In this U.S. Medicare database analysis, Eliquis®
(apixaban) was associated with significantly lower risk of stroke or
systemic embolism and lower rate of major bleeding compared to warfarin
PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--
Squibb Company (NYSE:BMY) and Pfizer
Inc. (NYSE:PFE) today announced findings from a real-world data
analysis of the U.S. Medicare database comparing the risk of stroke or
systemic embolism and rate of major bleeding among patients with
non-valvular atrial fibrillation who were treated with direct oral
anticoagulants versus warfarin. In the analysis, titled Effectiveness
and Safety of Apixaban, Dabigatran, and Rivaroxaban Compared to Warfarin
among Non-Valvular Atrial Fibrillation Patients in the U.S. Medicare
Population, Eliquis® (apixaban) was associated with a
significantly lower risk of stroke or systemic embolism and lower rate
of major bleeding compared to warfarin.i These data, which
supplement results from randomized trials, are being presented at the
American College of Cardiology’s (ACC) 66th Annual Scientific
Session in Washington, D.C.
In this observational analysis, medical and pharmacy claims were
evaluated from the U.S. Medicare fee-for-service database of
non-valvular atrial fibrillation patients age 65 and older who were
newly prescribed oral anticoagulation therapy between January 1, 2013,
and December 31, 2014 (n=186,132, following inclusion and exclusion
criteria). The analysis included 41,606 patients treated with Eliquis or
warfarin (20,803 patients each in the Eliquis and warfarin cohorts),
balanced according to select demographic and clinical characteristics.
The matched Eliquis-warfarin cohorts, followed for a mean of 5.7 and 6.5
months, respectively, had a mean age of 78 years, a CHA2DS2-VASc
score of 4.6 and 4.7, respectively, and a HAS-BLED score of 3.3. CHA2DS2-VASc
score is a method for estimating stroke risk in patients with atrial
fibrillation, and HAS-BLED score helps to estimate risk of major
bleeding in patients with atrial fibrillation. Real-world data analyses
cannot be used as stand-alone evidence to validate the efficacy and/or
safety of a treatment. Observational real-world studies can only
evaluate association and not causality.ii,iii Please see full
methodology and additional limitations below.
“Studies such as this large U.S. Medicare database analysis supplement
pivotal trials by broadening and deepening our scientific knowledge of
how patients respond to direct oral anticoagulants in everyday clinical
practice,” said Alpesh Amin, M.D., principal investigator and Professor
of Medicine, University of California, Irvine. “Given the diversity of
patients with non-valvular atrial fibrillation, analyses of real-world
data provide further information that adds to data generated in
randomized clinical trials.”
Eliquis, in this analysis, was associated with a significantly lower
risk of stroke or systemic embolism (HR: 0.40, 95% CI: 0.31-0.53;
p<0.0001) and lower rate of major bleeding (HR: 0.51, 95% CI: 0.44-0.58;
p<0.0001) than patients treated with warfarin. The findings from the
Eliquis-warfarin cohort complement the results of the randomized Phase 3
ARISTOTLE (Apixaban for Reduction In Stroke
and Other ThromboemboLic Events in Atrial
Fibrillation) trial.iv For data on other cohorts, please
refer to the full
“The U.S. Medicare system currently covers more than 57 million
Americans,v including over two million who have been treated
with anticoagulants,” said Rory O’Connor, M.D., Chief Medical Officer,
Pfizer Innovative Health. “Increasingly, real-world data analyses are
being utilized to enhance the understanding of data associated with
health interventions. With the advent of large, representative and
anonymized datasets, such as records from the Centers for Medicare &
Medicaid Services, we can provide additional information that clinicians
can use in their treatment decisions.”
“The Bristol-Myers Squibb and Pfizer Alliance continues to invest
heavily in research analyses that provide more information on care for
patients with non-valvular atrial fibrillation,” said Christoph Koenen,
M.D., MBA, VP, Development Lead, Eliquis, Bristol-Myers Squibb. “Our
real-world data program – ACROPOLIS™ – aims to generate evidence from
routine clinical practice settings by analyzing patient databases around
the world, including medical records, medical and pharmacy health
insurance claims data and national health data systems.”
In addition to the apixaban cohort, this analysis of the U.S. Medicare
database included cohorts comparing two other direct oral anticoagulants
(rivaroxaban and dabigatran) separately with warfarin. The analysis was
conducted in patients age 65 and older with non-valvular atrial
fibrillation who had not received an oral anticoagulant for at least one
year. Patients had to have continuous health plan enrollment with
medical and pharmacy benefits for at least 12 months pre-index date.
Patients with evidence of valvular heart disease, transient atrial
fibrillation, venous thromboembolism, valve replacement or surgery or
indication of pregnancy 12 months prior to the index date were excluded.
This analysis was designed according to the International Society for
Pharmacoeconomics and Outcomes Research (ISPOR) guidelines for
comparative effectiveness research, which include recommendations for
research question development, transparency of analytical plans and
control of confounding factors.vi,vii,viii One-to-one
propensity score matching methodology (PSM) was applied in the analysis
to balance select demographic and clinical characteristics. Cox
proportional hazards models were used to estimate the hazard ratio (HR)
of stroke/systemic embolism and major bleeding using primary ICD-9 codes
of inpatient claims.
