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<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_3278"
                     title="Investigation Reveals More Woes for Rosiglitazone"
                     score="0.015"
                     href="http://www.medpagetoday.com/Cardiology/Diabetes/tb/22050?impressionId=1283756576266"
                     
      &lt;p&gt;On July 15 -- a day after the FDA completed &lt;a href=&quot;http://www.medpagetoday.com/ProductAlert/Prescriptions/21161&quot; mce_href=&quot;http://www.medpagetoday.com/ProductAlert/Prescriptions/21161&quot; target=&quot;_blank&quot;&gt;two days of hearings&lt;/a&gt; on rosiglitazone (Avandia) -- a British advisory commission on drugs concluded that the product should be withdrawn from the market, according to an investigation conducted by &lt;em&gt;BMJ.&lt;/em&gt;&lt;/p&gt;
&lt;p&gt;The Commission on Human Medicines&apos; opinion was passed on to the U.K.&apos;s regulatory authority, the Medicines and Healthcare Products Regulatory Agency (MHRA), which has now told &lt;em&gt;BMJ &lt;/em&gt; that rosiglitazone &quot;no longer has a place on the U.K. market.&quot; The evidence for increased risk of cardiovascular events outweighs any potential benefit, according to an MHRA statement given to &lt;em&gt;BMJ&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Yet six weeks after the commission submitted its recommendations on rosiglitazone, the drug is still on the market in Britain. The MHRA has yet to share its negative assessment of the drug with either physicians or patients.&lt;/p&gt;
&lt;p&gt;Instead, on July 26 it sent providers a &quot;dear doctor&quot; letter suggesting merely that it would be wise to consider alternatives to rosiglitazone, wrote Deborah Cohen, features editor at &lt;em&gt;BMJ. &lt;/em&gt;&lt;/p&gt;
&lt;p&gt;The &lt;em&gt;BMJ &lt;/em&gt;investigation was detailed in a feature article published online today and also the subject of a BBC news report. The report appears to be the first confirmation that U.K. regulators are ready to withdraw the drug from the market.&lt;/p&gt;
&lt;p&gt;The lengthy article reveals no new information about the FDA&apos;s handling of rosiglitazone from its approval through two subsequent safety reviews, but it does give insight into the machinations of the approval process in Europe.&lt;/p&gt;
&lt;p&gt;For example, the European Medicines Agency initially rejected rosiglitazone, only to come back a year later in 2000 to approve the drug. As a condition of that approval, the EMA ordered a post-marketing study to verify the safety of the drug. That study, called RECORD, was an open-label trial that has been roundly criticized on both sides of the Atlantic for its poor design.&lt;/p&gt;
&lt;p&gt;Cohen quoted numerous sources who all pointed to the influence of the drug maker, GlaxoSmithKline (SmithKlineBeecham during the initial approval process), as the reason that the EMA reversed itself on rosiglitazone.&lt;/p&gt;
&lt;p&gt;&quot;According to Edwin Gale, a diabetologist and adviser to European regulators, in the years before rosiglitazone&apos;s approval diabetologists were also putting pressure on the regulators and clamouring to use this new class of drug. Some of this clamour was fuelled by pharmaceutical analysts touting its blockbuster potential, which at the time they said was crucial to Smithkline Beecham&apos;s future growth,&quot; Cohen wrote.&lt;/p&gt;
&lt;p&gt;Cohen also pointed out that the EMA does not publicly release names of members of advisory panels who review drugs for the EMA. By comparison, she wrote, the FDA process, often the subject of criticism in the U.S., is open and transparent.&lt;/p&gt;
&lt;p&gt;In a editorial that accompanied Cohen&apos;s article, Richard Lehman, PhD, of the University of Oxford, John S. Yudkin, MD, of University College in London, and Harlan Krumholz, MD, of Yale University, said there is plenty of blame to pass around in the rosiglitazone saga.&lt;/p&gt;
&lt;p&gt;Back in 1999, clinicians were &quot;strongly disposed to welcome a new drug for type 2 diabetes, and it was vigorously promoted to a receptive market,&quot; they wrote.&lt;/p&gt;
&lt;p&gt;&quot;Our mistake then -- and we have yet to put it right -- was that we did not demand better proof before we embarked on mass medication of a large group of patients who looked to us for advice and treatment.&quot;&lt;/p&gt;
