Ticlopidine is approved for prevention of stroke in patients with a history of a transient ischemic attack (TIA) or thrombotic stroke, and in combination with aspirin for prevention of coronary stent thrombosis. Adverse effects of ticlopidine include nausea, dyspepsia, and diarrhea in up to 20% of patients, hemorrhage in 5%, and, most seriously, leukopenia in 1%. The leukopenia is detected by regular monitoring of the white blood cell count during the first 3 months of treatment. Development of thrombotic thrombocytopenic purpura has also been associated with the ingestion of ticlopidine. The dosage of ticlopidine is 250 mg twice daily orally. Because of the significant side effect profile, the use of ticlopidine for stroke prevention should be restricted to those who are intolerant of or have failed aspirin therapy. Dosages of ticlopidine less than 500 mg/d may be efficacious with fewer adverse effects.
Clopidogrel is approved for patients with unstable angina or non-ST-elevation acute myocardial infarction (NSTEMI) in combination with aspirin; for patients with ST-elevation myocardial infarction (STEMI); or recent myocardial infarction, stroke, or established peripheral arterial disease. For NSTEMI, the dosage is a 300-mg loading dose orally followed by 75 mg daily of clopidogrel, with a daily aspirin dosage of 75–325 mg. For patients with STEMI, the dosage is 75 mg daily of clopidogrel orally, in association with aspirin as above; and for recent myocardial infarction, stroke, or peripheral vascular disease, the dosage is 75 mg/d.
Clopidogrel has fewer adverse effects than ticlopidine and is rarely associated with neutropenia. Thrombotic thrombocytopenic purpura has been reported. Because of its superior adverse effect profile and dosing requirements, clopidogrel is frequently preferred over ticlopidine. The antithrombotic effects of clopidogrel are dose-dependent; within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. The maintenance dosage of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. The duration of the antiplatelet effect is 7–10 days. Clopidogrel is a prodrug that requires activation via the cytochrome P450 enzyme isoform CYP2C19. Depending on the single nucleotide polymorphism (SNP) inheritance pattern in CYP2C19, individuals may be poor metabolizers of clopidogrel, and these patients may be at increased risk of cardiovascular events due to inadequate drug effect. The FDA has recommended CYP2C19 genotyping to identify such patients and advises prescribers to consider alternative therapies in poor metabolizers (see Chapter 5). However, more recent studies have questioned the impact of CYP2C19 metabolizer status on outcomes. Drugs that impair CYP2C19 function, such as omeprazole, should be used with caution.