• Extracts from 2010 CPR & ECC Science – Medications – Clopidogrel

    by Alan Batt. Last modified: 14/08/14

    ecc2010

    In this series of posts we will take extracts on medications and interventions from the 2010 CPR & ECC Guidelines and provide the links to their PubMed abstracts where available. We will also indicate which ones are available through open-access. A similar format is available directly through Circulation online (link below), but this does not utilise opening links through Read by QxMD.

    Clopidogrel

    Click here to access the full guidelines

    Clopidogrel is an oral thienopyridine prodrug that irreversibly inhibits the adenosine diphosphate receptor on the platelet, resulting in a reduction in platelet aggregation through a different mechanism than aspirin. Since the publication of the 2005 AHA Guidelines, several important clopidogrel studies have been published that document its efficacy for patients with both NSTEMI and STEMI.

    There is a reduction in combined event rate (cardiovascular mortality, nonfatal infarction, and nonfatal stroke) and/or mortality; with a resultant small increase in major bleeding when clopidogrel is administered by providers in the ED or in hospital to patients with NSTEMI ACS.254–256 Patients with ACS and a rise in cardiac biomarkers or ECG changes consistent with ischemia had reduced stroke and major adverse cardiac events if clopidogrel was added to aspirin and heparin within 4 hours of hospital presentation.257 Clopidogrel given 6 hours or more before elective PCI for patients with ACS without ST elevation reduces adverse ischemic events at 28 days.258

    The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial documented an increased rate of bleeding (but not intracranial hemorrhage) in the 2072 patients undergoing CABG within 5 to 7 days of administration. 259 Although a posthoc analysis of this trial reported a trend toward life-threatening bleeding257and a prospective study failed to show increased bleeding in 1366 patients undergoing CABG,260 a subsequent risk-to-benefit ratio analysis concluded that the bleeding risk with clopidogrel in patients undergoing CABG was modest. The use of clopidogrel in ACS patients with a high likelihood of needing CABG requires weighing the risk of bleeding if given against the potential for perioperative ACS events if withheld.

    The current ACC/AHA guidelines recommend withholding clopidogrel for 5 to 7 days in patients for whom CABG is anticipated. In patients up to 75 years of age with STEMI managed by fibrinolysis, a consistent improvement in combined event rate (cardiovascular mortality, nonfatal infarction, and nonfatal stroke) and/or mortality, with a resultant small increase in major bleeding, is observed when clopidogrel, in a 300-mg loading dose, was administered in addition to aspirin and heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]), at the time of initial management (followed by a 75 mg daily dose for up to 8 days in hospital).260 –265

    In patients with STEMI managed with PPCI, there is a reduction in combined event rate (cardiovascular mortality, nonfatal infarction, and nonfatal stroke) and/or mortality with a resultant small increase in major bleeding when clopidogrel is administered by ED, hospital, or prehospital providers.261,264 –267

    On the basis of these findings, providers should administer a loading dose of clopidogrel in addition to standard care (aspirin, anticoagulants, and reperfusion) for patients determined to have moderate- to high-risk non-ST-segment elevation ACS and STEMl (Class I, LOE A).257 In patients <75 years of age a loading dose of clopidogrel 300 to 600 mg with non-STE ACS and STEMI, regardless of approach to management, is recommended. It is reasonable to administer a 300-mg oral dose of clopidogrel to ED patients with suspected ACS (without ECG or cardiac marker changes) who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance (Class IIa, LOE B). Providers should administer a 300-mg oral dose of clopidogrel to ED patients up to 75 years of age with STEMI who receive aspirin, heparin, and fibrinolysis (Class I, LOE B).

    There is little evidence on the use of a loading dose of clopidogrel in patients aged ≥75 years of age with NSTEMI and STEMI treated by PPCI, and patients >75 years of age were excluded in the studies on STEMI treated by fibrinolysis, therefore the ideal dose of clopidogrel in patients over 75 years of age has yet to be delineated. In the ED the choice of immediate antiplatelet therapy (as well as protocols for STEMI and NSTEMI) should be guided by local interdisciplinary review of ongoing clinical trials, guidelines, and recommendations.

    References

    254.

