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2020-03-30

AstraZeneca: Brilinta reduced bleeding vs dual therapy in high-risk coronary patients in sub-analyses from Phase IV TWILIGH...

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 Brilinta and HR (95% Conclusion
Monotherapy aspirin CI)
(DAPT)
Diabetes Subgroup
(n=2,620)[i]
Primary endpoint: 4.5% 6.7% 0.65 Patients
BARC (0.47 receiving
(bleeding criteria) -0.91) Brilinta
type 2, 3 or monotherapy
5 bleeding had a 35%
lower risk
of bleeding
and a
similar
risk of
ischaemic
events
compared to
those
receiving
DAPT.
Secondary endpoint: 4.6% 5.9% 0.77
All-cause (0.55
mortality, heart -1.09)
attack or stroke
Complex PCI
Subgroup
(n=2,342)[ii]
Primary endpoint: 4.2% 7.7% 0.54(0.38 Patients
BARC type 2, 3 -0.76) receiving
or 5 bleeding Brilinta
monotherapy
had a 46%
lower risk
of bleeding
and a
similar
risk of
ischaemic
events
compared to
those
receiving
DAPT.
Secondary endpoint: 3.8% 4.9% 0.77(0.52
All-cause -1.15)
mortality, heart
attack or stroke

i. 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.

ii. 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 P2Y\12\ 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 t...

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