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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EDual antiplatelet therapy in patients with acute coronary syndromes is becoming more complex, making it difficult to select the optimal therapy. The optimal regimen; the potential risk for adverse events, bleeding in particular; and the role of genotyping are among the most important questions that remain unanswered.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EThrombotic Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EMyocardial Infarction Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EDual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS) is becoming more complex, making it difficult to select the optimal therapy, said Matthew J. Price MD, FACC, Scripps Clinic, La Jolla, California, USA. With several P2Y\u003Csub\u003E12\u003C\/sub\u003E ADP receptor antagonists that have been approved at varying doses, as well as three different doses of aspirin that are commonly used, there are multiple different combinations of oral DAPT. The American College of Cardiology Foundation\/American Heart Association (ACCF\/AHA) guidelines note the options for DAPT as clopidogrel, prasugrel, and ticagrelor but provide no guidance on the selection of a particular agent [Levine GN et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2011]. The optimal regimen; the potential risk for adverse events, bleeding in particular; and the role of genotyping are among the most important questions that remain unanswered.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EDrug Options for DAPT\u003C\/h2\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EClopidogrel, when combined with aspirin, leads to improved outcomes (compared with aspirin alone) for patients with ACS, regardless of whether they are undergoing percutaneous coronary intervention (PCI) or not. Despite better results, studies showed that inhibition of platelet aggregation with clopidogrel was \u201cvariable, unpredictable, and insufficient,\u201d said Paul Gurbel, MD, FACC, Sinai Center for Thrombosis Research, Baltimore, Maryland, USA [Gurbel PA et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2003].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EDAPT with prasugrel achieved more rapid, potent, and consistent inhibition of platelet function than clopidogrel + aspirin. In the TRITON\u2013TIMI 38 trial, prasugrel substantially reduced rates of ischemic events (9.9% vs 12.1%; HR, 0.81; 95% CI, 0.73 to 0.90; p\u0026lt;0.001), including stent thrombosis (1.1% vs 2.4%; HR, 0.48; 95% CI, 0.36 to 0.64; p\u0026lt;0.001), compared with clopidogrel in patients with ACS treated with coronary stenting [Wiviott SD et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2007]. However, prasugrel increased the rate of major bleeding (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03 to 1.68; p=0.03), including fatal bleeding (0.4% vs 0.1%; HR, 4.19; 95% CI, 1.58 to 11.11; p=0.002). Overall mortality was similar for the two drugs.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe most recently approved P2Y\u003Csub\u003E12\u003C\/sub\u003E antagonist, ticagrelor, has a rapid onset, consistent antiplatelet effect, and is reversible [Gurbel PA et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2009]. Ticagrelor was compared with clopidogrel in the PLATO trial and significantly reduced the rate of the primary composite endpoint (cardiovascular [CV]-related death, myocardial infarction [MI], and stroke) by 1.9% absolute (p=0.0003), including a significant reduction in CV mortality (4.0% vs 5.1%; HR, 0.79; 95% CI, 0.69 to 0.91; p=0.001) [Wallentin L et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2009]. The results were consistent in many subgroups including patients who were planned for an invasive strategy; those with ST\u2013elevation myocardial infarction (STEMI), renal dysfunction and, previous stroke; and those having coronary artery bypass grafting within 5 days of treatment. Ticagrelor was of benefit independently of the loading dose of clopidogrel (300 or 600 mg) [Cannon CP et al. \u003Cem\u003ELancet\u003C\/em\u003E 2010], and also regardless of the genetic \u003Cem\u003ECYP2C19\u003C\/em\u003E polymorphism that identifies low responders to clopidogrel [Wallentin L et al. \u003Cem\u003ELancet\u003C\/em\u003E 2010]. Ticagrelor achieves a greater pharmacodynamic effect than clopidogrel, irrespective of \u003Cem\u003ECYP2C19\u003C\/em\u003E genotype [Tantry US et al. \u003Cem\u003ECirc Cardiovasc Genet\u003C\/em\u003E 2010], which likely explains the higher rate of bleeding with ticagrelor compared with clopidogrel that is seen outside of the operating room.