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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=1283759817001"
                     
      &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on rosiglitazone (Avandia) -- a British advisory commission on drugs concluded that the product should be withdrawn from the market, according to an investigation conducted by &lt;em&gt;BMJ.&lt;/em&gt;&lt;/p&gt;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=1283759817001"
                     
      &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_3265"
                     title="PTSD May Be Risk Factor for Dementia (CME/CE)"
                     score="0.013"
                     href="http://www.medpagetoday.com/PublicHealthPolicy/MilitaryMedicine/tb/22032?impressionId=1283759817001"
                     
      &lt;p&gt;Older veterans with a history of post-traumatic stress disorder (PTSD) are at increased risk for developing dementia, even if they had not been wounded in battle, researchers found.&lt;/p&gt;
&lt;p&gt;Their risk of dementia was double that of veterans who did not have PTSD, including those who had received the Purple Heart, according to Mark E. Kunik, MD, MPH, of the Michael DeBakey VA Medical Center in Houston, and colleagues.&lt;/p&gt;
&lt;p&gt;But although the study sample was large  --  more than 10,000 former service members  --  it would be premature to conclude that PTSD causes dementia, the researchers cautioned in their study published online in the &lt;em&gt;Journal of the American Geriatrics Society&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;&quot;It could be that cognitive impairment in PTSD is an early marker of dementia, PTSD is an independent risk factor for dementia, or PTSD and dementia share a common risk factor such as low cognitive reserves,&quot; Kunik and colleagues wrote.&lt;/p&gt;
&lt;p&gt;&quot;It is essential to determine whether risk of dementia can be reduced by treating PTSD effectively,&quot; they added. &quot;This could have enormous implications for veterans returning from [Iraq].&quot;&lt;/p&gt;
&lt;p&gt;Similar results were published &lt;a href=&quot;http://www.medpagetoday.com/Psychiatry/GeneralPsychiatry/20528&quot; mce_href=&quot;http://www.medpagetoday.com/Psychiatry/GeneralPsychiatry/20528&quot; target=&quot;_blank&quot;&gt;earlier this year&lt;/a&gt; from another VA system-based data analysis.&lt;/p&gt;
&lt;p&gt;In an editorial accompanying the&lt;em&gt; &lt;/em&gt;study report, Soo Borson, MD, of the University of Washington in Seattle, pointed out that it may be exactly those veterans whose future clinical course will answer the questions raised by Kunik and colleagues.&lt;/p&gt;
&lt;p&gt;&quot;Long-term prospective follow-up of veterans returning from Iraq and Afghanistan will eventually tell us more, if funding for continued detailed tracking of these cohorts can be sustained,&quot; Borson wrote.&lt;/p&gt;
&lt;p&gt;Some existing data sets may be helpful, but these are smaller and many participants may have died already, she noted.&lt;/p&gt;
