Pharmacology Update

Ticagrelor Tablets (Brilinta™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A third oral antiplatelet inhibitor has been approved by the FDA to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). Ticagrelor is an adenosine diphosphate receptor P2Y12 inhibitor similar to clopidogrel and prasugrel. It is marketed by AstraZeneca as Brilinta.

Indications

Ticagrelor is indicated to reduce the rate of thrombotic cardiovascular events in patients with ACS.1 These include unstable angina (UA), ST (STEMI), or non-ST (NSTEMI) elevation myocardial infarction.

Dosage

The recommended dose is 180 mg as a loading dose along with 325 mg of aspirin,1 followed by ticagrelor, 90 mg twice daily and aspirin (75-100 mg) daily.

Ticagrelor is available as 90 mg tablets.

Potential Advantages

Ticagrelor is more effective than clopidogrel in reducing the combined endpoint of cardiovascular death, myocardial infarction, or stroke.1 In contrast to clodidogrel, ticagrelor is not a prodrug and is not dependant on gene-based metabolism to activate the drug.

Potential Disadvantages

Ticagrelor is associated with a higher rate (compared to clopidogrel) of non-coronary artery bypass surgery (CABG)-related major bleeding (4.5% vs. 3.8%, P = 0.03) and more episodes of intracranial bleeding (0.3% vs. 0.2%, P = 0.06), including fatal intracranial bleeding (0.1% vs 0.01%, P = 0.02).2 Dyspnea is reported more frequently with ticagrelor (13.8% vs 7.8%, P < 0.001). Ticagrelor is dosed twice daily compared to once daily dosing for clopidogrel and ticagrelor.

Comments

Ticagrelor is a reversible adenosine diphosphate receptor P2Y12 inhibitor compared to clopidogrel and prasugrel which are irreversible inhibitors. Ticagrelor has a higher maximum inhibition of platelet aggregation than clopidogrel but a faster offset leading to faster platelet recovery.1,3 After 6 weeks of therapy, the mean maximum inhibition of platelet aggregation (IPA) was 88% for ticagrelor and 62% for clopidogrel. Twenty-four hours after the last dose, mean IPA was similar between drugs, but after 48 hours, mean IPA was significantly lower with ticagrelor.

The efficacy and safety of ticagrelor compared to clopidogrel was studied in a large, randomized, double-blind study (n = 18,624; the Study of Platelet Inhibition and Patient Outcome [PLATO]).2 Patients hospitalized for an ACS were randomized to clopidogrel (300 mg loading dose followed by 75 mg daily) or ticagrelor (180 mg loading dose followed by 90 mg twice daily) for 12 months. All patients received aspirin (75-100 mg daily) unless they were intolerant (97% were on aspirin after randomization). The primary efficacy endpoint was time to the first occurrence of a composite of death from vascular causes, myocardial infarction, or stroke. A secondary efficacy analysis included the subgroup in which invasive management was planned at randomization. The ACS breakdown was 43% for NSTEMI, 38% STEMI, and 17% UA. The primary safety endpoint was the first occurrence of any major bleeding event (e.g., fatal bleeding, intracranial bleeding). At 12 months, the composite endpoint occurred in 9.8% of patients randomized to ticagrelor and 11.7% of patients randomized to clopidogrel (hazard ratio [HR], 0.84, 95% CI, 0.77, 0.92, P < 0.001). There was no difference in major bleeds (11.6% and 11.2%, respectively). There was a higher rate of major bleeds not associated with CABG and intracranial bleeds as well as fatal intracranial bleeds with ticagrelor. Benefit was seen for patients who planned for invasive management as well as noninvasive (medical) management. HRs (95% CI) were 0.84 (0.75, 0.94) and 0.85 (0.73, 1.00).4,5

A retrospective analysis of subjects who underwent CABG suggested that total and cardiovascular mortality were reduced with ticagrelor compared to clopidogrel.6 In the United States subgroup of the PLATO trial (n = 1413), subjects on ticagrelor had a higher rate of composite endpoints compared to clopidrogrel (12.6% vs 10.1), HR 1.27 (0.92, 1.75). A similar trend was observed in Canadian subjects (n = 401).5 FDA reviewers speculated that use of higher aspirin doses may be an explanation for the conflicting results although they suggest that there may potentially be multiple confounders and/or effect modifiers, including different baseline factors.5

Clinical Implications

Both ticagrelor and prasugrel have been shown to be more effective than clopidogrel in large studies, PLATO and TRITON TIMI.2,7 While there are no head-to-head comparisons between ticagrelor and prasugrel, an indirect comparison suggests similar efficacy between the two drugs.8 The conflicting North American results cast some concern about ticagrelor.

References

1. Brilinta prescribing Information. Wilmington, DE: AstraZeneca; July 2011.

2. Wallentin L, et al. Ticagrelor versus clopidogrel in pa-tients with acute coronary syndromes. N Engl J Med 2009;361:1045-1057.

3. Storey RF. Earlier recovery of platelet function after discontinuation of treatment with ticagrelor compared to clopidogrel in patients with high antiplatelet responses. J Thromb Haemost 2011; Jun 25. doi:10.1111/j.1538-7836.2011.044419.x. [Epub ahead of print]

4. James SK, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: Substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. BMJ 2011;342:d3527.doi:10.1136/bmj.d3527.

5. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Cardiovascular- andRenalDrugsAdvisoryCommittee/UCM221383.pdf. Accessed August 3, 2011.

6. Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: Results from the PLATO trial. J Am Coll Cardiol 2011;57:672-684.

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

8. Biondi-Zoccai G, et al. Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes. Int J Cardiol 2011;150:325-331.