ST elevation myocardial infarction thienopyridine therapy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
There are at present two agents available in this class, Ticlopidine and clopidogrel. Prasugrel is currently an investigational drug in this class. These agents inhibit the ADP-receptor and thereby reduce platelet activation. As an adjunct to fibrinolytic therapy, clopidogrel has been associated with improved patency in the CLARITY trial (300 mg loading dose and 75 mg/day maintenance dose), and a reduction in mortality in the COMMIT trial (75 mg/day loading and maintenance dose). Among STEMI patients treated with a fibrinolytic agent, co-administration of clopidogrel at a loading dose of 300 mg and a maintenance dose of 75 mg/day should be viewed as the standard of care.
Clinical Trial Data
The angiographic effectiveness of clopidogrel as adjunctive therapy to fibrinolytic administration was evaluated in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-TIMI 28 trial. [1] [2] [3] This study randomized 3,491 STEMI patients to treatement with either placebo or a 300 mg loading dose of clopidogrel followed by a maintenance dose of 75 mg/day. The trial demonstrated a 35% relative risk reduction in the incidence of an occluded artery on angiography, death, or MI associated with clopidogrel administration. [1] It is important to note that the following patient groups were excluded from participation, and the results of the study would not be applicable to these subgroups: patients over 75 years of age, those with creatinine > 2.5 mg/dL, patients with cardiogenic shock, or patients who had previously undergone coronary artery bypass grafting (CABG). This treatment benefit was observed regardless of the type of fibrinolytic (approximately two thirds of patients were treated with a fibrin-specific agent) or adjunctive antithrombin used (45.8% received UFH, 29.6% received LMWH, 24.5% received both or none). Importantly, no increase in major bleeding or ICH was observed, and the rate of all stroke was reduced by 46% (P = 0.052); the rate of PCI or CABG was high at ~63%.27 This may be attributed to the fact that most of the patients were recruited from Europe and the United States, and that there was a protocol-driven use of routine angiography.
Data from the CLARITY study demonstrate improved patency associated with the addition of clopidogrel to aspirin and a fibrinolytic agent, with no increase in the risk of intracranial hemmorhage.
Dosing
Data from the non-ST elevation MI population does demonstrate that a 600 mg oral dose achieves sustained inhibition more rapidly than a 300 mg dose. A 600 mg dose does not, however, achieve a higher level of inhibition. The FDA package insert loading dose is 300 mg, but in clinical practice both 300 and 600 mg doses are used.
Side Effects
Ticlopidine administration has been associated with neutropenia and thrombotic thrombocytopenia (TTP). It is as a result of these potential side effects that clopidogrel is often prescribed instead. Clopidogrel may also be preferred because of the lack of need for laboratory monitoring, and once-daily dosing. It should be noted, however, that approximately one third to one quarter of patients may be resistant to clopidogrel, which is a pro-drug. For those patients who develop stent thrombosis while on clopidogrel, ticlopidine may be an optimal substitution because it is not a pro-drug and is not metabolized by the same pathway as clopidogrel.
Guidelines (DO NOT EDIT)
- Class I
1. In patients who have undergone diagnostic cardiac catheterization and for whom PCI is planned, clopidogrel should be started and continued for at least 1 month after bare metal stent implantation, for several months after drug-eluting stent implantation (3 months for sirolimus, 6 months for paclitaxel), and up to 12 months in patients who are not at high risk for bleeding. (Level of Evidence: B)
2. In patients taking clopidogrel in whom CABG is planned, the drug should be withheld for at least 5 days, and preferably for 7 days, unless the urgency for revascularization outweighs the risks of excess bleeding. (Level of Evidence: B)
- Class IIa
Clopidogrel is probably indicated in patients receiving fibrinolytic therapy who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: C)
References
- ↑ 1.0 1.1 Sabatine MS, Cannon CP, Gibson CM; et al. (2005). "Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation". N. Engl. J. Med. 352 (12): 1179–89. doi:10.1056/NEJMoa050522. PMID 15758000. Unknown parameter
|month=ignored (help) - ↑ Sabatine MS, Morrow DA, Montalescot G; et al. (2005). "Angiographic and clinical outcomes in patients receiving low-molecular-weight heparin versus unfractionated heparin in ST-elevation myocardial infarction treated with fibrinolytics in the CLARITY-TIMI 28 Trial". Circulation. 112 (25): 3846–54. doi:10.1161/CIRCULATIONAHA.105.595397. PMID 16291601. Unknown parameter
|month=ignored (help) - ↑ Gibson CM, Murphy SA, Pride YB; et al. (2008). "Effects of pretreatment with clopidogrel on nonemergent percutaneous coronary intervention after fibrinolytic administration for ST-segment elevation myocardial infarction: a Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 study". Am. Heart J. 155 (1): 133–9. doi:10.1016/j.ahj.2007.08.034. PMID 18082504. Unknown parameter
|month=ignored (help)