&lt;p&gt;In a commentary, which was also published with the Cohen article, Nick Freemantle, PhD, of the University of Birmingham in England, argued that much of the controversy surrounding the thiazolidinediones can be laid at the feet of poor trial design -- so poor that critical questions were not answered.&lt;/p&gt;
&lt;p&gt;For example, regulators have been willing to permit high rates of loss to follow-up, especially in trials that rely on surrogate endpoints, a position that he contended &quot;makes no sense.&quot;&lt;/p&gt;
&lt;p&gt;And &quot;even when trials examine serious morbidity and mortality, loss to follow-up remains a problem. The RECORD trial, conducted to examine the safety of rosiglitazone and sponsored by GlaxoSmithKline in the UK, failed to follow-up survival in 127 participants (2.9%),&quot; he wrote. The loss to follow-up in RECORD meant that one could conclude that rosiglitazone &quot;was associated with either an increase or a decrease in mortality given different assumptions on the fate of those lost to follow-up.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;Cohen declared no competing interests.&lt;/p&gt;&lt;p&gt;Lehman, Yudkin and Krumholz all declared they had received no support for the submitted work; no financial relationships with any organization that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.&lt;/p&gt;&lt;p&gt;Freemantle declared no support for the submitted work, but he disclosed that he has received funding for research and travel and consulting fees from Novo Nordisk, Sanofi-Aventis, Johnson &amp;amp; Johnson, and Eli Lilly.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_3268"
                     title="ESC: Stockholm Take Home Message -- Watch the &apos;Not&apos; Warfarins"
                     score="0.014"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/22041?impressionId=1283756576266"
                     
      &lt;p&gt;STOCKHOLM  --  An investigational antiplatelet  --  ticagrelor (Brilinta)  --  emerged as a big winner from the five-day long European Society of Cardiology congress, but the buzz here focused instead on a trio of investigational oral anticoagulants  --  dabigatran, rivaroxaban, and apixaban.&lt;/p&gt;
&lt;p&gt;The buzz killer was margarine  --  more precisely omega-3 fatty acid fortified margarine  --  which flopped in the much anticipated &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21921&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21921&quot; target=&quot;_blank&quot;&gt;ALPHA-OMEGA &lt;/a&gt;trial of a possible role for n-3s in secondary prevention of heart attacks and strokes.&lt;/p&gt;
&lt;p&gt;Even simultaneous publication in the &lt;em&gt;New England Journal of Medicine&lt;/em&gt; failed to brighten the obvious disappointment of lead investigator Daan Kromhout, MPH, PhD, of Wageningen University in the Netherlands, and the true believers in the benefit of fish oil.&lt;/p&gt;
&lt;p&gt;In the end, Kromhout was left with the whole fish, which he said was still more beneficial than the sum of its parts.&lt;/p&gt;
&lt;p&gt;&lt;strong&gt;No End to Good News &lt;/strong&gt;&lt;/p&gt;
&lt;p&gt;By contrast, it was a &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21956&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21956&quot; target=&quot;_blank&quot;&gt;subset analysis&lt;/a&gt; from the landmark PLATO trial reported at ESC last year that bumped ticagrelor to prominence this year too.&lt;/p&gt;
&lt;p&gt;The primary findings from PLATO found ticagrelor to be superior to clopidogrel in preventing MI, and it also demonstrated a mortality benefit compared with clopidogrel.&lt;/p&gt;
&lt;p&gt;On top of those results, which were hailed as a &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/15752&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/15752&quot; target=&quot;_blank&quot;&gt;game-changer when first reported&lt;/a&gt;, the new genetic substudy found that there was no need for genetic testing to determine the antiplatelet response of ticagrelor.&lt;/p&gt;
&lt;p&gt;That stands in stark contrast with clopidogrel, which now carries an FDA black box warning about resistance.&lt;/p&gt;
&lt;p&gt;R. Scott Wright, MD, of the Mayo Clinic in Rochester, Minn., told &lt;em&gt;MedPage Today&lt;/em&gt; that clopidogrel resistance is not an insignificant concern since &quot;one in four people carries the allele&quot; that makes them poor metabolizers of clopidogrel. &quot;That is a concern as we treat patients.&quot;&lt;/p&gt;
