<?xml version="1.0" encoding="utf-8"?>
<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_3221"
                     title="ESC: Warfarin Good, Dabigatran Better (CME/CE)"
                     score="0.014"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/21975?impressionId=1283456815559"
                     
      &lt;p&gt;STOCKHOLM  --  Dabigatran, an investigational oral anticoagulant which does not require laboratory monitoring, may be an ideal anticoagulant for atrial fibrillation patients, especially those in centers that are less adept at managing patients taking warfarin, according to a post-hoc analysis from the 18,000-patient RE-LY trial.&lt;/p&gt;
&lt;p&gt;Even at centers where warfarin patients were consistently maintained within the therapeutic range of recommended clotting time, dabigatran, a direct thrombin inhibitor, was superior to warfarin for preventing stroke in patients with atrial fibrillation. But its greatest benefit was at centers where international normalized ratio (INR) control was spotty, Lars Wallentin, MD, PhD, of Uppsala Clinical Research Center University Hospital in Uppsala, Sweden, reported at the European Society of Cardiology meeting here. The paper was simultaneously published online by &lt;em&gt;Lancet.&lt;/em&gt;&lt;/p&gt;
&lt;p&gt;A year ago, the RE-LY investigators &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/15751&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ESCCongress/15751&quot; target=&quot;_blank&quot;&gt;reported&lt;/a&gt; that a 150-mg dose of dabigatran twice daily was more effective in preventing strokes in high-risk patients than warfarin, while a lower dose  --  110 mg bid  --  was comparable to warfarin.&lt;/p&gt;
&lt;p&gt;In the new analysis, the researchers assessed the three treatment groups  --  two dabigatran arms and the warfarin group  --  according to each center&apos;s mean time in therapeutic range. They then divided the groups into quartiles, with the lowest quartile representing centers where patients were in therapeutic range less than 57.1% of the time, followed by centers at 57.1 to 65.5%, 65.5 to 72.6%, and more than 72.6%.&lt;/p&gt;
&lt;p&gt;There were significant &quot;interactions between [mean time in therapeutic range] and effects of both 110 and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction &lt;em&gt;P &lt;/em&gt;=0.036 and &lt;em&gt;P &lt;/em&gt;=0.0006, respectively) and total mortality (interaction &lt;em&gt;P &lt;/em&gt;=0.066 and &lt;em&gt;P &lt;/em&gt;=0.052, respectively) with reduced event rates at low [mean time in therapeutic range] and similar rates at high [mean time in therapeutic range].&quot;&lt;/p&gt;
&lt;p&gt;Michael Ezekowitz, MB, ChB, DPhil, of the Lankenau Institute for Medical Research and Heart Center in Wynnewood, Pa., who was a co-investigator, told &lt;em&gt;MedPage Today&lt;/em&gt; that the analysis also demonstrated that even when INR was well controlled with warfarin, the superiority of the higher dose of dabigatran was still apparent as was the noninferiority of the lower dose.&lt;/p&gt;
&lt;p&gt;In the &lt;em&gt;Lancet&lt;/em&gt; paper, the authors wrote that &quot;there were no significant interactions between [time in therapeutic range] and stroke and systemic embolism in either dose of dabigatran versus warfarin.&quot;&lt;/p&gt;
&lt;p&gt;&quot;So this makes the findings from RE-LY even more powerful,&quot; Ezekowitz said in an interview that was monitored by a public relations person representing Boehringer Ingelheim, the sponsor of the RE-LY trial.&lt;/p&gt;
&lt;p&gt;In a commentary that accompanied the &lt;em&gt;Lancet&lt;/em&gt; study, Deirdre A. Lane, MD, and Gregory Y.H. Lip, MD, of the University of Birmingham Center for Cardiovascular Sciences in Birmingham, England, echoed Ezekowitz, noting &quot;this post-hoc analysis shows that despite very good [time in therapeutic range], either dose of dabigatran was associated with fewer adverse events than was warfarin.&quot;&lt;/p&gt;
