Patterns and Predictors of Use of Warfarin and Other Common Long-Term Medications in Patients with Atrial Fibrillation

Patterns and Predictors of Use of Warfarin andOther Common Long-Term Medicationsin Patients with Atrial FibrillationXue Song,1 Stephen D. Sander,2 Helen Varker1 and Alpesh Amin3

1 Truven Health Analytics, Cambridge, MA, USA

2 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA

3 School of Medicine, University of California, Irvine, CA, USA

Abstract Background and Objective: No study has been published that compared persistence and discontinuation of

warfarinwith other long-termmedications in patientswith atrial fibrillation (AF). The objective of this studywas

to evaluate persistence anddiscontinuationpatterns inAFpatients takingwarfarin andother common long-term

medications and identify predictors of persistence and discontinuation in this population.

Methods: Patients with warfarin prescription within 3 months after AF hospitalization discharge and

12-month data before and after the first prescription were evaluated using administrative claims data

(1 January 2005 – 31December 2007). For comparison, persistence patterns for other long-termmedications

for treatment of hypertension, hyperglycemia, heart disease, and dyslipidemia, including once- (od) and

twice- (bid) daily medications, were evaluated. Non-persistence was defined as the presence of a ‡60-day gapin medication use. Permanent discontinuation was defined as no use of the medication for ‡90 days until theend of the follow-up period. Multivariate analysis was conducted to identify predictors of warfarin non-

persistence and discontinuation.

Results: 28 384 patients with AF were identified; 16 036 (56.5%) had a warfarin prescription following AF

hospitalization. 53.5% of warfarin users were persistent for at least 1 year, similar to other long-term

medications commonly prescribed to the AF population (ranging between 45.2% and 61.3%). 42.6% of

warfarin users permanently discontinued warfarin within 1 year, also consistent with the discontinuation

rate of 32.9–52.0% of other long-term medications. Residence in the South and West regions of the US,

history of cardiac dysrhythmias, andwarfarin cost-sharing significantly decreased the likelihood of warfarin

persistence and increased the likelihood of discontinuation, while older age, history of ischemic stroke, and

warfarin use before hospitalization significantly increased warfarin persistence and decreased the likelihood

of discontinuation. Adherence of od and bid medications was similar.

Conclusion: Persistence and discontinuation with warfarin in patients with AF is consistent with other long-

term medications. Identifying factors associated with non-persistence and discontinuation with long-term

medications can help in developing targeted adherence programs.

Introduction

Nearly 2.3 million adults in the USA are currently diagnosed

with atrial fibrillation (AF), a common cardiac arrhythmia,

with more than 5.6 million projected by the year 2050.[1] The

prevalence of AF increases with age, occurring in about 9% of

adults 80 years and older.[1] AF is associated with a near 5-fold

increase in stroke incidence,[2] which can be reduced signif-

icantly with the use of antithrombotic therapy. A recent meta-

analysis demonstrated a 64% reduction in stroke incidence in

patients with AF receiving warfarin in tightly controlled ran-

domized trials; antiplatelet agents (e.g. acetylsalicylic acid

[aspirin]) were substantially less efficacious, reducing stroke by

22%.[3] Before the approval of dabigatran etexilate mesylate,

the American College of Chest Physicians strongly recommends

that AF patients with high risk or more than one moderate

ORIGINAL RESEARCH ARTICLEAm J Cardiovasc Drugs 2012; 12 (4): 245-253

1175-3277/12/0004-0245/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

stroke risk factor be treated with warfarin, patients with one

moderate risk factor be treated with warfarin or aspirin, and

patients with no risk factors be treated with aspirin.[4,5] Com-

pared with the 2001 anticoagulant therapy guidelines that

recommended using patient’s characteristics such as age, sex,

heart disease risk, and concurrent conditions to determine

proper therapies, the 2006 guidelines emphasized considera-

tion of stroke risk in determining the need for anticoagulant

therapy. Warfarin can also be used by patients undergoing

cardioversion or catheter ablation or for the prevention of

thromboembolism.[5] Thus patients with no risk factor of stroke

may still be temporarily treated with warfarin in anticipation of

cardioversion or catheter ablation.