&lt;p&gt;For the current study, Kunik and colleagues examined records of veterans seen at least twice from 1997 to 1999 in VA centers in the South Central U.S., who had either a diagnosis of PTSD at that time or had received the Purple Heart for combat-related wounds or injuries.&lt;/p&gt;
&lt;p&gt;They categorized these patients into three groups: 3,660 with PTSD and no Purple Heart; 153 with PTSD and a Purple Heart; and 1,503 with a Purple Heart and no PTSD.&lt;/p&gt;
&lt;p&gt;For comparison, Kunik and colleagues also identified 5,165 patients seen in the same VA centers from 1997 to 1999 who did not have PTSD or Purple Hearts.&lt;/p&gt;
&lt;p&gt;Medical records covering outpatient visits through September 2008 were included in the analysis. Dementia either at baseline or diagnosed during follow-up was identified from ICD-9 codes in their records.&lt;/p&gt;
&lt;p&gt;After adjusting for variables including age, sex, race, comorbidities, and number of primary care and mental health visits during the baseline period, Kunik and colleagues calculated the following odds ratios for new-onset dementia during follow-up:&lt;ul&gt; &lt;li&gt;PTSD without Purple Heart versus no PTSD or Purple Heart, 2.2 (95% CI 1.8 to 2.6, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001)&lt;/li&gt; &lt;li&gt;PTSD without Purple Heart versus Purple Heart and no PTSD, 1.7 (95% CI 1.4 to 2.2, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001)&lt;/li&gt; &lt;li&gt;PTSD with Purple Heart versus no PTSD and no Purple Heart, 1.4 (95% CI 0.7 to 2.7, &lt;em&gt;P&lt;/em&gt;=0.09)&lt;/li&gt; &lt;li&gt;PTSD with Purple Heart versus PTSD without Purple Heart, 0.6 (95% CI 0.4 to 1.1, &lt;em&gt;P&lt;/em&gt;=0.13)&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;Other comparisons yielded odds ratios close to 1 and not even approaching statistical significance.&lt;/p&gt;
&lt;p&gt;Findings were similar when the researchers looked at dementia prevalence, including patients with dementia during the baseline period as well as those receiving the diagnosis for the first time during follow-up.&lt;/p&gt;
&lt;p&gt;Overall, the patients with PTSD without a Purple Heart developed dementia during follow-up at an unadjusted rate of 9.5%, compared with rates of 4.0% to 6.8% for the other groups (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;Prevalence rates were also higher in the PTSD-without-Purple-Heart group, at 11.1% versus 4.5% to 7.2% in the other patients.&lt;/p&gt;
&lt;p&gt;Limitations to the analysis included the reliance on administrative records, lack of data on some potential confounders such as apolipoprotein E genotype, uncertain racial status for some patients, and the use of Purple Heart medals exclusively to indicate wounds and injuries.&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 a unit of the VA health system.&lt;/p&gt;&lt;p&gt;Study authors and the editorialist declared that they had no financial conflicts of interest. Several were VA employees.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_3212"
                     title="Genetic Variations Linked to ALS Risk (CME/CE)"
                     score="0.013"
                     href="http://www.medpagetoday.com/Neurology/GeneralNeurology/tb/21960?impressionId=1283759817001"
                     