&lt;p&gt;But it got even better for ticagrelor when the ESC included the drug as a Class 1B recommendation in its new &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21962?pfc=101&amp;amp;spc=224&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21962?pfc=101&amp;amp;spc=224&quot; target=&quot;_blank&quot;&gt;revascularization guidelines&lt;/a&gt; issued at the congress  --  even though the drug in not yet approved in any country.&lt;/p&gt;
&lt;p&gt;Although including an unapproved drug in guidelines is a &quot;novel&quot; approach, Sidney Smith, MD, of the University of North Carolina at Chapel Hill, said it was not an outrageous one.&lt;/p&gt;
&lt;p&gt;Moreover, he said he sympathized with the dilemma faced by the ESC guideline committee, which was faced with the task of issuing relevant guidelines for 52 member nations with healthcare systems that range from state-of-the-art to technologically challenged.&lt;/p&gt;
&lt;p&gt;And the ESC has an out that the U.S. guideline committees don&apos;t have  --  the final guidelines from the ESC are &quot;not really recommendations, but more a statement based on science,&quot; Smith said. Unlike the U.S. where third-party payers regularly use guidelines as performance measures, that is not the case in ESC member nations, he said.&lt;/p&gt;
&lt;p&gt;Moreover, Smith and others contacted by &lt;em&gt;MedPage Today&lt;/em&gt; noted that this could all be academic by the end of September, since ticagrelor is expected to receive approval in Europe and in the U.S. before the end of the month.&lt;/p&gt;
&lt;p&gt;&lt;strong&gt;The &quot;Not&quot; Warfarins&lt;/strong&gt;&lt;/p&gt;
&lt;p&gt;Getting a pass on genetic testing, combined with an ESC guideline recommendation, make the ticagrelor story a tough one to top, but that is what happened with the release of a bumper crop of data that portend a sea change for anticoagulant therapy.&lt;/p&gt;
&lt;p&gt;Warfarin (Coumadin) was introduced more than half a century ago, and for much of that time researchers have been seeking a safe and effective alternative.&lt;/p&gt;
&lt;p&gt;Ximelagatran was the first Factor Xa inhibitor investigated in clinical trials, and it was almost universally hailed as a breakthrough for anticoagulant therapy  --  until a liver signal emerged and the drug was linked to hepatoxicity in about 10% of patients. In 2005, the FDA refused to approve the drug for safety reasons.&lt;/p&gt;
&lt;p&gt;Researchers returned to the bench and came up with three alternatives, all of which have now posted positive results in clinical trials: rivaroxaban (Xarelto) and apixaban  --  both Factor Xa inhibitors  --  and dabigatran (Pradaxa), a direct thrombin inhibitor.&lt;/p&gt;
&lt;p&gt;Rivaroxaban is already approved in Europe for prevention of deep vein thrombosis, but despite receiving an advisory panel recommendation for approval, it has been stalled at the FDA since early 2009 when the agency told Boehringer Ingelheim that it wanted more information.&lt;/p&gt;
&lt;p&gt;The information offered here came from an open trial of 3,400 patients with symptomatic DVT randomized to rivaroxaban or standard therapy (enoxaparin followed by warfarin).&lt;/p&gt;
&lt;p&gt;The study, &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21976&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21976&quot; target=&quot;_blank&quot;&gt;EINSTEIN DVT&lt;/a&gt;, was a noninferiority trial and the drug provided ample evidence that it works as well and as safely as standard therapy. There were 36 recurrent DVTs in the rivaroxaban arm versus 51 in the controls.&lt;/p&gt;
&lt;p&gt;And there was no evidence of hepatoxicity nor was there evidence of increased cardiovascular events. Major bleeding, likewise, was not increased.&lt;/p&gt;
&lt;p&gt;It&apos;s unlikely that the DVT data will be enough to persuade the FDA to grant approval, but in November results of ROCKET-AF, a rivaroxaban study in atrial fibrillation, will be reported at the American Heart Association scientific sessions, and there is speculation that a positive result in that trial could tip the regulatory scale in favor of approval.&lt;/p&gt;
&lt;p&gt;The other Factor Xa inhibitor, apixaban, was compared with aspirin in the &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21974&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21974&quot; target=&quot;_blank&quot;&gt;AVERROES&lt;/a&gt; trial, which was stopped early when the study&apos;s data monitoring board determined that the study treatment was associated with a significant benefit.&lt;/p&gt;
