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Ticagrelor: A review of the data leading to FDA approval
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The thienopyridines clopidogrel and ticlopidine, along with aspirin, have been the mainstay of antiplatelet therapy in patients with acute coronary syndromes.
 Zachary A. Stacy |
 Valerie Raney |
However, ticlopidine (Ticlid, Roche) use has been limited because of its hematologic adverse effects, including neutropenia. Several limitations are now recognized with clopidogrel (Plavix, Sanofi-Aventis), including the need for early discontinuation before surgery and variable efficacy due to genetic abnormalities and drug interactions. A new thienopyridine, prasugrel (Effient, Eli Lilly), was approved in 2009 by the FDA. However, similar to the other thienopyridines, it requires conversion by the liver to an active moiety. Prasugrel also has a box warning for stroke due to an increase in death, along with an increased risk for bleeding in underweight (<60 kg) and elderly patients (>75 years).
Ticagrelor (Brilinta, AstraZeneca), a cyclopentyl-triazolo-pyrimidine, is a new antiplatelet agent with structural similarities to adenosine. Ticagrelor reversibly inhibits the P2Y12 receptors on platelets, preventing platelet activation and, consequently, aggregation. Unlike the thienopyridines, it does not require metabolic activation. The onset of action is 1.5 to 3 hours, with a steady state reached in 2 to 3 days, and an elimination half-life of 6 to 13 hours. This pharmacokinetic profile may translate into clinical advantages over clopidogrel, including a faster time to steady state and shorter time for reversal. Besides bleeding, several unique adverse effects were observed in ticagrelor clinical trials. Dyspnea, ventricular pauses of at least 3 seconds, and hyperuricemia are likely attributed to the structural similarity to adenosine.
Comparisons in trials
In the DISPERSE-2 trial, ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily and clopidogrel 300 mg once, followed by 75 mg daily, were compared to assess the safety and tolerability of ticagrelor. Rates of protocol-defined major or minor bleeding at 4 weeks were not significantly different between ticagrelor 90 mg (9.8%; P=.43), ticagrelor 180 mg (8%; P=.96) and clopidogrel (8.1%). However, this study found statistically significant increased rates of dyspnea and asymptomatic ventricular pauses with ticagrelor compared with clopidogrel.
The ONSET/OFFSET study compared ticagrelor 180 mg loading dose followed by 90 mg twice daily and clopidogrel 600 mg loading dose followed by 75 mg daily. The study found a greater inhibition of platelet aggregation (IPA) with ticagrelor within 24 hours (P<.0001) and 6 weeks (P<.0001) compared with clopidogrel. With regard to offset, those treated with ticagrelor had a lower IPA 72 to 120 hours after the last dose (P≤.05), but no differences between the groups were observed thereafter.
The RESPOND trial was a randomized, crossover investigation comparing ticagrelor and clopidogrel in patients with stable CAD identified as non-responders or responders to a prior dose of clopidogrel. Patients received either ticagrelor 180 mg loading dose followed by 90 mg twice daily or clopidogrel 600 mg loading dose followed by 75 mg daily. The primary outcome was the proportion of clopidogrel non-responders who responded to ticagrelor based on platelet aggregation measurements 4 hours after the last dose. In the non-responder cohort, more patients responded to ticagrelor than to clopidogrel (75% vs. 13%, P<.001). This study demonstrated that ticagrelor provides antiplatelet activity in patients who are not responsive to clopidogrel.
PLATO trial and FDA approval
The PLATO study compared ticagrelor 180 mg loading dose followed by ticagrelor 90 mg twice daily and clopidogrel 300 mg loading dose followed by clopidogrel 75 mg daily. PLATO enrolled more than 18,000 patients, all of whom had been diagnosed with ACS and who had received aspirin. The primary outcome, a composite of death from vascular causes, MI or stroke at 12 months, occurred in 9.8% of patients taking ticagrelor vs. 11.7% of patients given clopidogrel (HR=0.84; 95% CI, 0.77-0.92). This finding was driven by a significant reduction in MI and death from vascular causes; there was no difference in reduction of stroke. No differences in major bleeding (P=.43) or overall life-threatening/fatal bleeding (P=.70) were observed. However, ticagrelor was associated with more non-intracranial fatal bleeding (0.1% vs. 0.3%, P=.03) and fatal intracranial bleeding (0.1% vs. 0.01%, P=.02). Other adverse effects that occurred more often with ticagrelor included dyspnea (13.8% vs. 7.8%, P<.001); ventricular pauses of at least 3 seconds (5.8% vs. 3.6%, P=.01); hyperuricemia (14% vs. 7%, P<.001); and an increase in serum creatinine (10% vs. 8%, P<.001).
In 2010, the FDA postponed approval to better understand why patients treated with ticagrelor in the PLATO trial did worse based on the primary outcome in US centers compared with non-US centers (HR=1.25, 95% CI, 0.93-1.67). One proposed theory for this inconsistency includes the aspirin dose. The median dose of aspirin in the US patients was 325 mg daily compared with 100 mg daily in the non-US patients. Patients treated with 100 mg or less of aspirin (HR=0.77; 95% CI, 0.69-0.86) had a better outcome on ticagrelor compared with patients taking 300 mg or more (HR=1.45; 95% CI, 1.01-2.09). Clinicians should consider this clinically significant drug interaction when managing patients with ACS.
Ticagrelor was approved by the FDA in July with an indication to reduce the rate of thrombotic CV events in patients with ACS. Co-administration of low-dose aspirin is recommended with a box warning to avoid doses greater than 100 mg. Ticagrelor has shown promising pharmacokinetic advantages over clopidogrel, including a faster onset and shorter half-life. Although rapid, the offset is not immediate, so managing patients who require emergent surgery will still be challenging, with a 5-day washout period still encouraged. Clinicians should consider the role of ticagrelor by balancing the increased risk for bleeding with the significant reduction in vascular death and MI.
Zachary A. Stacy, PharmD, BCPS, is associate professor of pharmacy practice at the St. Louis College of Pharmacy; Valerie Raney, PharmD, is a clinical pharmacy specialist at St. Luke’s Hospital, Chesterfield, Mo.
Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board. For suggestions of future topics for this column, please contact Dr. Cooper-DeHoff, dehoff@cop.ufl.edu.
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Disclosure: Dr. Stacy serves on the speaker’s bureau for AstraZeneca and Bristol-Myers Squibb. Dr. Raney reports no relevant financial disclosures.