New indication expands use of BRILINTA
beyond cardiovascular disease to patients with mild-to-moderate
stroke
AstraZeneca’s BRILINTA® (ticagrelor) has been approved in the US
to reduce the risk of stroke, a leading cause of disability and
death worldwide, in patients with acute ischemic stroke (National
Institutes of Health Stroke Scale score ≤5) or high-risk transient
ischemic attack (TIA).
The approval by the US Food and Drug Administration (FDA) was
based on positive results from the THALES Phase III trial that
showed aspirin plus BRILINTA 90mg significantly reduced the rate of
the composite of stroke and death compared to aspirin alone in
patients with acute ischemic stroke or TIA.1 The decision follows
the Priority Review designation granted by the FDA in July
2020.
Dr. Clay Johnston, lead investigator for the THALES Phase III
trial and Dean of the Dell Medical School at The University of
Texas in Austin, US, said: “One in four patients who have had a
stroke will experience a second one, with the risk particularly
high within the first 30 days. The approval of BRILINTA in
combination with aspirin is an important advancement to reduce the
risk of recurrent stroke and much-awaited good news for physicians
and patients.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, said: “In the US, someone has a stroke every 40 seconds
and the impact on a person’s life can be truly devastating.
BRILINTA is a well-established medicine across patients with
coronary artery disease and with today’s approval, we can now
expand its potential to patients with an acute ischemic stroke or
transient ischemic attack.”
The THALES trial demonstrated that BRILINTA 90mg used twice
daily and taken with daily aspirin for 30 days, reduced the rate of
the primary composite endpoint of stroke and death by 17% (absolute
risk reduction = 1.1%; hazard ratio 0.83; 95% confidence interval
0.71-0.96, p=0.015), compared to aspirin alone in patients with an
acute ischemic stroke or TIA.1 This was a statistically significant
and clinically meaningful reduction. The primary composite endpoint
was driven by a reduction in stroke.
The risk for severe bleeding events was 0.5% in patients
receiving aspirin plus BRILINTA and 0.1% for aspirin alone. The
results were in line with the known safety profile of BRILINTA.1
Full data from the THALES Phase III trial can be found in The New
England Journal of Medicine.
Regulatory submissions to expand the approved indication are
also under regulatory review in China and in the EU where the
medicine’s name is Brilique.
BRILINTA is approved in more than 110 countries for the
prevention of atherothrombotic events in adult patients with acute
coronary syndrome (ACS) and in more than 70 countries for the
secondary prevention of cardiovascular events among patients who
are at high-risk and have experienced a heart attack. In May 2020,
the US FDA approved a new indication for BRILINTA to include the
reduction of the risk of a first heart attack or stroke in
high-risk patients with coronary artery disease.
INDICATIONS
- BRILINTA is indicated to reduce the risk 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 risk of stent
thrombosis in patients who have been stented for treatment of
ACS.
- BRILINTA is indicated to reduce the risk of a first MI or
stroke in patients with coronary artery disease (CAD) at high risk
for such events. While use is not limited to this setting, the
efficacy of ticagrelor was established in a population with type 2
diabetes.
- BRILINTA is indicated to reduce the risk of stroke in patients
with acute ischemic stroke (NIH Stroke Scale ≤5) or high-risk
transient ischemic attack (TIA).
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.
- In patients with CAD but no prior stroke or MI, administer 60
mg twice daily.
- In patients with acute ischemic stroke or high-risk TIA,
initiate treatment with a 180-mg loading dose of BRILINTA and then
continue with 90 mg twice daily for up to 30 days. The treatment
effect accrued early in the course of therapy. Use BRILINTA with a
loading dose of aspirin (300 to 325 mg)
- 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 WARNINGS:
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 IN PATIENTS WITH
ACS
- 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 more frequently with BRILINTA than in
patients treated with control agents. Dyspnea from BRILINTA is
often self-limiting
- In patients being treated for coronary artery disease,
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. Clinical trials excluded patients at increased risk of
bradyarrhythmias not protected by a pacemaker, and they may be at
increased risk of developing bradyarrhythmias
- 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 (>5%) associated with the
use of BRILINTA included bleeding and dyspnea
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.
Stroke
An ischemic stroke is caused by a blockage cutting off the blood
supply to a region of the brain. A transient ischemic attack, is a
temporary blockage of the blood supply to a region of the brain,
resulting in symptoms only lasting for a short amount of time.
Stroke is a leading cause of disability and death worldwide.2 In
the US, someone has a stroke every 40 seconds, and every four
minutes, someone dies of stroke.3 About one in four strokes are
recurrent, with the risk particularly high within 30 days after the
initial event and even higher when looking at time periods closer
to the initial event.4,5
THALES
THALES is an AstraZeneca-sponsored, randomized,
placebo-controlled, double-blinded, international, multicenter,
event-driven Phase III trial involving more than 11,000 patients
from 28 countries. It tested the hypothesis whether aspirin plus
BRILINTA is superior to aspirin alone in preventing the composite
of stroke and death in patients with non-cardioembolic acute
ischemic stroke or high-risk TIA. Patients were randomized within
24 hours of onset of acute ischemic stroke or high-risk TIA
symptoms and treated for 30 days. Study treatments were BRILINTA
180mg loading dose on day 1, followed by 90mg twice daily on days
2-30, or matching placebo. All patients received open-label aspirin
300-325mg on day 1, followed by 75-100mg once daily on days 2-30.
The primary efficacy outcome was the time to the composite endpoint
of stroke and death at 30 days. The primary safety outcome is time
to first severe bleeding event according to the Global Utilization
of Streptokinase and Tissue Plasminogen Activator for Occluded
Coronary Arteries (GUSTO) definition, which includes fatal
bleedings, intracranial hemorrhage; and bleeding causing
hemodynamic compromise requiring intervention.
AstraZeneca in CV, Renal & Metabolism (CVMD)
CV, renal and 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
co-morbidities. 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.
References
1. Brilinta (ticagrelor) prescribing information. AstraZeneca
Pharmaceuticals LP.
2. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and
aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J
Med 2020; 383:207-217.
3. Virani SS, Alonso A, Benjamin EJ et al. Heart disease and
stroke statistics—2020 update: a report from the American Heart
Association. Circulation. 2020;141(9):e139–e596.
4. Hankey GJ. Secondary stroke prevention. Lancet Neurol 2014;
13(2):178–94.
5. Coull AJ, Lovett JK, and Rothwell PM. Population based study
of early risk of stroke after transient ischaemic attack or minor
stroke: implications for public education and organisation of
services. BMJ. 2004;328:326.
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