Bristol-Myers
Squibb Company (NYSE: BMY) and Pfizer
Inc. (NYSE: PFE) today announced at the ESC Congress 2013, organized
by the European Society of Cardiology, results of a post-hoc subanalysis
from the Phase III ARISTOTLE trial, which was designed to demonstrate
the efficacy and safety of Eliquis compared to warfarin for the
prevention of stroke or systemic embolism in nonvalvular atrial
fibrillation (NVAF) patients. The ARISTOTLE trial excluded patients with
clinically significant mitral stenosis, or a mechanical prosthetic heart
valve. This subanalysis evaluated Eliquis compared to warfarin in
patients with or without other types of valvular heart disease (VHD) who
were eligible for enrollment in the ARISTOTLE trial, including mitral
regurgitation, mitral stenosis, aortic regurgitation, aortic stenosis,
tricuspid regurgitation, or valve surgery. Those 4,808 patients were the
focus of this subanalysis.
The results of this subanalysis were consistent with the results of the
overall ARISTOTLE trial and demonstrated that Eliquis compared
with warfarin reduced stroke or systemic embolism, caused fewer major
bleeding events, and reduced all-cause mortality in NVAF patients with
or without VHD. These results were presented in an oral session today at
the ESC Congress 2013 in Amsterdam, The Netherlands.
“This subanalysis provides better insight into the efficacy and safety
of apixaban in nonvalvular atrial fibrillation patients with certain
types of valvular heart disease, which are common in an elderly
population,” said study lead author Dr. Alvaro Avezum of the Dante
Pazzanese Institute of Cardiology in San Paulo, Brazil. ”These patients
are generally older and considered to be at greater risk for clinical
events than NVAF patients without VHD.”
This subanalysis evaluated data from 4,808 NVAF patients (26.4 percent
of the ARISTOTLE trial population) who had both VHD and NVAF. For the
purpose of this analysis, subjects with VHD were identified by any
history of at least moderate mitral regurgitation (N=3,526), mitral
stenosis (N=131), aortic regurgitation (N=384), aortic stenosis (N=887),
tricuspid regurgitation (N=2,124), or valve surgery (N=251). Note that
some of these patients had more than one valvular abnormality.
In this subanalysis, overall patients with these types of VHD had higher
rates of stroke or systemic embolism and of major bleeding than patients
without VHD, regardless of treatment. Moreover, patients randomized to Eliquis
had lower rates of stroke or systemic embolism and of major bleeding
compared with patients randomized to warfarin, both among patients with
and without VHD. All p-values for interaction (due to presence or
absence of VHD) were non-significant for the major outcomes of stroke
and systemic embolism, major bleeding, and death. This means that
patients in the ARISTOTLE trial had similar outcomes with Eliquis
regardless of whether they had VHD, and that the results of this
subanalysis were consistent with the overall results of the trial.
About ARISTOTLE
The ARISTOTLE study was designed to evaluate the efficacy and safety of Eliquis
versus warfarin for the prevention of stroke or systemic embolism. In
ARISTOTLE, 18,201 patients were randomized (9,120 patients to Eliquis
and 9,081 to warfarin). ARISTOTLE was an active-controlled, randomized,
double-blind, multi-national trial in patients with nonvalvular atrial
fibrillation or atrial flutter, and at least one additional risk factor
for stroke. Patients were randomized to treatment with Eliquis 5
mg orally twice daily (or 2.5 mg twice daily in selected patients,
representing 4.7 percent of all patients) or warfarin (target INR range
2.0-3.0), and followed for a median of 1.8 years.
About Atrial Fibrillation
Atrial fibrillation is the most common cardiac arrhythmia (irregular
heart beat). It is estimated that approximately 5.8 million Americans
and six million individuals in Europe have atrial fibrillation. The
lifetime risk of developing atrial fibrillation 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 atrial
fibrillation is the increased risk of stroke, which is five times higher
in people with atrial fibrillation than those without atrial
fibrillation. In fact, 15 percent of all strokes are attributable to
atrial fibrillation in the U.S. Additionally, strokes due to atrial
fibrillation are more burdensome than strokes due to other causes.
Atrial fibrillation-related strokes are more severe than other strokes,
with an associated 30-day mortality of 24 percent and a 50 percent
likelihood of death within one year in patients who are not treated with
an antithrombotic.
About Eliquis®
Eliquis® (apixaban) is an oral direct Factor Xa
inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquis
prevents thrombin generation and blood clot formation. Eliquis is
approved to reduce the risk of stroke and systemic embolism in patients
with nonvalvular atrial fibrillation in the United States, European
Union (which includes 28 member states plus Iceland and Norway), Japan
and a number of other countries around the world. Eliquis is
approved for prevention of venous thromboembolic events (VTE) in adult
patients who have undergone elective hip or knee replacement surgery in
the European Union (which includes 28 member states plus Iceland and
Norway) and a number of other countries around the world. Eliquis
is not approved for this indication in the U.S. or Japan.