Patients with AF are often treated with life-long stroke risk

reduction therapy. Therefore, the importance of taking and

remaining on anticoagulation cannot be underestimated in this

patient population. Medication adherence and persistence di-

rectly impact health outcomes and healthcare utilization in

persons with chronic diseases.[6-9] However, despite its efficacy in

stroke risk reduction, warfarin persistence in patients with chronic

AF is not ideal. Gallagher et al.[10] found that the 1-year persis-

tence with warfarin in a population of UK patients aged 40 years

and older with chronic AF was only 70%. A systemic review of

96 studies found that anticoagulant therapy was underused in AF

patients with elevated risk of stroke.[11] No study has been pub-

lished that compared persistence and discontinuation of warfarin

with other long-term medications in the AF population.

This study used a large national claims dataset to examine

persistence and continuation of warfarin and other long-term

medications commonly used in non-valvular AF (NVAF) pa-

tients, and to determine predictors of persistence and con-

tinuation, especially if patient cost-sharing and dosing sched-

ules have a significant impact on persistence.

Methods

Data Source

Two Truven Health AnalyticsMarketScan�Research Data-

bases, the Commercial Claims and Encounters (Commercial)

Database and the Medicare Supplement and Coordination of

Benefit (Medicare) Database, were used in this study. The

Commercial Database contains the inpatient, outpatient, and

outpatient prescription medication experience of employees

and their dependents, covered under a variety of fee-for-service

and capitated health plans. The Medicare Database contains

the healthcare experience of individuals with Medicare sup-

plemental insurance paid for by employers. Because it covers an

older population than the Commercial Database, theMedicare

Database is a key data source for this study. Both Medicare-

covered (represented as Coordination of Benefits Amount) and

employer-paid dollars are included in this database. During

2007, there were 23 million covered lives in the Commercial

Database and 2 million retirees enrolled in the Medicare

Database. Both databases areHealth Insurance Portability and

Accountability Act (HIPAA) compliant.

Study Population

The study period covered 1 January 2005 – 31 December

2007. Patients with AF hospitalizations identified by primary

or secondary diagnosis of AF (ICD-9-CM 427.31) between

1 January 2006 and 31 December 2006 were extracted. All pa-

tients were required to have continuous enrollment with med-

ication prescription benefit for at least 12 months prior to the

hospital admission date and at least 12 months following the

date of discharge. Patients with evidence of valvular disease of

AF (i.e. hyperthyroidism, pulmonary embolism, or cardiac

surgery) during the 12-month pre-period and up to 30 days

post-discharge were excluded from the study.

Long-Term Medications

To understand whether persistence with anticoagulant ther-

apy is better or worse than other commonly taken long-term

classes of medications in a population with non-valvular AF,

six medications were selected from the antihypertensive and anti-

hyperglycemic classes. These medications were selected because,

based on the frequency distribution of all medications used in AF

patients, they were the most commonly prescribed therapeutic

classes in the AF population. Metformin extended release (once

daily [od]), metformin non-extended release (twice daily [bid]),

pioglitazone (od), sitagliptin (od), carvedilol phosphate (od), and

carvedilol (bid) had different dosing schedules (e.g. od and bid

dosing), adequate sample size (at least 300 users), and a low

likelihood of being used short-term or ‘as needed’. In addition,

lisinopril, valsartan, and simvastatin were selected to represent

treatment of heart diseases and dyslipidemia. Dosing schedules for

these medication products were extracted from package inserts.

Study Period

For the warfarin persistence analysis, patients were required

to have at least one warfarin prescription within 3 months from

their AF hospitalization discharge date. The index date was the

first warfarin prescription date following the AF hospital-

246 Song et al.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Am J Cardiovasc Drugs 2012; 12 (4)

ization discharge. For the individual medication adherence

analysis, the index date was the first prescription of each in-

dividual medication. Patients were required to have 12-month

continuous enrollment with medication prescription benefit

prior to (pre-period) and 12-month continuous enrollment follow-

ing (post-period) the index date. Patients with prescriptions of

each of these nine individual medications in the 12-month pre-

period were excluded from the study to ensure that the index

date was the first prescription of such long-term medications.

