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<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_3278"
                     title="Investigation Reveals More Woes for Rosiglitazone"
                     score="0.014"
                     href="http://www.medpagetoday.com/Cardiology/Diabetes/tb/22050?impressionId=1284020653210"
                     
      &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on rosiglitazone (Avandia) -- a British advisory commission on drugs concluded that the product should be withdrawn from the market, according to an investigation conducted by &lt;em&gt;BMJ.&lt;/em&gt;&lt;/p&gt;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="0.013"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/22041?impressionId=1284020653210"
                     
      &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_3255"
                     title="ESC: In CABG, Two Grafts as Safe as One (CME/CE)"
                     score="0.012"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/22018?impressionId=1284020653210"
                     
      &lt;p&gt;STOCKHOLM  --  Using two internal mammary arteries instead of one for CABG does not increase mortality, MI, stroke, or revascularization, one-year results of the multicenter randomized Arterial Revascularization Trial (ART) showed.&lt;/p&gt;
&lt;p&gt;There was, however, an expected increase in sternal wound reconstruction from 0.6% of patients to 1.9%, David Taggart, MD, PhD, of John Radcliffe Hospital in Oxford, England, reported at the European Society of Cardiology congress here.&lt;/p&gt;
&lt;p&gt;&quot;ART shows that the routine use of bilateral internal mammary artery grafts is feasible in CABG patients,&quot; Taggart said.&lt;/p&gt;
&lt;p&gt;And, considering the low mortality rate of 2.3% and 2.5% in the two trial arms, &quot;ART also is a testament to the remarkable safety of contemporary coronary artery bypass grafting with one or two internal mammary arteries,&quot; he said.&lt;/p&gt;
&lt;p&gt;The trial will last 10 years to answer questions about the long-term mortality rate, costs, cost-effectiveness, and quality of life accompanying grafting with bilateral internal mammary arteries. Taggart said it should be completed in 2015.&lt;/p&gt;
&lt;p&gt;CABG remains the best therapy for severe coronary heart disease, as shown in the &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/15803&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/15803&quot; target=&quot;_blank&quot;&gt;SYNTAX trial&lt;/a&gt;, although it is limited by the high failure rate of vein grafts. About 50% to 75% of vein grafts fail within 10 years, Taggart said.&lt;/p&gt;
&lt;p&gt;Internal mammary artery grafts have much better survival with a 95% patency rate at 10 years. Studies have found that they last into the second and third decades of follow-up as well.&lt;/p&gt;
&lt;p&gt;Although a systematic review by Taggart&apos;s group found the use of two internal mammary arteries instead of one reduces mortality, bilateral grafting is not used much in clinical practice.&lt;/p&gt;
&lt;p&gt;Common reasons cited in the literature include the technical challenge, longer procedure time, an increase in early mortality and major morbidity, and sternal wound breakdown.&lt;/p&gt;
&lt;p&gt;ART is the first randomized trial to compare single and bilateral internal mammary artery grafting and involved 76 surgeons from 28 hospitals in seven countries.&lt;/p&gt;
&lt;p&gt;The researchers randomized 3,102 patients to one of the two techniques, with the option to use additional vein or artery grafts as needed. Roughly 82% of patients required at least three grafts.&lt;/p&gt;
&lt;p&gt;About 40% of the procedures were performed off-pump, which suggests a relatively high level of technical expertise, according to Taggart. The usual rate in Europe and the U.S. is less than 20%.&lt;/p&gt;
&lt;p&gt;The use of bilateral internal mammary arteries resulted in a longer operation (by 23 minutes) and more time spent on ventilation (by 105 minutes), in the intensive care unit (by three minutes), and in the hospital after surgery (by half a day). None of the differences, however, was statistically significant.&lt;/p&gt;
&lt;p&gt;Renal support, re-exploration for any cause, blood transfusion, and an intra-aortic balloon pump were required infrequently and at similar rates in both groups.&lt;/p&gt;
&lt;p&gt;One-month clinical outcomes were also similar in the two groups: &lt;ul&gt; &lt;li&gt;Mortality: 1.2% in both groups&lt;/li&gt; &lt;li&gt;Stroke: 1.2% with a single artery versus 1% with two arteries&lt;/li&gt; &lt;li&gt;MI: 1.5% versus 1.4%&lt;/li&gt; &lt;li&gt;Revascularization: 0.4% versus 0.7%&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;The absolute increase in the rate of sternal wound reconstruction with bilateral grafting was 1.3% (from 0.6% to 1.9%).&lt;/p&gt;
&lt;p&gt;The same patterns were seen at one year, with low rates of mortality, stroke, MI, and revascularization in each group.&lt;/p&gt;
&lt;p&gt;Pieter Kappetein, MD, PhD, of the Thoraxcenter in Rotterdam, the Netherlands, and a discussant at the presentation, said that ART is an important trial but that he has some concerns about treatment crossover and statistical power.&lt;/p&gt;
&lt;p&gt;He noted that 16.4% of patients in the bilateral group did not receive the assigned treatment, including 14% who received only one artery graft.&lt;/p&gt;
&lt;p&gt;Kappetein ran a computer simulation of the trial that accounted for this crossover and determined that the statistical power would be reduced from 90% to 47% by the end of the trial.&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;ART is funded by the U.K. Medical Research Council and the British Heart Foundation.&lt;/p&gt;&lt;p&gt;Taggart reported that he is the president of the Society for Cardiothoracic Surgery in Great Britain and Ireland and that he has served as a consultant to Medtronic, Novadaq, VGS, and Abbott.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_3248"
                     title="Increased Cardiac Events Seen With Sibutramine (CME/CE)"
                     score="0.012"
                     href="http://www.medpagetoday.com/Cardiology/MyocardialInfarction/tb/22008?impressionId=1284020653210"
                     
