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

Brilinta monotherapy reduced bleeding complications with no increased risk
of ischaemic events in patients with diabetes undergoing percutaneous coronary intervention

Consistent results were also observed in patients undergoing complex percutaneous coronary intervention

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 ischaemic 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 ischaemic 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 ischaemic 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

Brilinta Monotherapy Brilinta and aspirin (DAPT) HR (95% CI) Conclusion
Diabetes Subgroup (n=2,620)i
Primary endpoint: BARC (bleeding criteria) type 2, 3 or 5 bleeding 4.5% 6.7% 0.65 (0.47-0.91) Patients receiving Brilinta monotherapy had a 35% lower risk of bleeding and a similar risk of ischaemic events compared to those receiving DAPT.
Secondary endpoint: All-cause mortality, heart attack or stroke 4.6% 5.9% 0.77 (0.55-1.09)
Complex PCI Subgroup (n=2,342)ii
Primary endpoint: BARC type 2, 3 or 5 bleeding 4.2% 7.7% 0.54(0.38-0.76) Patients receiving Brilinta monotherapy had a 46% lower risk of bleeding and a similar risk of ischaemic events compared to those receiving DAPT.
Secondary endpoint: All-cause mortality, heart attack or stroke 3.8% 4.9% 0.77(0.52-1.15)
  1. Angiolillo D et al. Ticagrelor With And Without Aspirin In High-Risk Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: Insights From The TWILIGHT Trial. presented at: ACC Congress, 2020 March 28 - 30, Chicago, Illinois.
  2. Dangas G et al. Safety And Efficacy Of Ticagrelor Monotherapy After Complex PCI: The TWILIGHT-COMPLEX Substudy. presented at: ACC Congress, 2020 March 28 - 30, Chicago, Illinois.

Results from both sub-analyses of the TWILIGHT trial were presented on 30 March 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 co-administered with aspirin is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (ACS) or a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event. Patients taking Brilinta should also take a daily low maintenance dose of aspirin 75-150mg, unless specifically contraindicated.

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. An estimated 7.29 million myocardial infarctions or heart attacks, occurred in 2015.1 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 revascularisation performed in patients with heart disease.2

TWILIGHT

TWILIGHT was a randomised, 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 ischaemia 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 randomised 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).7 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).3

TWILIGHT-DM and TWILIGHT-COMPLEX

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

The TWILIGHT subgroup analyses included either patients with diabetes who had undergone a successful PCI (TWILIGHT-DM) or 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 an entry criteria of TWILIGHT (37% of the randomised population). In the TWILIGHT-COMPLEX pre-specified subgroup analysis, Complex PCI was performed in 2,342 patients (33% of the randomised population of high-risk patients undergoing PCI).

Brilinta

Brilinta is an oral, reversible, 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 CV events (myocardial infarction, stroke or CV death), in patients with ACS or a history of myocardial infarction (MI).

Brilinta, co-administered with aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, or for patients with a history of MI and a high risk of developing an atherothrombotic event.

AstraZeneca in CVRM

Cardiovascular, Renal and Metabolism (CVRM) together forms one of AstraZeneca’s three therapy areas and is 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 co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal and Metabolism, and Respiratory. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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References

1. Roth GA et al. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 2017; 70(1):1–25.

2. Banerjee S et al. Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery. J Am Coll Cardiol 2017; 69(14):1861–70.

3. Mehran R et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med 2019; 381(21):2032–42.

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