For example, patients treated with metformin extended release

in the pre-period were excluded from the metformin extended

release adherence study. This is shown graphically in figure 1.

Variable Definitions

Demographic and Clinical Characteristics

Demographic characteristics (age, sex, geographic region,

health plan type, and payer) were measured on the index

date. AF complications (congestive and chronic heart failure,

cardiac dysrhythmias other than AF, ischemic stroke), and

co-morbidities (pneumonia, chronic obstructive pulmonary

disease, coronary artery disease, acute myocardial infarction,

transient ischemic attack, hypovolemia, aspiration pneumonia,

urinary tract infection, hypertension, other thyroid disease,

diabetes mellitus, cardiomyopathies, and cancer) were mea-

sured during the 12-month pre-period. CHADS2, a score that

predicts the risk of stroke in patients with non-rheumatic AF

based on evidence of congestive heart failure, hypertension, age

>75 years, diabetes, and prior stroke or transient ischemic at-

tack, was also measured during the pre-period.

The number of unique medications prescribed during the pre-

period was counted. Patient cost-sharing burden wasmeasured as

co-pay and co-insurance of the index prescription claim.

Persistence and Discontinuation Measures

Persistence and discontinuation were calculated for warfarin

and each of the selected nine long-term medications during the

12-month post-period. Non-persistence or medication inter-

ruption was defined as a single gap of at least 60 days. Dis-

continuation was defined as the lack of subsequent claims with

evidence of a specific medication for patients who remained

enrolled for at least 90 days after discontinuation of the med-

ication. Consequently, only patients who had at least 90-day

enrollment after the discontinuation of the medication were

eligible for this measure. Because claims data do not have in-

formation on prescriptions during hospitalizations, inpatient

days were considered ‘adherent’ if the patient had a prescription

of that medication prior to the admission date.

Warfarin therapy requires constant monitoring and its

dosing needs to be titrated before a consistent therapeutic in-

ternational normalized ratio (INR) is established. Therefore,

medication possession ratio (MPR) could not be measured

accurately for warfarin due to its complex dosing and man-

agement. For consistency, MPR was not reported for other

long-term medications either.

Comparisons were conducted on persistence and discontinua-

tion between warfarin and other long-term medications.

Analytic Approach

SAS (SAS Institute, Cary, NC, USA) was used to build the

analytic file and to conduct the descriptive analysis. Stata (Stata-

Corp LP, College Station, TX, USA) was used for multivariate

analysis. Statistical tests of significance for persistence and dis-

continuation were carried out for bid versus od medications. Tests

of equal proportions were used to assess the statistical significance

of categorical variables; t-tests were used for continuous variables.

⎧ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎨ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎩

⎧⎪⎪⎪⎪⎪⎪⎪⎪⎨⎪⎪⎪⎪⎪⎪⎪⎪⎩

⎧⎪⎪⎪⎪⎪⎪⎪⎪⎨⎪⎪⎪⎪⎪⎪⎪⎪⎩

⎧⎪⎪⎪⎪⎨⎪⎪⎪⎪⎩

⎧ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎨ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎪ ⎩

Potential 12-month pre-period with no useof index medication (with exception of warfarin) Potential 12-month medication follow-up period

Index date (first prescriptionof medication of interest)

1 Jan 2005 1 Jan 2006 31 Dec 2006

AF hospitalizations

Potential 12-month post-hospitalization discharge date

Potential 12-month prior to hospitalization admission date

Fig. 1. Flow chart of the study period. AF= atrial fibrillation.

Persistence of Warfarin Treatment in AF patients 247


Multivariate analysis was conducted to examine the impact of

patient cost-sharing and dosing schedule on persistence and

discontinuation measures, holding all other factors constant.

The impact of dosing schedule was estimated for carvedilol (bid)

versus carvedilol phosphate (od) and metformin hydrochloride

non-extended release (bid) versus metformin hydrochloride ex-

tended release (od). Logistic regressionmodels were estimated to

examine whether a patient was persistent and whether a patient

discontinued therapy. Survival models were used to examine

time to non-persistence and time to discontinuation. All models

controlled for patients’ demographic (age, sex, region, payer)

characteristics, CHADS2, baseline AF complications (cardiac

dysrhythmias, heart failure, ischemic stroke), patient cost-sharing,

and number of medications in the pre-period.

