BRILINTA reduced bleeding vs dual therapy in high-risk coronary patients in sub-analyses from Phase IV TWILIGHT trial

Results from two subgroup analyses of the Phase IV independent TWILIGHT trial funded by AstraZeneca showed BRILINTA (ticagrelor) monotherapy reduced the risk of clinically relevant bleeding over 12 months compared to aspirin plus BRILINTA in high-risk coronary patients.

One subgroup analysis (TWILIGHT-DM) included patients with diabetes who had undergone a successful percutaneous coronary intervention (PCI), a procedure to open a blocked or narrowed coronary artery. The other (TWILIGHT-COMPLEX) included patients who had successfully undergone a complex PCI.

In both subgroups, BRILINTA monotherapy was associated with lower rates of clinically relevant bleeding without increasing the risk of ischemic events, between months three and 15 post PCI. This was compared to dual antiplatelet therapy (DAPT) with aspirin plus BRILINTA. These data were consistent with the overall trial results.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “Patients who receive dual antiplatelet therapy after a percutaneous coronary intervention have a higher risk of death due to bleeding in the two years after the procedure. These new TWILIGHT data showed that withdrawing aspirin and continuing treatment with BRILINTA alone reduced bleeding complications in high-risk patients, while still maintaining a similar effect on ischemic events.”

Roxana Mehran, TWILIGHT's Global Principal Investigator and Director of the Center for Interventional Cardiovascular Research and Clinical Trials at Mount Sinai Heart and Professor of Cardiology, and Population Health Science and Policy, at Icahn School of Medicine at Mount Sinai in New York, NY, said: “There is a clear medical need for strategies to lower the risk of bleeding in percutaneous coronary intervention patients, without losing ischemic protection. The results from the TWILIGHT sub-analyses offer important insights about ticagrelor as a monotherapy in these high-risk patients.”

Key data from the TWILIGHT sub-analyses

Results from both sub-analyses of the TWILIGHT trial were presented on March 30 at the American College of Cardiology’s 69th Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC) and published simultaneously in the Journal of the American College of Cardiology.

BRILINTA is not indicated for use without aspirin or in patients undergoing PCI who have not had an ACS event.

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.

Dosing: In the management of ACS, initiate BRILINTA treatment with a 180-mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg.

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
• In patients with Heparin Induced Thrombocytopenia (HIT): False negative results for HIT-related platelet functional tests, including the heparin-induced platelet aggregation (HIPA) assay, have been reported with BRILINTA. BRILINTA is not expected to impact PF4 antibody testing for HIT

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.

Acute coronary syndrome

Acute coronary syndrome (ACS) is a type of cardiovascular disease that occurs when a blood clot forms as a result of plaque rupture or erosion in the arteries of the heart, causing a severe reduction (unstable angina) or complete blockage (myocardial infarction) of blood supply to the heart muscle. Globally, an estimated 7.29 million myocardial infarctions or heart attacks occurred in 2015. Depending on the severity of the underlying condition, patients may undergo a mechanical intervention, such as PCI including stent placement. About three million individuals worldwide undergo a PCI each year, making it the most frequent form of coronary revascularization performed in patients with heart disease.

TWILIGHT

TWILIGHT was a randomized, double-blinded, placebo-controlled Phase IV trial. The study was designed and sponsored by the Icahn School of Medicine at Mount Sinai in New York, US. AstraZeneca provided study drug and funding through an investigator-initiated grant but had no influence on the study design or data analysis.

Patients were included in TWILIGHT if they had high-risk clinical and/or anatomical features for ischemia or bleeding after undergoing PCI with insertion of at least one drug-eluting stent (DES). ST-elevation myocardial infarction (STEMI) presentation was an exclusion criterion; 64% (5,739) of the overall cohort had non-ST-elevation acute coronary syndrome (NSTE-ACS). In TWILIGHT, all enrolled patients (9,006) received ticagrelor (90mg twice daily) and enteric-coated aspirin (81-100mg daily) for three months after PCI. Patients who remained event-free and were adherent to DAPT during the three months of treatment with aspirin and ticagrelor (7,119) were randomized 1:1 in a double-blind manner to either continue aspirin or switch to matched placebo for an additional 12 months, with continuation of open-label ticagrelor in both groups. The trial included 187 sites from across 11 countries, with the majority of patients recruited from the US.

Full results showed that BRILINTA monotherapy was associated with a 44% lower risk of Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding over a year, with an absolute risk reduction of 3.1% compared to BRILINTA plus aspirin (4.0% vs. 7.1% HR: 0.56; 95% CI: 0.45-0.68; p<0.001). Further, the risk of death from any cause, heart attack or stroke was similar in both groups (3.9% vs. 3.9%; HR: 0.99; 95% CI: 0.78-1.25; non-inferiority p<0.001).

TWILIGHT-DM and TWILIGHT-COMPLEX

In TWILIGHT-DM and TWILIGHT-COMPLEX, both subgroups completed three months of DAPT free of major bleeding or ischemic events, with open-label aspirin plus BRILINTA, before they were randomized to receive either placebo or aspirin, whilst continuing open-label BRILINTA, for an additional 12 months.

The TWILIGHT subgroup analyses evaluated patients with diabetes (TWILIGHT-DM) and patients who had successfully undergone a complex PCI (TWILIGHT-COMPLEX). Complex PCI was defined as any of the following: three vessels treated, at least three lesions treated, total stent length >60mm, bifurcation with two stents implanted, use of any atherectomy device, left main PCI, surgical bypass graft or chronic total occlusion as target lesion.

The TWILIGHT-DM pre-specified subgroup analysis included 2,620 diabetes patients, which was one of a clinical entry criteria of TWILIGHT (37% of the randomized population). In the TWILIGHT-COMPLEX subgroup analysis, Complex PCI was performed in 2,342 patients (33% of the randomized population of high-risk patients undergoing PCI).

BRILINTA

BRILINTA (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 (myocardial infarction [MI], stroke or CV death) in patients with acute coronary syndrome (ACS) or a history of MI.

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.

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.

US-38257 Last Updated 3/20

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