Discontinuation risk comparison among ‘real-world’ newly anticoagulated atrial fibrillation patients: Apixaban, warfarin, dabigatran, or rivaroxaban
Discontinuation risk comparison among `real- world' newly anticoagulated atrial fibrillation patients: Apixaban, warfarin, dabigatran, or rivaroxaban
Gregory Y. H. Lip 0 1 2
Xianying Pan 2
Shital Kamble 2
Hugh Kawabata 2
Jack Mardekian 2
Cristina Masseria 2
Hemant Phatak 2
0 Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University , Aalborg , Denmark , 3 Center for Observational Research and Data Science, Bristol-Myers Squibb Company (BMS), Princeton, New Jersey, United States of America, 4 Worldwide Health Economics and Outcomes Research, Bristol-Myers Squibb Company (BMS), Princeton, New Jersey, United States of America, 5 Outcomes & Evidence, Patient & Health Impact, Pfizer Inc. , New York, New York , United States of America
1 University of Birmingham Institute of Cardiovascular Sciences, City Hospital , Birmingham , United Kingdom
2 Editor: Pablo Garcia de Frutos, Institut d'Investigacions Biomediques de Barcelona , SPAIN
Discontinuation of oral anticoagulants may expose non-valvular atrial fibrillation (NVAF) patients to an increased risk of stroke. This study describes the real-world discontinuation rates and compared the risk of drug discontinuation among NVAF patients initiating apixaban, warfarin, dabigatran, or rivaroxaban. This retrospective cohort study evaluated newlyanticoagulated NVAF patients in the MarketScan® data population from 01/01/2012 through 12/31/2014. Discontinuation was defined as a lack of subsequent prescription of the index drug within 30 days after the last supply day of the last prescription. A Cox model was used to estimate the hazard ratio (HR) of discontinuation, adjusted for age, sex, and comorbidities. Among 45,361 eligible NVAF patients, 15,461 (34.1%) initiated warfarin; 7,438 (16.4%) apixaban; 4,661 (10.3%) dabigatran; and 17,801 (39.2%) initiated rivaroxaban treatment. Compared to warfarin, patients who initiated dabigatran (adjusted HR [aHR]: 0.84, 95% confidence interval [CI]: 0.80±0.87, P<0.001), rivaroxaban (aHR: 0.70, 95% CI: 0.68±0.73, P<0.001), or apixaban (aHR: 0.57, 95% CI: 0.55±0.60, P<0.001) were 16%, 30%, and 43% less likely to discontinue treatment, respectively. When compared to apixaban, patients who initiated dabigatran (aHR: 1.46, 95% CI: 1.38±1.54, P<0.001) or rivaroxaban (aHR: 1.23, 95% CI: 1.17±1.28, P<0.001) were more likely to discontinue treatment. Among newly-anticoagulated NVAF patients in the real-world setting, initiation on rivaroxaban, dabigatran, or apixaban was associated with a significantly lower risk of discontinuation compared to warfarin. When compared to apixaban, patients who initiated treatment with warfarin, dabigatran, or rivaroxaban were more likely to discontinue treatment.
Data Availability Statement: The data for these
analyses were made available to the authors by
third-party license from Truven MarketScan, a
commercial data provider in the US, and BMS
(who have a license for analysis of the Truven
MarketScan data). As such, the authors cannot
provide the raw data themselves. Other
researchers could access the data by purchase
through Truven MarketScan; and the inclusion
criteria specified in the Methods section would
allow them to identify the same cohort of patients
the authors used for these analyses. Interested
individuals may see http://truvenhealth.com/
marketscan-databases for more information on
accessing Truven MarketScan data. The authors
confirm that no authors had special privileges to
access data from Truven MarketScan via
thirdparty license, and that other researchers would be
able to access the data in the same manner as the
Funding: This study was sponsored by
BristolMyers Squibb Company, Princeton, NJ, USA and
Pfizer Inc., New York, New York, USA. The funder
provided support in the form of salaries for authors
XP, SK, HK, JM, CM, HM, but did not have any
additional role in the study design, data collection
and analysis, decision to publish, or preparation of
Competing interests: Gregory YH Lip has served
as a consultant for Bayer/Janssen, Merck, Sanofi,
Bristol-Myers Squibb Company/Pfizer Inc.,
DaiichiSankyo, Biotronik, Medtronic, Portola, and
Boehringer Ingelheim, and has been on the
speakers' bureau for Bayer, Bristol Myers Squibb
Company/Pfizer Inc., Boehringer Ingelheim,
Daiichi-Sankyo, and Medtronic. Ms. Pan, Dr.
