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).
This subanalysis 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
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.
- Active pathological bleeding
- Severe hypersensitivity reaction to ELIQUIS (apixaban) (i.e.,
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.
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.
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
Please see full Prescribing Information including BOXED WARNING and
Medication Guide available at www.bms.com.
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.
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
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.
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