Electrophysiology

Reasons for warfarin discontinuation in the

Outcomes Registry for Better Informed
Treatment of Atrial Fibrillation (ORBIT-AF)
Emily C. OBrien, PhD, a DaJuanicia N. Simon, MS, a Larry A. Allen, MD, MHS, b Daniel E. Singer, MD, MA, c
Gregg C. Fonarow, MD, d Peter R. Kowey, MD, e Laine E. Thomas, PhD, a Michael D. Ezekowitz, MD, e
Kenneth W. Mahaffey, MD, f Paul Chang, MD, g Jonathan P. Piccini, MD, MHS, a and Eric D. Peterson, MD, MPH a
Durham, NC; Aurora, CO; Boston, MA; Los Angeles, Philadelphia, PA; Stanford, CA; and Raritan, NJ

Background Warfarin reduces thromboembolic risks in atrial fibrillation (AF), but therapeutic durability remains a concern.
Methods We used clinical data from ORBIT-AF, a nationwide outpatient AF registry conducted at 176 sites with follow-up
data at 6 and 12 months, to examine longitudinal patterns of warfarin discontinuation. We estimated associations between
patient and provider characteristics and report of any warfarin discontinuation using discrete time proportional odds models.

Results Of 10,132 AF patients enrolled in ORBIT-AF from June 2010 to August 2011, 6,110 (60.3%) were prescribed
warfarin, had follow-up data, and were not switched to an alternative oral anticoagulant enrolled from June 2010 to August
2011. Over 1 year, 617 patients (10.1% of baseline warfarin users) discontinued warfarin therapy. Among incident warfarin
users (starting therapy within 1 year of baseline survey), warfarin discontinuation rates rose to 17.1%. The most commonly
reported reasons for warfarin discontinuation were physician preference (47.7%), patient refusal/preference (21.1%),
bleeding event (20.2%), frequent falls/frailty (10.8%), high bleeding risk (9.8%), and patient inability to adhere to/monitor
therapy (4.7%). In multivariable analysis, the factors most strongly associated with warfarin discontinuation were bleeding
hospitalization during follow-up (odds ratio 10.91, 95% CI 7.91-15.03), prior catheter ablation (1.83, 1.37-2.45),
noncardiovascular/nonbleeding hospitalization (1.77, 1.40-2.24), cardiovascular hospitalization (1.64, 1.33-2.03), and
permanent AF (0.25, 0.17-0.36).
Conclusions Discontinuation of warfarin is common among patients with AF, particularly among incident users.
Warfarin is most commonly discontinued because of physician preference, patient refusal, and bleeding events. (Am Heart J
2014;168:487-94.)

Atrial fibrillation (AF) is the most common cardiac

rhythm disorder and an important independent risk
factor for stroke. 1,2 Oral anticoagulation (OAC) with
vitamin K antagonists such as warfarin reduces the risk of
thromboembolic events associated with AF. 3,4 However,
warfarin management of high-risk AF is inherently
challenging because of the need for ongoing international
From the aDuke Clinical Research Institute, Durham, NC, bUniversity of Colorado School of
Medicine, Aurora, CO, cHarvard Medical School and Massachusetts General Hospital,
Boston, MA, dUCLA Division of Cardiology, Los Angeles, CA, eJefferson Medical College,
Philadelphia, PA, fStanford School of Medicine, Stanford, CA, and gJanssen Scientific
Affairs, Raritan, NJ.
William G. Stevenson, MD served as guest editor of this article.
Submitted April 4, 2014; accepted July 3, 2014.
Reprint requests: Emily OBrien, PhD, Duke Clinical Research Institute, 2400 Pratt St,
Durham, NC 27705.
E-mail: emily.obrien@duke.edu
0002-8703
2014, The Authors. Published by Elsevier Inc. on behalf of Mosby, Inc. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
http://dx.doi.org/10.1016/j.ahj.2014.07.002

normalized ratio monitoring and dose adjustments.