&lt;p&gt;Clyde Yancy, MD, of Baylor University Medical Center in Dallas, told &lt;em&gt;MedPage Today&lt;/em&gt; that he was concerned about the ways in which the analysis might be used to promote dabigatran. &quot;If the message is that centers who don&apos;t do a good job of controlling INR should simply switch to this drug, I find that concerning,&quot; he said &quot;The ideal would be to get centers to improve INR control.&quot; Yancy is past president of the American Heart Association.&lt;/p&gt;
&lt;p&gt;Lane and Lip agreed with the need to improve current treatment, recommending that until &quot;the new oral anticoagulants become widely available (a positive advance), we should advocate tight INR control at conventional levels, for which there is a wealth of evidence for benefit, and promote strategies to improve the management of therapy with vitamin K antagonists.&quot;&lt;/p&gt;
&lt;p&gt;Beyond its post-hoc design, Wallentin said the new RE-LY analysis was also limited by the decision to use mean time in therapeutic range as a proxy for INR control, noting that it &quot;might not appropriately represent INR control of individual patients and might not represent the full effect of INR control on outcome.&quot;&lt;/p&gt;
&lt;p&gt;Additionally, they cautioned that time in therapeutic range &quot;does not show the effect of good and poor treatment response.&quot;&lt;/p&gt;
&lt;p&gt;Dabigatran will be the subject of a Sept. 20 FDA advisory committee meeting, at which the committee will discuss whether the drug should be approved for preventing stroke in atrial fibrillation patients.&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 RE-LY trial was funded by Boehringer Ingelheim.&lt;/p&gt;&lt;p&gt;Wallentin has received consulting and lecture fees, honoraria, and research grants from Boehringer Ingelheim; research grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough; honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Schering-Plough; consultant fees from Athera Biotechnologies, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Regado Biotechnologies; and lecture fees from AstraZeneca and Eli Lilly.&lt;/p&gt;&lt;p&gt;Ezekowitz has received consulting fees and grant support from Boehringer Ingelheim, ARYx Therapeutics, Daiichi Sankyo, and Portola Pharmaceuticals; and consulting fees from sanofi-aventis, Pfizer, Bristol-Meyers Squibb, AstraZeneca, and Medtronic.&lt;/p&gt;&lt;p&gt;Yancy declared no financial conflicts.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_3220"
                     title="ESC: Novel Drug Beats Aspirin in Afib Patients (CME/CE)"
                     score="0.014"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/21974?impressionId=1283456815559"
                     
      STOCKHOLM  --  A novel anticoagulant  --  apixaban  --  cut the rate of stroke in half among patients with atrial fibrillation unsuitable for vitamin K antagonist therapy, according to preliminary results from a phase III trial halted because of the clear benefit.&lt;br&gt;
&lt;br&gt;The multinational AVERROES trial, conducted among 5,600 patients, was stopped early on May 28 after a planned interim analysis showed an obvious advantage for apixaban, according to Stuart Connolly, MD, of the Population Health Research Institute at McMaster University in Hamilton, Ontario.&lt;br&gt;
&lt;br&gt;Through a median follow-up of one year, the analysis revealed an annual rate of stroke or systemic embolic event  --  the primary endpoint  --  of 1.6% in the apixaban group and 3.6% in the aspirin group (RR 0.46, 95% CI 0.33 to 0.64), Connolly reported at the European Society of Cardiology Congress here.&lt;br&gt;
&lt;br&gt;Moreover, the benefit for apixaban was not accompanied with an increase in major bleeding or evidence of liver toxicity.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;Serving as a discussant at Connolly&apos;s presentation, Harald Arnesen, MD, PhD, of Oslo University Hospital Ullev&amp;#229;l in Norway, called AVERROES a landmark study and said &quot;the results will obviously, in my opinion, have an impact on guidelines in atrial fibrillation, and the use of aspirin will probably be drastically reduced.&quot;&lt;/p&gt;
&lt;p&gt;Arnesen cautioned, however, that compliance could be a problem because of apixaban&apos;s twice-daily dosing schedule.&lt;/p&gt;
