Prasugrel for acute coronary syndromes: Faster, more potent, but higher bleeding risk
ABSTRACTPrasugrel (Effient) has been approved for reducing the risk of thrombotic complications in patients with acute coronary syndromes who are to undergo percutaneous coronary intervention. In a large clinical trial (N Engl J Med 2007; 357:2001–2005), prasugrel was superior to clopidogrel (Plavix), another drug of its class, in this situation. However, bleeding complications were more frequent with prasugrel, and so this drug should be avoided in patients at higher risk of bleeding.
KEY POINTS
- The thienopyridines—ticlopidine (Ticlid), clopidogrel (Plavix), and now prasugrel—reduce the risk of death from and serious complications of acute coronary syndromes by inhibiting platelet aggregation.
- Compared with clopidogrel, prasugrel is more potent, faster in onset, and more consistent in inhibiting platelets.
- Prasugrel should be avoided in patients at higher risk of bleeding, including those with a history of stroke or transient ischemic attack, those age 75 or older, or those who weigh less than 60 kg.
PRASUGREL, THE NEWEST THIENOPYRIDINE
Prasugrel, FDA-approved in July 2009 for the treatment of acute coronary syndromes, is given in an oral loading dose of 60 mg followed by an oral maintenance dose of 10 mg daily.
Pharmacology of prasugrel vs clopidogrel
As noted previously, the thienopyridines are prodrugs that require hepatic conversion to exert antiplatelet effects.
Metabolism. Prasugrel’s hepatic activation involves a single step, in contrast to the multiple-step process required for activation of clopidogrel. Clopidogrel is primarily hydrolyzed by intestinal and plasma esterases to an inactive terminal metabolite, with the residual unhydrolized drug undergoing a two-step metabolism that depends on cytochrome P450 enzymes. Prasugrel is also extensively hydrolyzed by these esterases, but the intermediate product is then metabolized in a single step to the active sulfhydryl compound, mainly by CYP3A4 and CYP2B6.
Thus, about 80% of an orally absorbed dose of prasugrel is converted to active drug, compared with only 10% to 20% of absorbed clopidogrel.
Time to peak effect. With clopidogrel, maximal inhibition of platelet aggregation occurs 3 to 5 days after starting therapy with 75 mg daily without a loading dose, but within 4 to 6 hours if a loading dose of 300 to 600 mg is given. In contrast, a prasugrel loading dose produces more than 80% of its platelet inhibitory effects by 30 minutes, and peak activity is observed within 4 hours.12 The platelet inhibition induced by prasugrel at 30 minutes after administration is comparable to the peak effect of clopidogrel at 6 hours.13
Dose-response. Prasugrel’s inhibition of platelet aggregation is dose-related.
Prasugrel is about 10 times more potent than clopidogrel and 100 times more potent than ticlopidine. Thus, treatment with 5 mg of prasugrel results in inhibition of platelet activity (distributed in a gaussian curve) very similar to that produced by 75 mg of clopidogrel. On the other hand, even a maintenance dose of 150 mg of clopidogrel inhibits platelet activity to a lesser degree than 10 mg of prasugrel (46% vs 61%),14 so clopidogrel appears to reach a plateau of platelet inhibition that prasugrel can overcome.
At the approved dose of prasugrel, inhibition of platelet aggregation is significantly greater and there are fewer “nonresponders” than with clopidogrel.
Interactions. Drugs that inhibit CYP3A4 do not inhibit the efficacy of prasugrel, but they can inhibit that of clopidogrel. Some commonly used drugs that have this effect are the statins (eg, atorvastain [Lipitor]) and the macrolide antibiotics (eg, erythromycin). Furthermore, whereas proton pump inhibitors have been shown to diminish the effect of clopidogrel by reducing the formation of its active metabolite, no such effect has been noted with prasugrel.
Prasugrel in phase 2 trials: Finding the optimal dosage
A phase 2 trial compared three prasugrel regimens (loading dose/daily maintenance dose of 40 mg/7.5 mg, 60 mg/10 mg, and 60 mg/15 mg) and standard clopidogrel therapy (300 mg/75 mg) in patients undergoing elective or urgent percutaneous coronary intervention.15 No significant difference in outcomes was seen in the groups receiving the three prasugrel regimens. However, more “minimal bleeding events” (defined by the criteria of the TIMI trial16) occurred with high-dose prasugrel than with lower-dose prasugrel or with clopidogrel, leading to use of the intermediate-dose prasugrel regimen (60-mg loading dose, 10-mg daily maintenance) for later trials.
Another phase 2 trial randomized 201 patients undergoing elective percutaneous coronary intervention to receive prasugrel 60 mg/10 mg or clopidogrel 600 mg/150 mg.14 In all patients, the loading dose was given about 1 hour before cardiac catheterization. As soon as 30 minutes after the loading dose, platelet inhibition was superior with prasugrel (31% vs 5% inhibition of platelet aggregation), and it remained significantly higher at 6 hours (75% vs 32%) and during the maintenance phase (61% vs 46%).