Furthermore, patient and provider concerns about
bleeding risk associated with warfarin use may decrease
long-term adherence to recommended OAC regimens. As
a result, a substantial proportion of AF patients starting
anticoagulation will discontinue therapy within 1 year,
resulting in increased risk for embolic stroke. Recent
studies have suggested that warfarin discontinuation rates
in community practice are much higher than those
observed in clinical trials. 5,6
Unfortunately, many of these data were limited to a
single geographic region and did not have information
available on specific reasons for discontinuation. Additionally, the major demographic and clinical factors
associated with stopping therapy have not been welldefined. Finally, whether discontinuation patterns are
similar among prevalent warfarin users compared with
newly treated patients has not been fully explored.
Therefore, we examined (1) patterns of discontinuation

488 OBrien et al

among warfarin-treated patients in an outpatient AF

setting, both overall and among those in their first year
of therapy; (2) baseline clinical and demographic factors
associated with discontinuation; and (3) clinical and
demographic factors associated with event-related and
patient-related warfarin discontinuation.

Methods
Study population
We used data from Outcomes Registry for Better
Informed Treatment of Atrial Fibrillation (ORBIT-AF) to
assess patterns of warfarin discontinuation over 1 year of
follow-up. Details of the ORBIT-AF study design have
been published. 7 Briefly, ORBIT-AF is a US-based,
prospective outpatient registry of AF conducted at 176
sites nationwide. The Duke Clinical Research Institute
was responsible for ORBIT-AF site selection and study
management. Eligible patients were 18 years old with
electrocardiographically confirmed AF. Enrolling providers included cardiologists, electrophysiologists, and
primary care providers. Site personnel entered information on demographics, medical history, cardiovascular
risk factors, AF management strategy, and provider
characteristics into a standardized, Web-based collection
form. Following initial enrollment, longitudinal information was collected during clinic visits at approximately 6-month intervals up to 24 months and included
information on hospitalizations, bleeding events, medication regimens, procedures, and quality of life.
Approximately 10,132 patients were enrolled in ORBIT-AF
from June 2010 to August 2011. We excluded patients
without follow-up data at the 6- and 12-month clinic visit
(8.6%), patients who were not receiving warfarin at baseline
entry into ORBIT-AF (25.7%), patients who switched to
dabigatran during follow-up (5.3%), and patients who were
missing information on warfarin discontinuation during
follow-up (0.2%), for a final study population of 6,110
patients at 171 participating sites. Of these, 1,011 patients
began warfarin therapy within 1 year prior to study enrollment.
Warfarin discontinuation
The primary outcome of interest was the first reported
discontinuation of warfarin therapy without resumption at
either 6 or 12 months following enrollment. Additionally,
patients who reported that they were not receiving warfarin
at their 6- and/or 12-month follow-up were considered to be
discontinued from warfarin therapy. For all who discontinued, providers were asked to identify one or more primary
and secondary reasons for discontinuation from a prespecified list. Primary and secondary reasons were treated as
equivalent. Reasons for discontinuation included dual
antiplatelet therapy, pregnancy, frequent falls/frailty, high
bleeding risk, gastrointestinal upset, prior intracranial hemorrhage, unable to adhere/monitor warfarin, bleeding event,
allergy, physician preference, patient refusal/preference,

American Heart Journal

October 2014

comorbid illness, occupational risk, and other. The list of

reasons for discontinuation collected was selected and
approved by the ORBIT-AF executive committee based on
clinical relevance during the study development phase.