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EComparisons across the trials of P2Y\u003Csub\u003E12\u003C\/sub\u003E antagonists are difficult due to differences in the study designs in which the efficacy and safety of the drugs are evaluated (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E). Dr. Price suggested that physicians look at the study designs to see where their patients \u201cfit\u201d in terms of the type of MI (NSTEMI or STEMI), management strategy, pretreatment with clopidogrel, start of treatment before coronary angiography, potential need for CABG, and clinical characteristics (eg, advanced age, low body weight, previous stroke - each of which increases the risk of major bleeding).\u003C\/p\u003E\n         \u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/14005\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/14005\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14005\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003EComparative Study Designs Testing the Safety and Efficacy of the P2Y\u003Csub\u003E12\u003C\/sub\u003E Antagonists in ACS.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ERisk of Bleeding\u003C\/h2\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EThe risk of bleeding is the greatest safety concern with DAPT. \u201cIt\u0027s been difficult, if not impossible, to disassociate a reduction in things like, stent thrombosis, from increases in bleeding,\u201d said Deepak L. Bhatt MD, MPH, Brigham and Women\u0027s Hospital, Boston, Massachusetts, USA. The potential for increased risk of bleeding must be an important factor in selecting an antiplatelet regimen. It is wise to factor gastrointestinal (GI) bleeding risk in particular, whether the patient is older, has a history of ulcers, has \u003Cem\u003EH. pylori\u003C\/em\u003E, or is on an anticoagulant, corticosteroids, or an NSAID, advised Dr Bhatt.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EProton pump inhibitors (PPIs) have been used widely to reduce the risk of upper GI bleeding that is associated with clopidogrel, but studies have shown a pharmacodynamic interaction between PPIs and clopidogrel, potentially reducing its clinical effectiveness. However, the clinical significance of this interaction has not been substantiated in more recent data. An analysis from TRITON\u2013TIMI 38 indicated no influence of PPIs on outcomes in patients who are treated with clopidogrel [O\u0027Donoghue ML et al. \u003Cem\u003ELancet\u003C\/em\u003E 2009]. Likewise, recent analyses from PLATO showed no interaction of clopidogrel with PPI, with a consistent benefit of ticagrelor, regardless of PPI treatment [Goodman S et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EThe best clinical data that have evaluated the interaction of PPIs and clopidogrel are from the prospectively designed, randomized, double\u2013blinded COGENT trial, in which prophylactic use of omeprazole reduced the rate of upper GI bleeding compared with placebo (HR, 0.13; 95% CI, 0.03 to 0.56; p=0.001) [Bhatt DL et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010]. There was no apparent CV interaction between clopidogrel and omeprazole (HR in patients who were randomized to omeprazole, 0.99; 95% CI, 0.68 to 1.44; p=0.96), but the study could not rule out a potentially clinically meaningful difference in CV events due to use of a PPI.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003ETo help provide insight on the issue, the ACC and AHA worked with the American College of Gastroenterology to develop an Expert Consensus Document on the use of PPIs and thienopyridines [Abraham NS et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2010]. The consensus document, recommends using a PPI to reduce GI bleeding among patients with a history of upper GI bleeding, stating that PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. The document also indicates that the routine use of a PPI is not recommended for patients who are at lower risk of upper GI bleeding.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EThe risk of bleeding with prasugrel is higher than it is with clopidogrel. In particular, prasugrel should not be used in patients who have had a prior stroke or transient ischemic attack, and is not recommended for patients aged \u0026gt;75 years, except in high\u2013risk situations. \u201cThis recommendation is derived from the data evaluating the net clinical benefit. [If] patients have high ischemic risk, they will benefit overall from prasugrel because the ischemic benefit outweighs the risk of bleeding, and that was seen in elderly patients with diabetes or prior MI,\u201d said Dr. Price. He also added that dose adjustment in lightweight patients should be considered.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EConcerns were initially raised about using ticagrelor for patients who had prior stroke as there was nearly a doubling of intracranial hemorrhage (ICH; HR, 1.87; 95% CI, 0.98 to 3.58; p=0.06) that was associated with ticagrelor compared with clopidogrel among all patients in the PLATO trial. However, further analysis showed that patients who had a prior stroke actually fared substantially better with ticagrelor than with clopidogrel in terms of the primary endpoint (HR, 0.62; 95% CI, 0.42 to 0.91). This suggests any increased risk of ICH in patients who were treated with ticagrelor (compared with clopidogrel) was counterbalanced by a larger benefit in the reduction of ischemic events.