&lt;p&gt;Ralph Sacco, MD, president of the American Heart Association, told &lt;em&gt;MedPage Today&lt;/em&gt; that apixaban, if approved, would likely be cost-effective  --  considering that many patients with atrial fibrillation do not receive adequate anticoagulation  --  as well as the major detrimental effect that stroke has on quality of life.&lt;/p&gt;
&lt;p&gt;&quot;So when we weigh stroke as an outcome here, I think without knowing the cost of [apixaban] it may be with this kind of magnitude of effect that we will show cost-efficacy,&quot; said Sacco, a stroke neurologist at the University of Miami in Florida who served on the data safety and monitoring board for AVERROES.&lt;/p&gt;
&lt;p&gt;Apixaban is a novel selective direct Factor Xa inhibitor with a 12-hour half life and multiple excretion pathways. There is no need for the routine coagulation monitoring inherent in treatment with warfarin.&lt;/p&gt;
&lt;p&gt;In up to 50% of patients with atrial fibrillation, vitamin K antagonist therapy to prevent stroke is not appropriate because of difficult-to-control INR, increased bleeding risk, drug interactions, and patient reluctance.&lt;/p&gt;
&lt;p&gt;Aspirin is the usual care in these patients, and apixaban is aimed at changing that.&lt;/p&gt;
&lt;p&gt;The AVERROES trial was a double-blind, randomized study conducted at 522 centers in 36 countries. All 5,600 patients (mean age 70) had atrial fibrillation and at least one risk factor, as well as demonstrated or expected unsuitability to vitamin K antagonist therapy.&lt;/p&gt;
&lt;p&gt;Expected unsuitability was determined by interviewing the patients and uncovering factors such as drinking problems, a history of canceling healthcare visits, an unwillingness to undergo the rigor of regular INR checks, and potential drug interactions.&lt;/p&gt;
&lt;p&gt;Patients received either apixaban 5 mg twice daily (94% of patients received this dose, but some patients received a half dose) or aspirin 81 to 324 mg/day (91% of patients received 162 mg a day or less).&lt;/p&gt;
&lt;p&gt;In addition to the primary endpoint, the rates of ischemic stroke, systemic embolic events, and cardiovascular hospitalization were also significantly reduced with apixaban (RRs of 0.38, 0.15, and 0.79, respectively).&lt;/p&gt;
&lt;p&gt;Both nondisabling (RR 0.56, 95% CI 0.32 to 0.96) and disabling or fatal strokes (RR 0.45, 95% CI 0.29 to 0.69) were reduced as well.&lt;/p&gt;
&lt;p&gt;Apixaban did not, however, significantly reduce the annual rate of fatal stroke (0.5% with apixaban versus 0.8% with aspirin, &lt;em&gt;P&lt;/em&gt;=0.18) or total death (3.4% versus 4.4%, &lt;em&gt;P&lt;/em&gt;=0.07).&lt;/p&gt;
&lt;p&gt;Major bleeding occurred at low rates in both groups. There was a significant increase in minor bleeding with apixaban (5.2% versus 4.1%, &lt;em&gt;P&lt;/em&gt;=0.04), but these generally did not require intervention or result in discontinuation, Connolly said at a press briefing.&lt;/p&gt;
&lt;p&gt;Apixaban was well tolerated. Patients in the apixaban group were less likely to permanently discontinue their treatment (RR 0.88, 95% CI 0.78 to 1.00, &lt;em&gt;P&lt;/em&gt;=0.04) and were less likely to have a serious adverse event (21.7% versus 26.6%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;Nervous system disorders occurred at a higher rate with aspirin (6.3% versus 3%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001), largely related to excess of stroke.&lt;/p&gt;
&lt;p&gt;Connolly calculated that for every 1,000 patients treated with apixaban instead of aspirin for one year, 18 strokes (mostly larger strokes) and 31 cardiovascular hospitalizations would be prevented.&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 sponsored by Bristol-Myers Squibb and Pfizer, which are jointly developing apixaban.&lt;/p&gt;&lt;p&gt;Connolly reported receiving research grants and lecture and consulting fees from both companies.&lt;/p&gt;&lt;p&gt;Sacco reported that he served on the data safety and monitoring committee for AVERROES.&lt;/p&gt;&lt;p&gt;Arnesen said he had no conflicts of interest.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_3193"
