Regulatory Decision Summary for Brilinta

A single Phase 3 clinical trial was provided to support the proposed new indication (THEMIS trial; 19,220 patients). THEMIS was a randomised, double-blind, placebo-controlled study to assess the prevention of cardiovascular events with Brilinta combined with acetylsalicylic acid (ASA) (75-150 mg once daily [od]), compared with ASA used alone, in patients with coronary artery disease (CAD) and Type 2 Diabetes Mellitus (DM) and at high risk of an atherothrombotic event.

Brilinta, in combination with ASA, statistically significantly reduced the incidence of the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction (MI) and stroke, compared to ASA used alone (hazard ratio [95% confidence interval]; 0.90 [0.81, 0.99]; p = 0.0378). The treatment effect observed was mainly driven by the individual components of MI and stroke as no significant cardiovascular (CV) death benefit was observed.

In the overall THEMIS population, an increased incidence of thrombolysis in myocardial infarction (TIMI) major bleedings was reported with Brilinta compared to ASA alone and was associated with a higher incidence of fatal bleeding and intracranial hemorrhage. The benefit-harm analysis revealed that, for the overall THEMIS study population, treating 1,000 patients for 3 years with Brilinta combined with ASA, instead of ASA alone, is estimated to result in the prevention of 7 events of all-cause mortality, MI, or stroke, at the cost of 11 events of TIMI major bleeding. The benefit risk-profile was therefore not deemed favourable in the overall THEMIS population.

The pre-specified subgroup of patients with a history of percutaneous coronary intervention (PCI), which accounted for 58% of the THEMIS trial population, was however identified as a subpopulation with a favourable benefit-risk profile. In this subgroup, Brilinta in combination with ASA, compared to ASA used alone, reduced the incidence of the primary composite endpoint (hazard ratio [95% confidence interval]: 0.85 [0.74, 0.97], p = 0.0133). In the subgroup of patients with a history of PCI, there was no increase in fatal bleeding and intracranial hemorrhage with Brilinta combined to ASA versus ASA alone. The higher incidence of major bleedings reported with Brilinta was mostly due to an increased incidence of "other TIMI major bleedings", known to be serious and clinically important, but manageable events. The benefit-harm analysis in the subgroup of patients with a history of PCI revealed that treating 1,000 patients for 3 years with Brilinta combined with ASA instead of ASA alone is estimated to prevent 12 events of cardiovascular death, MI or stroke at the cost of 8 events of TIMI major bleeding events (that is, "other major bleeding" category).

Dyspnea and gout-related adverse events were more frequently reported with Brilinta than with ASA alone. The 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. In general, the safety profile of Brilinta in the THEMIS trial was consistent with that observed in previous studies.

A cautionary statement was included in the Warnings and Precautions section regarding the unfavourable benefit-risk profile for the overall THEMIS population. The statement also indicates that before initiating treatment in patients with CAD, Type-2 diabetes and a history of PCI, it should be confirmed that the patient is at high risk of atherothrombotic events and low risk of bleeding.

Based on the information submitted for review, the benefit-risk profile of Brilinta, co-administered with a low-dose ASA (75-150 mg), for the prevention of a first MI or stroke in patients with CAD, Type-2 DM, and a history of PCI, who are also at high risk of developing an atherothrombotic event, is considered favourable.