Kamble, and Dr. Kawabata are employees of
Bristol-Myers Squibb Company with ownership of
stocks in Bristol-Myers Squibb Company. Drs.
Masseria and Mardekian are employees of Pfizer
Inc, with ownership of stocks in Pfizer Inc. Dr.
Phatak was an employee of Bristol-Myers Squibb
Company at the time of research and has
ownership of stocks in Bristol-Myers Squibb
Company. The authors have indicated that they
have no other conflicts of interest regarding the
content of this article. There are no patents,
products in development, or marketed products to
declare. This does not alter our adherence to PLOS
ONE policies on sharing data and materials.
While warfarin is highly effective for preventing stroke in patients with atrial fibrillation (AF),
there is significant inter- and intra-patient variability in dose requirements, thus necessitating
regular anticoagulation monitoring. Warfarin is also associated with many diet and drug
interactions and can be associated with a significant rate of major bleeding, particularly intracranial
]. Given these difficulties, many at-risk AF patients do not receive warfarin or
receive an inadequate dose, and often discontinue therapy [
]. As a result, approximately
30±50% of patients have been undertreated with either suboptimal warfarin treatment, aspirin,
or no anticoagulation [
]. In recent years, 4 non-Vitamin K antagonist oral anticoagulants
(NOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have been approved in
the United States for stroke prevention in NVAF patients. The NOACs have advantages over
warfarin in that there is no need for regular International Normalized Ratio (INR) monitoring,
and there are fewer drug and food interactions. In clinical trials assessing warfarin, dabigatran,
rivaroxaban, apixaban, and edoxaban, all have been shown to be safe and effective [4±7].
Among all NOACs approved for non-valvular AF (NVAF), apixaban is the only drug that has
shown, in its respective clinical trial(s), to have a significantly lower discontinuation rate than
warfarin (or aspirin) possibly due to its significantly better safety and tolerability profile
]. Due to the moderate half-life of NOACs, it is important for patients to continue to take
medications daily, as indicated. For both warfarin and NOACs, drug discontinuation and
missing doses (ie, lower adherence) may expose AF patients to an increased risk of stroke.
Consequently, studies of discontinuation and adherence associated with NOACs are
important in understanding treatment patterns and associated gaps [
]. It would be important
to investigate discontinuation rates and time to discontinuation associated with various
NOACs to understand the ability of patients to continue long-term NOAC use in real-world
settings. The objective of this study was to describe the `real-world' discontinuation rates and
compare the risk of drug discontinuation among patients initiating apixaban, dabigatran,
rivaroxaban, and warfarin. For the purposes of this analysis, there were insufficient real-world
data available for edoxaban in the United States.
A retrospective cohort study was conducted using the Truven MarketScan1 Commercial
Claims & Encounters and Medicare Supplemental & Coordination of Benefits database
(January 2012 through December 2014) to evaluate the discontinuation rates among AF patients
who initiated apixaban, warfarin, dabigatran, or rivaroxaban treatment [
]. The database
includes health insurance claims for over 60 million employees, spouses, retirees, and their
dependents, enrolled in employer-sponsored commercial and Medicare advantage plans. The
geographical distribution is approximately the same as the US population distribution. The
database includes fully-integrated health information, including inpatient and outpatient
health care resource utilization and detailed drug information. The pharmaceutical claims file
includes complete records of prescriptions, including mail-order or card program prescription
drug claims [
NVAF patients aged 18 years (identified based on presence of at least 1 claim for a
primary or secondary diagnosis of AF in the inpatient or outpatient setting using ICD-9-CM
code 427.31 or 472.32) with a 1-year baseline period with continuous health plan enrollment
were included if they were newly prescribed oral anticoagulants from January 1, 2013 through
December 31, 2014 [
]. The ICD-9 codes have been validated for identifying AF patients with
a median positive predictive value of 89% [
]. In other words, a contemporary cohort of
NOAC and warfarin initiators without prior oral anticoagulant treatment during the 1-year
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Fig 1. Study period depiction. Study period for patients initiating apixaban, dabigatran, rivaroxaban, and warfarin. AF: atrial fibrillation.
baseline period was selected for this study. The index drug was defined as the first
anticoagulation treatment prescribed to patients included in the study. The index date was defined as the
first index drug prescription date, after NVAF diagnosis. The index date is depicted in Fig 1.