                     title="ESC: Reports Conflict on Clopidogrel Response Genetics (CME/CE)"
                     score="0.013"
                     href="http://www.medpagetoday.com/MeetingCoverage/ESCCongress/tb/21922?impressionId=1283456815559"
                     
      &lt;p&gt;STOCKHOLM  --  Genetic variants that have been associated with reduced clopidogrel (Plavix) efficacy and increased cardiovascular events were not related to rates of major cardiovascular events in a substudy of a randomized clinical trial.&lt;/p&gt;
&lt;p&gt;In the CURE trial of patients with acute coronary syndromes without ST-segment elevation, clopidogrel significantly reduced the rate of cardiovascular death, MI, or stroke compared with placebo, regardless of &lt;em&gt;CYP2C19 &lt;/em&gt;genotype (HR 0.71, 95% CI 0.60 to 0.84), according to Guillaume Pare, MD, of McMaster University in Hamilton, Ontario, and colleagues.&lt;/p&gt;
&lt;p&gt;Compared with placebo, there was a 31% reduction in events among carriers of at least one loss-of-function allele of the &lt;em&gt;CYP2C19&lt;/em&gt; gene (HR 0.69, 95% CI 0.49 to 0.98) compared with a 28% reduction in non-carriers (HR 0.72, 95% CI 0.59 to 0.87) (&lt;em&gt;P&lt;/em&gt;=0.84 for the interaction).&lt;/p&gt;
&lt;p&gt;Within the clopidogrel group, patients who carried at least one of the loss-of-function alleles, known as *2 and *3, did not have an increased risk of cardiovascular events.&lt;/p&gt;
&lt;p&gt;The results, presented at the European Society of Cardiology Congress here and published simultaneously online in the &lt;em&gt;New England Journal of Medicine&lt;/em&gt;, suggested that the presence of these variants, which impair activation of clopidogrel (a prodrug) in vivo, does not influence outcomes.&lt;/p&gt;
&lt;p&gt;That contradicts previous findings leading the FDA to &lt;a href=&quot;http://www.medpagetoday.com/ProductAlert/DevicesandVaccines/18982&quot; mce_href=&quot;http://www.medpagetoday.com/ProductAlert/DevicesandVaccines/18982&quot; target=&quot;_blank&quot;&gt;mandate a boxed warning&lt;/a&gt; on clopidogrel in March, about carriers of these variants who poorly metabolize the drug at standard doses and have higher cardiovascular event rates.&lt;/p&gt;
&lt;p&gt;The finding also runs counter to those of two studies newly published online in &lt;em&gt;The Lancet&lt;/em&gt;, one of which will also be presented at the ESC Congress.&lt;/p&gt;
&lt;p&gt;The first, by Lars Wallentin, MD, of Uppsala University in Sweden, and colleagues, explored the effect of genetic variants on response to ticagrelor, an investigational antiplatelet, and clopidogrel among participants in the PLATO trial, all of whom had acute coronary syndromes with or without ST-segment elevation.&lt;/p&gt;
&lt;p&gt;The main trial results &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;demonstrated&lt;/a&gt; a significant advantage for ticagrelor in reducing the rate of cardiovascular death, MI, or stroke, although that was accompanied by an increase in the rate of major bleeding not related to CABG.&lt;/p&gt;
&lt;p&gt;In the genetic substudy, both results remained consistent, regardless of variations in the &lt;em&gt;CYP2C19&lt;/em&gt; or &lt;em&gt;ABCB1&lt;/em&gt; genes (&lt;em&gt;P&lt;/em&gt;&amp;gt;0.05 for both interactions). The 3435C-to-T polymorphism in the latter gene is believed to affect drug transport.&lt;/p&gt;
&lt;p&gt;In the clopidogrel group only, however, patients who had one of eight &lt;em&gt;CYP2C19&lt;/em&gt; loss-of-function alleles (*2 through *8) had a higher 30-day rate of major cardiovascular events compared with those who did not have the alleles (5.7% versus 3.8%, &lt;em&gt;P&lt;/em&gt;=0.028). The difference disappeared when the entire 12-month follow-up was considered (10.7% versus 9.4%, &lt;em&gt;P&lt;/em&gt;=0.25).&lt;/p&gt;
&lt;p&gt;Wallentin and colleagues suggested that ticagrelor would be preferable to clopidogrel because of its increased efficacy and the lack of need for genotyping patients.&lt;/p&gt;
