Secondary endpoint of non-inferiority achieved for the risk of composite of MI, death or stroke
Results presented at TCT 2019 conference and published in the New England Journal of Medicine
New data from TWILIGHT, a Phase IV independent trial (funded by AstraZeneca), showed that in patients at high-bleeding risk who underwent PCI and completed three months of dual antiplatelet therapy, BRILINTA (ticagrelor) monotherapy (90 mg twice daily) reduced the risk of BARC (Bleeding Academic Research Consortium) type 2, 3 or 5 bleeding compared to BRILINTA plus low-dose aspirin after 12 months.
In the trial, 9,006 patients received open-label ticagrelor (90 mg twice daily) and aspirin (81-100 mg daily) for three months after a PCI. The 7,119 patients that remained event-free of major bleeding or an ischemic event during the three months of treatment with ticagrelor and aspirin were randomized to either double-blinded aspirin or placebo for an additional 12 months, with continuation of open-label ticagrelor.
Ticagrelor monotherapy was associated with a 44% lower risk of BARC 2, 3 or 5 bleeding over one year, with an absolute risk reduction of 3.1%, compared to ticagrelor plus aspirin. The incidence of the primary endpoint, time to first occurrence of BARC type 2, 3 or 5 bleeding between month 3 and 15, was 4.0% in patients treated with ticagrelor plus placebo compared to 7.1% in patients treated with ticagrelor plus aspirin (HR 0.56; 95% CI 0.45 to 0.68; p<0.001).
The incidence of BARC 3 or 5 bleeding was also lower (1.0% vs 2.0%, HR 0.49; 95% CI 0.33 to 0.74) with ticagrelor plus placebo versus ticagrelor plus aspirin. Rates of the composite of all-cause death, myocardial infarction (MI) or stroke, a key secondary endpoint, were similar between the two groups, 3.9% and 3.9%, respectively for ticagrelor plus placebo and ticagrelor plus aspirin (HR 0.99; 95% CI 0.78 to 1.25; non-inferiority p<0.001).
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, said “In high-risk PCI patients, further ischemic events remain a life-threatening concern. As seen in TWILIGHT, in patients who tolerated three months of dual antiplatelet therapy, lowering the risk of major bleeding while preserving the ischemic benefit using ticagrelor monotherapy is an important clinical advance for these patients.”
Danilo Verge, Vice President, Global Medical Affairs, Cardiovascular, Renal and Metabolism said: “The benefit of BRILINTA in reducing thrombosis following the placement of a stent is well established and recommended in guidelines in patients with acute coronary syndromes. The results from the TWILIGHT trial show that following percutaneous coronary intervention in high-risk patients, the withdrawal of aspirin while continuing ticagrelor monotherapy resulted in a lower bleeding rate, while showing non-inferiority for the risk of composite of death, MI, or stroke versus dual antiplatelet therapy.”
Results from TWILIGHT were presented on Thursday, September 26, 2019 at Transcatheter Cardiovascular Therapeutics (TCT) 2019, the annual scientific conference of the Cardiovascular Research Foundation, in San Francisco, and published simultaneously in the New England Journal of Medicine.
BRILINTA is not indicated for use without aspirin or in patients undergoing PCI who have not had an acute coronary syndrome (ACS) event.
BRILINTA is indicated to reduce the rate of cardiovascular (CV) death, MI, and stroke in patients with 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
- 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
- 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%)
- 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
- Lactation: Breastfeeding not recommended
NOTES TO EDITORS
The TWILIGHT study was designed and sponsored by the Icahn School of Medicine at Mount Sinai. AstraZeneca provided study drug and funding through an investigator-initiated grant.
Patients were included 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). STEMI presentation was an exclusion criteria; 65% of the overall cohort had NSTE-ACS. All enrolled patients (9006) received ticagrelor (90 mg twice daily) and enteric-coated aspirin (81-100 mg daily) for three months after PCI. Patients that remained event-free during the three months of treatment with ticagrelor and aspirin (7119) 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.
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.
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 Media Line
+1 302 885 2677
US-33252 Last Updated 9/19