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.
Phase 3 trial of prasugrel vs clopidogrel: TRITON-TIMI 38
Only one large phase 3 trial of prasugrel has been completed: TRITON-TIMI 38 (the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction),17 which enrolled adults with moderate-risk to high-risk acute coronary syndromes scheduled to undergo a percutaneous coronary intervention. In this trial, 10,074 patients were enrolled who had moderate-to high-risk unstable angina or non-ST-elevation MI, and 3,534 patients were enrolled who had ST-elevation MI.
Patients were randomized to receive prasugrel (a 60-mg loading dose, then 10 mg daily) or clopidogrel (a 300-mg loading dose, then 75 mg daily) and were treated for 6 to 15 months. All patients also received aspirin.
These benefits came at a price of more bleeding. Of those patients who did not undergo coronary artery bypass grafting, more experienced bleeding in the prasugrel group than in the clopidogrel group (2.4% vs 1.8%, P = .03), including a higher rate of life-threatening bleeding (1.4% vs 0.89%, P = .01) and fatal bleeding (0.4% vs 0.1%, P = .002). More patients discontinued prasugrel because of hemorrhage (2.5% vs 1.4%, P < .001). In patients who proceeded to coronary artery bypass grafting, the rate of major bleeding was more than four times higher in those who received prasugrel than in those who received clopidogrel (13.4% vs 3.2%, P < .001).
A higher rate of adverse events related to colon cancer was also noted in patients treated with prasugrel, although the authors suggest this may have resulted from the stronger antiplatelet effects of prasugrel bringing more tumors to medical attention due to bleeding.
Overall death rates did not differ significantly between the treatment groups.
In a post hoc analysis,18 prasugrel was superior to clopidogrel in preventing ischemic events both during the first 3 days following randomization (the “loading phase”) and for the remainder of the trial (the “maintenance phase”). Whereas bleeding risk was similar with the two drugs during the loading phase, prasugrel was subsequently associated with more bleeding during the maintenance phase.
Certain patient subgroups had no net benefit or even suffered harm from prasugrel compared with clopidogrel.17 Patients with previous stroke or transient ischemic attack had net harm from prasugrel (hazard ratio 1.54, P = .04) and showed a strong trend toward a greater rate of major bleeding (P = .06). Patients age 75 and older and those weighing less than 60 kg had no net benefit from prasugrel.
Cost of prasugrel
Prasugrel is currently priced at 18% more than clopidogrel, with average wholesale prices per pill of $6.65 for prasugrel 10 mg compared with $5.63 for clopidogrel 75 mg. (Prasugrel 10-mg pills cost $6.33 at drugstore.com or $7.60 at CVS; clopidogrel 75-mg pills cost $5.33 at drugstore.com or $6.43 at CVS.) The patent on clopidogrel expires in November 2011, after which the price differential is expected to become significantly greater.
TICAGRELOR, A REVERSIBLE ORAL AGENT
Ticagrelor, the first reversible oral P2Y12 receptor antagonist, is an alternative to thienopyridine therapy for acute coronary syndromes.
Ticagrelor is quickly absorbed, does not require metabolic activation, and has a rapid antiplatelet effect and offset of effect, which closely follow drug-exposure levels. In a large randomized controlled trial in patients with acute coronary syndromes with or without STsegment elevation, treatment with ticagrelor compared with clopidogrel resulted in a significant reduction in death from vascular causes, MI, or stroke (9.8% vs 11.7%).19
Given its reversible effect on platelet inhibition, ticagrelor may be preferred in patients whose coronary anatomy is unknown and for whom coronary artery bypass grafting is deemed probable. It is still undergoing trials and is not yet approved.
