Bristol-Myers
Squibb Company (NYSE: BMY) and Pfizer
Inc. (NYSE: PFE) today announced results of a post-hoc subanalysis
from the Phase III ARISTOTLE trial. Patients with nonvalvular atrial
fibrillation (NVAF) who are anticoagulated to reduce the risk of stroke
often undergo procedures for which temporary discontinuation of the
anticoagulant prior to and following the procedure is sometimes
warranted. This subanalysis describes the overall rates of key
post-procedural outcomes, such as stroke or systemic embolism and major
bleeding, among Eliquis and warfarin patients who underwent a
procedure during the ARISTOTLE trial, and examined any differences in
post-procedural events according to whether or not study drug was
interrupted. This subanalysis was presented today at the ESC Congress
2013, organized by the European Society of Cardiology, in Amsterdam, The
Netherlands.
The results showed that in the 30-day period following a procedure,
rates of clinical events (stroke or systemic embolism, major bleeding,
and all-cause death) were comparable in the Eliquis and warfarin
treatment arms.
Among patients treated with Eliquis, event rates in the 30-day
period following a procedure were similar whether Eliquis was
stopped prior to the procedure or continued during the procedure. In
patients taking warfarin, there was at least a twofold higher rate of
major bleeding and death during the 30-day period following a procedure
when warfarin was continued during the procedure compared to when
warfarin was stopped prior to the procedure.
“For patients with NVAF who undergo procedures, the rate of
anticoagulation-related adverse events appears to be similar whether the
patient is chronically anticoagulated with apixaban or warfarin,” said
study lead investigator Dr. Renato Lopes of Duke University Medical
Center in Durham, North Carolina. “For NVAF patients for whom
interruption of anticoagulation for a procedure is required, these
findings suggest that using apixaban instead of warfarin, which is more
challenging to stop and restart, may simplify the management of
peri-operative anticoagulation in NVAF patients.”
There were 11,417 procedures in 6,162 patients from the 18,201 patients
enrolled in the ARISTOTLE trial. The most common procedures were dental
extraction/oral surgery, colonoscopy, upper endoscopy, and ophthalmic
surgery. For 4,082 (35.8 percent) procedures, study drug was not
stopped. In the 7,335 procedures (64.2 percent) where study drug was
stopped, the median time of study drug stop was four days before the
procedure for both Eliquis and warfarin-treated patients. The
procedures were classified as major if they required general anesthesia,
and procedures were also classified as emergent or non-emergent by
investigators.
Among patients undergoing procedures in the ARISTOTLE trial, stroke and
systemic embolism were uncommon and the 30-day post-procedure rates for
these events were not statistically different in the two treatment arms
(0.33 percent for Eliquis vs. 0.53 percent for warfarin). Major
bleeding occurred in a comparable number of patients 30 days
post-procedure in the two treatment arms (1.57 percent for Eliquis
vs. 1.81 percent for warfarin). In patients taking Eliquis, the
rates of post-procedural stroke or systemic embolism and major bleeding
were similar whether Eliquis was interrupted or continued. In
patients taking warfarin, the rates of post-procedure major bleeding and
death appeared higher when warfarin was continued compared to when it
was interrupted.
“The current results do not include analyses for individual procedure
types and therefore decisions whether to interrupt apixaban or warfarin
prior to procedures should be based on consideration of procedural
bleeding risk and patient thrombotic risk,” said Dr. Lopes. “In
addition, further analyses, including analyses according to type of
procedures and timing, are ongoing to better define these relationships.”
The U.S. Prescribing Information for Eliquis states that 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.
The U.S. Prescribing Information for Eliquis also includes a
Boxed Warning for patients who discontinue treatment. Patients on Eliquis
who discontinue treatment are at an increased risk of thrombotic events.
About ARISTOTLE
The ARISTOTLE study was designed to demonstrate 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 or 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 August 31, 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