ST elevation myocardial infarction thienopyridine therapy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Mechanism of Benefit
Currently there are two agents 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.
Clinical Trial Data
THE ROLE OF THIENOPYRIDINES AND PLATELET INHIBITION
The role of the thienopyridine clopidogrel as an adjunct to fibrinolysis was recently evaluated in the randomized Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-TIMI 28 trial.27,28 This study of 3491 patients demonstrated a RR reduction of ~35% in the incidence of an occluded artery on angiography, death, or MI with the addition of clopidogrel (300-mg load followed by 75 mg once daily) to the standard regimen of ASA and a fibrinolytic.27 Patients excluded from the analysis were those aged >75 years and those with creatinine >2.5 mg/dL, cardiogenic shock, or prior coronary artery bypass graft (CABG).27,28 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.
A prospective, non-randomized analysis of the 2860 patients in CLARITY-TIMI 28 who received either UFH or LMWH (enoxaparin in 85% of cases) lends further support to the use of LMWH in adjunctive fibrinolytic therapy.28 Enoxaparin was associated with a significantly lower rate of a closed-infarct–related artery or death/recurrent MI prior to angiography (13.5% vs 22.5% for UFH; P = 0.027). At 30 days, the respective incidence of the hard clinical end point of cardiovascular death or recurrent MI was 6.9% for LMWH vs 11.5% for UFH (P = 0.03). The respective rates of TIMI major bleeding (1.6% for LMWH vs 2.2% for UFH; P = 0.34) and ICH (0.6% for LMWH vs 0.8% for UFH; P = 0.50) were similar between the 2 agents. The advantage of LMWH over UFH in terms of an open artery at the time of angiography widened as the time to angiography was prolonged. This was consistent with the results of the Second Trial of Heparin and Aspirin Reperfusion Therapy (HART II)29 and the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT) Plus study.30 This quadruple therapy of a fibrin-specific lytic agent, 150 to 325 mg of non–enteric-coated ASA (on day 1, followed by a reduced dose), a 300-mg load of clopidogrel, and an LMWH appears to be an efficacious and safe reperfusion strategy.27,28 The efficacy and safety of 600 mg of clopidogrel after fibrinolytic administration have not been assessed.
While the combination of clopidogrel with fibrinolytic agents is not part of the current ACC / AHA guidelines, clinical trial data from the CLARITY study did demonstrate imporved patency associated with their combination, with no increase in the risk of intracranial hemmorhage. The combination of clopidogrel combined with aspirin has been associated with a reduced risk of stent thrombosis following coronary stent implantation (576-580). Among patients with aspirin sensitivity where aspirin is contraindicated, clopidogrel may reduce the risk of reocclusion (581). The ACC / AHA guidelines do not recommend routine administration of clopidogrel as pretreatment "in patients who have not yet undergone diagnostic cardiac catheterization and in whom CABG surgery would be performed within 5 to 7 days if warranted (431)."
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