Clopidogrel studies

Recent studies have suggested that combination antiplatelet therapy may be synergistic in reducing the risk of IHD-related events. In patients with ACS, the combination of aspirin and clopidogrel 75 mg daily for up to 9 months was more effective than aspirin alone in decreasing the risk of... 

Lactation Studies in rats have shown that clopidogrel and its metabolites are excreted in milk. It is not known whether this drug is excreted in human breast milk. Chiidren Safety and efficacy have not been established. 

Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC, Tanguay JF, Steinhubl SR, Berger PB, O Connor CM, Hennekens CH. Absence of interaction between atorvastatin or other statins and clopidogrel results from the interaction study. Arch Intern Med 2004 164(18) 2051-7. 

I 5 Kastrati A, Mehilli J, Schuhlen H, et al. Intracoronary stenting and antithrombotic regimen-rapid eariy action for coronary treatment study investigators. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004 350 232-238. 

Clopidogrel inhibits platelet aggregation in a dose-dependent fashion, Several studies have shown that a loading dose of clopidogrel results in a much more rapid onset of platelet inhibition than that achieved by regular low doses (II), and recommended loading doses in acute coronary syndromes (ACS) management are 300 mg followed by 75 mg once daily. 

A single dose of 400 mg induces 40% inhibition of platelet aggregation two hours later (12), and the level of platelet inhibition can be maintained with a daily dose of 75 mg. However, larger loading doses (450-600 mg) have been used in recent studies (13). Two recent trials have clearly addressed this matter. In the ALBION study, Montalescot and coworkers have demonstrated that a loading dose of 600 mg of clopidogrel achieves a better level of platelet inhibition than... 

In addition to the risk of bleeding, which will be detailed in the different studies, thienopyridines are able to cause skin disorders (rashes or prurit) and gastrointestinal disorders (diarrhea). In the CLASSICS study, these side effects were observed in 8.2% of patients treated with ticlopidine and in 3.5% of those taking clopidogrel treatment. The most serious problem was related to hematologic disorders neutropenia or thrombocytopenia. These disorders are much less frequent with clopidogrel than with ticlopidine 0.04% of neutropenia in the CAPRIE study and 0.05% in the CURE trial, Thrombotic thrombocytopenic purpura are exceptional one for 200,000 patients. 

This indication was considered in three trials. The first was the PCI-CURE study (44) (n = 2658 patients), a prespecified subgroup analysis of CURE. This trial studied the benefit of pretreatment with clopidogrel (median 10 days) before PCI. At one-month follow-up, there was a significant (P = 0.04) reduction of cardiovascular death and Ml (from 4.4% to 2.9%). 

ACS represents a prothrombotic state not just confined to the culprit lesion, with evidence of a pan coronary process and generalized platelet activation. Multiple vulnerable plaques in nonculprit vessels have been identified by angioscopy or intravascular ultrasound in ACS. Protracted treatment with clopidogrel induces antiplatelet activity that provides early benefits, and may limit thrombotic events within the following months. In the CURE study, the curves of major vascular events continue to diverge and showed an additional benefit from one-month follow-up to one year. 

CAPRIE (52) was a randomized, blinded, international study designed to assess the relative efficacy of clopidogrel... 

The study design included three comparisons ACTIVE W ACTIVE A, and ACTIVE I in 14,000 patients, (Maximum follow-up was for 48 months), The primary endpoint was the time to first vascular event (stroke, Ml, vascular death, systemic emboli). ACTIVE W arm was halted when 6600 patients were enrolled because there a clear benefit from warfarin treatment compared to clopidogrel + aspirin 3.63% of vascular events versus 5,64% (P = 0,0002). Subgroup analysis showed that these disappointing results were observed in patients on warfarin prior to study (HR = 1.5, P = 0.0006), but there was no difference between the two strategies—when the patients were not on warfarin prior to study (HR = 1.32, P = 0,17), Nevertheless, further results are awaited from the ACTIVE-A arm (ASA or ASA + clopidogrel) in patients who cannot or would not take OAC. 

Sabatine MS, Cannon CP Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics the PCI-CLARITY study. JAMA 2005 294 1224-1232. 

Bertrand ME, Rupprecht HJ, Urban R Gershlick AH, Investigators FT, Double-blind study ofthe safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000 102 624-629,... 

Antagonists of the ADP P2Y, 2 receptor, ticlopidine and its safer successor clopidogrel, are also potent inhibitors of platelet aggregation and have demonstrated their efficacy alone and on top of ASA in numerous in clinical studies. The results of the CAPRIE study, a large study involving 19,185 patients with recent Ml, stroke, or established peripheral arterial disease (PAD) demonstrated an 8.7% overall risk reduction versus ASA in the combined endpoints of the first occurrence of Ml, stroke, or other vascular death (30). 

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