BRILINTA monotherapy reduced bleeding
complications with no increased risk of ischemic 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 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
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 ischemic
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 ischemic
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)
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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