     
    Alexander D1, Ou FS, Roe MT, Pollack CV Jr, Ohman EM, Cannon CP, Gibler WB, Fintel DJ, Peterson ED, Brown DL; American College of Cardiology/American Heart Association. Use of and inhospital outcomes after early clopidogrel therapy in patients not undergoing an early invasive strategy for treatment of non-ST-segment elevation myocardial infarction: results from Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines (CRUSADE). Am Heart J. 2008 Sep;156(3):606-12. PMID: 18760147.

    255. openaccess 

     
    Chan AW1, Moliterno DJ, Berger PB, Stone GW, DiBattiste PM, Yakubov SL, Sapp SK, Wolski K, Bhatt DL, Topol EJ; TARGET Investigators. Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival: results from the Do Tirofiban and ReoProGive Similar Efficacy Outcome Trial (TARGET). J Am Coll Cardiol. 2003 Oct 1;42(7):1188-95. PMID: 14522478.

    256.

     
    Zeymer U1, Gitt AK, Zahn R, Jünger C, Bauer T, Köth O, Heer T, Wienbergen H, Gottwik M, Senges J. Clopidogrel in addition to aspirin reduces one-year major adverse cardiac and cerebrovascular events in unselected patients with non-ST segment elevation myocardial infarction. Acute Card Care. 2008;10(1):43-8. PMID: 17924233.

    257. openaccess 

     
    Fox KA1, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S; Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation. 2004 Sep 7;110(10):1202-8. PMID: 15313956.

    258.

     
    Steinhubl SR1, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002 Nov 20;288(19):2411-20. PMID: 12435254.

    259. openaccess 

     
    Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. PMID: 11519503.

    260. openaccess 

     
    Sabatine MS1, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005 Mar 24;352(12):1179-89. PMID: 15758000.

    261.

     
    Sabatine MS1, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005 Sep 14;294(10):1224-32. PMID: 16143698.

    262.

     
    Verheugt FW1, Montalescot G, Sabatine MS, Soulat L, Lambert Y, Lapostolle F, Adgey J, Cannon CP. Prehospital fibrinolysis with dual antiplatelet therapy in ST-elevation acute myocardial infarction: a substudy of the randomized double blind CLARITY-TIMI 28 trial. J Thromb Thrombolysis. 2007 Jun;23(3):173-9. PMID: 17160548.

    263.

     
    Chen ZM1, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1607-21. PMID: 16271642.

    264.

     
    Zeymer U1, Gitt A, Jünger C, Bauer T, Heer T, Koeth O, Mark B, Zahn R, Senges J, Gottwik M. Clopidogrel in addition to aspirin reduces in-hospital major cardiac and cerebrovascular events in unselected patients with acute ST segment elevation myocardial. Thromb Haemost. 2008 Jan;99(1):155-60. PMID: 18217148.

    265. openaccess 

     
    Zeymer U1, Gitt AK, Jünger C, Heer T, Wienbergen H, Koeth O, Bauer T, Mark B, Zahn R, Gottwik M, Senges J; Acute COronary Syndromes (ACOS) registry investigators. Effect of clopidogrel on 1-year mortality in hospital survivors of acute ST-segment elevation myocardial infarction in clinical practice. Eur Heart J. 2006 Nov;27(22):2661-6. PMID: 17043060.

    266.

     
    Lev EI1, Kornowski R, Vaknin-Assa H, Brosh D, Fuchs S, Battler A, Assali A. Effect of clopidogrel pretreatment on angiographic and clinical outcomes in patients undergoing primary percutaneous coronary intervention for ST-elevation acute myocardial infarction. Am J Cardiol. 2008 Feb 15;101(4):435-9. PMID: 18312753.

    267. openaccess 

     
    Vlaar PJ1, Svilaas T, Damman K, de Smet BJ, Tijssen JG, Hillege HL, Zijlstra F. Impact of pretreatment with clopidogrel on initial patency and outcome in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a systematic review. Circulation. 2008 Oct 28;118(18):1828-36. PMID: 18852370.

     

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    Alan Batt

    Alan Batt

    Paramedic, educator, researcher
    Alan is a critical care paramedic, paramedic educator and prehospital researcher, currently working around the world as an educator and researcher. He has previously worked and studied across Europe, North America and the Middle East. He holds a Graduate Certificate in Intensive Care Paramedic Studies, and an MSc in Critical Care. His main interests are in care of the elderly, end-of-life care, patient safety, professionalism (including role and identity), and paramedic education.

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