Regulatory Decision Summary for BRILINTA

A single pivotal trial was provided in this submission in support of the new indication (PEGASUS trial: 21,162 patients). Brilinta 60 mg and 90 mg, combined with ASA, were both shown to statistically significantly reduce the incidence of the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI) and stroke compared to ASA therapy alone. Both doses resulted in a similar extent of benefit. Each individual component (CV death, MI and stroke) contributed to the effect seen for the primary composite endpoint. The impact of Brilinta on the primary efficacy endpoint was shown to be comparable whether analysing the incidence from 1 to 360 days or from 361 days and onwards. The benefit of the Brilinta 60 mg dose combined with ASA was also reflected across the two secondary endpoints, with a numerical decrease in both CV death and all-cause mortality compared to ASA alone, but this did not reach statistical significance. For the Brilinta 90 mg dose combined with ASA, there was also a numerical decrease in CV deaths, but no impact on all-cause mortality, compared to ASA alone.

An increased incidence of TIMI (Thrombolysis In Myocardial Infarction - a risk score for bleeding) major bleedings was reported with Brilinta compared to ASA alone. There was however no excess of fatal bleeding, nor increase in the rate of intracranial hemorrhage. The higher incidence of major bleedings reported with Brilinta was therefore mostly due to an increased incidence of “other TIMI major bleedings”, known to be serious and clinically important, but manageable events. Dyspnea, bradycardia (including sinus bradycardia) and gout-related adverse events were more frequently reported with Brilinta than with ASA alone. The Brilinta Product Monograph (PM) already contains information in the Warnings and Precautions section about these events and mentions that caution should be exercised for some particular patient populations.

The 90 mg dose of Brilinta was shown to result in similar efficacy as the 60 mg dose, but resulted in a less favorable safety profile in terms of major bleedings, dyspnea events, and treatment discontinuation. Therefore, only the Brilinta 60 mg dose was considered acceptable for the proposed new indication. The benefit/risk analysis revealed that treating 1,000 patients for 3 years with Brilinta 60 mg instead of ASA alone is estimated to result in the prevention of 12 events of all-cause mortality, MI, or stroke, with no extra events of fatal bleeding or intracranial hemorrhage.

There was no evidence of benefit (no reduction in the primary composite endpoint of CV death, MI and stroke), but an increase in major bleedings when Brilinta 60 mg twice daily was introduced in clinically stable patients more than 2 years after the qualifying MI, or more than one year after stopping previous adenosine diphosphate (ADP) receptor antagonist treatment. This also resulted in numerical increases in CV deaths and all-cause mortality. Therefore, treatment initiation should occur within two years from MI or within one year from previous use of ADP receptor antagonist.

Some uncertainties remained after the review of the PEGASUS trial. The efficacy and safety data were insufficient to establish whether the benefit/risk ratio would remain positive for Brilinta after three years of treatment in the patient population encompassed by the new indication, thus, the use was limited up to three years. Furthermore, patients with history of stroke were excluded from the PEGASUS trial because previous studies showed that combination use of antiplatelet agents (not ticagrelor) was associated with increased risks of intracranial hemorrhage. Therefore, a paragraph pertaining to patients with history of stroke was included in the Warnings and Precautions section of the Brilinta PM. Treatment beyond one year in patients with ischemic stroke is not recommended.

Based on the information submitted for review, the benefit/risk ratio of Brilinta 60 mg twice daily, co-administered with low-dose acetylsalicylic acid (ASA: 75-150 mg), for the secondary prevention of atherothrombotic events in patients with a history of myocardial infarction (occurred at least one year ago) and a high risk of developing an atherothrombotic event was considered to be favorable.