&lt;p&gt;The second &lt;em&gt;Lancet&lt;/em&gt; study, by Jessica Mega, MD, of Brigham and Women&apos;s Hospital and Harvard in Boston, and colleagues, reported a similar analysis of the TRITON-TIMI 38 trial, which compared clopidogrel with prasugrel (Effient) in patients with acute coronary syndromes undergoing percutaneous coronary intervention.&lt;/p&gt;
&lt;p&gt;The main trial results &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/AHA/7217&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/AHA/7217&quot; target=&quot;_blank&quot;&gt;showed&lt;/a&gt; that prasugrel significantly reduced major ischemic events but increased major bleeding.&lt;/p&gt;
&lt;p&gt;In the clopidogrel group  --  but not the prasugrel group  --  ischemic events were independently associated with polymorphisms in both the &lt;em&gt;ABCB1&lt;/em&gt; (HR 1.72, 95% CI 1.22 to 2.44) and &lt;em&gt;CYP2C19&lt;/em&gt; (HR 1.77, 95% CI 1.11 to 2.80) genes.&lt;/p&gt;
&lt;p&gt;About half (47%) of the patients in the clopidogrel group had at least one risk-associated polymorphism, and these patients had nearly double the rate of ischemic events (HR 1.97, 95% CI 1.38 to 2.82).&lt;/p&gt;
&lt;p&gt;&quot;As clinicians, professional societies, and patients integrate information about genetic factors affecting the response to thienopyridines, the roles of both &lt;em&gt;ABCB1&lt;/em&gt; and &lt;em&gt;CYP2C19&lt;/em&gt; should be considered,&quot; Mega and her colleagues wrote.&lt;/p&gt;
&lt;p&gt;Pare and his colleagues speculated that their study did not identify a relationship between CYP2C19 loss-of-function alleles and major cardiovascular events because of the low number of patients  --  18%  --  who underwent PCI in the CURE trial. They noted that the greatest benefit of clopidogrel and the newer P2Y12 inhibitors appears to be in reducing stent thrombosis.&lt;/p&gt;
&lt;p&gt;The 18% rate of stent placement in CURE compares with 64% of patients in the PLATO analysis and close to 100% in the TRITON-TIMI 38 analysis.&lt;/p&gt;
&lt;p&gt;Although the CURE analysis did not find a difference in the impact of the &lt;em&gt;CYP2C19&lt;/em&gt; variants according to the receipt of PCI, neither could it rule out an interaction.&lt;/p&gt;
&lt;p&gt;Another possible reason offered for the discrepant results was the lack of a randomized control group in many of the previous analyses, making it impossible to exclude potential pleiotropic effects of these genetic variants beyond the effects on metabolism.&lt;/p&gt;
&lt;p&gt;&quot;This... highlights the importance of including a placebo group to control for potential confounding in analyses of pharmacogenetic data,&quot; Pare and his colleagues wrote.&lt;/p&gt;
&lt;p&gt;If the genetic variation actually does not affect clinical outcomes, it would make clopidogrel much easier to work with by simplifying the decision-making process, according to Alfred Bove, MD, of Temple University in Philadelphia.&lt;/p&gt;
&lt;p&gt;Once clopidogrel becomes generic, eliminating the need for genetic testing might also make cardiologists less willing to switch to one of the newer drugs in the class, which have been shown to have greater platelet inhibition but would cost much more, said Bove, a former president of the American College of Cardiology.&lt;/p&gt;
&lt;p&gt;&quot;The insurers will be pushing it too, particularly if [genetic variability is] not an issue.&quot;&lt;/p&gt;
&lt;p&gt;But genotype-related efficacy issues may take a back seat to adherence as the main concern for clinicians, he said, pointing out that many patients on long-term clopidogrel treatment stop taking the drug.&lt;/p&gt;
&lt;p&gt;&quot;That&apos;s probably more of a problem than the genetic variation right now,&quot; said Bove.&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 CURE and ACTIVE A studies were funded by sanofi-aventis and Bristol-Myers Squibb, which co-market clopidogrel.&lt;/p&gt;&lt;p&gt;Pare reported receiving consulting fees from sanofi-aventis and Bristol-Myers Squibb. His co-authors reported relationships with AstraZeneca, Eli Lilly, Novartis, Bristol-Myers Squibb, Eisai, The Medicines Company, Bayer, Johnson &amp;amp; Johnson, and Boehringer Ingelheim. One of the authors of the authors is employed by and owns stock in Bristol-Myers Squibb.