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.
Angiographic efficacy of Clopidogrel as adjunctive therapy to fibrinolysis in STEMI patients
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]
Safety of Clopidogrel in CLARITY
Clopidogrel administration was not associated with an increase in TIMI major bleeding or intracranial hemorrhage (ICH). Indeed, the incidence of all causes of stroke was reduced by 46% (P = 0.052).
Generalizability of results from CLARITY
There was no heterogeneity in the treatment benefit (that is a consistent benefit was observed) irrespective of:
- Type of fibrinolytic (2/3rds of patients were treated with a fibrin-specific agent such as tPA, rPA, nPA, or TNK) or
- Tyep of antithrombin administered (45.8% received UFH, 29.6% received enoxaparin, 24.5% received both or none).
It is important to note that the following patient groups were excluded from participation in CLARITY, and the results of CLARITY are not 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). It should also be noted that the rate of PCI or CABG was high at 63%. This may be due to the fact protocol-mandated angiography was performed in countries with a high rate of adjunctive PCI such as Europe and the United States.
Reduction in mortality associated with clopidogrel administration in conjunction with fibrinolytic agents: Results of COMMIT
The COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group evaluated the safety and efficacy of clopidogrel as an adjunct to fibrinolytic therapy in 45,852 patients at 1250 Chinese hospitals who presented in the first 24 hours of STEMI (93% had ST segment elevation or left bundle branch block, the rest had ST segment depression). [4] As adjunctive therapy to 162 mg of aspirin daily, patients were randomized to clopidogrel 75 mg daily without a 300 mg loading dose which continued until discharge or up to 4 weeks in hospital (mean 15 days in survivors)(n=22,961) or placebo (n=22,891). Clopidogrel administration was associated with a 9% relative reduction (95% CI 3-14) in the co-primary endpoint of death, reinfarction, or stroke (2121 [9.2%] clopidogrel vs 2310 [10.1%] placebo; p=0.002). This would translate into to nine fewer deaths, re MIs or strokes per 1000 patients treated for two weeks. Likewise, there was a 7% relative risk reduction (95% CI 1-13) in all cause death (1726 [7.5%] vs 1845 [8.1%]; p=0.03). The benefits were consistent across a broad range of subgroups, antithrombins and fibrinolytic agents.
With respect to safety, there was no excess of fatal stroke or intracranial hemmorhage associated with clopidogrel administration, either in patients of all ages (134 [0.58%] vs 125 [0.55%]; p=0.59), or among patients who were over 70 years of age.
Dosing of clopidogrel in STEMI
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. A loading dose of 600 mg of clopidogrel has not been studied in conjunction with fibrinolytic therapy and cannot be recommended. The optimal loading dose in patients with STEMI undergoing primary PCI has not been rigorously evaluated in randomized trials.
Side effects of thienopyridines
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.
ACC / AHA 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) - ↑ Chen ZM, Jiang LX, Chen YP; et al. (2005). "Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial". Lancet. 366 (9497): 1607–21. doi:10.1016/S0140-6736(05)67660-X. PMID 16271642. Unknown parameter
|month=ignored (help)