IMPORTANT SAFETY INFORMATION FOR ELIQUIS
BOXED WARNING: DISCONTINUING ELIQUIS IN PATIENTS WITHOUT ADEQUATE
CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE.
Discontinuing ELIQUIS places patients at an increased risk of
thrombotic events. An increased rate of stroke was observed following
discontinuation of ELIQUIS in clinical trials in patients with
nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS must be
discontinued for a reason other than pathological bleeding, coverage
with another anticoagulant should be strongly considered.
CONTRAINDICATIONS
- Active pathological bleeding
- Severe hypersensitivity reaction to ELIQUIS (apixaban) (i.e.,
anaphylactic reactions)
WARNINGS AND PRECAUTIONS
Increased Risk of Stroke with Discontinuation of ELIQUIS: Discontinuing
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
patients with nonvalvular atrial fibrillation. If ELIQUIS must be
discontinued for a reason other than pathological bleeding, 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 anti-platelet agents, other anticoagulants, heparin,
thrombolytic agents, SSRIs, SNRIs, and NSAIDs. Patients should be made
aware of signs or symptoms of blood loss and instructed to immediately
report to an emergency room. Discontinue ELIQUIS in patients with active
pathological hemorrhage. There is no established way to reverse the
anticoagulant effect of apixaban, which can be expected to persist for
about 24 hours after the last dose (i.e., about two half-lives). A
specific antidote for ELIQUIS is not available. Because of high plasma
protein binding, apixaban is not expected to be dialyzable. Protamine
sulfate and vitamin K would not be expected to affect the anticoagulant
activity of apixaban. There is no experience with antifibrinolytic
agents (tranexamic acid, aminocaproic acid) in individuals receiving
apixaban. There is neither scientific rationale for reversal nor
experience with systemic hemostatics (desmopressin and aprotinin) in
individuals receiving apixaban. Use of procoagulant reversal agents such
as prothrombin complex concentrate, activated prothrombin complex
concentrate, or recombinant factor VIIa may be considered but has not
been evaluated in clinical studies. Activated charcoal reduces
absorption of apixaban thereby lowering apixaban plasma concentrations.
Prosthetic Heart Valves: The safety and efficacy of ELIQUIS has
not been studied in patients with prosthetic heart valves and is not
recommended in these patients.
ADVERSE REACTIONS
The most common and most serious adverse reactions reported with ELIQUIS
(apixaban) were related to bleeding.
DISCONTINUATIONS 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.
DRUG INTERACTIONS
Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of CYP3A4
and P-gp increase exposure to apixaban and increase the risk of
bleeding. Decrease the dose of ELIQUIS to 2.5 mg twice daily when
coadministered with drugs that are strong dual inhibitors of CYP3A4 and
P-gp, (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin).
In patients already taking ELIQUIS at a dose of 2.5 mg twice daily,
avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp.
Strong Dual Inducers of CYP3A4 and P-gp: Inducers of CYP3A4 and
P-gp decrease exposure to apixaban and increase the risk of stroke.
Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and
P-gp (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 WARNING 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 Eliquis, 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, please
visit http://www.bms.com
or follow us on Twitter at http://twitter.com/bmsnews.
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, Pfizer has worked to make a difference for all who
rely on us. To learn more, please visit us at www.pfizer.com.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding product development. Such forward-looking statements are based
on current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. No forward-looking statement can be guaranteed.
Among other risks, there can be no guarantee that Eliquis will be
approved for the prevention and treatment of VTE in the U.S.
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, 2012, in our Quarterly Reports on Form 10-Q and
our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement, whether as
a result of new information, future events or otherwise.
PFIZER DISCLOSURE NOTICE:
The information contained in this release is as of September 3, 2013.
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. Such risks and uncertainties include, among
other things, (i) the uncertainties inherent in research and
development; (ii) uncertainties regarding the commercial success of
Eliquis; (iii) whether and when Eliquis will be approved in the
EU for the treatment of venous thromboembolic events (VTE) or in the
U.S. and other markets for the prevention and treatment of VTE, as
well as the decisions of regulatory authorities in those jurisdictions
regarding labeling and other matters that could affect the availability
or commercial potential of those additional indications; and (iv)
competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K/A for the fiscal year ended December
31, 2012 and in its reports on Form 10-Q and Form 8-K.
Copyright Business Wire 2013