Results

Patients’ Demographic and Clinical Characteristics

Of 28 384 AF patients identified, 16 036 (56.5%) patients

receiving warfarin met the study criteria, with a mean age of

73.0 years (standard deviation [SD] 11.1), 56.5% of whom were

men (table I). The largest age group was ages 75–84 years

(39.0%), followed by ages 65–74 years (24.4%). Consistent with

the age distribution, Medicare served as the primary payer for

77.4% of the population. The majority of patients lived in the

North Central (41.2%) and South (33.3%) regions of the US, a

reflection of the regional distribution inMarketScan databases,

and not necessarily reflective of the actual regional distribution

of AF patients treated with warfarin in the US. Compared with

non-persistent warfarin users, persistent users were on average

1 year older, more likely to live in the North Central region, and

less likely to live in the South and West regions.

The mean CHADS2 was 1.59 (SD 1.10, table II). About one

in three patients had congestive or chronic heart failure, and

four in ten had cardiac dysrhythmias in the pre-period. Hy-

pertension (56.7%), coronary artery disease (42.6%), diabetes

(26.2%), and chronic obstructive pulmonary disease (21.3%)

were the four most common co-morbidities. No significant

differences in most co-morbidities were found between war-

farin persistent users and non-persistent users, but persistent

users were significantly more likely to have baseline transient

ischemic attack and ischemic stroke than non-persistent users.

Non-persistent users were more likely than persistent users to

Table I. Demographic characteristics of warfarin users, overall and by persistence status

Characteristic All warfarin users Persistent warfarin users Non-persistent warfarin users p-Value

(n =16 036) [%] (n= 8586) [%] (n = 7450) [%]

Age group (y)

<45 1.2 0.7 1.8 <0.001

45–54 5.3 4.7 5.8 0.002

55–64 16.9 16.2 17.7 0.009

65–74 24.4 25.1 23.6 0.024

75–84 39.0 39.5 38.5 0.219

85+ 13.2 13.8 12.6 0.027

Mean (SD) age 73.0 (11.1) 73.5 (10.7) 72.5 (11.4) 0.435

Sex

Male 56.5 56.6 56.4 0.793

Female 43.5 43.4 43.6 0.793

Primary payer

Commercial 22.6 21.1 24.4 <0.001

Medicare 77.4 78.9 75.6 <0.001

US geographic region

Northeast 11.7 12.0 11.3 0.13

North Central 41.2 43.0 39.0 <0.001

South 33.3 31.9 35.0 <0.001

West 13.6 12.9 14.5 0.003

Unknown 0.2 0.2 0.2 0.853

248 Song et al.


have hypovolemia, although the rate was very low in both co-

horts (0.4% v. 0.1%). Warfarin users on average used 13.2 (SD

7.1) different medications in the 12-month pre-period, with

mean cost-sharing totaling $US9.06 (SD $US8.26) for index

warfarin prescription. Persistent users had slightly more med-

ications in the pre-period and lower cost-sharing for warfarin

than non-persistent users.

Warfarin Persistence and Discontinuation Measures

During the 12-month post-period, slightly more than half

(53.5%) of warfarin users were persistent on therapy, and about

four in ten (42.6%) warfarin users discontinued warfarin

treatment, i.e. there was a gap of at least 90 days without any

warfarin use by the end of the follow-up. The remaining 3.9%warfarin users were not persistent but they did not discontinue

warfarin either. On average, it took 122.2 (SD 83.4) days from

the first warfarin prescription to non-persistence and 113.6

(SD 75.1) days to warfarin discontinuation.

Kaplan-Meier survival estimates are plotted in figure 2 for

new and continuing warfarin users. New warfarin users did not

have any warfarin claims during the 12-month pre-period,

while continuing users had at least one warfarin claim in the

pre-period. The proportion of persistent warfarin users de-

creased over time from the index date, and new users had

consistently lower persistence rates than continuing users. By

100 days, 78.5% of continuing users were persistent with ther-

apy compared with 72.4% of new users; by 200 days, 66.7% of

continuing users were still persistent compared with 58.9% of

new users (p < 0.001 in both cases).

