AUGUSTUS is the largest trial in this
high-risk patient population requiring both anticoagulant and
antiplatelet therapies
The Bristol-Myers Squibb-Pfizer Alliance today announced results
from the Phase 4 AUGUSTUS trial evaluating Eliquis® (apixaban)
versus vitamin K antagonists (VKAs) in patients with non-valvular
atrial fibrillation (NVAF) and recent acute coronary syndrome (ACS)
and/or undergoing percutaneous coronary intervention (PCI). Results
show that in patients receiving a P2Y12 inhibitor with or without
aspirin (antiplatelet therapies), the proportion of patients with
major or clinically relevant non-major (CRNM) bleeding at six
months was significantly lower for those treated with Eliquis
compared to those treated with a VKA (10.5% vs. 14.7%,
respectively; hazard ratio [HR]: 0.69, 95% confidence interval
[CI]: 0.58-0.81; p-superiority<0.001). These data are featured
as a late-breaking oral presentation at the American College of
Cardiology’s (ACC) 68th Annual Scientific Session 2019 in New
Orleans, LA (Abstract 405-08) and simultaneously published in the
New England Journal of Medicine.
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AUGUSTUS, which evaluated 4,614 patients, is an open-label,
prospective, randomized clinical trial designed to assess two
independent hypotheses:
- Whether or not Eliquis 5mg* twice daily
is non-inferior or superior to VKAs for the outcome of major or
CRNM bleeding, as defined by the International Society on
Thrombosis and Haemostasis (ISTH), in patients with NVAF and recent
ACS and/or undergoing PCI with planned concomitant antiplatelet
therapy (a P2Y12 inhibitor with or without low-dose aspirin).
- Whether or not single antiplatelet
therapy with a P2Y12 inhibitor is superior to dual antiplatelet
therapy with a P2Y12 inhibitor and low-dose aspirin for the outcome
of ISTH major or CRNM bleeding in patients with NVAF and recent ACS
and/or undergoing PCI and planned concomitant anticoagulant therapy
(either Eliquis 5mg* twice daily or VKA).
*2.5mg twice daily if patients met two or more of the following
dose-reduction criteria: age ≥ 80 years, weight ≤ 60 kg or
creatinine ≥ 1.5mg/dL (133 micromol/L).
Independent of the Eliquis versus VKA comparison, results also
showed that in patients receiving a P2Y12 inhibitor and an
anticoagulant, the proportion of patients with major or CRNM
bleeding at six months was significantly higher for those receiving
aspirin compared to those receiving placebo (16.1% vs. 9.0%,
respectively; HR: 1.89, 95% CI: 1.59-2.24; p<0.001).
Please note that Eliquis increases the risk of bleeding compared
with placebo and can cause serious, potentially fatal, bleeding.
Please see below for Important Safety Information, including
information from the APPRAISE-2 clinical trial that was terminated
early due to higher rates of bleeding for apixaban compared to
placebo in post-ACS patients without an indication for oral
anticoagulant.1
“Due to concern for major bleeding, there have been ongoing
questions about treating non-valvular atrial fibrillation patients
with acute coronary syndrome and/or undergoing percutaneous
coronary intervention,” said Renato D. Lopes, M.D., M.H.S, Ph.D.,
Director, Clinical Events Classification, Duke Clinical Research
Institute and Principal Investigator of AUGUSTUS. “Results from
this study provide additional information for physicians treating
these high-risk patients.”
The investigators also analyzed the pre-defined secondary
composite outcomes of death or hospitalization and death or
ischemic events (including myocardial infarction, stroke, definite
or probable stent thrombosis or urgent revascularization). At six
months, patients receiving a P2Y12 inhibitor with or without
aspirin who were treated with Eliquis had lower rates of death or
hospitalization (23.5% vs. 27.4%, respectively; HR: 0.83, 95% CI:
0.74-0.93; p=0.002) and similar rates of death or ischemic events
(6.7% vs. 7.1%, respectively; HR: 0.93, 95% CI: 0.75-1.16; p=NS)
compared to those assigned to VKA. Patients receiving a P2Y12
inhibitor and an anticoagulant who were treated with aspirin had
similar rates of death or hospitalization (26.2% vs. 24.7%,
respectively; HR: 1.08, 95% CI: 0.96-1.21; p=NS) and similar rates
of death or ischemic events (6.5% vs. 7.3%, respectively; HR: 0.89,
95% CI: 0.71-1.11) compared to those assigned to placebo.