&lt;/p&gt;&lt;p&gt;PLATO was designed through a collaboration of academic members of the executive committee and representatives from AstraZeneca, which funded the study and is developing ticagrelor. Genetic analyses were conducted by AstraZeneca.&lt;/p&gt;&lt;p&gt;Wallentin reported receiving research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Schering Plough, honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Schering Plough, and Eli Lilly, consultancy fees from Regado Biotechnologies, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, and Eli Lilly, and lecture fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. His co-authors reported extensive relationships with industry. Three of the authors are employed by AstraZeneca.&lt;/p&gt;&lt;p&gt;The TIMI study group received research support from Daiichi Sankyo, Eli Lilly, sanofi-aventis, Bristol-Myers Squibb, AstraZeneca, Schering Plough/Merck, Johnson &amp;amp; Johnson, and Bayer Healthcare.&lt;/p&gt;&lt;p&gt;Mega reported receiving grant support from the NIH and consulting fees from sanofi-aventis, Bristol-Myers Squibb, and AstraZeneca. Her co-authors reported extensive relationships with industry. Two of the study authors are employed by Eli Lilly and one is employed by Daiichi Sankyo.&lt;/p&gt;&lt;p&gt;Bove reported that he had no relationships with relevant commercial entities.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_3055"
                     title="&apos;System Delay&apos; Doubles MI Death Rate (CME/CE)"
                     score="0.003"
                     href="http://www.medpagetoday.com/EmergencyMedicine/EmergencyMedicine/tb/21730?impressionId=1283456815559"
                     
      &lt;p&gt;So-called &quot;system delay&quot; in treating patients with heart attacks  --  the time from the first ambulance call to the start of angioplasty or other reperfusion treatment  --  does worsen outcomes, researchers said.&lt;/p&gt;
&lt;p&gt;Retrospective review of more than 6,000 patient records from Denmark indicated that patients with ST-segment elevation myocardial infarction (STEMI) whose &quot;door-to-balloon&quot; time was more than two hours had nearly double the mortality rate of patients treated in one hour or less, reported Christian Juhl Terkelsen, MD, PhD, of Aarhus University, and colleagues.&lt;/p&gt;
&lt;p&gt;The death rate in patients with delay times of up to one hour was 15.4%, compared with 28.1% in patients with delays of 121 to 180 minutes and 30.8% in those treated more than three hours after arrival at a treatment facility, according to the researchers&apos; report in the Aug. 18 issue of the &lt;em&gt;Journal of the American Medical Association&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Previous studies failed to document a clear association between treatment delay and mortality in MI patients, Terkelsen and colleagues noted, perhaps because they focused on the time between onset of symptoms  --  often difficult to identify  --  and initiation of treatment.&lt;/p&gt;
&lt;p&gt;They suggested that the time elapsing from various encounters with the healthcare system to the start of treatment would provide a more reliable test of whether prompt reperfusion treatment improves outcomes.&lt;/p&gt;
&lt;p&gt;Terkelsen and colleagues examined records of 6,209 patients treated for STEMI at three high-volume angioplasty centers in western Denmark from 2002 to 2008. The data included times for the call for emergency service, arrival at healthcare facilities, and initiation of reperfusion therapy.&lt;/p&gt;
&lt;p&gt;About one-third of the patients were field triaged directly to the angioplasty centers, while the rest were initially seen at a hospital and transferred to the centers. &quot;System delay&quot; was defined as the total time from the first emergency call to the start of angioplasty.&lt;/p&gt;
&lt;p&gt;In the case of patients triaged by first responders, it was simply the transportation time plus door-to-balloon time. For those taken first to a local hospital, the system delay comprised transportation to the hospital, the time they spent there, transportation time to the angioplasty center, and delays there before treatment began.&lt;/p&gt;