Multivariate regression models suggested that patients with

baseline ischemic stroke (odds ratio [OR] = 1.376; 95% con-

fidence interval [CI] 1.194, 1.586 for persistence; OR = 0.698;CI 0.597, 0.816 for discontinuation) and patients who were

Table II. Clinical characteristics during the 12-month pre-period, by warfarin persistence status

Characteristic All warfarin users Persistent warfarin users Not persistent warfarin users p-Value

(n =16 036) [%] (n= 8586) [%] (n= 7450) [%]

Mean CHADS2 (SD) 1.59 (1.10) 1.62 (1.10) 1.55 (1.10) <0.001

Complications

Heart failure (congestive or chronic) 33.4 33.4 33.4 0.951

Cardiac dysrhythmias 42.2 41.5 43.0 0.051

Ischemic stroke 7.9 8.9 6.7 <0.001

Co-morbidities

Pneumonia 12.6 12.4 12.9 0.385

COPD 21.3 21.2 21.4 0.805

Coronary artery disease 42.6 42.2 42.9 0.375

AMI 5.0 4.8 5.2 0.171

TIA 6.5 7.0 5.9 0.005

Hypovolemia 0.3 0.1 0.4 <0.001

Aspiration pneumonia 0.9 0.9 1.0 0.487

UTI 11.7 11.5 12.0 0.335

Hypertension 56.7 56.5 57.0 0.519

Other thyroid disease 7.2 7.1 7.4 0.46

Diabetes 26.2 26.5 25.9 0.42

Cardiomyopathies (including LVH and HCM) 9.6 9.5 9.8 0.603

PVD 11.4 11.4 11.3 0.803

Cancer 13.9 14.1 13.6 0.382

Mean (SD) number of different medications used 13.2 (7.1) 13.4 (7.0) 12.9 (7.2) <0.001

Mean (SD) warfarin cost-sharing, $US 9.06 (8.26) 8.86 (8.12) 9.30 (8.42) 0.001

AMI= acute myocardial infarction; CAD= coronary artery disease; COPD= chronic obstructive pulmonary disease; HCM= hypertrophic cardiomyopathy;

LVH= left ventricular hypertrophy; PVD= peripheral vascular disease; TIA= transient ischemic attack; UTI= urinary tract infection.



receiving warfarin therapy at baseline (OR = 1.431; 95% CI

1.337, 1.531 for persistence; OR = 0.585; 95% CI 0.543, 0.630

for discontinuation) were more likely to be persistent and less

likely to discontinue warfarin. In addition, patients in the South

and West regions (compared with North Central), having

baseline cardiac dysrhythmias other than AF (compared with

patients who did not have cardiac dysrhythmias; OR = 0.933;95% CI 0.875, 0.994 for persistence; OR = 1.110; 95% CI 1.035,

1.189 for discontinuation), and higher warfarin cost-sharing

(OR = 0.991; 95% CI 0.987, 0.995 for persistence; OR = 1.009;95% CI 1.005, 1.013) were less likely to be persistent and more

likely to discontinue (p < 0.05 in all cases, table III). A 1-year

increase in age was associated with a lower hazard of becoming

non-persistent (hazard ratio [HR] = 0.996; 95%CI 0.992, 1.000)

and discontinuing warfarin (HR = 0.995; 95% CI 0.991, 0.999).

Persistence and Discontinuation Measures for Long-Term

Medications with Different Dosing Schedules

Discontinuation rates were not significantly different be-

tween carvedilol phosphate od versus carvedilol bid (35.0% vs

32.9%, p = 0.489), and metformin extended release od versus

metformin non-extended release bid (48.9% vs 52.0%, p = 0.375;table IV) during the 1-year follow-up period. Kaplan-Meier

curves for persistence with long-term medications and new

warfarin users are plotted in figure 3. The percentage of patients

who remained persistent decreased over time to approximately

50% at the end of the 1-year follow-up for all medications. By

100 days, 67.9% (metfomin bid) to 80.0% (carvedilol bid) of

patients were still persistent with therapy; by 200 days, 52.8%(metformin bid) to 69.3% (carvedilol phosphate od) were still

persistent. Persistence was consistently higher for carvedilol

ContinuingNew

1.00

0.75

0.50

0.25

0

0 100 200

Kap

lan-

Mei

er s

urvi

val e

stim

ates

Analysis time (days)300 400

Fig. 2. Kaplan-Meier curve on warfarin persistence: new warfarin users vs

continuing warfarin users.