“The AUGUSTUS trial evaluated antithrombotic regimens for the
often difficult-to-treat non-valvular atrial fibrillation patient
population that presents with acute coronary syndrome and/or
receives percutaneous coronary intervention,” said James Rusnak,
M.D., Ph.D., Chief Development Officer, Internal Medicine, Pfizer.
“These findings add to evidence from previous studies that
demonstrate the safety profile of Eliquis versus a vitamin K
antagonist in patients with non-valvular atrial fibrillation.”
Atrial fibrillation is the most common arrhythmia in the world,
affecting an estimated 33 million people in 2010.2 It is estimated
that approximately 20-to-30 percent of people with atrial
fibrillation also have concomitant coronary artery disease,3,4
which may result in ACS or require PCI. Additionally, five-to-ten
percent of patients who undergo PCI have atrial
fibrillation.5,6,7,8 While oral anticoagulants and dual
antiplatelet therapy help reduce the risk of stroke and recurrent
ischemic events, respectively, the combination leads to an
increased risk of bleeding. Therefore, additional research has been
needed to help inform antithrombotic regimens available for these
high-risk patients.
“Advancing care for patients at risk for stroke due to
non-valvular atrial fibrillation is a key focus of the BMS-Pfizer
Alliance,” said Christoph Koenen, M.D., Head of Cardiovascular
Development, Bristol-Myers Squibb. “The AUGUSTUS trial represents
our ongoing commitment to understanding anticoagulation among
higher-risk patients.”
About AUGUSTUS
AUGUSTUS is an international, multicenter, open-label,
randomized controlled trial with a two-by-two factorial design to
compare Eliquis (apixaban) with vitamin K antagonists (VKAs) and
aspirin with placebo in 4,614 patients with non-valvular atrial
fibrillation (NVAF) and recent acute coronary syndrome (ACS) and/or
undergoing percutaneous coronary intervention (PCI), and are
receiving a P2Y12 inhibitor for at least six months. The treatment
regimen comparing Eliquis with VKA was open-label; however, the
regimen comparing aspirin with aspirin placebo was double blind.
Patients were evaluated for eligibility during their ACS and/or PCI
hospitalization. 37.3 percent of patients included in the study had
ACS undergoing PCI, 23.9 percent of patients had medically-managed
ACS and 38.8 percent of patients underwent elective PCI. The
primary outcome is the composite of major or clinically relevant
non-major (CRNM) bleeding defined by the International Society on
Thrombosis and Haemostasis (ISTH).9 A key secondary outcome is the
composite of death or first hospitalization. Other secondary
outcomes include the composite of death or ischemic events
(myocardial infarction, stroke, definite or probable stent
thrombosis or urgent revascularization). AUGUSTUS was designed to
be a safety study and did not include a primary efficacy
endpoint.
About Atrial Fibrillation
Atrial fibrillation (AF) is the most common type of arrhythmia,
or irregular heartbeat. Nonvalvular atrial fibrillation (NVAF)
refers to cases in which the AF occurs in the absence of rheumatic
mitral valve disease, a prosthetic heart valve, or mitral valve
repair. It was estimated that in 2014, 6.4 million people in the
U.S. and in 2010, over six million individuals in Europe, had AF.
The lifetime risk of AF is estimated to be approximately 25 percent
for individuals 40 years of age or older. One of the most serious
medical concerns for individuals with AF is the increased risk of
stroke, which is five times higher in people with AF than those
without AF. Additionally, AF-related strokes tend to be more severe
than other strokes with an associated 30-day mortality rate of 24
percent and a 50 percent likelihood of death within one year.
About Acute Coronary Syndrome
Acute coronary syndrome (ACS) is a term used to describe
situations in which the blood supplied to the heart muscle is
suddenly blocked, and includes myocardial infarction (MI), also
known as a heart attack, and unstable angina (sudden, severe chest
pain that typically occurs when a person is at rest). ACS affects
an estimated 1.4 million people in the U.S. and an estimated 1.38
million people in Europe. ACS is a subcategory of coronary artery
disease (CAD), the most common type of cardiovascular disease.
