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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

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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. Although current guidelines recommend early initiation of clopidogrel in patients with non-ST-segment elevation myocardial infarction (NSTEMI), the degree to which it has been adopted in clinical practice remains unclear. We sought to determine patterns of early (<24 hours of arrival) clopidogrel [...]

255.  

 

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. We sought to examine if clopidogrel treatment initiated before coronary stenting improved clinical outcomes among patients receiving aspirin and a glycoprotein (GP) IIb/IIIa inhibitor. [...]

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. We sought to assess the effect of clopidogrel on one-year ischemic events in unselected patients with NSTEMI. [...]

257.  

 

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. Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. [...]

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. Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical d [...]

259.  

 

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. Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients. [...]

260.  

 

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. A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery, leading to an increased risk of complications and death. [...]

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. The benefit of clopidogrel pretreatment before percutaneous coronary intervention (PCI) remains debated and its use has not been universally adopted. [...]

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. Fibrinolytic therapy for acute ST-elevation myocardial infarction (STEMI) is frequently limited by delays in administration and by incomplete reperfusion or reocclusion of the infarct-related artery. Intensified prehospital management of STEMI may shorten time to treatment and improve outcomes. [...]

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. Despite improvements in the emergency treatment of myocardial infarction (MI), early mortality and morbidity remain high. The antiplatelet agent clopidogrel adds to the benefit of aspirin in acute coronary syndromes without ST-segment elevation, but its effects in patients with ST-elevation MI were [...]

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. We sought to assess the effect of clopidogrel on in-hospital events in unselected patients with acute ST elevation myocardial infarction (STEMI). In a retrospective analysis of consecutive patients enrolled in the Acute Coronary Syndromes (ACOS) registry with acute STEMI we compared outcomes of eith [...]

265.  

 

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. We sought to assess the effect of clopidogrel on clinical events 1 year after discharge in survivors of ST-elevation myocardial infarction (STEMI) in clinical practice. [...]

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. Pretreatment with clopidogrel before elective primary percutaneous coronary intervention (PCI) has been shown to reduce ischemic complications. There are limited data about the value of clopidogrel pretreatment in the setting of PCI for ST-elevation myocardial infarction (STEMI). We aimed to examine [...]

267.  

 

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. The main goal of the initial treatment of ST-segment elevation myocardial infarction is prompt reperfusion of the infarct-related artery. The value of pretreatment with clopidogrel before primary percutaneous coronary intervention is currently unclear. [...]