Patients with claims including ICD-9-CM diagnosis codes for transient AF (pericarditis,
hyperthyroidism, thyrotoxicity), valvular heart disease, venous thromboembolism, cardiac
surgery, or pregnancy during the baseline period (any time prior to or on the index date) were
excluded (Fig 2; S1 Table).
Discontinuation was defined as a gap in therapy when a subsequent prescription for the
index treatment occurred >30 days, plus the days supply of the previous prescription [
Patients who did not discontinue treatment were followed until the date of a switch to another
anticoagulant, end of the study period, inpatient death, or interruption in continuous health
plan enrollment, whichever occurred earliest. A sensitivity analysis was completed by changing
the discontinuation gap to 60 days and 90 days.
A second sensitivity analysis was also performed. Due to varying mean length of follow-up
across treatment cohorts, only patients who had at least 100 days of follow-up were included,
in order to assess the robustness of the estimated risk of discontinuation.
In the study population, categorical and continuous variables were compared across
treatments using the Pearson chi-square test and the Wilcoxon rank-sum test, respectively. The
proportions of patients discontinuing therapy during the study follow-up period were
computed as the number of patients who discontinued treatment divided by the total number of
patients initiating the treatment within the study period. The cumulative incidence of
discontinuation was presented using Kaplan±Meier curves. A Cox proportional hazards model was
used to estimate the hazard ratios (HRs) of discontinuation for each drug compared to
apixaban, adjusted for a pre-specified set of baseline demographic and clinical factors including age,
sex, embolic or primary ischemic stroke, dyspepsia or stomach discomfort, congestive heart
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Fig 2. Patient selection criteria. Study population flow chart with inclusion and exclusion criteria used to select 45,361 patients. NOAC: non-vitamin
K antagonist oral anticoagulant; VTE: venous thromboembolism.
failure, coronary artery disease, diabetes mellitus, hypertension, renal disease, myocardial
infarction, history of stroke, or transient ischemic attack, and history of bleeding (S1 Table).
As warfarin is the standard of care, we have analyzed and presented the primary results
using warfarin as a reference comparator. Lower discontinuation rates were observed for
NOACs in real-world studies and clinical trials; therefore, we also analyzed apixaban as a
reference cohort to understand the discontinuation risk associated with NOACs and warfarin in
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the real-word setting. All analyses were performed with SAS System version 9.2. An a priori
significance level of 0.05 was used for the purposes of these analyses.
Among 45,361 patients, 15,461 (34.1%) initiated warfarin treatment with a mean (SD)
followup of 164 (±162) days; 7,438 (16.4%) initiated apixaban with a mean follow-up of 148 (±138)
days; 4,661 (10.3%) initiated dabigatran with a mean follow-up of 177 (±179) days; and 17,801
(39.2%) patients initiated rivaroxaban with a mean follow-up of 176 (±171) days (Table 1).
Approximately 60% of patients in each treatment group were male. The mean age of warfarin,
apixaban, dabigatran, and rivaroxaban patients was 71.7±12.0, 68.5±12.4, 66.5±12.4, and
Apixaban (n = 7,438)
Fig 3. Cumulative incidence of discontinuation among newly anticoagulated non-valvular atrial fibrillation patients. (Upper panel)
Cumulative incidence of discontinuation during the follow-up period. The unadjusted cumulative incidence of discontinuation was
lower among patients initiated on apixaban compared to patients inititated on other oral anticoagulants. (Lower panel) The number of
patients at risk for discontinuation at varying points during the follow-up.
67.1±12.3 years, respectively. Patients initiating warfarin were older and were at higher risk in
terms of the CHA2DS2-VASc score (3.2±1.7) and had higher mean Charlson comorbidity
index (CCI) scores of 2.3±2.3 (Table 1).
Fig 3 shows the discontinuation rates of all drugs across the study period. The cumulative
incidence of discontinuation at one-year was 50.5%, 64.7%, 57.8%, and 71.6% for apixaban,
dabigatran, rivaroxaban, and warfarin patients, respectively. When the 60- and 90-day gap was
used, the rates of discontinuation were lower but the trend was consistent (S2 Table, S2 and S3
Figs). Across the four cohorts, around 3±10% of patients switched from index OAC to another
OAC during the follow-up period.
When compared to warfarin, patients who initiated dabigatran (adjusted HR [aHR]: 0.84,
95% confidence interval [CI]: 0.80±0.87), rivaroxaban (aHR: 0.70, 95% CI: 0.68±0.73,
P<0.001), or apixaban (aHR: 0.57, 95% CI: 0.55±0.60, P<0.001) were 16%, 30%, and 43% less
likely to discontinue treatment, respectively.
