2011 American Society of Consultant Pharmacists (ASCP) Annual Meeting and Exhibition: Page 2 of 2

January 16, 2012

Brilinta for Acute Coronary Syndrome

The US Food and Drug Administration (FDA) approved Brilinta (ticagrelor) in July 2011 to improve cardiac outcomes in patients with acute coronary syndrome (ACS). In a product theater sponsored by AstraZeneca and held at the 2011 ASCP annual meeting, associate professor of pharmacy practice Zachary Stacy, PharmD, BCPS, St. Louis College of Pharmacy, MO, said the blood-thinning agent is poised to challenge Plavix (clopidogrel) and Effient (prasugrel) and change the management of cardiovascular disease in patients with ACS. Stacy reviewed Brilinta’s prescribing information and clinical evidence supporting its use in ACS.

Approval was largely based on data from PLATO (Platelet Inhibition and Patient Outcomes), a multicenter, double-blind, randomized trial (N=18,624). The trial compared the effectiveness of Brilinta versus Plavix in preventing cardiovascular events in patients with ACS with or without ST-segment elevation. After 6 to 12 months, Brilinta reduced the rate of myocardial infarction and cardiovascular death (the composite endpoint) by 16%, which Stacy said was significant. No difference in stroke risk was found between the agents.

Patients were randomized to a 180-mg loading dose of Brilinta followed by a 90-mg maintenance dose twice daily or to a 300- to 600-mg loading dose of Plavix followed by a 75-mg maintenance dose. Patients able to tolerate aspirin also received a 75- to 100-mg dose of aspirin. Stacy said a subgroup analysis favored restricting the concomitant dose of aspirin to <100 mg to avoid diminishing the effectiveness of Brilinta. The rate of dyspnea was higher in the Brilinta group compared with the Plavix group (14% vs 8%, respectively), but she said few patients in either group discontinued the study because of dyspnea, which was generally mild to moderate in intensity and resolved with continued treatment.

PLATO researchers had excluded patients with an increased risk of bradycardic events because Brilinta has the potential to increase the occurrence of bradyarrhythmias, including ventricular pauses. A post hoc analysis of data for a subset of 3000 patients enrolled in PLATO found that patients taking Brilinta were more likely to have ventricular pauses than were patients randomized to Plavix in the trial’s acute phase (6% vs 3.5%, respectively); after 1 month of therapy, rates dropped to 2.2% and 1.6%, respectively.

Stacy said that, unlike its competitors, Brilinta and its major metabolite (AR-C124910XX) are equipotent and reversibly interact with the adenosine diphosphate platelet P2Y12 receptor to prevent signal transduction. Median time to peak plasma concentration can occur as early as 2 hours after dosing.

Like other antiplatelet agents, Brilinta is associated with an increased risk of minor and major bleeding events. However, PLATO researchers observed no statistically significant difference between Brilinta and Plavix on any of the secondary bleeding endpoints, including major life-threatening bleeding events (11.6% vs 11.2%, respectively). About half the bleeding events occurred within the first 30 days of starting therapy. A trend toward increased risk of bleeding during a noncoronary artery bypass graft (CABG) procedure was reported with Brilinta, but Stacy said this was not significant.

For patients with ACS initiating therapy with Brilinta, prescribing instructions recommend a 180-mg loading dose (two 90-mg tablets) followed by maintenance therapy of 90 mg twice daily. For aspirin-tolerant patients, a loading dose of 325 mg is recommended followed by a lower maintenance dose of 75 mg to 100 mg per day; Stacy emphasized that the daily dose of aspirin should not exceed 100 mg. She noted that patients with ACS who have already received a loading dose of Plavix can be treated with Brilinta. If a patient routinely taking Brilinta misses a dose, he or she should receive the next dose at the scheduled time. Brilinta can be administered with or without food.

Based on PLATO’s findings, the FDA has required black box warnings for Brilinta related to bleeding risk, especially when coronary artery bypass graft surgery is planned, there is concomitant use of aspirin, or dyspnea is present. Because Brilinta undergoes hepatic metabolism primarily by the CYP3A4/5 enzyme, the package insert warns against using Brilinta with CYP3A inhibitors and potent CYP3A inducers and with simvastatin or lovastatin doses >30 mg. Clinicians should also monitor patient’s digoxin levels when initiating or changing therapy with Brilinta, due to the risk of inhibition of the P-glycoprotein transporter.

—David Despain

This product theater was sponsored by Astra Zeneca.