&lt;p&gt;The trial enrolled roughly 5,500 high-risk patients with an average age of 70.&lt;/p&gt;
&lt;p&gt;And the benefit was undeniable  --  a 54% reduction in stroke or systemic embolic event.&lt;/p&gt;
&lt;p&gt;And with apixaban, as with rivaroxaban, there was no significant increase in bleeding and no sign of hepatotoxicity.&lt;/p&gt;
&lt;p&gt;The third investigational agent, dabigatran, is a direct thrombin inhibitor. It was studied in atrial fibrillation patients and found to be superior to warfarin for reducing stroke in a trial called RE-LY . The principal findings of that study were reported at the ESC congress last year.&lt;/p&gt;
&lt;p&gt;This year, the RE-LY investigators followed up with a &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21975?pfc=101&amp;amp;spc=224&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/21975?pfc=101&amp;amp;spc=224&quot; target=&quot;_blank&quot;&gt;post-hoc analysis&lt;/a&gt; aimed at demonstrating that dabigatran can do the job when warfarin can&apos;t  --  not because of problems with warfarin efficacy, but rather because of problems with the way warfarin patients are managed. That is, in centers that didn&apos;t do a good job of INR control, dabigatran looked even better.&lt;/p&gt;
&lt;p&gt;But Clyde Yancy, MD, of Baylor University Medical Center in Dallas, told &lt;em&gt;MedPage Today&lt;/em&gt; that he was a little concerned about the message in the RE-LY post-hoc analysis.&lt;/p&gt;
&lt;p&gt;&quot;Rather than suggesting that centers that do a poor job of INR management should switch to a different drug, I think we should be promoting better INR control at all centers,&quot; he said.&lt;/p&gt;
&lt;p&gt;As these three agents inch closer to market, Yancy and others told &lt;em&gt;MedPage Today&lt;/em&gt; that they are concerned about how clinicians will use the new agents.&lt;/p&gt;
&lt;p&gt;Yancy pointed out that these three  --  and other oral anticoagulants that are now in phase III trials  --  are being studied for specific indications, &quot;but as soon as one is approved, I&apos;m concerned that it will simply be used wholesale as a substitute for warfarin.&quot;&lt;/p&gt;
&lt;p&gt;Fausto Pinto, MD, PhD, of the University of Lisbon in Portugal, agreed that there was a potential for off-label use of these agents. &quot;And that is why it will be necessary for us [ESC] to work with other groups such as the AHA and the ACC to develop guidelines for use of these compounds,&quot; he said. (Pinto served as chair of the ESC program committee, so he was instrumental in selecting AVERROES and EINSTEIN DVT as Hot Line trials here.)&lt;/p&gt;
&lt;p&gt;Elliott Antman, MD, of Harvard Medical School, agreed that off-label use would be a real concern if the FDA approves one or more of these agents.&lt;/p&gt;
&lt;p&gt;He noted that rivaroxaban is currently approved in the Netherlands for DVT, &quot;but I hear that they are already using it there for atrial fibrillation.&quot;&lt;/p&gt;
&lt;p&gt;Yancy noted that wholesale substitution of the new drugs for warfarin would also raise economic concerns since the new agents are likely to be much more expensive than warfarin, which is available as a generic.&lt;/p&gt;
&lt;p&gt;&quot;The other issue is post-market safety data,&quot; Yancy said. &quot;We have decades of warfarin safety data; we have no idea what will happen to people after two, three or 10 years on a Factor Xa inhibitor or a direct thrombin inhibitor.&quot;&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20100101_19_3248"
                     title="Increased Cardiac Events Seen With Sibutramine (CME/CE)"
                     score="0.013"
                     href="http://www.medpagetoday.com/Cardiology/MyocardialInfarction/tb/22008?impressionId=1283756576266"
                     
      &lt;p&gt;Overweight patients with cardiovascular risks who took the weight-loss drug sibutramine (Meridia) had a 16% increased likelihood of experiencing a cardiac event, a large randomized trial found.&lt;/p&gt;
&lt;p&gt;The overall hazard ratio for a fatal or nonfatal cardiovascular event was 1.16 (95% CI 1.03 to 1.31, &lt;em&gt;P&lt;/em&gt;=0.02) among patients receiving sibutramine compared with those receiving placebo, according to W. Philip T. James, MD, of the London School of Hygiene and Tropical Medicine, and colleagues.&lt;/p&gt;