When compared to apixaban, patients who initiated warfarin (aHR: 1.74, 95% CI: 1.67±
1.82, P<0.001), dabigatran (aHR: 1.46, 95% CI: 1.38±1.54, P<0.001), and rivaroxaban (aHR:
1.23, 95% CI: 1.17±1.28, P<0.001) were significantly more likely to discontinue treatment,
after adjusting for baseline characteristics (Table 2 and Fig 3).
For sensitivity analysis, discontinuation was assessed among patients with at least 100 days
of follow-up, given the varied mean follow-up length across treatment cohorts in the main
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Adjusted hazard ratios were estimated from a Cox proportional hazards model with factors for age, sex, embolic or primary ischemic stroke, dyspepsia or stomach
discomfort, congestive heart failure, coronary artery disease, diabetes, hypertension, renal disease, myocardial infarction, history of stroke or transient ischemic attack,
and history of bleeding.
When compared to those who initiated warfarin, patients who initiated dabigatran,
rivaroxaban, or apixaban were less likely to discontinue treatment after adjusting for baseline
characteristics. Further, when compared to apixaban, patients who initiated treatment with warfarin,
dabigatran, or rivaroxaban were more likely to discontinue treatment.
This study used real-world claims data from the US population to provide critical insights
regarding the risk of discontinuation in an adult NVAF population who initiated anticoagulant
treatment with apixaban, warfarin, rivaroxaban, or dabigatran therapy. Importantly, these
`real-world' results are consistent with the clinical trial findings for the respective NOACs and
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warfarin. In the ARISTOTLE trial, for example, fewer patients in the apixaban group (25.3%)
compared to the warfarin group (27.5%) discontinued the study drug before the end of the
study (p = 0.001) [
]. In the ROCKET-AF trial, the proportion of patients who permanently
stopped their assigned therapy before an end-point event and before the termination date was
23.7% in the rivaroxaban group and 22.2% in the warfarin group [
]. In the RE-LY trial, the
rates of discontinuation for 110 mg of dabigatran, 150 mg of dabigatran, and warfarin were
14.5%, 15.5%, and 10.2%, respectively, at 1 year and 20.7%, 21.2%, and 16.6%, respectively, at 2
The robustness of these findings through sensitivity analysis was also assessed, which largely
concurred with our primary findings by demonstrating a lower risk of discontinuation with
NOAC initiation as compared to warfarin, and a higher risk of discontinuation with initiation
on other anticoagulants as compared to apixaban.
Our results also confirm findings from recent `real-world' studies. A long-term study of the
different NOACs in clinical practice showed that discontinuation rates were lower for
apixaban (10%) compared to dabigatran (30%) and rivaroxaban (25%; p<0.001 for both) [
Another study of NVAF patients who initiated oral anticoagulants showed significantly higher
1-year persistence rates with apixaban (86%) and warfarin (85%) than with dabigatran (74%)
or rivaroxaban (77%) [
]. Furthermore, in a propensity score-matched analysis, patients who
initiated dabigatran (63%) had higher persistence rates at 1 year compared to patients who
initiated warfarin (39%) [
Discontinuation of anticoagulation or poor adherence to thromboprophylaxis is not
inconsequential. Indeed, previous studies have found that warfarin discontinuation is associated
with increased risk of ischemic stroke. For example, Ewen, et al. [
] found that patients with 1
or 2 or more warfarin interruptions (defined as prescription gaps over 45 days) had higher
stroke incidence than those without warfarin interruption (relative risk: 2.29; 95% CI: 1.29±
4.07). Deitelzweig, et al. also found that stroke risk was higher with warfarin discontinuation
than during continuous warfarin therapy (HR: 1.60; 95% CI: 1.35±1.90) [
]. Similarly, in a
study by Spivey et al., discontinuation versus persistent use of warfarin was associated with
increased risk of ischemic stroke (HR: 2.04; 95% CI: 1.47±2.84) and ischemic stroke or TIA
(HR: 1.50; 95% CI: 1.20±1.87) [
The anticoagulant effect of NOACs decreases rapidly; therefore, poor adherence and
treatment discontinuation may diminish the benefit of NOAC treatment [
]. A higher risk of
thromboembolism was noted at the end of the double-blind trials during the transition from
rivaroxaban to open-label warfarin [
]. A recent analysis from the ROCKET-AF trial showed
an increased risk of stroke and non-central nervous system embolism among
rivaroxabantreated versus warfarin-treated AF patients who temporarily or permanently discontinued
anticoagulation (HR: 1.50, 95% CI: 1.05±2.15) [
]. Furthermore, a longitudinal outcomes
study using a national cohort from the Veterans Health Administration showed that lower
adherence to dabigatran was associated with an increased risk of combined all-cause mortality
and stroke (HR: 1.13, 95% CI: 1.07±1.19 per 10% decrease in proportion of days covered) [
However, several `real-world' studies have demonstrated reduced or similar ischemic stroke
risk among patients treated with NOACs compared with warfarin, suggesting adequate
adherence to maintain the benefits of NOACs [
Our results are also consistent with indirect comparisons that combined data from the
RELY, ROCKET-AF, and ARISTOTLE studies in relation to the discontinuation of treatment
]. While the reasons for discontinuation, causality between any particular attribute, and
discontinuation of therapy cannot be determined in this retrospective study, the safety and
tolerability profile of a drug likely plays a critical role in patients' ability to use NOACs continuously.