Table III. Multivariate regression results on warfarin persistence and discontinuation

Variable Survival model (Weibull

distribution): time to non-

persistence

Logistic model: whether

persistent

Survival model (Weibull

distribution): time to

discontinuation

Logistic model: whether

discontinued

Hazard ratio p-Value Odds ratio p-Value Hazard ratio p-Value Odds ratio p-Value

Age 0.996 0.029 1.005 0.079 0.995 0.011 0.994 0.033

Male 0.965 0.136 1.038 0.263 0.944 0.033 0.937 0.069

Region

Northeast 1.035 0.385 0.969 0.549 1.054 0.233 1.063 0.291

South 1.158 <0.001 0.840 <0.001 1.189 <0.001 1.225 <0.001

West 1.208 <0.001 0.796 <0.001 1.235 <0.001 1.295 <0.001

Unknown 0.958 0.856 0.997 0.993 1.204 0.446 1.381 0.348

Medicare 0.982 0.679 1.055 0.393 0.974 0.594 0.939 0.357

Clinical characteristics

CHADS2 1.011 0.453 0.989 0.590 1.021 0.208 1.025 0.257

Cardiac dysrhythmias 1.053 0.028 0.933 0.032 1.082 0.003 1.110 0.003

Heart failure 1.018 0.489 0.966 0.316 1.016 0.570 1.037 0.343

Ischemic stroke 0.758 <0.001 1.376 <0.001 0.734 <0.001 0.698 <0.001

Warfarin cost sharing 1.006 <0.001 0.991 <0.001 1.006 <0.001 1.009 <0.001

No. of medications in pre-period 1.004 0.050 0.995 0.029 0.999 0.706 0.999 0.756

Used warfarin in pre-period 0.742 <0.001 1.431 <0.001 0.636 <0.001 0.585 <0.001

250 Song et al.


and sitagliplin users than for metformin and pioglitazone users,

but there were no clearly different patterns of persistence be-

tween od and bid medications. The impact of dosing schedule

on persistence and discontinuation is presented in table V.

Multivariate regression found no significant relationship be-

tween dosing schedule and persistence or discontinuation.

Discussion

While existing studies report the adherence to guidelines for

AF management and use of oral anticoagulant in the AF pop-

ulation,[10-14] few studies have examined warfarin persistence.[10]

This studywas the first to examinewarfarin persistence aswell as

the impact of dosing schedules on persistence and discontinua-

tionmeasures of commonly prescribed long-termmedications in

the AF population using a large national managed-care claims

database. Although warfarin use requires constant INR mon-

itoring, its persistence rate was found to be similar to medi-

cations that treat hypertension, hyperglycemia, heart disease, or

dyslipidemia, which do not have a similar monitoring require-

ment. About half (53.5%) of warfarin users remained persistent

by the end of a 1-year follow-up period, consistent with other

long-term medications used by AF patients (45.2–61.3%). The

percentage of patients who continued onwarfarin therapy at the

end of 1-year follow-upwas 57.4%, lower than the 70% found by

Gallagher and colleagues[10] for patients with chronic AF and

aged 40 years or older. This difference could be the result of the

Table IV. Persistence and discontinuation of other long-term medications

Variable Carvedilol phosphate

(od) [n =326]Carvedilol (bid)