&lt;p&gt;The median system delays for field-triaged patients and those transferred from a hospital were 97 and 139 minutes, respectively.&lt;/p&gt;
&lt;p&gt;All patients underwent percutaneous balloon angioplasty within 12 hours of recorded symptom onset.&lt;/p&gt;
&lt;p&gt;The primary outcome was death during a median 3.4 years of follow-up.&lt;/p&gt;
&lt;p&gt;Among all patients in the study, the crude hazard ratio for long-term mortality associated with each hour of system delay was 1.22 (95% CI 1.15 to 1.29).&lt;/p&gt;
&lt;p&gt;However, when the data were adjusted for sex, body mass index, previous MI history, and treatment for hypertension, the hazard ratio for death was somewhat lower, 1.10 (95% CI 1.04 to 1.16) for each hour of system delay.&lt;/p&gt;
&lt;p&gt;Both the &quot;prehospital&quot; system delay (time from emergency call to arrival at the angioplasty center) and door-to-balloon time (time of arrival to initiation of treatment) were significantly associated with long-term mortality.&lt;/p&gt;
&lt;p&gt;For each hour of prehospital delay, the hazard ratio was 1.10 (95% CI 1.02 to 1.18). For door-to-balloon time, the hazard ratio for each hour was 1.14 (95% CI 1.05 to 1.24).&lt;/p&gt;
&lt;p&gt;So-called patient delay  --  the time from perceived onset of symptoms to the emergency call  --  was not a significant predictor of mortality (hazard ratio 1.00, 95% CI 0.98 to 1.03) for each hour in the multivariate analysis.&lt;/p&gt;
&lt;p&gt;But Terkelsen and colleagues noted that symptom onset is frequently difficult to pin down accurately.&lt;/p&gt;
&lt;p&gt;&quot;[It] may be uncertain because of recall bias and because the onset of acute myocardial infarction may have been preceded by hours of unstable angina,&quot; they pointed out.&lt;/p&gt;
&lt;p&gt;That&apos;s one reason why some previous studies failed to demonstrate a relationship between total treatment delay and mortality, Terkelsen and colleagues argued. Another is that patients presenting quickly for treatment may be fundamentally different from those presenting late.&lt;/p&gt;
&lt;p&gt;The latter, they asserted, &quot;are typically low-risk patients who have already survived the prehospital phase and benefit less from reperfusion therapy. On the other hand, those who present early get a substantial benefit from reperfusion, such that those treated promptly &quot;ultimately have nearly the same mortality as those presenting late.&quot;&lt;/p&gt;
&lt;p&gt;One &lt;a href=&quot;http://www.medpagetoday.com/Cardiology/MyocardialInfarction/20417&quot; mce_href=&quot;http://www.medpagetoday.com/Cardiology/MyocardialInfarction/20417&quot; target=&quot;_blank&quot;&gt;recent study&lt;/a&gt;, however, did show that treatment delays boost the risk of short-term STEMI mortality.&lt;/p&gt;
&lt;p&gt;Terkelsen and colleagues suggested that &quot;increased focus on the total healthcare system delay&quot; may be the best way to improve survival in STEMI patients  --  if only because &quot;system delay and its components appear to be the only risk factors that can be modified in the acute phase.&quot;&lt;/p&gt;
&lt;p&gt;Limitations to the study included possible underestimates of system delay because encounters with primary care physicians were not recorded; potentially faulty data on emergency transports; and the use of balloon inflation, rather than first wiring of the vessel, to indicate time of reperfusion.&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 the Helga and Peter Kornings Foundation and the Health Research Fund of Central Denmark Region.&lt;/p&gt;&lt;p&gt;One co-author reported a research grant from Falck EMS of Denmark for studies unrelated to the current project. No other conflicts of interest were reported.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_2993"
                     title="Tailored Therapy Tames Overactive Platelets (CME/CE)"
                     score="-0.002"
                     href="http://www.medpagetoday.com/Cardiology/PCI/tb/21648?impressionId=1283456815559"
                     
