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Costs and clinical consequences of suboptimal

atrial fibrillation management

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Clinico Economics and Outcomes Research
24 March 2012
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Steven N Singh Abstract: Atrial fibrillation (AF) places a considerable burden on the US health care system,
Department of Cardiology, Veterans society, and individual patients due to its associated morbidity, mortality, and reduced health-
Affairs Medical Center, Washington, related quality of life. AF increases the risk of stroke, which often results in lengthy hospital
DC, USA stays, increased disability, and long-term care, all of which impact medical costs. An expected
increase in the prevalence of AF and incidence of AF-related stroke underscores the need for
optimal management of this disorder. Although AF treatment strategies have been proven
effective in clinical trials, data show that patients still receive suboptimal treatment. Adherence
to AF treatment guidelines will help to optimize treatment and reduce costs due to AF-associated
events; new treatments for AF show promise for future reductions in disease and cost burden
due to improved tolerability profiles. Additional research is necessary to compare treatment
costs and outcomes of new versus existing agents; an immediate effort to optimize treatment
based on existing evidence and guidelines is critical to reducing the burden of AF.
Keywords: atrial fibrillation, pharmacoeconomics, stroke, health-related quality of life

Introduction
Atrial fibrillation (AF), the ineffective and uncoordinated contraction of the atria, is
the most common sustained heart rhythm disturbance seen in clinical practice.1,2 An
estimated 3.03 million Americans had AF in 2005, and the prevalence is expected to
rise to 7.56 million by 2050.3 Between 1985 and 1999, the number of hospitalizations
with AF as a principal diagnosis increased by 144% according to the National ­Hospital
Discharge Survey.4 These numbers are probably even greater, since arrhythmias
represented 10.6% of patients with a principal diagnosis related to the circulatory
system.5 Research demonstrates a potential link between AF and atherosclerotic
vascular disease, hypertension, chronic inflammation, and metabolic syndrome.6 AF
is also associated with substantial morbidity (stroke, heart failure), mortality, and poor
health-related quality of life.7–14 Based on these issues, AF imposes a considerable cost
burden on the patient, the health care system, and society.15–17
AF treatment is complex. Comprehensive management of the patient with AF requires
a multifaceted approach directed at first identifying any underlying, reversible, treatable
causes,18 and then controlling symptoms and protecting the patient from central and
peripheral embolism.19,20 The American College of Cardiology Foundation, American
Correspondence: Steven N Singh
Department of Cardiology, Veterans
Heart Association, and Heart Rhythm Society (ACCF/AHA/HRS) task force recommend
Affairs Medical Center, 50 Irving St NW, that AF management involve three nonmutually exclusive objectives: rate control,
Washington, DC 20422, USA
Tel +1 202 745 8115
prevention of thromboembolism, and correction of the rhythm disturbance (Figure 1).19
Email steve.singh@med.va.gov The initial management decision is either a rate-control or rhythm-control strategy.