[n =1786]p-Value Metformin HCl

(ER, od) [n= 305]Metformin HCl

(non-ER, bid) [n= 917]p-Value

Mean SD Mean SD Mean SD Mean SD

Age 72.4 11.6 73.6 11.4 0.095 69.1 12.4 70.8 11.4 0.030

CHADS2 1.56 1.00 1.69 1.10 0.049 1.98 1.07 1.99 1.09 0.820

Cost sharing, $US 29.45 28.31 19.48 15.79 <0.001 10.90 14.43 7.61 6.25 <0.001

Persistence (n, %) 200 61.3% 1074 60.1% 0.684 138 45.2% 428 46.7% 0.649

Discontinuation (n, %) 114 35.0% 588 32.9% 0.489 149 48.9% 422 52.0% 0.375

Days to non-persistence 121 82 122 84 0.756 108 76 109 81 0.651

Days to discontinuation 117 78 113 78 0.604 102 70 101 73 0.983

Variable Pioglitazone HCl

(od) [n =469]Sitagliptin phosphate

(od) [n= 366]p-Value Lisinopril (n= 3030) Valsartan (n = 881) Simvastatin

(n = 2249)

Mean SD Mean SD Mean SD Mean SD Mean SD

Age 71.1 10.8 70.9 10.5 0.858 73.8 11.7 74.5 10.7 73.0 10.9

CHADS2 2.03 1.00 2.04 1.91 0.933 1.73 1.12 1.89 1.08 1.71 1.16

Cost sharing, $US 26.73 24.44 27.77 25.81 0.553 6.66 5.25 23.86 20.53 13.84 15.06

Persistence (n, %) 231 49.3% 209 57.1% 0.025 1462 48.3% 479 54.4% 1,182 52.6%

Discontinuation (n, %) 209 44.6% 130 35.5% 0.012 1386 50.5% 354 44.8% 924 45.0%

Days to non-persistence 111 80 122 84 0.009 107 82 110 81 103 78

Days to discontinuation 102 73 107 74 0.658 98 73 103 74 96 72

bid= twice daily; ER= extended release; HCl =hydrochloride; od = once daily; SD= standard deviation.

Carvedilol phosphate (od)Lisinopril (od)Metformin (od)Simvastatin (od/tid)Valsartan (od/bid)

Carvedilol (bid)Metformin (bid)Pioglitazone (od)Sitagliptin (od)Warfarin new users

Kap

lan-

Mei

er s

urvi

val e

stim

ates 1.00

0.75

0.50

0.25

0

0 100Analysis time (days)

200 300 400

Fig. 3. Kaplan-Meier curve for persistence on selected long-term medi-

cations. bid= twice daily; od= once daily; tid = three times daily.



different study populations included in theGallagher et al. study

and our study. All patients in our study hadAF hospitalizations

while their patients did not require AF hospitalization. Their

patients were 40 years or older and we included patients under

the age of 40 years. In addition, the vastmajority of their patients

were 65 years or older (93.7%), compared with only 76.6% of

patients in our study. Both the Gallagher et al. study and our

study found that older patients were more likely to continue on

warfarin therapy.

Although warfarin persistence decreased over time for all

warfarin users, continuing warfarin users consistently had better

persistence than new warfarin users, which was not surprising

as bleeding events tend to occur soon after initiation of warfarin

therapy. Consistent with the literature that older patients gen-

erally have better adherence than younger patients,[7,15] older

patients in our study were also estimated to be more likely to be

persistent and less likely to discontinue therapy. Compared

with patients who had no baseline ischemic stroke, patients

with baseline ischemic stroke were significantly more likely to

be persistent and less likely to discontinue therapy. Living in the

South and West regions, having baseline cardiac dysrhythmias

other than AF, and having higher warfarin cost-sharing sig-

nificantly decreased the likelihood of persistence and increased

the likelihood of discontinuation. Consistent with the exist-

ing literature regarding the impact of patient cost-sharing on

medication adherence,[7,16,17] we found higher cost-sharing

negatively related with warfarin persistence. Also consistent

with published studies, patients on od medications had similar

persistence to patients on bid medications.[18] Age, cost-sharing,

having baseline ischemic stroke or cardiac dysrhythmias were

not significant factors on persistence and discontinuation

measures in od and bid study populations, possibly because the

od versus bid cohorts had very similar characteristics as the

medications in comparison were the same medication with

different dosing schedules. This study did not find appropriate

medications taken three or four times daily with sufficient

sample size thus no comparison was conducted between three-

or four-times-daily medications and od medications.

