths not counted in the modified intention-to-treat analysis may just be the "tip of the iceberg." Because the percentage of patients whose ultimate vital status remains unknown is much greater than the reported differences in mortality rates, the claimed mortality benefits are not reliable. The majority of the panel sided with Marciniak. For example, Dr Sanjay Kaul (University of California, Los Angeles) voted "no" because "there was enough uncertainty in the quality and robustness of the data that dissuaded me from voting yes. . . . The 'missingness' of the data doesn't invalidate it, but it certainly makes it hard to infer [the conclusion]." Dr Steven Nissen (Cleveland Clinic, OH) said that the decision to use the modified intention-to-treat analysis had a "profound impact" on the interpretability of the data. "It's saying we don't care what happens after 30 days, [and] that colored the trial in ways we couldn't recover from." Given the risk of major bleeding, "I want to see better evidence that this strategy of adding an Xa inhibitor or a direct thrombin inhibitor or something else to a good antiplatelet agent is robustly better for the patient," Nissen said. He recommends that the companies run a new trial of the 2.5 twice-daily dose of rivaroxaban using a strict intention-to-treat approach, but, he said, "I don't expect the death benefit to be too robust." Several panelists said they were concerned that the patients who dropped out of the trial were disproportionately likely to have a bleeding event, which led them to quit the trial, or a "protopathic" event, as statistician Dr Scott Emerson (University of Washington, Seattle) put it. "We're worried that an impending event is what is changing their behavior. We see that all the time in clinical trials--that regularly measured end points do not pick up [all of] the events," he said. He said that since the company was only able to contact 183 of the over 1200 patients who dropped out, it is possible that the dropouts skew the outcomes comparison of the trial. "Differential event rates after dropout are the number-one thing we're afraid of, so you have to explore it" in a statistical sensitivity analysis of the potential impact of these unknown outcomes. "It would not surprise me if, at the end of the day, these data did not hold up under a proper sensitivity analysis," he said. "What I want to know is, among the people who had events, how differential was the follow-up, but I can tell you by just looking at it, there was a very slightly different amount of follow-up of the people in the treatment arm. But I don't know whether everyone in the treatment arm was cured and they were trekking in the Himalayas and everyone in the placebo arm went home to die. I don't know that that's not the case." Dr Maury Krantz (University of Colorado, Denver) voted in favor of approval but said he does not know how rivaroxaban would perform in general clinical practice, especially when used with aspirin and clopidogrel. "I felt very much torn by this. This isn't a simple paradigm shift. It means going to triple therapy, which is really a three-headed monster in many ways. I think that what you're going to see in practice, if this is not done carefully with the proper labeling and secondary studies, is really dramatic magnification of bleeding and perhaps minimization of the efficacy benefit."
May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting , the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel , or ticlopidine . Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the ri...
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