Subanalysis of Phase III ARISTOTLE Trial of Eliquis® (apixaban) Demonstrated Consistent Results Versus Warfarin in Patients

  Subanalysis of Phase III ARISTOTLE Trial of Eliquis® (apixaban) Demonstrated
  Consistent Results Versus Warfarin in Patients with Nonvalvular Atrial
  Fibrillation with or without Valvular Heart Disease

  Data show consistent results in reductions in stroke or systemic embolism,
        fewer major bleeding events, and reductions in all-cause death

   Post-hoc subanalysis of Phase III ARISTOTLE trial presented today at ESC
                                Congress 2013

Business Wire

PRINCETON, N.J. & NEW YORK -- September 3, 2013

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


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.



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


- Active pathological bleeding

- Severe hypersensitivity reaction to ELIQUIS (apixaban) (i.e., anaphylactic


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

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

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.


The most common and most serious adverse reactions reported with ELIQUIS
(apixaban) were related to bleeding.


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.


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.


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

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
or follow us on Twitter at

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

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.


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

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.


Bristol-Myers Squibb
Chrissy Trank, 609-252-3418
Ranya Dajani, 609-252-5330
Ryan Asay, 609-252-5020
Pfizer Inc.
Jennifer Kokell, 212-733-2596
Suzanne Harnett, 212-733-8009
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