Event-related and patient-related discontinuation

Because the predefined set of reported reasons
represents a wide variety of explanations for warfarin
discontinuation, we conducted a set of analyses to
examine factors associated with 2 secondary outcomes:
event-related discontinuation and patient-related discontinuation. Event-related discontinuation was defined as
any discontinuation of warfarin with one of the following
reasons listed: allergy, pregnancy, comorbid illness, prior
intracranial hemorrhage, and bleeding event. Patientrelated discontinuation was defined as discontinuation
with any nonevent-related reason listed. Patients who
discontinued and listed more than one reason for
discontinuation could be classified as both patient related
and event related.
Statistical analysis
We compared baseline characteristics between patients
who discontinued warfarin over 1 year and patients who
persisted using Pearson 2 tests for categorical variables
and Wilcoxon rank sum tests for continuous variables. We
also examined warfarin discontinuation by estimated stroke
risk using the CHADS2 score (C, congestive heart failure
[1 point]; H, hypertension [1 point]; A, age >75 years
[1 point]; D, diabetes [1 point]; S, prior stroke or transient
ischemic attack [2 points]) 8 and the CHA2DS2-VASc
score (C, congestive heart failure [1 point]; H, hypertension [1 point]; A, age>75 years [2 points]; D, diabetes
mellitus [1 point]; S, prior stroke or transient ischemic
attack [2 points]; V, vascular disease [1 point]; A, age
65-74 years [1 point]; S, female sex [1 point]) 9. To
determine factors associated with warfarin discontinuation, we constructed a multivariable proportional odds
model for discrete time because warfarin discontinuation
was captured in discrete time intervals. This method fits a
logistic regression for the binary occurrence of discontinuation at each discrete time point (6 or 12 months) and
combines the results to provide a single odds ratio for
the effect of covariates. Additionally, this model was fit
using generalized estimating equations with exchangeable
working correlation matrix to account for within-site
clustering. 10 Because warfarin discontinuation may
directly result from a clinical event, we included
cause-specific hospitalizations (bleeding, cardiovascular,
noncardiovascular, nonbleeding) that occurred during
follow-up (assumed the hospitalization preceded discontinuation) in a secondary analysis. Intervening events
were included as time-dependent covariates. Candidate
variables in the regression model included demographics,
relevant clinical comorbidities, management strategy, prior

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Volume 168, Number 4

procedures and interventions, laboratory values, and

vital signs. Continuous variables were evaluated for
nonlinearity with the outcome, and nonlinear relationships were addressed by using linear splines. Missing
data were multiply-imputed, and final estimates and
standard errors reflect the combined analysis over 5
imputed data sets (all the candidate variables had b2%
missing except for the following variables: level of
education [4.0%], serum creatinine [7%], hemoglobin
[10%)] and hematocrit [10%]). Model selection using
backward selection with a stay criterion of 0.05 using the
first imputed data set was used to obtain a set of factors in
which each factor was independently associated with
warfarin discontinuation within 1 year. We repeated this
strategy for the secondary outcomes of event-related
discontinuation (vs no event-related discontinuation) and
patient-related discontinuation (vs no patient-related
discontinuation). In the study of event-related discontinuation, patient-related discontinuation resulted in
censoring, and vice versa.
All P values presented are 2-sided. All statistical analyses
for this study were performed using SAS software
(version 9.3; SAS, Cary, NC). Written informed consent
was obtained for all study participants. The Duke
Institutional Review Board approved the ORBIT-AF
Registry, and all participating sites obtained approval
from local institutional review boards prior to entering
patient data.

Funding sources
The ORBIT-AF registry is sponsored by Janssen
Scientific Affairs, LLC, Raritan, NJ.
This project was supported (in part) by funding from
the Agency of Healthcare Research and Quality through
cooperative agreement number 1U19 HS021092.

Results
Baseline characteristics of the overall study population
by warfarin discontinuation during follow-up are shown
in Table I. Of the 6,110 patients who reported warfarin
use at baseline, 617 (10.1%) discontinued warfarin over
12 months. Among 1,011 patients who began warfarin
during the year prior to enrollment, 173 (17.1%)
discontinued within 1 year. Patients who discontinued
warfarin were 3 years younger on average than patients
who persisted. Patients who persisted on warfarin had a
greater comorbidity burden, with higher rates of heart
failure, prior stroke, prior MI, hypertension, and chronic
obstructive pulmonary disease compared with patients
who discontinued. Patients who discontinued were also
more likely to be newly diagnosed with AF, whereas
patients who persisted were more likely to have a
diagnosis of permanent AF. Any prior warfarin use was
associated with decreased discontinuation, with patients
beginning warfarin at baseline study entry more likely to