&lt;p&gt;Specifically, the hazard ratio for nonfatal myocardial infarction was 1.28 (95% CI 1.04 to 1.57, &lt;em&gt;P&lt;/em&gt;=0.02), and the hazard ratio for nonfatal stroke was 1.36 (95% CI 1.04 to 1.77, &lt;em&gt;P&lt;/em&gt;=0.03), the researchers reported in the Sept. 1 &lt;em&gt;New England Journal of Medicine&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;A &lt;a href=&quot;http://www.medpagetoday.com/ProductAlert/Prescriptions/17147&quot; mce_href=&quot;http://www.medpagetoday.com/ProductAlert/Prescriptions/17147&quot; target=&quot;_blank&quot;&gt;preliminary analysis&lt;/a&gt;&lt;a target=&quot;_blank&quot;&gt; &lt;/a&gt;of data from the SCOUT (Sibutramine Cardiovascular Outcomes) trial previously suggested this increased risk, and the FDA required stronger &lt;a href=&quot;http://www.medpagetoday.com/ProductAlert/DevicesandVaccines/18088&quot; mce_href=&quot;http://www.medpagetoday.com/ProductAlert/DevicesandVaccines/18088&quot; target=&quot;_blank&quot;&gt;cautionary language&lt;/a&gt; in the drug&apos;s labeling.&lt;/p&gt;
&lt;p&gt;The final publication has now confirmed it, with James and colleagues stating, &quot;On the basis of these results, sibutramine should continue to be excluded from use in patients with preexisting cardiovascular disease.&quot;&lt;/p&gt;
&lt;p&gt;Sibutramine is a norepinephrine and serotonin reuptake inhibitor that has sympathomimetic effects and therefore can increase blood pressure and pulse rate. Because even small increases in blood pressure and pulse rate are associated with an increased likelihood of cardiovascular events, the SCOUT investigators wanted to determine the drug&apos;s long-term cardiovascular risk.&lt;/p&gt;
&lt;p&gt;They enrolled 9,804 obese or overweight patients who were at least 55 years old. All participants had a history of cardiovascular disease and/or type 2 diabetes.&lt;/p&gt;
&lt;p&gt;The study consisted of a six-week lead-in period in which all patients received 10 mg/day of sibutramine, after which they were randomized to the active treatment or placebo.&lt;/p&gt;
&lt;p&gt;Mean duration of treatment was 3.4 years, and slightly more than 40% of patients in both groups discontinued treatment.&lt;/p&gt;
&lt;p&gt;All patients also participated in individualized diet and exercise programs designed for cardioprotection, and blood pressure decreased in both groups during the lead-in phase.&lt;/p&gt;
&lt;p&gt;However, after randomization the sibutramine group had small but consistent increases in blood pressure and resting pulse rate.&lt;/p&gt;
&lt;p&gt;While there were increases in the nonfatal events, there was no between-group difference for cardiovascular death (HR 0.99, 95% CI 0.82 to 1.19, &lt;em&gt;P&lt;/em&gt;=0.90) or death from any cause (HR 1.04, 95% CI 0.91 to 1.20, &lt;em&gt;P&lt;/em&gt;=0.54).&lt;/p&gt;
&lt;p&gt;The investigators noted that fewer than half of the events they had expected at the outset of the trial occurred during its six-year overall duration, and that during that time the incidence of cardiovascular disease decreased in most of Europe and Australia, where most of the study centers were located.&lt;/p&gt;
&lt;p&gt;They also pointed out that the study was limited by the lack of a true placebo group, the inclusion of only high-risk patients, and the longer-than-recommended time of treatment (one to two years).&lt;/p&gt;
&lt;p&gt;In an accompanying editorial, Gregory D. Curfman, MD, executive editor of &lt;em&gt;NEJM, &lt;/em&gt;and colleagues commented that the cardiovascular risk findings of SCOUT need to be considered in light of the potential clinical benefit of the weight loss seen among those on sibutramine.&lt;/p&gt;
&lt;p&gt;Patients on the drug lost 4.3 kg at one year, but regained about 0.5 kg thereafter, for a net loss of less than 4 kg from a baseline average weight of 96 kg.&lt;/p&gt;
&lt;p&gt;In January 2010, after the preliminary analysis of the SCOUT data, the European Medicines Agency suspended marketing authorizations for sibutramine-containing medications throughout the European Union.&lt;/p&gt;
&lt;p&gt;On Sept. 15, an advisory committee of the FDA plans to meet to decide whether additional regulatory action should be taken here as well.&lt;/p&gt;