Limitations of Real-World Data Analyses and of the U.S. Medicare
Real-world data have the potential to supplement randomized clinical
trial data by providing additional information about how a medicine
performs in routine medical practice. Real-world data analyses have
several limitations. For example, the source and type of data used may
limit the generalizability of the results and of the endpoints. It is
important to note that there are no head-to-head clinical trials
comparing direct oral anticoagulants.
In the U.S. Medicare database analysis, laboratory results and time in
therapeutic range information were not available. Diagnoses were
identified through ICD-9 codes, and drug prescriptions were identified
through prescription claims. PSM methodology was used to mimic
randomization by balancing pre-defined demographic and clinical
characteristics at baseline for both treatment cohorts. As an
observational study using PSM, unobserved cofounders (e.g., laboratory
values and patient preferences) may exist for which the analysis did not
control. As with any real-world data analysis, missing values, coding
errors and lack of clinical accuracy may have introduced bias.
Due to these limitations, real-world data analyses cannot be used as
stand-alone evidence to validate the efficacy and/or safety of a
treatment. Observational real-world studies can only evaluate
association and not causality.ii,iii
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By
inhibiting Factor Xa, a key blood clotting protein, Eliquis
decreases thrombin generation and blood clot formation. Eliquis is
approved for multiple indications in the U.S. based on efficacy and
safety data from seven Phase 3 clinical trials. Eliquis is a
prescription medicine indicated to reduce the risk of stroke and
systemic embolism in patients with nonvalvular atrial fibrillation
(NVAF); for the prophylaxis of deep vein thrombosis (DVT), which may
lead to pulmonary embolism (PE), in patients who have undergone hip or
knee replacement surgery; for the treatment of DVT and PE; and to reduce
the risk of recurrent DVT and PE, following initial therapy.
ELIQUIS Important Safety Information
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE
RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
(A) Premature discontinuation of any oral anticoagulant,
including ELIQUIS, increases the risk of thrombotic events. If
anticoagulation with ELIQUIS is discontinued for a reason other than
pathological bleeding or completion of a course of therapy, consider
coverage with another anticoagulant.
(B) Epidural or spinal hematomas may occur in patients treated
with ELIQUIS who are receiving neuraxial anesthesia or undergoing
spinal puncture. These hematomas may result in long-term or
permanent paralysis. Consider these risks when scheduling patients
for spinal procedures. Factors that can increase the risk of
developing epidural or spinal hematomas in these patients include:
use of indwelling epidural catheters
concomitant use of other drugs that affect hemostasis, such
as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet
inhibitors, other anticoagulants
a history of traumatic or repeated epidural or spinal
a history of spinal deformity or spinal surgery
optimal timing between the administration of ELIQUIS and
neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of
neurological impairment. If neurological compromise is noted, urgent
treatment is necessary.
Consider the benefits and risks before neuraxial intervention in
patients anticoagulated or to be anticoagulated.
Active pathological bleeding
Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic
WARNINGS AND PRECAUTIONS
Increased Risk of Thrombotic Events after Premature
Discontinuation: Premature discontinuation of any oral
anticoagulant, including 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 atrial fibrillation
patients. If ELIQUIS is discontinued for a reason other than
pathological bleeding or completion of a course of therapy, 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 antiplatelet agents,
other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs,
Advise patients of signs and symptoms of blood loss and to report
them immediately or go 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 at least 24 hours
after the last dose (i.e., about two half-lives). A specific
antidote for ELIQUIS is not available.
Spinal/Epidural Anesthesia or Puncture: Patients treated with
ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop
an epidural or spinal hematoma which can result in long-term or
The risk of these events may be
increased by the postoperative use of indwelling epidural catheters or
the concomitant use of medicinal products affecting hemostasis.
Indwelling epidural or intrathecal catheters should not be removed
earlier than 24 hours after the last administration of ELIQUIS. The
next dose of ELIQUIS should not be administered earlier than 5 hours
after the removal of the catheter. The risk may also be increased by
traumatic or repeated epidural or spinal puncture. If traumatic
puncture occurs, delay the administration of ELIQUIS for 48 hours.
patients frequently and if neurological compromise is noted, urgent
diagnosis and treatment is necessary. Physicians should consider the
potential benefit versus the risk of neuraxial intervention in ELIQUIS
Prosthetic Heart Valves: The safety and efficacy of ELIQUIS
have not been studied in patients with prosthetic heart valves and is
not recommended in these patients.
Acute PE in Hemodynamically Unstable Patients or Patients who
Require Thrombolysis or Pulmonary Embolectomy: Initiation of
ELIQUIS is not recommended as an alternative to unfractionated heparin
for the initial treatment of patients with PE who present with
hemodynamic instability or who may receive thrombolysis or pulmonary
The most common and most serious adverse reactions reported with
ELIQUIS were related to bleeding.