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EA higher rate of non\u2013CABG bleeding was also more common with ticagrelor than clopidogrel (2.8% vs 2.2%; HR, 1.25; 95% CI, 1.03 to 1.53; p=0.03), similar to the excess that was seen with prasugrel versus clopidogrel. However there was no difference in perioperative CABG bleeding between ticagrelor and clopidogrel, and a study by Held et al. found that the mortality rate after CABG was significantly lower for patients who were treated with ticagrelor versus clopidogrel (4.7% vs 9.7%; p\u0026lt;0.01) [Held et al. \u003Cem\u003EJACC\u003C\/em\u003E 2011]. Because ticagrelor \u003Cem\u003Ereversibly\u003C\/em\u003E binds the P2Y\u003Csub\u003E12\u003C\/sub\u003E receptor, the rate of recovery of platelet function is faster after ticagrelor than clopidogrel [Gurbel PA et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2009]. However, since ticagrelor achieves a higher steady\u2013state level of platelet inhibition than clopidogrel, it is recommended that both be stopped for 5 days before CABG, compared with 7 days prior to CABG for prasugrel.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EGenotyping\u003C\/h2\u003E\n         \u003Cp id=\u0022p-16\u0022\u003ESome of the variability in platelet inhibition with clopidogrel can be explained by the presence of \u003Cem\u003ECYP2C19\u003C\/em\u003E polymorphisms [Shuldiner AR et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2009]. Loss\u2013of\u2013function alleles are common, occurring in \u223c30% of white individuals, \u223c35% of African\u2013Americans, and 55% of East Asians, said Malcolm R. Bell, MBBS, FRACP, FACC, Mayo Clinic, Rochester, Minnesota, USA. However, patients with these polymorphisms make up less than 20% of patients with a low response to clopidogrel, and other factors also contribute to the variability in platelet inhibition [Hochholzer et al. \u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EIn 2011, the ACCF\/AHA published an update to its unstable angina\/NSTEMI guidelines, with two new class IIb recommendations, noting that platelet function testing or genotyping for \u003Cem\u003ECYP2C19\u003C\/em\u003E loss\u2013of\u2013function variants may be considered if the testing may alter management [Wright RS et al. \u003Cem\u003EJACC\u003C\/em\u003E 2011]. However, a benefit of altering management based on platelet function or genetic testing has never been demonstrated in a large\u2013scale prospective trial.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EEuropean Society of Cardiology 2011 ACS Guideline\u003C\/h2\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EUnlike the ACCF\/AHA guidelines, the European Society of Cardiology guidelines now recommend the newer P2Y\u003Csub\u003E12\u003C\/sub\u003E inhibitors (ticagrelor or prasugrel) over clopidogrel in patients with NSTE\u2013ACS. Ticagrelor has a Class I, level B recommendation, with the guidelines stating that a 180\u2013mg loading dose, followed by 90 mg given twice daily, is recommended for \u201call patients at moderate\u2013to\u2013high risk of ischemic events, regardless of initial treatment strategy, and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is commenced)\u201d [Hamm CW et al. \u003Cem\u003EEur Heart J\u003C\/em\u003E 2011]. Ticagrelor is of benefit regardless of type of ACS, a noninvasive or invasive strategy (including CABG), renal function and diabetes, use of PPIs, or \u003Cem\u003ECYP2C19\u003C\/em\u003E polymorphism. Prasugrel also has a Class I, level B recommendation; a 60\u2013mg loading dose, followed by a 10\u2013mg daily dose, is recommended for \u201cP2Y\u003Csub\u003E12\u003C\/sub\u003E\u2013inhibitor\u2013na\u00efve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of life\u2013threatening bleeding or other contraindications.\u201d In contrast, clopidogrel is recommended only if patients are not candidates for ticagrelor or prasugrel (Class I, level A). Prof. Wallentin concluded that compared with clopidogrel, one life would be saved for every 54 ACS patients who are treated with ticagrelor for one year.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-5\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EScience Advisor\u0027s Note:\u003C\/h2\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EWhether the benefits of ticagrelor and prasugrel over clopidogrel that were observed in a rigorous randomized trials will hold up in routine practice, the side effect profile, and anticipated use in patients who would not have qualified for a clinical trial remains to be seen.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/4\/23.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznhip\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_tables.js?nznhip\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}