OBrien et al 489

Table I. Baseline characteristics of AF patients by warfarin

discontinuation at 1 year

Variable
Age (y),
median (IQR)
Male gender
Black race
Comorbidities
Heart failure
Prior stroke
Prior MI
Hypertension
Diabetes
COPD
Smoking
Obstructive sleep apnea
CHADS2, median (IQR)
CHA2DS2-VASC,
median (IQR)
ATRIA bleeding risk
score, median (IQR)
HAS-BLED bleeding
risk score,
median (IQR)
AF diagnosis
First detected/
new onset
Paroxysmal
Persistent
Permanent
Anticoagulation
clinic mgmt.
Geographic region
Midwest
Northeast
South
West
Education
Some high school
High school
College
Postgraduate
Provider specialty
Cardiology
Internal medicine/
primary care
Electrophysiology
Neurology

Discontinued
(n = 617;
10.1%)

Persisted
(n =5493;
89.9%)

73.0
(64.0-80.0)
57.5
5.0

76.0
(69.0-82.0)
57.4
4.7

b.0001

32.3
7.8
14.3
80.9
31.6
15.4
47.8
18.5
2.0 (1.0-3.0)
4.0 (2.0-5.0)

35.7
9.9
16.9
85.6
30.9
16.6
49.4
18.6
2.0 (2.0-3.0)
4.0 (3.0-5.0)

.09
.09
.10
.002
.71
.43
.45
.96
b.0001
b.0001

3.0 (1.0-3.0)

3.0 (1.0-4.0)

.003

2.0 (1.0-2.0)

2.0 (1.0-2.0)

.31

7.6

2.5

b.0001

54.0
19.5
19.0
42.1

45.3
17.4
34.8
45.3

.13

26.1
20.6
36.3
17.0

26.9
26.6
34.2
12.3

.0003

12.5
52.0
22.2
7.9

14.5
52.3
21.8
7.5

.25

79.7
65.2

81.0
69.2

.45
.04

19.5
2.1

16.8
2.6

.10
.5

P value

.94
.02

IQR, interquartile range; MI, myocardial infarction; COPD, chronic obstructive

pulmonary disease.
All data presented as percentages unless otherwise indicated
P values are based Pearson 2 for categorical variables and Wilcoxon rank sum for
continuous variables
Modified HAS-BLED calculated without labile international normalized ratio.

discontinue than patients reporting prior warfarin use

(16.3% vs 9.7%). The highest rates of warfarin discontinuation were observed among warfarin-naive patients with
low or moderate stroke risk (CHADS2 b 2), whose rate of
discontinuation was more than twice that of prior
warfarin users with similar stroke risk (30.1% vs 13.6%).

American Heart Journal

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490 OBrien et al

Table II. Documented reasons for warfarin discontinuation overall and by stroke risk, patient age, and time on therapy (%)
CHADS2

CHA2DS2-VASC

Patient age (y)

Time on warfarin
therapy (y)

Reason for
discontinuation

Overall
(n = 407)

b2
(n = 143)

N2
(n = 264)

b2
(n = 61)

N2
(n = 346)

b75
(n = 232)

N75
(n = 175)

b1
(n = 252)

N1
(n = 120)

Physician preference
Other
Patient refusal
Bleeding event
Frequent falls/frailty
High bleeding risk
Unable to adhere
GI upset
Prior ICH
Comorbid Illness
Need for dual APT
Allergy
Pregnancy
Occupational Risk