TEMPORARY INTERRUPTION 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. Bridging
anticoagulation during the 24 to 48 hours after stopping ELIQUIS and
prior to the intervention is not generally required. ELIQUIS should be
restarted after the surgical or other procedures as soon as adequate
hemostasis has been established.
Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of
cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) increase
exposure to apixaban and increase the risk of bleeding. For patients
receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose
of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are
strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole,
itraconazole, ritonavir, or clarithromycin). In patients already
taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with
strong dual inhibitors of CYP3A4 and P-gp.
Strong Dual Inducers of CYP3A4 and P-gp: 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 and increase the risk of
stroke and other thromboembolic events.
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 WARNINGS and
Medication Guide, available at www.bms.com.
ACROPOLIS™ (Apixaban ExperienCe Through Real-WOrld
POpuLatIon Studies) is the Eliquis
(apixaban) global real-world data program designed to generate
additional evidence from routine clinical practice settings to further
inform healthcare decision makers, including healthcare providers and
payers. The ACROPOLIS program will include retrospective, outcomes-based
analyses from over 10 databases around the world, including medical
records, medical and pharmacy health insurance claims data, and national
health data systems.
Analyses of real-world data allow for a broader understanding of patient
outcomes associated with Eliquis outside of the clinical trial setting,
as well as insight into other measures of healthcare delivery, such as
hospitalization and costs.
ARISTOTLE (Apixaban for Reduction In STroke
and Other ThromboemboLic Events in Atrial
Fibrillation) 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 the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide
collaboration to develop and commercialize apixaban, 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 about
Bristol-Myers Squibb, visit us at BMS.com
or follow us on LinkedIn,
About 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, we have worked to make a difference for all who
rely on us. We routinely post information that may be important to
investors on our website at www.pfizer.com.
In addition, to learn more, please visit us on www.pfizer.com
and follow us on Twitter at @Pfizer
and like us on Facebook at Facebook.com/Pfizer.
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.
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, 2016, 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 March 17, 2017.
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 that could cause actual results to differ
materially from those expressed or implied by such statements. Risks and
uncertainties include, among other things, the uncertainties inherent in
research and development, including, without limitation, the ability to
meet anticipated clinical trial commencement and completion dates as
well as the possibility of unfavorable clinical trial results, including
unfavorable new clinical data and additional analyses of existing
clinical data; decisions by regulatory authorities regarding labeling
and other matters that could affect the availability or commercial
potential of Eliquis; and competitive developments.
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, 2016 and in its subsequent reports on Form 10-Q, including in the
sections thereof captioned “Risk Factors” and “Forward-Looking
Information and Factors That May Affect Future Results”, as well as in
its subsequent reports on Form 8-K, all of which are filed with the SEC
and available at www.sec.gov
i Amin A, Keshishian A, Trocio J, et al. Effectiveness
and safety of apixaban, dabigatran, and rivaroxaban compared to
warfarin among non-valvular atrial fibrillation patients in the US
Medicare population. Presented at the 66th Annual American College
of Cardiology (ACC) Scientific Session; March 17, 2017; Washington,
ii Garrison LP, Neumann PJ, Erickson P, Marshall D,
Mullins CD. Using real-world data for coverage and payment
decisions: the ISPOR real-world data task force report. Value
iii Hannan EL. Randomized clinical trials and
observational studies. J Am Coll Cardiol Intv. 2008;1:211-217.
iv Granger, CB, Alexander JH, McMurray JJV, et al.
Apixaban versus warfarin in patients with atrial fibrillation. N
Engl J Med. 2011;365:981-992.
v Centers for Medicare & Medicaid Services. Medicare
Enrollment Dashboard. Accessed March 7, 2016. Available at https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Dashboard/Medicare-Enrollment/Enrollment%20Dashboard.html.
vi Berger ML, Mamdani M, Atkins D, Johnson ML. Good
Research Practices for Comparative Effectiveness Research:
Defining, Reporting and Interpreting Nonrandomized Studies of
Treatment Effects Using Secondary Data Sources: The ISPOR Good
Research Practices for Retrospective Database Analysis Task Force
Report—Part I. Value in Health. 2009:12(8):1044-1052.
vii Cox E, Martin BC, Van Staa T, et al. Good Research
Practices for Comparative Effectiveness Research: Approaches to
Mitigate Bias and Confounding in the Design of Nonrandomized
Studies of Treatment Effects Using Secondary Data Sources: The
International Society for Pharmacoeconomics and Outcomes Research
Good Research Practices for Retrospective Database Analysis Task
Force Report—Part II. Value in Health. 2009:12(8):1053-1061.
viii Johnson ML, Crown W, Martin BC, Dormuth CR,
Siebert U. Good Research Practices for Comparative Effectiveness
Research: Analytic Methods to Improve Causal Inference from
Nonrandomized Studies of Treatment Effects Using Secondary Data
Sources: The ISPOR Good Research Practices for Retrospective
Database Analysis Task Force Report—Part III. Value in Health.
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Source: Bristol-Myers Squibb and Pfizer