OCTOBER 25, 2010
Anna D. Garrett, PharmD, BCPS, CPP
Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes
Clopidogrel and aspirin are widely used for patients who have acute coronary syndromes or are undergoing percutaneous coronary intervention (PCI). Evidence-based guidelines for dosing have not been established for either agent, however.
A recent study randomly assigned 25,086 patients with an acute coronary syndrome who were referred for an invasive procedure to 1 of 2 clopidogrel/ aspirin dosages. Primary outcomes were cardiovascular death, myocardial infarction (MI), or stroke at 30 days. Patients received either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either highdose aspirin (300 to 325 mg daily) or lowdose aspirin (75 to 100 mg daily).
The primary outcomes occurred in 4.2% of patients assigned to doubledose clopidogrel, compared with 4.4% assigned to standard-dose clopidogrel. Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group. Doubledose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI. There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% and 4.4%, respectively) or major bleeding.
The authors concluded there was no significant difference between a 7-day double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the outcomes of cardiovascular death, MI, or stroke.
Dabigatran (Pradaxa) Endorsed After RE-LY trial
An FDA advisory panel has voted unanimously to recommend approval of dabigatran etexilate for prevention of stroke related to atrial fibrillation (AF). Dabigatran will offer the first new treatment option for stroke prevention in 50 years and will likely replace warfarin in a significant number of patients. The drug was approved based on data from the 18,000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, which compared warfarin administration with that of 2 doses of dabigatran (110 mg twice daily and 150 mg twice daily).
The RE-LY trial showed that use of dabigatran twice daily was noninferior to warfarin at the lower dose and superior at a higher dose for preventing stroke in patients with an irregular heartbeat. Warfarin is the oldest, most widely used, and one of the most effective drugs for prevention of ischemic stroke.
According to the researchers, the 110-mg dose of dabigatran was linked to fewer bleeding events than warfarin, while the 150-mg dose was associated with about the same bleeding risks, although the bleeds tended to be less serious than those seen with warfarin.
There is still controversy regarding which dose should be approved. Six members of the panel favored approval of both doses, whereas 4 supported the higher dose.
From a practical standpoint, questions remain about the consequences of nonadherence and pricing. Dabigatran is expected to be significantly more expensive than warfarin. A final FDA decision is expected in the next month.
Approval Issued for Generic Low-Molecular-Weight Heparin
Over the objections of several experts and professional organizations involved in anticoagulation and patient safety, the FDA has issued to approve a new low-molecular-weight heparin (LMWH) product. The drug is classified as the generic equivalent of, and interchangeable with, Lovenox (enoxaparin).
There is considerable controversy on this issue, most of which centers around the complexity of the manufacturing process and the potential for immune-mediated adverse effects.
According to experts, it is possible that different LMWHs produced from different sources of unfractionated heparin through different production methods may yield products that have different efficacy, safety, and immunogenicity profiles. These differences cannot be determined in the absence of clinical trials.
Sanofi-aventis filed a lawsuit immediately after the decision requesting that the FDA suspend and withdraw its approval of the generic product. A judge has denied the injunction; however, a final decision is pending.
Dr. Garrett is manager of the Health Education Center at Mission Hospitals in Asheville, North Carolina.