&lt;p&gt;Curfman and colleagues concluded, &quot;Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome cardiovascular risk profile, and a plausible mechanism to explain the cardiovascular risk, it is difficult to discern a credible rationale for keeping this medication on the market.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was funded by Abbott Laboratories.&lt;/p&gt;&lt;p&gt;Several of the SCOUT investigators reported serving on advisory boards and receiving fees from multiple pharmaceutical companies, including Abbott, sanofi-aventis, Merck, Johnson &amp;amp; Johnson, Novo Nordisk, GlaxoSmithKline, and Boehringer Ingelheim.&lt;/p&gt;&lt;p&gt;In addition, three of the investigtors were full-time employees of Abbott and had equity interest in the company.&lt;/p&gt;&lt;p&gt;Aside from Curfman&apos;s position with &lt;em&gt;NEJM&lt;/em&gt;, the editorialists had no disclosures.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_3235"
                     title="ESC: New Anticoagulants Create Buzz"
                     score="0.013"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/21988?impressionId=1283756576266"
                     
      &lt;p&gt;STOCKHOLM  --  After years of waiting for an alternative to warfarin (Coumadin), there are now three wending their way through the regulatory process. In this exclusive InFocus video report we review each of these new agents.&lt;/p&gt;
&lt;p&gt;Two factor Xa inhibitors  --  apixiban and rivaroxaban  --  along with the direct thrombin inhibitor, dabigatran, are competing to be the first warfarin alternatives to gain FDA approval and that is good news according to Fausto Pinto, MD, PhD, the program chair at this year&apos;s European Society of Cardiology congress, where the new agents were featured in a number of sessions.&lt;/p&gt;
&lt;p&gt;Ralph L. Sacco, MD, president of the American Heart Association agreed that the news was good, but noted that, as the agents come to market, developing new guidelines for their use will be a critical task for the AHA and the ESC.&lt;/p&gt;
&lt;p&gt;Pinto and Sacco discussed the potential benefits  --  and challenges  --  of the new agents with &lt;em&gt;MedPage Today&lt;/em&gt; executive editor Peggy Peck.&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20100101_19_3191"
                     title="ESC: It&apos;s Not Butter and It&apos;s Not Better (CME/CE)"
                     score="0.012"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/21921?impressionId=1283756576266"
                     
      STOCKHOLM  --  Adding margarine enriched with omega-3 fatty acids as a dietary intervention did not prevent second heart attacks in older men and women at risk for worsening heart disease, researchers said here.&lt;br&gt;
&lt;br&gt;The study results are doubly disappointing since the margarine intervention did initially reduce events, but by 30 months the evidence of that benefit had disappeared, said Daan Kromhout, MPH, PhD, of Wageningen University in the Netherlands.&lt;br&gt;
&lt;br&gt;After more than 40 months, consumption of the omega-3 fatty acid fortified margarines &quot;had no effect on the rate of major cardiovascular events,&quot; he reported at a Hot Line session today at the European Society of Cardiology meeting. The findings were simultaneously published online by the &lt;em&gt;New England Journal of Medicine.&lt;/em&gt;&lt;/p&gt;
&lt;p&gt;The ALPHA-OMEGA trial randomized 4,837 MI survivors, 60 to 80 years old, to margarine supplemented with a combination of eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA), or with 2 grams of the plant-derived fatty acid alpha-linolenic acid (ALA), or a third supplemented with all three versus a placebo margarine.&lt;/p&gt;
&lt;p&gt;The primary endpoint was the combined rate of fatal and non-fatal cardiovascular events and cardiac interventions.&lt;/p&gt;
&lt;p&gt;Neither EPA-DHA nor ALA reduced this endpoint, the researchers reported (hazard ratio with EPA-DHA, 1.01; 95% confidence interval 0.87 to 1.17, &lt;em&gt;P &lt;/em&gt;=0.93).&lt;/p&gt;
&lt;p&gt;A prespecified subgroup analysis in women found that use of the ALA-fortified margarine reduced the rate of cardiovascular events compared with placebo or with the EPA-DHA margarine, but the difference failed to reach statistical significance (HR 0.73, 95% CI 0.51 to 1.03, &lt;em&gt;P&lt;/em&gt;=0.07).&lt;/p&gt;
&lt;p&gt;Alfred Bove, MD, of Temple University in Philadelphia, said the findings surprised him &quot;because most of the data on omega-3 fatty acids come from epidemiologic studies and those were positive.&quot;&lt;/p&gt;
&lt;p&gt;He likened the situation to hormone therapy, which had been widely recommended to reduce cardiovascular risk in postmenopausal women based on data from epidemiologic studies.&lt;/p&gt;