Costs associated with AF are very high. Coyne and col-

leagues[19] estimated that the annual cost of AF was $6.65

billion in the USA and Kim et al.[20] estimated an incremental

AF-specific cost of $6 billion in the USA. Numerous studies

have shown that non-adherence is associated with higher rates

of complications and increased healthcare utilization (espe-

cially inpatient admissions and emergency room visits) and

costs.[7-9] Understanding the factors that affect persistence and

discontinuation of warfarin and other long-term medication

therapy in the AF population is important as medical plans and

policy makers can develop targeted intervention programs that

help improve persistence and adherence of long-term medi-

cations in this population.

Several limitations related to the use of administrative medi-

cal claims data should be considered when evaluating the

findings. First, because this study was based on claims data,

persistence and discontinuation was measured among patients

who had at least one prescription. Information on those patients

who received a prescription but never filled it is not available. In

addition, we could only look at refill rates, not actualmedication

consumption, which might overestimate persistence and under-

estimate discontinuation. Because our AF study population in-

cluded patients with secondary AF causes, such as urinary tract

infection and pneumonia, non-persistence of warfarin was likely

to be overestimated relative to the primary AF population. In-

cluding AF patients who had no risk factor of stroke but used

warfarin in anticipation of cardioversion or catheter ablation in

the study population could also overestimate non-persistence of

warfarin as these patients would stop using warfarin shortly.

Second, clinical information such as chart review or INR

laboratory values are not available in the claims data, therefore

we could not determine if patients discontinuedwarfarin because

of adverse events (for example, major bleeding), in preparation

for surgery, or other reasons. Further research should in-

corporate clinical data on side effects or INR values to better

understand the reasons for warfarin non-persistence and dis-

continuation. Third, some explanatory variables such as race

and household income were not available. The effects of patient

Table V. Estimated impact of dosing schedule on persistence and discontinuation measures

Hazard model Logistic model Hazard model Logistic model

Time to non-persistence Whether persistent Time to discontinuation Whether discontinued

Hazard ratio p-Value Odds ratio p-Value Hazard ratio p-Value Odds ratio p-Value

Carvedilol phosphate (od) vs carvedilol (bid) 1.065 0.531 0.921 0.524 0.930 0.496 0.910 0.491

Metformin ER (od) vs metformin (bid) 0.990 0.916 1.012 0.931 0.952 0.613 0.940 0.669

bid= twice daily; ER= extended release; od = once daily.

252 Song et al.


cost-sharing on adherence may be larger when the proportion of

income spent on healthcare is higher. Fourth, this study com-

pared persistence and discontinuation of medications with dif-

ferent dosing schedules. Medications that differ in dosing

schedulesmay differ in other ways (for example, side effects) that

could influence adherence, something not captured in this ana-

lysis. Additionally, long-term medications were included in the

study if there were at least 300 users in ourAFpopulation, which

was a random threshold. More or fewer medications would be

selected into the study if a different threshold on sample size was

used. Finally, because of the continuous enrollment criteria, very

sick AF patients who died within less than 1 year of AF hospi-

talizations were excluded from the study sample. The impact of

this exclusion on persistence and discontinuationmeasures is not

obvious. In addition, the claims data only included patients with

commercial and Medicare supplemental insurance. Thus find-

ings of this study may not be representative of the whole AF

population in the USA.

Conclusion

Persistence and continuationwith warfarin is consistent with

that of other long-term medications among patients with AF.

Higher medication cost-sharing is associated with lower per-

sistence and higher likelihood of discontinuation with warfarin.

Factors associated with non-persistence can be used to identify

patients appropriate for adherence programs.

Acknowledgments

This study was funded by Boehringer Ingelheim Pharmaceuticals, Inc.

One author (Stephen Sander) is an employee of Boehringer Ingelheim

Pharmaceuticals, Inc.

Conference presentation: A poster of the study results was presented at

the International Society of Pharmacoeconomics and Outcome Research

(ISPOR) 15thAnnual InternationalMeeting,May2010,Atlanta,GA,USA.

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Correspondence: Dr Xue Song, PhD, Truven Health Analytics, 150

Cambridge Park Dr., 2nd Floor, Cambridge, MA 02140, USA.

E-mail: [email protected]



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Patterns and Predictors of Use of Warfarin and Other Common Long-Term Medications in Patients with Atrial Fibrillation