Dual antiplatelet therapy in coronary artery disease: A case-based approach
ABSTRACTCurrent guidelines support dual antiplatelet therapy with aspirin and clopidogrel (Plavix) in a number of clinical scenarios, ie, in ST-segment-elevation myocardial infarction (MI), non-ST-elevation MI, and percutaneous coronary intervention. The guidelines are based on strong evidence from several large randomized clinical trials over the last 10 years. The authors present several cases to show how to put this evidence into day-to-day clinical practice.
KEY POINTS
- Dual antiplatelet therapy is recommended after ST-elevation MI or non-ST-elevation acute coronary syndromes, with aspirin indefinitely and clopidogrel for up to 1 year.
- Dual antiplatelet therapy is recommended for at least 1 month after placement of a bare-metal stent and for at least 1 year (or possibly indefinitely) after placement of a drug-eluting stent.
- There is no compelling indication for clopidogrel in patients with chronic coronary artery disease.
- Compared with clopidogrel, prasugrel (Effient) is associated with lower rates of MI, urgent target-vessel revascularization, and in-stent thrombosis, but at the cost of a higher risk of major bleeding.
CASE 4: HIGH-RISK CORONARY ARTERY DISEASE
A 67-year-old woman presents to your office to establish care. She has a history of diabetes and established coronary artery disease with two bare-metal stents placed 2 years ago. She is taking aspirin 81 mg.
What would be the value of adding clopidogrel to her regimen?
No indication for clopidogrel in chronic coronary artery disease
The CHARISMA trial (Clopidogrel for High Atherothrombotic and Ischemic Stabilization, Management, and Avoidance)23 randomized 15,603 patients with stable cardiovascular disease or multiple risk factors to receive either clopidogrel plus low-dose aspirin or placebo plus low-dose aspirin and followed them for a median of 28 months (Table 1).
The primary end point (a composite of MI, stroke, or death) was 6.8% with clopidogrel plus aspirin and 7.3% with aspirin alone, indicating no significant benefit with clopidogrel plus aspirin compared with aspirin alone in reducing the rate of MI, stroke, or cardiovascular death in patients with high-risk but stable atherothrombotic disease. A marginal statistical benefit with dual antiplatelet therapy was noted in the subgroup of patients with previously documented coronary, cerebrovascular, or peripheral vascular disease—6.9% with aspirin plus clopidogrel vs 7.9% with aspirin alone (relative risk 0.88; 95% CI 0.77–0.998; P = .046).
Consequently, there is no compelling reason to start clopidogrel in this patient.
PRASUGREL, THE NEWEST THIENOPYRIDINE
Prasugrel was recently approved by the FDA as antiplatelet treatment for patients with acute coronary syndromes planning to undergo a percutaneous coronary intervention.24 It has been shown to inhibit adenosine-diphosphate-induced platelet activation in a more consistent and effective manner than clopidogrel.25,26
Although both clopidogrel and prasugrel are prodrugs, 80% of absorbed clopidogrel is metabolized by esterases into inactive metabolites, and the availability of active metabolite can vary, as it is significantly influenced by polymorphisms in the cytochrome P450 system. 27 In contrast, prasugrel is not degraded by esterases, and its conversion to active metabolite by the cytochrome P450 system is not influenced by common genetic polymorphisms, particularly CYP2C19*2.
TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) provided most of the evidence for the approval of prasugrel for clinical use.28,29 In this trial, a 60-mg loading dose of prasugrel followed by a daily maintenance dose of 10 mg was significantly superior to the current clopidogrel regimen in preventing death from cardiovascular causes, nonfatal MI, or nonfatal stroke during a study period of 15 months.28 Also observed was a 24% lower rate of MI, a 34% lower rate of urgent target-vessel revascularization, and a 52% lower rate of stent thrombosis.
These benefits, however, came at the cost of a significantly higher risk of major bleeding, including the potential for three excess fatal bleeding events for every 1,000 patients treated. Patients at highest risk at the dosages evaluated included the elderly (age 75 and older), patients who weigh less than 60 kg, and patients with a history of stroke or transient ischemic attack. Based on these results, we recommend caution with the use of prasugrel in these patient subsets.
Clinical use of prasugrel is likely to be highest in patients presenting with ST-elevation MI who are undergoing a primary percutaneous coronary intervention. There is currently no evidence from any randomized clinical trial to support the safety of prasugrel given in the emergency room or “upstream” in the setting of non-ST-elevation acute coronary syndromes.
Of note, patients with non-ST-elevation acute coronary syndromes in the TRITON trial were randomized only after angiographic definition. As a result, only 179 patients exposed to prasugrel were referred for coronary artery bypass surgery, but the rate of surgery-related major bleeding in this group was 13.4% (vs 3.2% in the clopidogrel group). Based on these data, prasugrel should be withheld for at least 1 week prior to any surgery.
