Subgroup Analysis of TWILIGHT Trial Patients With Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) Who Underwent PCI Showed BRILINTA Monotherapy Reduced the Risk of Clinically Relevant Bleeding Compared With Dual Antiplatelet Therapy (DAPT)

New results from a pre-specified subgroup analysis of the TWILIGHT trial showed that BRILINTA (ticagrelor) monotherapy reduced the risk of clinically relevant bleeding compared to dual antiplatelet therapy (DAPT) over 12 months in high-risk patients with non-ST elevation acute coronary syndromes (NSTE-ACS).

The pre-specified subgroup analysis included 5,739 patients (64% of the overall TWILIGHT trial cohort of 9,006 patients) who had undergone successful percutaneous coronary intervention (PCI) with at least one drug eluting stent (DES) for NSTE-ACS. Following a three-month open-label treatment phase with ticagrelor (90mg BID) plus low-dose aspirin (81–100mg daily), 4,614 patients, who were free from major ischemic or bleeding events, were randomized to either continue low-dose aspirin or matching placebo for an additional 12 months, with continuation of open-label ticagrelor.

Results of the NSTE-ACS subgroup analysis showed:

• Ticagrelor monotherapy was associated with a 53% relative reduction in the risk of the primary endpoint – Bleeding Academic Research Consortium (BARC) type 2, 3 or 5 bleeding – over one year, with an absolute risk reduction of 4.0%, compared to ticagrelor plus aspirin (3.6% vs. 7.6%, HR 0.47; 95% CI: 0.36-0.61).
• Also seen was the BARC 3 or 5 bleeding for ticagrelor monotherapy versus ticagrelor plus aspirin at one year (0.8% vs. 2.1%).
• Thrombolysis in Myocardial Infarction (TIMI) major bleeding at one year was 0.5% for ticagrelor plus placebo and 1.0% for ticagrelor plus aspirin.
• Rates of the key secondary endpoint – composite outcome of all-cause death, myocardial infarction (MI) or stroke – were similar between the two groups at one year (4.3% for ticagrelor plus placebo and 4.4% for ticagrelor plus aspirin [HR 0.97; 95% CI: 0.74-1.28]).
• Rates of other secondary endpoints also were similar between the two groups at one year – all-cause death (1.0% for ticagrelor plus placebo and 1.5% for ticagrelor plus aspirin), MI (3.1% and 3.1%), ischemic stroke (0.5% and 0.3%), and definite or probable stent thrombosis (0.4% and 0.6%).

Danilo Verge, Vice President Global Medical Affairs, Cardiovascular, Renal and Metabolism said: “The TWILIGHT trial provided important information about the longer-term management of high-risk patients who had undergone PCI. In this pre-specified subgroup analysis of patients with NSTE-ACS enrolled in TWILIGHT, treatment with ticagrelor monotherapy, without aspirin, after three months of DAPT was associated with a lower risk of bleeding compared with standard 12 months of dual antiplatelet therapy with ticagrelor plus aspirin.”

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, US, said: “The finding that ticagrelor monotherapy was not associated with an increased risk of all-cause death, MI or stroke compared to continuation of DAPT in NSTE-ACS patients enrolled in TWILIGHT, a finding which was also observed in the overall trial cohort, is important given that there was also a reduction in bleeding in this cohort.”

Usman Baber, Chair of the TWILIGHT Clinical and Data Coordinating Center and Assistant Professor of Medicine and Cardiology at Icahn School of Medicine at Mount Sinai in New York, presented the findings during a late-breaking session at the AHA, said: “These findings challenge the conventional paradigm for maintenance of aspirin as a long-term component of dual antiplatelet therapy in high-risk patients with NSTE-ACS.”

Results of the TWILIGHT sub-analysis were presented in a late breaker oral presentation on 17 November 2019 at the American Heart Association (AHA) Scientific Sessions 2019 in Philadelphia, US.

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 myocardial infarction. 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.

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

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.

– ENDS –

NOTES TO EDITORS

About 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 DES. STEMI presentation was an exclusion criterion; 64% (5,739) of the overall cohort had 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 ticagrelor and aspirin (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.

Results from the TWILIGHT full study population were presented in September 2019 at Transcatheter Cardiovascular Therapeutics (TCT) 2019, the annual scientific conference of the Cardiovascular Research Foundation, and published simultaneously in The New England Journal of Medicine.

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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