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Singh Dovepress

Table 1 CHADS2 index stroke risk in patients with nonvalvular

AF not treated with anticoagulation and recommended
antithrombotic therapy by risk factorsa
Rate Rhythm
CHADS2 risk criteria Score
control control
Prior stroke or TIA 2
Atenolol, amiodarone, Amiodarone,
digoxin, diltiazem, Age . 75 years 1
disopyramide, dofetilide,
esmolol, metoprolol, dronedarone, flecainide, Hypertension 1
propranolol, propafenone, sotalol Diabetes mellitus 1
verapamil OR Heart failure 1
Risk categoryb Recommended therapy
No risk factors Aspirin, 81 to 325 mg daily
1 moderate risk factor Aspirin, 81 to 325 mg daily, or warfarin
(INR 2.0 to 3.0, target 2.5)
Anticoagulation
Any high risk factor or .1 Warfarin (INR 2.0 to 3.0, target 2.5)
(unless
moderate risk factor
contraindicated)
Notes: aGuideline-based therapy recommendations include consideration of
Aspirin, vitamin-K CHADS2 and other risk factors; bmoderate risk factors: all CHADS2 risk factors
antagonists (warfarin) with a score of 1 as well as left ventricular ejection fraction # 35%; high risk factors:
prior stroke, TIA, or embolism; mitral stenosis; prosthetic heart valve (if mechanical
valve, target INR . 2.5).
Copyright© 2011, Elsevier. Adapted with permission from Fuster V, Ryden LE, Cannom
DS, et al. 2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/
Figure 1 AF treatment. Drugs are listed alphabetically.19
ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation A Report
Abbreviation: AF, atrial fibrillation.
of the American College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines Developed in partnership with the European Society of
Cardiology and in collaboration with the European Heart Rhythm Association and
Using the rate-control strategy, the ventricular rate is controlled the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101–e198.19
Abbreviations: TIA, transient ischemic attack; INR, international normalized ratio.
with no commitment to restore or maintain sinus rhythm, unlike
the rhythm-control strategy, which attempts restoration and
maintenance of sinus rhythm.19 assessments of AF treatments. A recent national survey
Anticoagulation therapy is to be considered regardless of estimated that direct medical costs were 73% higher in
which rate or rhythm control therapy is prescribed, because patients with AF compared with matched control subjects,
current agents used for rate and rhythm control do not reduce representing a net incremental cost of $8705 per patient
stroke risk and cannot be substituted for antithrombotic per year and a national incremental cost between $6.0 and
treatment.21,22 The CHADS2 scoring system, which utilizes $26.0  billion (2008 US dollars [USD]).26 A 2001 study
age and comorbid conditions to stratify a patient’s stroke risk, found that approximately 234,000 hospital outpatient
is recommended to aid in the decision to use antithrombotic department visits, 276,000 emergency room visits,
therapy (Table  1).19,23 Despite the guidelines, AF may be 350,000 hospitalizations, and 5  million office visits were
managed suboptimally due to the complexity of treatment. attributable annually to AF.15 It has been shown that in the
It has been shown that compliance with some antiarrhythmic year following index hospitalization, 12.5% of chronic AF
agents is poor and patients who discontinue treatment are patients and 10.1% of newly diagnosed AF patients are
unlikely to restart therapy.24 Suboptimal management of AF readmitted for AF.27 The total annual medical cost for the
could result in a delay in reverting the patient to normal sinus treatment of AF in the inpatient, emergency department, and
rhythm, which in turn could promote atrial remodeling, mak- hospital outpatient settings was estimated at $6.65  billion
ing future sinus rhythm maintenance difficult.25 This article (2005 USD; inflation-adjusted to 7.71  billion 2011 USD)
discusses the clinical consequences and associated costs of (Figure 2), and is likely an underestimate as costs for long-
suboptimal management of AF in the United States (US), as term anticoagulation, stroke prevention, inpatient drugs,
well as treatment strategies that may reduce the burden of and hospital-based physician services were not included.15
AF and improve patient outcomes. This assessment included billed hospital charges and costs
of procedures for which AF was the principal discharge
Overall economic burden diagnosis ($2.93 billion), incremental inpatient costs due to
of AF in the US AF as a comorbid diagnosis ($1.95 billion), and physician
Although there are numerous cost-comparison studies of fees, drugs, procedures, and facility costs for ambulatory/
different AF treatments, there are few US-based direct cost outpatient treatment of AF ($1.76 billion).15

