A Cogent Discussion of Prasugrel and Neurologic Concerns

While I have not tended to use this space to indicate my opinions about the opinions of others, this will be an exception. Prasugrel (trade name Effient) was recently approved by the FDA for a very narrow indication: Percutaneous coronary intervention patients with unstable angina, or MI with or without ST segment elevation. In such patients, the risk of subsequent non-fatal MI was reduced from 9.1% to 7.0%. This is a clinically significant reduction.

This agent is another platelet ADP receptor inhibitor, in the same class as clopidogrel (Plavix). The manufacturer posits that prasugrel is a significant advance as it mitigates the variability in response seen in some patients taking clopidogrel. Prasugrel metabolism is reportedly more efficient, and possibly more consistent, leading to a higher degree of platelet aggregation inhibition. This results in a higher degree of efficacy in PCI patients, but also a higher hemorrhage risk.

These concerns are well dissected in a NEJM editorial. The primary focus is a comparative trial of prasugrel v. clopidogrel, added to aspirin. The author discusses a number of important concerns. One is the required duration of antiplatelet therapy, as a comparison trial between prasugrel and clopidogrel was of 15 months' duration. However, it is not clear that increasing the duration increases efficacy. Also well covered are issues of differences in response in low weight and older patients, and availability of various doses to address this.

However, In my opinion, the biggest concern is hemorrhage. An excess fatal hemorrhage rate of 3/1000 was seen in the prasugrel group. And, the major hemorrhage rate in patients who progress from PCI to CABG was over four times higher in the prasugrel group: 13.4% v. 3.2%. Of particular neurologic interest: Patients with a history of symptomatic cerebrovascular disease (including stroke) and older patients had a significantly higher intracranial hemorrhage risk compared to the entire cohort. The author recommends avoiding adjunctive prasugrel use in patients with a history of cerebrovascular disease.

Another concern: Prasugrel requires the Cytochrome P450 3A4 enzyme for activation. Whether there will be problematic drug-drug interactions with many calcium channel agents, azole antifungal agents, and other commonly used 3A4 inhibitors remains to be seen. It often takes time for problems related to drug to drug interactions to become evident with new drugs.

The FDA was careful to approve this drug for only a well circumscribed set of indications. Despite this, there is already a material "buzz" in neurologic circles about this agent and its possible application for stroke prevention and other such uses. Some such discussions do not seem to properly account for the hemorrhage risk, the lack of data in stroke, or the excess hemorrhage rates in stroke patients in the comparative trial. I do hope that neurologists and primary care providers who elect to prescribe prasugrel off-label for neurologic indications avail themselves of the important data about these concerns.