47.7
27.3
21.1
20.2
10.8
9.8
4.7
3
1.2
1
1
0.7
0.3
0.3

58.7
37.8
25.2
12.6
2.8
4.9
3.5
2.1
0.0
0.7
0.0
0.7
0.0
0.0

41.7
21.6
18.9
24.4
15.2
12.5
5.3
3.4
1.9
1.1
1.5
0.8
0.4
0.4

59.0
39.3
34.4
4.9
0.0
1.6
1.6
3.3
0.0
0.0
0.0
1.6
0.0
0.0

45.7
25.1
18.8
22.8
12.7
11.3
5.2
2.9
1.5
1.2
1.2
0.6
0.3
0.3

54.7
34.1
25.0
16.4
2.2
4.3
2.6
3.5
0.9
0.9
0.9
0.9
0.0
0.0

38.3
18.3
16.0
25.1
22.3
17.1
7.4
2.3
1.7
1.1
1.1
0.6
0.6
0.6

44.1
25.4
19.4
23.0
12.7
10.3
6.0
2.8
0.8
0.4
0.8
0.8
0.4
0.4

50.8
32.5
21.7
18.3
6.7
10.0
2.5
2.5
2.5
2.5
1.7
0.0
0.0
0.0

Abbreviations: CV, cardiovascular; OR, odds ratio; CI, confidence interval.

Among patients who listed a reason for discontinuation.
Respondents could select more than one reason for discontinuation.

At baseline, the majority of patients were classified as

high stroke risk (76.5% with CHADS2 2 and 93.7%
CHA2DS2-VASC N2). Unadjusted rates of warfarin discontinuation varied inversely with CHADS2, with higher rates
of discontinuation among patients with low or moderate
stroke risk. Approximately 21.2% of patients with
CHADS2 = 0 discontinued warfarin within 1 year,
followed by 13.3% with CHADS2 = 1 and 8.7% with
CHADS2 2. Similar patterns were observed by
CHA2DS2-VASC, with discontinuation rates of 29.7%,
20.7%, and 9.3% in patients with scores of 0, 1, or 2,
respectively. Patients who discontinued were more likely
to be seen by an electrophysiologist than patients who
persisted (19.5% vs 16.8%, P = .10). By geographic
region, the highest rates of discontinuation were reported
in the West (13.5%) and the lowest in the Northeast
(8.0%, P = .0003).
Of those patients discontinuing warfarin, 66% of
patients reported a reason for discontinuation. The
distribution of reported reasons for discontinuation is
shown in Table II. The most commonly reported reasons
were physician preference, other, patient refusal/preference, bleeding event, frequent falls and frailty, and high
bleeding risk. Similar patterns of documented discontinuation reasons were observed by patient age, with a
higher proportion of patients N75 years old reporting
discontinuation due to frequent falls and frailty, bleeding
event, and high bleeding risk compared with patients
b75 years old. Reported discontinuation reasons were
highly variable by CHADS2 risk stratum. Compared with
patients with a CHADS2 score of 0 or 1, patients with
high stroke risk (CHADS2 2) were significantly more
likely to report discontinuation due to high bleeding risk

(12.5% vs 4.9%, P = .014), frequent falls or frailty (15.2%

vs 2.8%, P = .0001), or bleeding event (24.4% vs 12.6%,
P = .0052). In contrast, patients with low or moderate
stroke risk were more likely to report physician preference
(58.7% vs 41.7%, P = .001) and patient refusal/preference
(25.2% vs 18.9%, P = .14). Similar patterns were observed
when stratifying by CHA2DS2-VASC b 2 and CHA2DS2-VASC
2 (Table II).
Of the newly treated patients who discontinued
warfarin over 12 months of follow-up, the most
commonly documented reason for discontinuation was
physician preference (44.1%). When compared with
patients who had been taking warfarin for 1 year
prior to enrollment, newly treated patients were more
likely to discontinue because of a bleeding event (23.0%
vs 18.3%, P = .30), frequent falls or frailty (12.7 vs 6.7%,
P = .08), and inability to adhere (6.0% vs 2.5%, P = .15).
To further explore the reasons behind discontinuations
due to physician preference and given that reported
reasons were not mutually exclusive, we examined the
distributions of additional discontinuation reasons among
the 194 patients who listed Physician preference. Among
these patients, the most common additional reason was
other (25.3%), followed by patient refusal/preference
(17.5%), bleeding event (7.2%), and frequent falls/frailty
(5.2%). Among patients listing physician preference as a
reason for discontinuation, none listed occupational risk,
allergy, pregnancy, or need for dual antiplatelet therapy as
an additional reason for discontinuation.