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Dovepress Clinical consequences and costs of AF

was attributable to the incidence of stroke and heart failure

1 year after diagnosis.17 In another study, inpatient costs were
$11,307 (2006 USD; $12,699 2011 USD) and ­outpatient
costs were $2827 ($3175 2011 USD) for primary AF
Outpatient, 23%
­hospitalization; for hospitalized patients with ­secondary AF,
AF-related inpatient costs were $5181 ($5819 2011 USD) and
outpatient costs were $1376 ($1545 2011 USD).28 Table 2
contains recently published data on direct health care costs
Direct inpatient, 44%
Drugs, 4% attributable to an AF diagnosis, including cost ­adjustments
to 2011 USD (differing costs may reflect variations in study
designs and data sets).28–30
Inpatient drug initiation and costs of adverse events and
Indirect inpatient, 29%
adverse-event monitoring significantly add to the overall
­economic burden of AF treatment. A recent analysis ­examined
the costs associated with initiating sotalol and dofetilide in
the inpatient setting.31 Treatment guidelines ­recommend
­inpatient initiation of dofetilide, while the ­initiation of
sotalol is ­mandated by the US Food and Drug Administration
Figure 2 Distribution of total medical costs for treating AF in the United States
(2005).
(FDA), with a recommended minimum ­hospital stay of 3 days
Copyright© 2006, John Wiley and Sons. Reprinted with permission from Coyne KS, to assess for ventricular proarrhythmia.19,32,33 Mean total
Paramore C, Grandy S, Mercader M, Reynolds M, Zimetbaum P. Assessing the direct
costs of treating nonvalvular atrial fibrillation in the United States. Value Health.
­inpatient costs per patient were $3278 in the sotalol group
2006;9(5):348–356.15 and $3610 in the dofetilide group (2007 USD; $3580 and
Abbreviation: AF, atrial fibrillation.
$3942 2011 USD, respectively). The greatest costs were for
room and board followed by cardiology/electrocardiograms.31
One study estimated the direct and indirect costs of The incidence and cost of suspected adverse events and
AF (2002 USD) in a privately insured US population adverse-event monitoring during AF rhythm control and/or
aged ,65 years. The direct annual cost of AF was $15,553 rate-control therapy was also high.34 Overall, 50.1% of treated
per patient compared with $3204 for enrollees without AF. patients had a suspected adverse event and/or function test for
These costs were adjusted to $19,575 and $4809  in 2011 adverse-event monitoring (45.5% with rate control, 53.5%
USD.16 Indirect costs (ie, disability claims and absenteeism) with rhythm control, and 61.2% with combined rhythm/rate
were $2134 higher annually for AF patients compared control). The mean cost of adverse events and adverse-event
with enrollees without AF ($2847 [$3583 2011 USD] vs monitoring among treated patients was $3089 per patient
$713 [$897 2011 USD], respectively). Regarding patients (2006 USD; $3469 2011 USD).34
aged .65 years, a Medicare database study found that
the adjusted mean incremental treatment cost of AF was Cost of stroke in patients with AF
$14,199 (2004 USD; $17,019 2011 USD) in patients diag- Stroke is a leading cause of death in the world and a
nosed with AF and followed for 1 year.17 Some of this cost leading cause of morbidity in adults aged .60 years.35

Table 2 Recently published AF health care costs

Study Diagnosis Patient population Inpatient Outpatient Total AF-related
(USD) costsa costsa costsa
Patel29 Nontransient 32,905 patients in US claims database $22,582 ($25,362) $15,688 ($17,620) $38,270 ($42,982)
(2006 USD) AF/AFL (mean age 74 years, 56% male, 1/04–12/07)
Kim28 Primary AF 35,255 patients in US claims database $11,307 ($12,699) $2827 ($3175) $14,134 ($15,874)
(2006 USD) (mean age 64 years, 65% male, 1/05–12/06)
Secondary AF $5181 ($5819) $1376 ($1545) $6557 ($7364)
Kim30 AF 3605 patients in US claims database $3872 ($4228) $2293 ($2504) $6165 ($6732)
(2007 USD) (mean age 63 years, 69% male, 4/01–3/07)
Note: aCosts inflation-adjusted to 2011 USD using the Bureau of Labor Statistics CPI inflation calculator.
Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; USD, United States dollars.