Cardiovascular diseases are the number-one cause of death
worldwide. According to the World Health Organization, CAD alone
resulted in 7.4 million deaths during 2012.
About Percutaneous Coronary Intervention
Percutaneous coronary intervention (PCI), also known as coronary
angioplasty, is a procedure used to open blocked or narrowed
coronary arteries. Angioplasty also is used as an emergency
procedure during a heart attack. According to the Centers for
Disease Control and Prevention, there are approximately 500,000
PCIs performed annually in the U.S. alone.
About Eliquis
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By
inhibiting Factor Xa, a key blood clotting protein, Eliquis
decreases thrombin generation and blood clot formation. Eliquis is
approved for multiple indications in the U.S. based on efficacy and
safety data from multiple Phase 3 clinical trials. Eliquis is a
prescription medicine indicated to reduce the risk of stroke and
systemic embolism in patients with nonvalvular atrial fibrillation
(NVAF); for the prophylaxis of deep vein thrombosis (DVT), which
may lead to pulmonary embolism (PE), in patients who have undergone
hip or knee replacement surgery; for the treatment of DVT and PE;
and to reduce the risk of recurrent DVT and PE, following initial
therapy.
ELIQUIS Important Safety
Information
WARNING: (A) PREMATURE DISCONTINUATION
OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B)
SPINAL/EPIDURAL HEMATOMA
(A)
Premature discontinuation of any oral
anticoagulant, including ELIQUIS, increases the risk of thrombotic
events. If anticoagulation with ELIQUIS is discontinued for a
reason other than pathological bleeding or completion of a course
of therapy, consider coverage with another anticoagulant.
(B)
Epidural or spinal hematomas may occur
in patients treated with ELIQUIS who are receiving neuraxial
anesthesia or undergoing spinal puncture. These hematomas may
result in long-term or permanent paralysis. Consider these risks
when scheduling patients for spinal procedures. Factors that can
increase the risk of developing epidural or spinal hematomas in
these patients include:
•
use of indwelling epidural
catheters
•
concomitant use of other drugs that
affect hemostasis, such as nonsteroidal anti-inflammatory drugs
(NSAIDs), platelet inhibitors, other anticoagulants
•
a history of traumatic or repeated
epidural or spinal punctures
•
a history of spinal deformity or spinal
surgery
•
optimal timing between the
administration of ELIQUIS and neuraxial procedures
•
is not known
Monitor patients frequently for signs
and symptoms of neurological impairment. If neurological compromise
is noted, urgent treatment is necessary.
Consider the benefits and risks before
neuraxial intervention in patients anticoagulated or to be
anticoagulated.
CONTRAINDICATIONS
- Active pathological bleeding
- Severe hypersensitivity reaction to
ELIQUIS (e.g., anaphylactic reactions)
WARNINGS AND PRECAUTIONS
- Increased Risk of Thrombotic Events
after Premature Discontinuation: Premature discontinuation of
any oral anticoagulant, including ELIQUIS, in the absence of
adequate alternative anticoagulation increases the risk of
thrombotic events. An increased rate of stroke was observed during
the transition from ELIQUIS to warfarin in clinical trials in
atrial fibrillation patients. If ELIQUIS is discontinued for a
reason other than pathological bleeding or completion of a course
of therapy, consider coverage with another anticoagulant.
- Bleeding Risk: ELIQUIS increases
the risk of bleeding and can cause serious, potentially fatal,
bleeding.
- Concomitant use of drugs affecting
hemostasis increases the risk of bleeding, including aspirin and
other antiplatelet agents, other anticoagulants, heparin,
thrombolytic agents, SSRIs, SNRIs, and NSAIDs.
- Advise patients of signs and symptoms
of blood loss and to report them immediately or go to an emergency
room. Discontinue ELIQUIS in patients with active pathological
hemorrhage.
- The anticoagulant effect of apixaban
can be expected to persist for at least 24 hours after the last
dose (i.e., about two half-lives). An agent to reverse the
anti-factor Xa activity of apixaban is available. Please visit
www.andexxa.com for more information on availability of a reversal
agent.
