Bristol-Myers Squibb and Pfizer Announce Publication of ARISTOTLE Subanalysis in Circulation

  Bristol-Myers Squibb and Pfizer Announce Publication of ARISTOTLE
  Subanalysis in Circulation

  *Subgroup analysis demonstrates that the treatment effects of Eliquis^®
    (apixaban) vs. warfarin, across a broad range of warfarin control, are
    consistent with primary results of ARISTOTLE
  *ARISTOTLE studied Eliquis vs. warfarin for the reduction of the risk of
    stroke and systemic embolism in patients with nonvalvular atrial

Business Wire

PRINCETON, N.J. & NEW YORK -- May 7, 2013

Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer Inc. (NYSE: PFE) today
announced that results from a prespecified subanalysis of the ARISTOTLE trial
were published in Circulation, the peer-reviewed journal of the American Heart
Association. Results from this subanalysis showed that the reductions in
stroke or systemic embolism, number of major bleeding events and mortality
demonstrated with Eliquis^® (apixaban) compared to warfarin in the ARISTOTLE
trial were consistent across subgroups defined based on levels of
International Normalized Ratio (INR) control in patients with nonvalvular
atrial fibrillation.

“Concerning the quality of warfarin treatment, there is a large variation in
time in therapeutic range among different countries and centers, which affects
outcomes. This subanalysis was conducted to determine whether the treatment
effects of apixaban were similar in centers and patients with high quality
warfarin care,” said study lead author Dr. Lars Wallentin of Uppsala
University in Uppsala, Sweden. “These additional analyses supported that the
primary results of ARISTOTLE were consistent across a broad range of quality
of warfarin management.”

Variations in time in therapeutic range (TTR) can affect outcomes for atrial
fibrillation patients being treated with Vitamin K antagonists such as
warfarin for stroke prevention, leading to an increased risk of stroke when
INR levels are below, or bleeding when INR levels are above, the therapeutic
range. For patients in the ARISTOTLE trial, the quality of warfarin management
was defined by TTR, with a target INR of 2.0 – 3.0. In the ARISTOTLE trial,
patients in the warfarin group had an INR in the therapeutic range (2.0 to
3.0) for a median of 66.0% of the time. For context, the median time for INR
in the therapeutic range varies across the globe. In clinical practice
settings in the United States, it is approximately 57-59%.

The ARISTOTLE trial randomized 18,201 patients from 1,034 clinical centers in
39 countries. In this subanalysis, for each patient, a center average TTR
(cTTR) was estimated using a linear mixed model based on the real TTRs in
warfarin treated patients with a fixed effect for country and random effect
for center. Study centers were placed into one of four similarly sized
quartile groups based on cTTR (<60.5%; 60.6%-66.3%; 66.4%-71.1%; and>71.2%).
The rates of stroke or systemic embolism, major bleeding and mortality were
consistently lower with Eliquis than warfarin across the cTTR quartiles.
Similar results were seen when an individual TTR (iTTR), predicted using a
model including patient characteristics, was examined in a post-hoc analysis.

While demonstrating consistency across a broad range of warfarin control,
results of this subanalysis suggest a trend toward reduction of the treatment
effects at centers and in patients with predicted excellent INR control. In
these centers, interaction tests are less reliable because of low numbers of
events, and thereby lack statistical power.

Based on the results of the subanalysis, the benefits of Eliquis compared with
warfarin for stroke or systemic embolism, bleeding, and mortality appear
similar across the range of centers’ and patients’ quality of INR control.

About ARISTOTLE Trial Design

The ARISTOTLE study was designed to demonstrate the efficacy and safety of
Eliquis versus warfarin for the prevention of stroke or systemic embolism in
patients with nonvalvular atrial fibrillation. 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 more than 5.8 million Americans and 6 million
individuals in Europe have atrial fibrillation. Nonvalvular atrial
fibrillation, or NVAF, is the most common type of 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

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, Canada, Japan, Korea, Mexico, Columbia, Russia,
Israel and Australia. Eliquis is approved for prevention of venous
thromboembolic events (VTE) in adult patients who have undergone elective hip
or knee replacement surgery in a total of 17 regions: Argentina, Australia,
Brazil, Canada, Colombia, European Union (which includes 27 member states plus
Iceland and Norway), Hong Kong, India, Indonesia, Israel, Peru, Russia, South
Korea, Switzerland, Thailand, Turkey and the United Arab Emirates.



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 investigational 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 become a commercially successful product.
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 May 6, 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)
that involves substantial risks and uncertainties. Such risks and
uncertainties include, among other things, (i) the uncertainties regarding the
commercial success of ELIQUIS for the reduction of the risk of stroke and
systemic embolism in patients with nonvalvular atrial fibrillation; (ii)
decisions by regulatory authorities in jurisdictions in which applications are
pending or may be filed for ELIQUIS for the prevention of stroke and systemic
embolism in patients with nonvalvular atrial fibrillation regarding whether
and when to approve such applications, as well as their decisions regarding
labeling and other matters that could affect the availability or commercial
potential of that indication in such jurisdictions; and (iii) competitive

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, 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.
MacKay Jimeson, 212-733-2324
Suzanne Harnett, 212-733-8009
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