BRILINTA Reduced the Risk of Cardiovascular Events in Patients With Coronary Artery Disease and Type 2 Diabetes in Phase III THEMIS Trial

AstraZeneca today announced detailed results from the positive Phase III THEMIS trial, which showed BRILINTA (ticagrelor) plus aspirin reduced the relative risk for the composite of cardiovascular (CV) death, heart attack, or stroke by 10% (7.7% vs 8.5%) compared with aspirin alone, a statistically significant reduction.

The overall THEMIS trial population was patients with coronary artery disease (CAD) and type 2 diabetes (T2D) with no prior heart attack or stroke.

Additionally, in a clinically meaningful and prespecified sub-analysis of patients who had previously undergone a percutaneous coronary intervention (PCI), a procedure to open a blocked or narrowed coronary artery, a 15% (7.3% vs 8.6%) relative risk reduction was observed for BRILINTA plus aspirin for the composite of CV death, heart attack, or stroke, compared with aspirin alone.

The safety profile for BRILINTA was consistent with the known profile of the medicine with an increased risk of bleeding events observed in both THEMIS and the THEMIS-PCI sub-analysis.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: "These positive results show that BRILINTA reduced the risk of cardiovascular events in patients with coronary artery disease and type 2 diabetes, and we hope this will make a difference because their risk of heart attack or stroke is almost twice as high as it is among diabetes patients without cardiovascular disease. Also, for the first time, these new data identified an easily-recognizable sub-group of stable patients who may benefit most from BRILINTA – those with type 2 diabetes who have undergone PCI."

Deepak L. Bhatt, MD, MPH, THEMIS Co-Chair and Executive Director of Interventional Cardiovascular Programs at Brigham and Women's Hospital, and Professor of Medicine at Harvard Medical School, Boston, US, said: "So far, treatment options have been limited for patients with coronary artery disease and type 2 diabetes. The results from THEMIS greatly advance our understanding of cardiovascular risk reduction and refine our understanding of the role of dual antiplatelet therapy in patients across the cardiovascular spectrum."

Gabriel Steg, MD, THEMIS Co-Chair and Professor at Université de Paris, said: "Patients with type 2 diabetes who had undergone a percutaneous coronary intervention face a similar risk of a cardiovascular event as those who have had a heart attack. The PCI population is a sizeable and easily identifiable group of patients that we hope in the future will be considered for long-term therapy with BRILINTA and aspirin."

AstraZeneca will work with regulatory authorities to explore an update to the BRILINTA label based on these results.

Results from THEMIS and THEMIS-PCI were presented on Sunday, September 1, 2019 at ESC Congress 2019 (the annual meeting of the European Society of Cardiology) in Paris, France. The results for the overall THEMIS trial were published simultaneously in the New England Journal of Medicine and results from THEMIS-PCI were published in The Lancet.

BRILINTA is not approved for use in patients with CAD and T2D who have not yet had a heart attack or stroke.

BRILINTA is indicated to reduce the rate of CV death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

IMPORTANT SAFETY INFORMATION FOR BRILINTA^® (ticagrelor) 60-MG AND 90-MG TABLETS

WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

A. BLEEDING RISK

• BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal bleeding
• Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
• Do not start BRILINTA in patients undergoing urgent coronary artery bypass graft surgery
• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

• Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided

CONTRAINDICATIONS

• BRILINTA is contraindicated in patients with a history of intracranial hemorrhage or active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

• Dyspnea was reported in about 14% of patients treated with BRILINTA, more frequently than in patients treated with control agents. Dyspnea resulting from BRILINTA is often self-limiting
• Discontinuation of BRILINTA will increase the risk of MI, stroke, and death. When possible, interrupt therapy with BRILINTA for 5 days prior to surgery that has a major risk of bleeding. If BRILINTA must be temporarily discontinued, restart as soon as possible
• Ticagrelor can cause ventricular pauses. Bradyarrhythmias including AV block have been reported in the post-marketing setting. PLATO and PEGASUS excluded patients at increased risk of bradyarrhythmias not protected by a pacemaker, and they may be at increased risk of developing bradyarrhythmias with ticagrelor
• Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor and there are no studies of BRILINTA in these patients

ADVERSE REACTIONS

• The most common adverse reactions associated with the use of BRILINTA included bleeding and dyspnea: In PLATO, for BRILINTA vs clopidogrel, non-CABG PLATO-defined major bleeding (3.9% vs 3.3%) and dyspnea (14% vs 8%); in PEGASUS, BRILINTA vs aspirin alone, TIMI Total Major bleeding (1.7% vs 0.8%) and dyspnea (14% vs 6%)

DRUG INTERACTIONS

• Avoid use with strong CYP3A inhibitors and strong CYP3A inducers. BRILINTA is metabolized by CYP3A4/5. Strong inhibitors substantially increase ticagrelor exposure and so increase the risk of adverse events. Strong inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor
• As with other oral P2Y₁₂ inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor. Consider use of a parenteral anti-platelet in ACS patients requiring co-administration
• Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse events
• Monitor digoxin levels with initiation of, or change in, BRILINTA therapy

SPECIAL POPULATIONS

• Lactation: Breastfeeding not recommended

Please read full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About THEMIS

THEMIS (Effect of Ticagrelor on Health Outcomes in DiabEtes Mellitus Patients Intervention Study) is an AstraZeneca-sponsored, multi-national, randomized, double‑blinded trial in patients with CAD and T2D with no prior myocardial infarction or stroke. THEMIS was designed to test the hypothesis that BRILINTA plus aspirin would reduce major adverse cardiovascular events (MACE), a composite of CV death, myocardial infarction or stroke, compared with aspirin alone. CAD was defined as a prior percutaneous coronary intervention (PCI), or coronary artery bypass graft, or at least a 50% narrowing of a coronary artery. More than 19,000 patients were randomized across 42 countries in Europe, Asia, Africa, North and South America.

THEMIS-PCI is a clinically meaningful and prespecified sub-analysis of patients (11,154 which is 58% of total patients) who had previously undergone PCI.

About BRILINTA

BRILINTA is an oral, reversibly binding, direct-acting P2Y₁₂ receptor antagonist that works by inhibiting platelet activation. BRILINTA, together with aspirin, has been shown to significantly reduce the risk of major adverse cardiovascular events (myocardial infarction, stroke or CV death) in patients with acute coronary syndrome (ACS) or a history of MI.

About AstraZeneca in CVMD

CV, renal & metabolism together form one of AstraZeneca's main therapy areas and a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling comorbidities. Our ambition is to modify or halt the natural course of CVMD diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

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