Modeling results
Results from the proportional odds model for patient
and clinical factors associated with warfarin

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OBrien et al 491

Figure 1

Factors associated with warfarin discontinuation. *.This figure displays factors associated with warfarin discontinuation over 12 months of followup. *Multivariable pooled logistic regression using generalized estimating equations.

discontinuation are shown in Figure 1. In the first-phase

regression model (not accounting for events occurring
during follow-up), we found that older age (N75 years),
history of hypertension, paroxysmal AF (vs first detected/
new onset), permanent AF, and persistent AF were
associated with decreased odds of discontinuation. Prior
catheter ablation, site region (West vs South), and sinus
rhythm on electrocardiogram were associated with
increased odds of discontinuation. When cause-specific
hospitalizations occurring during follow-up were added
to the regression model (second phase), baseline variable
associations were similar in magnitude and direction to
those estimated from first-phase models. Cause-specific
hospitalizations were strongly associated with
warfarin discontinuation, with the largest associations
observed for bleeding hospitalization, followed by noncardiovascular/nonbleeding hospitalization and cardiovascular hospitalization.
Because factors related to discontinuation may vary by
length of time on the medication, we repeated regression
analyses among patients who had been taking warfarin for
12 months prior to enrollment (Figure 2). Among
prevalent users, older age, hypertension, and diagnosis
type were no longer significantly associated with discontinuation over 1 year. The associations between discontinuation and geographic region, prior catheter ablation, and
hospitalizations were similar in magnitude and direction to
those observed among the entire study population.

Event- and patient-related discontinuation

Overall, 22.9% of discontinuations were classified as
event-related; and 88.9% were classified as patient-related.
Event-related discontinuation was more likely in patients
with CHADS2 2, those with CHA2DS2-VASC 2, and

those older than 75 years, whereas patient-related discontinuation was more likely in younger patients and those
with CHADS2 or CHA2DS2-VASCof 0 or 1. In the first-phase
model of event-related discontinuation, only hematocrit
was significantly associated with warfarin discontinuation,
with a 39% decrease in odds of discontinuation for every 5%
increase in hematocrit. In second-phase models of eventrelated discontinuation, we observed large positive associations between cause-specific hospitalizations and discontinuation (Figure 3). Bleeding hospitalizations were most
strongly associated with event-related discontinuation,
followed by noncardiac, nonbleeding hospitalization and
cardiovascular hospitalization. Models of patient-related
discontinuation yielded essentially identical results to
models of overall discontinuation, with similar patterns
observed in second-phase models accounting for hospitalizations during follow-up.

Discussion
Over 1 year of follow-up, approximately 1 (10.1%) in 10
patients discontinued warfarin therapy. This discontinuation rate was significantly higher (17.1%) among patients
who started warfarin therapy in the prior year. We also
observed differential persistence by AF diagnosis type,
which varies with age. Compared with new-onset
patients, lower discontinuation rates were documented
for patients with paroxysmal, persistent, or permanent
AF, who are more likely to be older compared with newly
diagnosed patients. The majority of warfarin discontinuations were classified as patient related (88.9%), compared with only 22.9% that were classified as event
related. Finally, the most commonly documented reasons

492 OBrien et al

American Heart Journal

October 2014

Figure 2

Factors associated with warfarin discontinuation among prevalent users. *This figure displays factors associated with warfarin discontinuation over
12 months among prevalent warfarin users. *Prevalent warfarin users defined as patients who had been taking warfarin for 1 year.
Multivariable pooled logistic regression using generalized estimating equations.