      &lt;p&gt;Almost 90% of percutaneous coronary intervention patients (PCI) with an altered platelet reactivity genotype responded to tailored clopidogrel (Plavix) therapy, French investigators reported.&lt;/p&gt;
&lt;p&gt;Clopidogrel loading dose adjustment based on platelet reactivity monitoring allowed patients to overcome high on-treatment platelet reactivity resulting from a cytochrome CYP 2C19 2* loss-of-function polymorphism, according to an article published online in the &lt;em&gt;Journal of the American College of Cardiology&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;The study is the &quot;first to demonstrate that, despite having reduced clopidogrel metabolism, most carriers of the loss-of-function CYP 2C19 2* can reach optimal platelet reactivity index [PRI] using a strategy of tailored loading dose according to PRI monitoring,&quot; Laurent Bonello, MD, of the University of the Mediterranean in Marseilles, and colleagues wrote in conclusion.&lt;/p&gt;
&lt;p&gt;&quot;These data reinforce the potential of PRI monitoring to improve the outcome of patients undergoing PCI for an acute coronary syndrome.&quot;&lt;/p&gt;
&lt;p&gt;High on-treatment platelet reactivity after a clopidogrel loading dose has been shown to predict worse outcomes in PCI, and the vasodilator-stimulated phosphoprotein (VASP) index is the most specific assay for assessing clopidogrel&apos;s effect on platelets, the authors noted.&lt;/p&gt;
&lt;p&gt;Bonello and colleagues previously reported that tailoring a clopidogrel loading dose according to platelet reactivity index in patients with high on-treatment platelet reactivity can improve clinical outcomes (&lt;em&gt;J Am Coll Cardiol &lt;/em&gt; 2008; 51: 1404-1411, &lt;em&gt;Am J Cardiol&lt;/em&gt; 2009; 103: 5-10). They continued their investigation by evaluating a strategy of clopidogrel loading dose adjustment based on platelet reactivity monitoring in carriers of the CYP 2C19 2* polymorphism.&lt;/p&gt;
&lt;p&gt;The investigators prospectively evaluated platelet reactivity by the VASP index in 411 patients undergoing PCI for non-ST-segment acute coronary syndromes. They defined high on-treatment platelet reactivity as a VASP index &amp;#8805;50% and determined CYP 2C19 status by means of allele-specific polymerase chain reaction.&lt;/p&gt;
&lt;p&gt;A total of 134 patients (35.3%) were carriers of at least one 2C19 2* allele (11 homozygous and 123 heterozygous). Carriers of the polymorphism had a significantly higher mean VASP index compared with patients who were homozygous for wild-type alleles (61.7% versus 49.2%, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001).&lt;/p&gt;
&lt;p&gt;The authors determined that 103 of the 134 patients had high on-treatment platelet reactivity following an initial clopidogrel loading dose, as did 154 of the 277 patients who were homozygous for wild-type alleles.&lt;/p&gt;
&lt;p&gt;After as many as three additional 600-mg loading doses of clopidogrel, 137 (89%) of the patients with wild-type alleles achieved a platelet reactivity index &amp;lt;50%.&lt;/p&gt;
&lt;p&gt;Following administration of a second 600-mg loading dose, the mean VASP index declined significantly from 69.7% to 50.6% (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001). Subsequently, 87 of 99 patients (88%) reached a VASP index &amp;lt;50% after as many as three additional 600-mg loading doses.&lt;/p&gt;
&lt;p&gt;The total clopidogrel dose required to achieve a VASP index &amp;lt;50% averaged 1,400 mg in homozygous and heterozygous carriers of the 2C19 2* allele.&lt;/p&gt;
&lt;p&gt;Inhospital adverse events consisted of one stroke in a patient with wild-type genotype, one case of stent thrombosis among patients with heterozygous 2C19 2* genotype, and four minor bleeds in the wild-type group.&lt;/p&gt;
&lt;p&gt;The authors acknowledged that their study was a small one, did not assess other genetic polymorphisms that might have been involved in the clopidogrel response, and did not evaluate the &quot;prognostic impact&quot; of the therapeutic intervention.&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 authors had no relevant disclosures.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
</recommendedContent>