BRILINTA's Phase III THEMIS Trial Met Primary Endpoint in Patients with Established Coronary Artery Disease and Type-2 Diabetes

Business Wire 25-Feb-2019 7:00 AM

BRILINTA reduced cardiovascular events in these patients with no prior heart attack or stroke

The Phase III THEMIS trial met its primary endpoint which demonstrated that BRILINTA^® (ticagrelor) tablets, taken in conjunction with aspirin, showed a statistically-significant reduction in major adverse cardiovascular events (MACE, a composite of cardiovascular death, heart attack and stroke) compared to aspirin alone.

THEMIS was conducted in over 19,000 patients with coronary artery disease (CAD) and type-2 diabetes (T2D) with no prior heart attack or stroke. Preliminary safety results were consistent with the known profile of BRILINTA. A full evaluation of the THEMIS data will be presented at a forthcoming medical meeting.

Elisabeth Björk, Senior Vice President, Head of late Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, said: "Approaches to help reduce cardiovascular morbidity further in patients with coronary artery disease and type-2 diabetes are urgently needed. The positive result from the THEMIS trial may offer a potential benefit for this high-risk patient population."

Deepak L. Bhatt, MD, MPH, THEMIS co-Chair and Executive Director of Interventional Cardiovascular Programs at Brigham and Women's Hospital and a Professor at Harvard Medical School said: "The THEMIS trial is the largest randomized trial of patients with type-2 diabetes performed to date and was designed to evaluate whether more-intense antiplatelet therapy is a promising approach. The results could help us refine our understanding of the role of dual antiplatelet therapy in patients across the atherothrombotic spectrum."

Gabriel Steg, MD, THEMIS co-Chair and Professor at Université Paris-Diderot, Paris and Professor at the National Heart and Lung Institute, Imperial College, London said: "Patients who have both stable coronary artery disease and diabetes are a sizeable group which remains at particularly high risk of major adverse cardiac events. The optimal long-term antiplatelet therapy in that group is not fully established. We look forward to presenting the full results from the THEMIS trial later this year."

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 cardiovascular 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 TABLETSWARNING: (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 Medication Guide and Prescribing Information, including Boxed WARNINGS, for BRILINTA.

About THEMISTHEMIS (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 MI 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, MI or stroke, in patients with CAD and T2D with no prior MI or stroke, vs. aspirin alone. CAD was defined as a prior percutaneous coronary intervention (PCI), coronary artery bypass grafting or at least a 50% narrowing of a coronary artery.

The trial was initiated in early 2014, duration was event-driven across 42 countries and more than 19,000 randomized patients were recruited in order to collect 1,385 independently-adjudicated primary endpoint events.

About BRILINTABRILINTA (ticagrelor) 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 (MI, stroke or CV death), in patients with acute coronary syndrome (ACS) or a history of MI.

About AstraZenecaAstraZeneca 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 main therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. 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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