&lt;p&gt;That hypothesis was initially questioned when a randomized controlled trial (Estrogen/Progestin Replacement Study [HERS]) linked hormones to increased risk of events. The HERS finding was confirmed in the landmark Women&apos;s Health Initiative trial in which ischemic events were more common among women randomized to estrogen/progestin.&lt;/p&gt;
&lt;p&gt;R. Scott Wright, MD, of the Mayo Clinic in Rochester, Minn., told &lt;em&gt;MedPage Today&lt;/em&gt; that the trial design was faulty, in that margarine was a bad choice of vehicle for omega-3 fatty acids.&lt;/p&gt;
&lt;p&gt;&quot;It needs to be combined with another food  --  bread,&quot; he said. &quot;So this not a good option for Americans because it would mean eating more bread, which is likely to lead to weight gain and bread is high in sodium, so blood pressure would be a factor.&quot;&lt;/p&gt;
&lt;p&gt;Wright noted that the ALPHA-OMEGA study did not include information on weight or blood pressure, so he considered the findings at best incomplete.&lt;/p&gt;
&lt;p&gt;All of the patients received &quot;state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy,&quot; according to Kromhout and colleagues, in addition to margarine, and it may have been that optimal therapy that limited the potential for an omega-3 benefit.&lt;/p&gt;
&lt;p&gt;Statin therapy, along with other improvements in cardiovascular care, means &quot;a beneficial effect of low doses of EPA-DHA is difficult to prove,&quot; the authors wrote.&lt;/p&gt;
&lt;p&gt;Wright said he wasn&apos;t persuaded by that explanation since, even after optimal therapy, there is about a 30% residual risk. &quot;There is plenty of room to show a benefit,&quot; he declared.&lt;/p&gt;
&lt;p&gt;Most of the patients in ALPHA-OMEGA were men (78%) and 24% were obese, but they differed from the typical high-risk American in at least one way: at baseline they consumed about three times more fish than does the typical American, a median of 15 grams a day.&lt;/p&gt;
&lt;p&gt;According to a report from the Environmental Protection Agency, average fish consumption in the U.S. works out to 4.58 &amp;#177; 0.42 grams a day.&lt;/p&gt;
&lt;p&gt;The authors conducted a post hoc exploratory analysis in patients with diabetes, finding significant reductions in events among patients in the EPA-DHA group. But the authors noted that &quot;[the] results with respect to patients with diabetes are only hypothesis-generating and do not permit definitive conclusions to be drawn.&quot;&lt;/p&gt;
&lt;p&gt;Bove, a former president of the American College of Cardiology, added that the results from the subset analysis in diabetics was reassuring, since patients with diabetes and elevated triglycerides are the patients that &quot;we have believed would be most likely to benefit&quot; from omega-3 fatty acids.&lt;/p&gt;
&lt;p&gt;The margarines used in the trial were supplied by Unilever, an international maker of food and consumer goods, and included the well-known &quot;I Can&apos;t Believe It&apos;s Not Butter,&quot; which contains 420 mg of ALA per serving.&lt;/p&gt;

&lt;p&gt;In a statement released after the ALPHA-OMEGA trial findings were presented, Unilever said the &quot;study outcome for EPA and DHA is surprising considering the weight of evidence published to date. This could be the result of methodological issues such as the relatively low daily dosage compared with previous studies or the fact that in this study serious cardiovascular events were much lower than in studies performed in the past. This is probably due to extensive drug treatment that is nowadays applied. The finding needs further study, but given the totality of evidence does not immediately impact the current advice on fish and fish oil consumption for prevention of cardiovascular disease.&quot;&lt;/p&gt;

&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The trial was supported by the Netherlands Heart Foundation, the National Institutes of Health, and Unilever.&lt;/p&gt;&lt;p&gt;Kromhout reported that his institution received grant support form Unilever to cover distribution of the trial margarines to patients. His institution also received a grant from the Product Board for Margarine Fats and Oils to support research on polyunsaturated fats and cardiovascular diseases done by a PhD student.&lt;/p&gt;&lt;p&gt;Bove said he had no financial conflicts.&lt;/p&gt;&lt;p&gt;Wright said he consults for Roche and Genentech and conducts trial work for 3M/Littman.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
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