- Spinal/Epidural Anesthesia or
Puncture: Patients treated with ELIQUIS undergoing
spinal/epidural anesthesia or puncture may develop an epidural or
spinal hematoma which can result in long-term or permanent
paralysis.The risk of these events may be increased by the
postoperative use of indwelling epidural catheters or the
concomitant use of medicinal products affecting hemostasis.
Indwelling epidural or intrathecal catheters should not be removed
earlier than 24 hours after the last administration of ELIQUIS. The
next dose of ELIQUIS should not be administered earlier than 5
hours after the removal of the catheter. The risk may also be
increased by traumatic or repeated epidural or spinal puncture. If
traumatic puncture occurs, delay the administration of ELIQUIS for
48 hours.Monitor patients frequently and if neurological compromise
is noted, urgent diagnosis and treatment is necessary. Physicians
should consider the potential benefit versus the risk of neuraxial
intervention in ELIQUIS patients.
- Prosthetic Heart Valves: The
safety and efficacy of ELIQUIS have not been studied in patients
with prosthetic heart valves and is not recommended in these
patients.
- Acute PE in Hemodynamically Unstable
Patients or Patients who Require Thrombolysis or Pulmonary
Embolectomy: Initiation of ELIQUIS is not recommended as an
alternative to unfractionated heparin for the initial treatment of
patients with PE who present with hemodynamic instability or who
may receive thrombolysis or pulmonary embolectomy.
ADVERSE REACTIONS
- The most common and most serious
adverse reactions reported with ELIQUIS were related to
bleeding.
TEMPORARY INTERRUPTION FOR SURGERY AND OTHER
INTERVENTIONS
- ELIQUIS should be discontinued at least
48 hours prior to elective surgery or invasive procedures with a
moderate or high risk of unacceptable or clinically significant
bleeding. ELIQUIS should be discontinued at least 24 hours prior to
elective surgery or invasive procedures with a low risk of bleeding
or where the bleeding would be noncritical in location and easily
controlled. Bridging anticoagulation during the 24 to 48 hours
after stopping ELIQUIS and prior to the intervention is not
generally required. ELIQUIS should be restarted after the surgical
or other procedures as soon as adequate hemostasis has been
established.
DRUG INTERACTIONS
- Combined P-gp and Strong CYP3A4
Inhibitors: Inhibitors of P-glycoprotein (P-gp) and cytochrome
P450 3A4 (CYP3A4) increase exposure to apixaban and increase the
risk of bleeding. For patients receiving ELIQUIS doses of 5 mg or
10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS
is coadministered with drugs that are combined P-gp and strong
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or ritonavir).
In patients already taking 2.5 mg twice daily, avoid
coadministration of ELIQUIS with combined P-gp and strong CYP3A4
inhibitors.
Clarithromycin
Although clarithromycin is a combined P-gp and strong CYP3A4
inhibitor, pharmacokinetic data suggest that no dose adjustment is
necessary with concomitant administration with ELIQUIS.
- Combined P-gp and Strong CYP3A4
Inducers: Avoid concomitant use of ELIQUIS with combined P-gp
and strong CYP3A4 inducers (e.g., rifampin, carbamazepine,
phenytoin, St. John’s wort) because such drugs will decrease
exposure to apixaban.
- Anticoagulants and Antiplatelet
Agents: Coadministration of antiplatelet agents, fibrinolytics,
heparin, aspirin, and chronic NSAID use increases the risk of
bleeding. APPRAISE-2, a placebo-controlled clinical trial of
apixaban in high-risk post-acute coronary syndrome patients treated
with aspirin or the combination of aspirin and clopidogrel, was
terminated early due to a higher rate of bleeding with apixaban
compared to placebo.
PREGNANCY CATEGORY B
- There are no adequate and
well-controlled studies of ELIQUIS in pregnant women. Treatment is
likely to increase the risk of hemorrhage during pregnancy and
delivery. ELIQUIS should be used during pregnancy only if the
potential benefit outweighs the potential risk to the mother and
fetus.
Please see full Prescribing Information, including BOXED
WARNINGS and Medication Guide, available at
www.bms.com.
