Antiplatelet Options for Secondary Stroke Prevention

This article was updated on November 16, 2017.

All antiplatelets are not created equal, especially when it comes to secondary stroke prevention.

There are 4 options for antiplatelet therapy: aspirin; clopidogrel; prasugrel; and ticagrelor. All are approved for use in acute coronary syndrome but have varying other therapeutic intricacies, especially for use after ischemic stroke or transient ischemic attack (TIA).

Aspirin

Aspirin has been the mainstay therapy for secondary prevention of stroke after noncardioembolic ischemic stroke or TIA in patients without any other compelling comorbidity. It is an irreversible platelet inhibitor with inhibition onset about 1 hour after administration of immediate-release tablets and duration of action of about 10 days, the lifetime of the platelet.

The American College of Chest Physicians recommends a loading dose of 160 mg to 325 mg, followed by 75 mg to 100 mg, once daily. The American Heart Association/American Stroke Association recommend an initial dose of 325 mg within 24 to 48 hours after a stroke but don’t reference a maintenance dose in their guidelines.

Clopidogrel (Plavix)

Clopidogrel is an irreversible P2Y12 inhibitor. Because it is a prodrug activated by CYP2C19, patients with reduced function of this enzyme would be at risk of decreased antiplatelet efficacy.

P2Y12 inhibition can be monitored through a platelet function test that should be interpreted carefully. A higher platelet function would correlate to lower platelet inhibition and P2Y12 activity.

Clopidogrel gained FDA approval for secondary stroke prevention in 2013 after the CHANCE trial showed superiority of combination clopidogrel/aspirin therapy over aspirin monotherapy for secondary prevention of ischemic or hemorrhagic stroke. The safety endpoint was severe hemorrhage, which was 0.3% in both groups. Notably, the trial did not address any potential genetic polymorphisms of the CYP2C19 allele in patients receiving clopidogrel and did not perform P2Y12 platelet function tests.¹

Prasugrel (Effient)

Unlike clopidogrel and prasugrel, ticagrelor is orally active and does not have to undergo metabolism from prodrug to active form. It does, however, have drug CYP3A4 drug interactions to consider, including strong inducers and inhibitors that decrease or increase the effectiveness of the drug.

Prasugrel is contraindicated in patients with a history of stroke or TIA because of the increased risk of significant or fatal bleeding, which was established in the 2007 TRITON-TIMI-38 trial comparing dual antiplatelet therapy of prasugrel/aspirin with clopidogrel/asirin in more than 13,000 patients. The rate of major hemorrhage unrelated to coronary artery bypass grafting was higher in the prasugrel group than the clopidogrel group and included a significantly higher rate of life-threatening bleeding in the prasugrel group. Fatal major bleeding also occurred more often in the prasugrel group.²

Ticagrelor (Brilinta)

Ticagrelor is different from the other antiplatelet therapies in that it is a reversible P2Y12 inhibitor. Like clopidogrel and prasugrel, however, it is a prodrug and must be activated by CYP3A4 or CYP3A5, which poses problems for potential drug interactions. The reversibility of ticagrelor is convenient perioperatively, decreasing the amount of time that patients need to be without their antiplatelet.

The 2016 SOCRATES trial compared the use of ticagrelor/aspirin with aspirin monotherapy in more than 13,000 patients for secondary stroke prevention after an acute ischemic stroke or TIA. In it, ticagrelor was shown to be nonsuperior to aspirin for the prevention of stroke (ischemic or hemorrhagic), myocardial infarction, or death at 90 days of treatment. These primary events occurred less often in the ticagrelor group, but this result was insignificant. Meanwhile, the safety endpoint of major bleeding was similar in both groups.³

Secondary stroke prevention is an extremely important topic, as about 1 in 4 patients who have a stroke or TIA will experienced a second event within their lifetime, and the risk is even higher in the first 90 days. Although the best secondary prevention method is still unclear, it is important to know the differences among the available products.

References

1. Wang Y, Want Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-19.

2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

3. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375:35-43.