In a Subanalysis, Eliquis® (apixaban) Reduced the Risk of Stroke and Demonstrated Fewer Major Bleeding Events versus Warfarin

  In a Subanalysis, Eliquis® (apixaban) Reduced the Risk of Stroke and
  Demonstrated Fewer Major Bleeding Events versus Warfarin Consistently across
  Age Groups, Including Older Patients with Nonvalvular Atrial Fibrillation

 Data from Phase 3 ARISTOTLE trial pre-specified subanalysis published in the
                            European Heart Journal

Business Wire

PRINCETON, N.J. & NEW YORK -- February 21, 2014

Bristol-Myers Squibb Company (NYSE:BMY) and Pfizer Inc. (NYSE:PFE) today
announced results of a pre-specified subanalysis of the Phase 3 ARISTOTLE
trial in relation to patient age. ARISTOTLE was designed to evaluate the
efficacy and safety of Eliquis compared to warfarin for reducing the risk of
stroke or systemic embolism in patients with nonvalvular atrial fibrillation
(NVAF). Thissubanalysis found consistent results across age groups for
reducing the risk of stroke and systemic embolism and reducing the risk of
all-cause death with fewer bleeding events. Owing to the higher risk at older
age (age 75 and older), the absolute benefit to patients with NVAF was greater
with Eliquis in the older population. These data were published today in the
European Heart Journal.

Eliquis was more effective than warfarin in reducing the risk of stroke and
reducing mortality across age groups, and was associated with less major
bleeding, less total bleeding and less intracranial hemorrhage, regardless of
age. The p-value for interaction across age groups was non-significant (p>0.11
for all)for the major outcomes of stroke and systemic embolism, major
bleeding, and death, meaning that the results of this subanalysis were
consistent with the overall results of the ARISTOTLE trial.

“Patients with atrial fibrillation are at an increased risk of major
cardiovascular events such as stroke, and this risk increases substantially
with age,” said study lead author Dr. Sigrun Halvorsen, Department of
Cardiology, Oslo University Hospital, Norway. “Eliquis has demonstrated
superiority versus warfarin for reducing the risk of stroke and all-cause
mortality with fewer major bleeding events in patients with NVAF with
consistency across age groups, including patients 75 and older and the very
elderly over the age of 80.”

Although the ARISTOTLE trial was neither designed nor powered to investigate
the differences for safety and efficacy of Eliquis compared to warfarin for
individual age groups, a pre-specified subanalysis of the ARISTOTLE trial was
performed according to age. The efficacy and safety of Eliquis compared with
warfarin were assessed according to age during the 1.8 years median follow-up.
Of the trial population, 30 percent were under age 65, 39 percent were 65 to
74 years old and 31 percent were 75 years or older. In the overall ARISTOTLE
trial population, the rates of stroke, major bleeding and death were higher in
the older age groups (p<0.001 for all) across treatment groups.

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 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
heartbeat). 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), Iceland,
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), Iceland, Norway, and a
number of other countries around the world. Eliquis is not approved for this
indication in the U.S. or Japan.

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.

Contact:

Bristol-Myers Squibb
Media:
Shelly Mittendorf, 609-252-5799
shelly.mittendorf@bms.com
or
Investors:
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Ryan Asay, 609-252-5020
ryan.asay@bms.com
or
Pfizer Inc.
Media:
Jennifer Kokell, 212-733-2596
jennifer.kokell@pfizer.com
or
Investors:
Ryan Crowe, 212-733-8160
ryan.crowe@pfizer.com
 
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