for warfarin discontinuation were physician preference,

patient refusal/preference, or a bleeding event.
Our overall rate of discontinuation, although still
substantial, was lower than in prior studies, where
reported discontinuation rates have ranged from 20% to
more than 50%. 5,6,11 An analysis of the MarketScan
database reported a discontinuation rate of 51.7% over 30
months of follow-up. 12 However, this analysis was
conducted using administrative claims and during a
period where discount pharmacy programs were introduced; so the rate of discontinuation may be artificially
inflated because of patients switching to low-cost
generics. Another study of approximately 41,000 AF
patients in the General Practice Research Database of
Great Britain reported a 1-year discontinuation rate
of 30%. However, this study included a small proportion
of patients with CHADS2 N 2 and did not include data on
patients who were managed in anticoagulation clinics,
factors we found to be strongly associated with warfarin
persistence. A recent study of warfarin-treated AF
patients in Ontario reported a discontinuation rate of
31.8%, with the highest discontinuation rates reported for
those enrolled in earlier study years. The higher rates of
persistence observed in ORBIT-AF may reflect contemporary trends toward better utilization of resources for
therapeutic monitoring. 13 Furthermore, patients who are
willing to participate in a clinical registry may represent a
subpopulation more likely to persist on recommended
therapies than the overall AF population.
Another possibility for the lower observed rates of
warfarin discontinuation in ORBIT-AF is the high
proportion of study participants who recently began
taking warfarin. Prior studies have noted important

differences in warfarin persistence among new users

compared with prevalent users. The ATRIA study
reported a 1-year warfarin discontinuation rate of 26.3%
among 4,188 newly treated patients. Furthermore,
patients who persisted on warfarin therapy during the
first year were more likely to remain on therapy
thereafter. Another analysis of recently hospitalized AF
patients reported greater likelihood of discontinuation
among new starts compared with those who were taking
warfarin prior to hospitalization. 14 These results are
consistent with our findings, with a substantially higher
rate of 1-year discontinuation among new starts (17.1%)
compared to the overall study population (10.1%).
Prevalent warfarin users likely represent a subset of
patients who are able to adhere to therapy and in whom
warfarin is well tolerated, as evidenced by the lower rates
of both discontinuation and bleeding events compared
with newly diagnosed patients previously reported. 6
Correspondingly, we found that newly treated patients
were more likely to report discontinuation due to a
bleeding event or inability to adhere than prevalent
warfarin users. Additionally, median time in therapeutic
range was higher for those who persisted on warfarin
therapy than for those who discontinued. The lower
median time in therapeutic range among those who
discontinued may reflect suboptimal OAC adherence
during the first year of therapy, consistent with the 6.0%
of new start patients with inability to adhere/monitor
listed as the reason for warfarin discontinuation, compared with 2.5% of prevalent warfarin users.
In the present study, younger patients and those with
lower stroke risk were more likely to discontinue than
older and higher-risk patients. These results are

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OBrien et al 493

Figure 3

Factors associated with event-related* discontinuation. This figure displays factors associated with event-related warfarin discontinuation over
12 months of follow-up. *Event-related reasons included allergy, pregnancy, comorbid illness, prior intracranial hemorrhage, and bleeding event.
Multivariable proportional odds model using generalized estimating equations.

