AUGUSTUS Demonstrates Favorable Safety Results of Eliquis® Versus Vitamin K Antagonists in Non-Valvular Atrial Fibrillation Patients with Acute Coronary Syndrome and/or Undergoing Percutaneous Coronary Intervention
March 17, 2019
AUGUSTUS is the largest trial in this high-risk patient population
requiring both anticoagulant and antiplatelet therapies
PRINCETON, N.J. & NEW YORK–(BUSINESS WIRE)–lt;a href="https://twitter.com/search?q=%24BMY&src=ctag" target="_blank"gt;$BMYlt;/agt;–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.
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.
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ELIQUIS Important Safety Information |
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WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE |
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Premature discontinuation of any oral anticoagulant, including |
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Epidural or spinal hematomas may occur in patients treated with |
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use of indwelling epidural catheters |
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concomitant use of other drugs that affect hemostasis, such as |
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a history of traumatic or repeated epidural or spinal punctures |
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a history of spinal deformity or spinal surgery |
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optimal timing between the administration of ELIQUIS and |
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is not known |
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Monitor patients frequently for signs and symptoms of |
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Consider the benefits and risks before neuraxial intervention |
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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.
-
Concomitant use of drugs affecting hemostasis increases the risk
-
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,
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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
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expand access to reliable, affordable health care around the world. For
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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.
_________________________
i Alexander JH et al. Apixaban with Antiplatelet Therapy
after Acute Coronary Syndrome. New England Journal of Medicine.
2011;365:699-708
ii Peterson ED, Pokorney SD. New
Treatment Options Fail to Close the Anticoagulation Gap in Atrial
Fibrillation. Journal of the American College of Cardiology. 2017;69(20)
iii
The AFFIRM Investigators. Baseline characteristics of patients with
atrial fibrillation: the AFFIRM study.
Contacts
Bristol-Myers Squibb
Media: Chrissy Trank, 609-252-5609, [email protected]
Investors:
Timothy Power, 609-252-7509, [email protected]
Pfizer Inc.
Media: Steven Danehy 212-733-1538, [email protected]
Investors:
Ryan Crowe, 212-733-8160, [email protected]