For example, a 2012 study showed the rate of discontinuation of dabigatran was 25.4%, with
8 / 11
dyspepsia being the most common reason for discontinuation [
]. Further, a single clinical
center cross-sectional study in the United States reported that the most common reasons for
discontinuation with dabigatran were adverse reactions and cost [
The study's strengths are that we assessed the real-world risk of discontinuation of
treatment among patients initiating warfarin versus dabigatran, rivaroxaban, and apixaban using
the comprehensive MarketScan1 claims database, which incorporates all medical and
pharmacy patient claims and allows for longitudinal analysis of a nationally-representative sample.
The medications being studied are relatively new to the market, and this database,
encompassing both commercial and Medicare beneficiaries, allows for the selection of a
nationally-representative sample for this study [
As with any retrospective analysis, researchers are limited to only study associations
between variables; additionally, as with any retrospective observational database study, there is
a potential for selection bias. We conducted rigorous and thorough multivariate and sensitivity
analyses for discontinuation to ensure the robustness of our findings. Baseline comorbidities
(eg, presence of renal impairment) were determined by the presence of a diagnosis code in the
baseline period and were not based on actual laboratory test result values or clinical
assessment. As this study is an analysis of claims data, there is the potential for coding errors or
missing data (ie, we must assume that patients do not have a condition if it was not coded).
Additionally, refill data may not reflect actual medication use. Discontinuation rates of
warfarin, as assessed by a 30-day gap in pharmacy claims, may vary more due to dose adjustments
to manage fluctuation in INR values compared to NOACs. As apixaban had entered the
market recently when the analysis was performed, patients treated with apixaban tended to have a
shorter follow-up than those treated with warfarin.
Further analyses using propensity-matched cohorts as well as large-scale prospective studies
may be necessary to understand the reasons for and predictors of discontinuation, and to
examine the impact of discontinuation on clinical outcomes.
Among newly-anticoagulated AF patients in the real-world setting, treatment initiation with
rivaroxaban, dabigatran, or apixaban was associated with a significantly lower risk of
discontinuation as compared to warfarin. Treatment discontinuation risk was significantly higher
among patients initiating dabigatran, rivaroxaban, or warfarin, as compared to those initiating
S1 Fig. Cumulative incidence of discontinuation: With a 60-day gap.
S2 Fig. Cumulative incidence of discontinuation: With a 90-day gap.
S3 Fig. Cumulative incidence of discontinuation: Minimum 100 days follow-up.
S1 Table. ICD-9-CM codes for selection criteria and comorbid conditions.
S2 Table. Cumulative incidence of discontinuation at 1 year.
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S3 Table. Patient characteristics: Minimum 100 days follow-up.
S4 Table. Adjusted risk of discontinuation: Minimum 100 days follow-up.
Hemant Phatak was an employee of BMS at the time of this research. The authors are
grateful to Todd Durham (Pre-doctoral Fellow, Worldwide Health Economics and Outcomes
Research, Bristol-Myers Squibb Company) for his editorial assistance in the preparation of
Conceptualization: Gregory Y. H. Lip, Shital Kamble, Jack Mardekian, Cristina Masseria,
Formal analysis: Xianying Pan, Hugh Kawabata.
Methodology: Xianying Pan, Shital Kamble, Hugh Kawabata, Jack Mardekian.
Writing ± original draft: Gregory Y. H. Lip, Shital Kamble, Hemant Phatak.
Writing ± review & editing: Gregory Y. H. Lip, Xianying Pan, Shital Kamble, Hugh Kawabata,
Jack Mardekian, Cristina Masseria, Hemant Phatak.
10 / 11
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