      &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_3244"
                     title="ESC: Pre-Procedure Statins May Cut MI Risk (CME/CE)"
                     score="0.012"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/22001?impressionId=1284020653210"
                     
      &lt;p&gt;STOCKHOLM  --  Statins delivered before invasive procedures appear to reduce the occurrence of cardiovascular events, a meta-analysis showed.&lt;/p&gt;
&lt;p&gt;In pooled data from 21 trials, giving statins before percutaneous coronary intervention (PCI), CABG, or noncardiac surgery resulted in a reduction in post-procedural MI (RR 0.57, 95% CI 0.46 to 0.70), according to Anthony Bavry, MD, MPH, of the University of Florida, in Gainesville.&lt;/p&gt;
&lt;p&gt;The reduction in MI was significant only after PCI (7.5% versus 13.3%) and noncardiac surgical procedures (3.5% versus 7.6%; &lt;em&gt;P&lt;/em&gt;&amp;lt;0.05 for both).&lt;/p&gt;
&lt;p&gt;Bavry reported the findings, which were also published online in the &lt;em&gt;Journal of the American College of Cardiology&lt;/em&gt;, at the European Society of Cardiology Congress here.&lt;/p&gt;
&lt;p&gt;&quot;The routine use of statins before invasive procedures should be considered,&quot; he and his colleagues wrote in their paper.&lt;/p&gt;
&lt;p&gt;Current guidelines for CABG, elective PCI, and acute coronary syndrome recommend statins only for use after such procedures.&lt;/p&gt;
&lt;p&gt;&quot;None of these guidelines specifically recommend the use of statins before invasive procedures for the express purpose of preventing periprocedural complications such as MI and atrial fibrillation,&quot; the researchers wrote. &quot;Our analysis adds strength to current recommendations and potentially expands the use of these agents before PCI and surgical procedures.&quot;&lt;/p&gt;
&lt;p&gt;Bavry and his colleagues conducted a meta-analysis of 21 randomized controlled trials involving 4,805 patients in which statins were administered one to seven days before PCI, CABG, or noncardiac surgery. The control interventions included placebo, usual care, or lower doses of statins.&lt;/p&gt;
&lt;p&gt;PCI was usually elective, although four studies included patients with acute coronary syndrome.&lt;/p&gt;
&lt;p&gt;Most of the patients had never received statins before, but one study included patients on long-term statin therapy.&lt;/p&gt;
&lt;p&gt;The reduction in post-procedural MI observed with pre-procedural statins was strengthened when only placebo-controlled trials were considered (RR 0.43).&lt;/p&gt;
&lt;p&gt;Pre-procedural statins also reduced post-CABG atrial fibrillation (19% versus 37%; RR 0.54, 95% CI 0.43 to 0.68), although they did not affect all-cause mortality (RR 0.66, 95% CI 0.37 to 1.17).&lt;/p&gt;
&lt;p&gt;The researchers noted in their paper that the optimal dose, statin type, and timing were unclear.&lt;/p&gt;
&lt;p&gt;&quot;Only a dedicated trial specifically exploring the relationship of dose and type of statin therapy before invasive procedures can answer this question,&quot; they wrote.&lt;/p&gt;
&lt;p&gt;The studies included in the meta-analysis did not report adverse effects, so the researchers could not perform a formal analysis of potential drawbacks to pre-procedural statin use. They noted, however, that statins have a well-established safety record.&lt;/p&gt;
&lt;p&gt;In an accompanying editorial, Kim Eagle, MD, and Vineet Chopra, MD, of the University of Michigan, in Ann Arbor, wrote that the benefits of statins in this context likely came from their pleiotropic effects  --  the enhancement of endothelial function, stabilization of vulnerable plaque, and reduction in adhesion molecules and circulating biomarkers.&lt;/p&gt;
&lt;p&gt;&quot;Therefore, before endothelial injury during coronary procedures, statin treatment likely mitigates the inflammatory cascade by decreasing vascular reactivity and stabilizing plaque, both at the site of intervention and at other &apos;vulnerable&apos; lesions,&quot; they wrote.&lt;/p&gt;
&lt;p&gt;Eagle and Chopra said that it appears statins should be routinely given to patients before undergoing coronary procedures, although questions remain regarding optimal dose and type of statin and whether such a strategy&lt;strong&gt; &lt;/strong&gt;would work in all patient subgroups. Also, they said the possibility of adverse effects still needs to be explored.&lt;/p&gt;
&lt;p&gt;Nevertheless, they wrote, &quot;Given the strong biological rationale and the sum of the clinical data, no patient should undergo coronary procedures without statin therapy unless clear contraindications exist. Indeed, it is time to consider a new indication for an old friend.&quot;&lt;/p&gt;
&lt;p&gt;Bavry and his colleagues acknowledged some limitations of the analysis, including the use of a control group mixing placebo, usual care, and lower statin doses, the fact that some of the surgical trials did not include MI as a primary outcome, and the lack of information on some of the methodological characteristics of the trials, like blinding or randomization technique.&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 supported by an unrestricted grant from the Florida Heart Research Institute.&lt;/p&gt;&lt;p&gt;The study authors and the editorialists reported that they did not have any conflicts of interest.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
</recommendedContent>