About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a
worldwide collaboration to develop and commercialize apixaban, an
oral anticoagulant discovered by Bristol-Myers Squibb. This global
alliance combines Bristol-Myers Squibb's long-standing strengths in
cardiovascular drug development and commercialization with Pfizer’s
global scale and expertise in this field.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube and Facebook.
About Pfizer Inc.: Working together for a healthier
world®
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products. Our global portfolio includes medicines and vaccines as
well as many of the world's best-known consumer health care
products. Every day, Pfizer colleagues work across developed and
emerging markets to advance wellness, prevention, treatments and
cures that challenge the most feared diseases of our time.
Consistent with our responsibility as one of the world's premier
innovative biopharmaceutical companies, we collaborate with health
care providers, governments and local communities to support and
expand access to reliable, affordable health care around the world.
For more than 150 years, we have worked to make a difference for
all who rely on us. We routinely post information that may be
important to investors on our website at www.pfizer.com. In
addition, to learn more, please visit us on www.pfizer.com and
follow us on Twitter at @Pfizer and @PfizerNews, LinkedIn, YouTube
and like us on Facebook at Facebook.com/Pfizer.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding the research, development and commercialization of
pharmaceutical products. All statements that are not statements of
historical facts are, or may be deemed to be, forward-looking
statements. Such forward-looking statements are based on historical
performance and current expectations and projections about our
future financial results, goals, plans and objectives and involve
inherent risks, assumptions and uncertainties, including internal
or external factors that could delay, divert or change any of them
in the next several years, and could cause our future financial
results, goals, plans and objectives to differ materially from
those expressed in, or implied by, the statements. These risks,
assumptions, uncertainties and other factors include, among others,
that Eliquis may not receive regulatory approval for the additional
indication described in this release and, if approved, whether
Eliquis for such additional indication described in this release
will be commercially successful. No forward-looking statement can
be guaranteed. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that
affect Bristol-Myers Squibb’s business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb’s Annual Report on Form 10-K for the year ended December 31,
2018, as updated by our subsequent Quarterly Reports on Form 10-Q,
Current Reports on Form 8-K and other filings with the Securities
and Exchange Commission. The forward-looking statements included in
this document are made only as of the date of this document and
except as otherwise required by federal securities law,
Bristol-Myers Squibb undertakes no obligation to publicly update or
revise any forward-looking statement, whether as a result of new
information, future events, changed circumstances or otherwise.
Pfizer Disclosure Notice
The information contained in this release is as of March 17,
2019. Pfizer assumes no obligation to update forward-looking
statements contained in this release as the result of new
information or future events or developments.
This release contains forward-looking information about Eliquis
(apixaban), including its potential benefits, that involves
substantial risks and uncertainties that could cause actual results
to differ materially from those expressed or implied by such
statements. Risks and uncertainties include, among other things,
the uncertainties inherent in research and development, including,
without limitation, the ability to meet anticipated clinical
endpoints, commencement and/or completion dates for our clinical
trials, as well as the possibility of unfavorable clinical trial
results, including the possibility of unfavorable new clinical data
and further analyses of existing clinical data; decisions by
regulatory authorities impacting labeling, manufacturing processes,
safety and/or other matters that could affect the availability or
commercial potential of Eliquis; and competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2018 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results”, as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
Eliquis® and the Eliquis logo are trademarks of Bristol-Myers
Squibb Company.
_________________________
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undergoing coronary angiography and intervention. Coronary Artery
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Comparative effects of antiplatelet, anticoagulant, or combined
therapy in patients with valvular and nonvalvular atrial
fibrillation: a randomized multicenter study. Journal of the
American College of Cardiology. 2004;44:1557-66viii Lip GY, Huber
K, Andreotti, et al. Management of antithrombotic therapy in atrial
fibrillation patients presenting with acute coronary syndrome
and/or undergoing percutaneous coronary intervention/stenting.
Thrombosis and Haemostasis. 2010;103:13-28ix Kaatz S., Ahmad D.,
Spyropoulos AC, et al. Definition of clinically relevant non‐major
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Bristol-Myers SquibbMedia: Chrissy Trank, 609-252-5609,
christina.trank@bms.comInvestors: Timothy Power,
609-252-7509, timothy.power@bms.com
Pfizer Inc.Media: Steven Danehy 212-733-1538,
steven.danehy@pfizer.comInvestors:
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