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
Bristol-Myers 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
abstract.
“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.”
Methodology
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 Database Analysis
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
About Eliquis
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
punctures
- 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.
CONTRAINDICATIONS
- Active pathological bleeding
- Severe hypersensitivity reaction to
ELIQUIS (e.g., anaphylactic reactions)
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, and NSAIDs.
- 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 permanent
paralysis.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.Monitor 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 patients.
- 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 embolectomy.
ADVERSE REACTIONS
- 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.
DRUG INTERACTIONS
- 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.
About ACROPOLIS™
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.
About ARISTOTLE
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, Twitter, YouTube and Facebook.
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 @PfizerNews, LinkedIn, YouTube
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 and
www.pfizer.com.
________
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,
D.C. 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 Health.
2007;10:326-335. 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. 2009:12(8):1062-1073.
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