consistent with those of the ATRIA study, which found

that patients with CHADS2 of 0 or 1 were more than twice
as likely to discontinue warfarin as those with CHADS2 of
4 to 6. 11 Patients with higher stroke risk may perceive a
more favorable risk-benefit ratio of anticoagulation than
those in the lower risk categories, which may promote
more optimal monitoring and adherence. Notably, physician preference and patient preference were more
commonly listed as discontinuation reasons among patients with CHADS2 b 2 compared with CHADS2 N 2, which
may reflect a perceived lack of benefit associated with
warfarin therapy. Younger age has been reported as a risk
factor for warfarin discontinuation in a number of prior
studies. 11,15 Existing evidence suggests that older patients
are less likely to be initiated on warfarin than younger
patients, even after accounting for eligibility. 16,17 Thus,
older warfarin-treated patients may represent a preselected
population perceived to be more likely to persist on
therapy and to have a lower risk of complications.
In addition to overall discontinuation, we assessed
factors associated with 2 discontinuation subtypes based
on reported reasons for stopping warfarin: event-related
and patient-related discontinuation. Only hematocrit was
modestly associated with event-related discontinuation in
baseline characteristics models. This result may reflect
heterogeneity in the reasons we identified as event
related or in the baseline characteristics of patients
who discontinue for these reasons. As expected, we
observed strong associations between cardiovascularrelated, bleeding-related, and noncardiovascular-/non
bleeding-related hospitalizations and both patient- and
event-related discontinuation when including clinical
events in secondary regression models.
Although hospitalization events were strongly associated with increased odds of discontinuation, recent
evidence suggests that the estimated risk-benefit ratio
of adverse warfarin-related events to reduced stroke

risk may be overestimated in clinical practice. In a

Swedish cohort of 182,000 AF patients, anticoagulation
was associated with a net clinical benefit for all crossclassifications of CHADS2 and HAS-BLED bleeding risk
score; only a very small minority (0.4%) was identified
in which net clinical benefit was outweighed by
bleeding risk. 18 Despite this evidence, provider concerns about anticoagulant safety persist and may
substantially affect OAC treatment decisions. 19 Hylek
and colleagues reported that physician safety concerns
were cited as the reason for 81% of observed warfarin
discontinuations among newly treated patients. 6 Data
from a recent series of interviews of cardiologists and
internal medicine physicians reported that a major
treatment barrier was clinician reluctance due to safety
concerns. 20 These results are consistent with those
from the present study, where the most commonly
reported reason for warfarin discontinuation was
physician preference. Because reasons for discontinuation were not mutually exclusive, it is possible that
physician preference included discontinuations that
were also due to bleeding risk. However, bleeding risk
was only identified as a reason for discontinuation in
9.8% of patients, suggesting that physician preference
may encompass additional factors beyond concerns
about bleeding.

Limitations
There are several limitations to our study. First, as
with all observational analyses, we cannot exclude the
possibility of residual measured or unmeasured confounding, which may have influenced study findings.
Second, although ORBIT-AF participating sites were
selected to be representative of the national AF
population, results may not be generalizable to all
patients with AF. Third, patients may have discontinued

American Heart Journal

October 2014

494 OBrien et al

warfarin use for reasons not collected in our study.

Fourth, the discrete timing of warfarin discontinuation,
captured only at 6 months and 12 months, made it
impossible to determine the exact temporal ordering of
hospitalizations and discontinuation. In our analysis,
clinical events occurring during follow-up within the
same interval as discontinuation were assumed to occur
before the discontinuation. Fifth, because we excluded
8.6% of patients without 6- or 12-month follow-up data,
actual discontinuation rates may have been higher than
observed rates. Finally, we had information on
warfarin use for 1 year following study enrollment; so
our results may not represent factors associated with
longer-term discontinuation.

5.

6.

7.

8.

9.

Conclusions
One in ten patients in an outpatient AF setting discontinued warfarin over 1 year of follow-up. Discontinuation
was more common in younger patients, those who began
warfarin in the year prior to study enrollment, those with a
prior catheter ablation, and patients who were hospitalized
during follow-up. Only 22.9% of discontinuations were
classified as event related, compared with 88.9% that were
classified as patient related. Physician preference was the
reason listed for nearly half of all discontinuations, whereas
bleeding risk was listed in only 9.8%. Future studies
examining factors associated with warfarin discontinuation
over the long term are needed.

Author contributions
The authors are solely responsible for the design and
conduct of this study, all study analyses, the drafting and
editing of the paper, and its final contents.

Acknowledgements

10.
11.

12.

13.

14.

15.

16.

The authors would like to thank the staff and

participants of the ORBIT-AF Registry for their important
contributions to this work.

17.

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