      &lt;p&gt;Two separate studies have found genetic variations that may be associated with an increased risk of amyotrophic lateral sclerosis (ALS) located on chromosomes previously linked to ALS  --  particularly chromosome nine.&lt;/p&gt;
&lt;p&gt;The studies, published online in &lt;em&gt;The Lancet Neurology&lt;/em&gt;, used genome-wide association techniques to look for single-letter DNA changes that were associated with the disease, commonly called &quot;Lou Gehrig&apos;s disease&quot; after the famed New York Yankees slugger who died of ALS.&lt;/p&gt;
&lt;p&gt;Neither study found a gene that actually confers susceptibility to the disorder  --  but the findings &quot;emphasize the importance&quot; of chromosome nine, previously associated with ALS, according to Guy Rouleau, MD, PhD, and colleagues at the University of Montreal, who were not involved in either study.&lt;/p&gt;
&lt;p&gt;On the other hand, they wrote in an accompanying commentary, neither study replicated several genetic variants previously reported to be associated with greater ALS risk. The absence of replication probably means the earlier findings were false positives or were population-specific, Rouleau and colleagues wrote.&lt;/p&gt;
&lt;p&gt;&quot;These studies show the challenges in interpreting (genome-wide association study) results,&quot; Rouleau and colleagues commented, adding that replication of the current findings is an important next step.&lt;/p&gt;
&lt;p&gt;In the first &lt;em&gt;Lancet Neurology&lt;/em&gt; study, Bryan Traynor, MD, of the National Institute on Aging, and colleagues, analyzed single nucleotide polymorphisms (SNPs) in samples from 405 Finnish patients with ALS and 497 controls  --  as well as from 40 people with two copies of a variant on chromosome 21 known to increase the risk of the disorder, who served as positive controls.&lt;/p&gt;
&lt;p&gt;DNA samples were collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland, according to the report.&lt;/p&gt;
&lt;p&gt;Analysis showed two regions whose association with ALS exceeded a prespecified level (&lt;em&gt;P&lt;/em&gt;=1.52x10&lt;sup&gt;-7&lt;/sup&gt;) for genome-wide significance, they reported:&lt;ul&gt; &lt;li&gt;On chromosome 21, the SNP rs13048019 was significant at&lt;em&gt; P&lt;/em&gt;=2.58x10&lt;sup&gt;-8&lt;/sup&gt;. The locus corresponds to the autosomal recessive D90A allele of the superoxide dismutase 1 gene (&lt;em&gt;SOD1&lt;/em&gt;), which is known to cause ALS in Scandinavian populations.&lt;/li&gt; &lt;li&gt;On chromosome nine, the SNP rs3849942, detected in a 232-kilobase region previously identified in linkage studies of families with ALS, was significant at &lt;em&gt;P&lt;/em&gt;=9.11x10&lt;sup&gt;-11&lt;/sup&gt;.&lt;/li&gt; &lt;li&gt;Within that region, a 42-SNP haplotype, or pattern of genetic variation, was associated with a 21-fold increase in the risk when people with familial ALS were compared with control. The increased risk was significant at &lt;em&gt;P&lt;/em&gt;=7. 47x10&lt;sup&gt;-33&lt;/sup&gt;.&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;In the second study, researchers led by Ammar Al-Chalabi, PhD, of King&apos;s College London, collected DNA samples from 599 patients with sporadic ALS from 20 hospitals in the U.K. and compared them with samples from 4,144 controls.&lt;/p&gt;
&lt;p&gt;They also undertook a joint genome-wide analysis that combined data from the independent set with published data from studies performed in the UK, US, the Netherlands, Ireland, Italy, France, Sweden, and Belgium.&lt;/p&gt;
&lt;p&gt;In the independent set, Al-Chalabi and colleagues reported, they found two SNPs in a region on chromosome 9 that were associated with ALS: the rs3849942 SNP found in the study of Finnish patients and a second SNP  --  dubbed rs2814707. The second one was also seen in the Finnish analysis but did not reach genome-wide significance in that study.&lt;/p&gt;
&lt;p&gt;The rs3849942 SNP, the researchers found, was significantly associated with a risk of ALS (at &lt;em&gt;P&lt;/em&gt;=2.22x10&lt;sup&gt;-6&lt;/sup&gt;) and yielded an odds ratio of 1.39, with a 95% confidence interval from 1.21 to 1.59.&lt;/p&gt;
&lt;p&gt;The second SNP was significant at &lt;em&gt;P&lt;/em&gt;&lt;em&gt;&lt;/em&gt;=3.32x10&lt;sup&gt;-6&lt;/sup&gt; and yielded an odds ratio of 1.38, with a 95% confidence interval from 1.20 to 1.58.&lt;/p&gt;
&lt;p&gt;Both SNPs remained significantly associated with ALS in the joint analysis, they reported.&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 Finnish study had support from the NIH, the National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University. Traynor reported he had no conflicts.&lt;/p&gt;&lt;p&gt;The U.K. study had support from the ALS Therapy Alliance, the Angel Fund, the Medical Research Council, the Motor Neurone Disease Association of Great Britain and Northern Ireland, the Wellcome Trust, and the National Institute for Health Research Dementias and Neurodegenerative Diseases Research Network. Al-Chalabi reported financial links with Trophos and several other authors reported financial links with industry.&lt;/p&gt;&lt;p&gt;The commentary authors reported they had no conflicts.&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="0.013"
                     href="http://www.medpagetoday.com/Cardiology/MyocardialInfarction/tb/22008?impressionId=1283759817001"
                     
      &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>
</recommendedContent>