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AF independently increases the risk of ischemic stroke by the overlap between AF-attributable stroke and the age of
four- to fivefold.36 In the absence of antithrombotic therapy, Medicare eligibility. The need for optimal anticoagulation
the annual risk of stroke in patients with AF (with risk fac- was demonstrated in a pooled analysis of five large,
tors including history of hypertension, diabetes, and history randomized, controlled AF antithrombotic trials, which
of prior stroke/transient ischemic attack [TIA]) is 4.9% in showed that warfarin reduced the frequency of all strokes by
patients aged ,65 years and 8.1% in patients aged .75 years.37 68% (95% confidence interval [CI]: 50%–79%); the efficacy
Because the prevalence of AF increases with age and older age of aspirin was less consistent.37 A conservative economic
confers an increased risk of stroke, the proportion of strokes model estimated a Medicare saving of $1.14 billion annually
attributable to AF increases with age.37 (2003 USD; $1.4  billion 2011 USD) through maintaining
Stroke is associated with substantial inpatient and long- patients eligible for anticoagulation on therapeutic doses of
term costs.38 A review of published data on AF prevalence warfarin.43 Depending on the study population, anticoagulant
found that survivors of AF-related stroke were more likely therapy has been shown to decrease the risk of stroke by
to have longer hospital stays, disability, and need for long- 42% to 86%.44
term care, all of which increase health care costs.39 A review Although several randomized clinical trials have
of 14 studies found that patients with AF-related stroke had ­d ocumented the benef its of warfarin in preventing
worse outcomes than patients with non-AF-related stroke, ­AF-related stroke, a growing body of evidence indicates
including higher mortality, severity, recurrence, functional that ­anticoagulants are routinely underutilized for stroke
impairment, and dependency.40 A retrospective chart review prevention in patients with AF.45,46 It has been estimated that
showed that patients with AF-associated ischemic stroke half of the patients receiving warfarin do not receive the
were 2.23 times more likely to be bedridden than patients appropriate ­anticoagulant therapy.44 Anticoagulant therapy
who had strokes from other causes.41 Importantly, previously with ­warfarin has a ­narrow therapeutic index requiring
diagnosed AF patients in this chart review were not receiving coagulation monitoring by a physician or, in some cases,
therapeutic anticoagulation at the time of their stroke.41 pharmacists and nurses;47,48 this requirement, along with the
A recent retrospective observational cohort study inherent properties of warfarin related to its bleeding risk,
­utilized medical and pharmacy claims from a managed may contribute to its low levels of utilization.45 A comparative
care organization to identify continuously benefit-eligible study between usual medical care and a clinical pharmacist-
AF patients without prior valvular disease or warfarin use run anticoagulation clinic showed that pharmacist supervi-
between 2000 and 2002 (costs adjusted to 2004 USD).42 sion improved ­anticoagulation control, reduced bleeding
All patients were followed for at least 6 months, until plan and thromboembolic event rates, and saved $162,058 per
termination or the end of study follow-up. Stroke risk was 100 patients annually (1998 USD; $225,112 2011 USD) in
assessed using the CHADS2 index. Inpatient and outpa- reduced hospitalizations and ­emergency ­department visits.49
tient cost benchmarks were utilized to estimate total direct Figure  3 presents a disease model showing the effects of
health care costs (pre- and post-AF index claim). Total direct ­suboptimal versus optimal oral ­anticoagulation on stroke
health care costs were also assessed for patients with TIA, rates. The economic model considers a stable ­population of
ischemic stroke (IS), and major bleed (MB). Pre- versus patients with AF, such as that which might be found in a man-
post-AF diagnosis total direct health care costs were $412 and aged care organization or a state’s Medicare group; it allows
$1235 per member per month (pmpm), respectively ($494 and for movement of individuals with AF in and out of the popula-
$1480 2011 USD, respectively). Of the 448 (12%) patients tion during the course of a year. Scenarios are created (eg, “if
with a TIA, IS, or MB, pmpm costs post-AF diagnosis ranged half of all those who currently do not receive anticoagulation
from $2235 to $3135 ($2679–$3758 2011 USD) correlating were to receive well-controlled warfarin”) to represent the
with CHADS2 stroke-risk status and exposure to warfarin. current situation in the population of interest compared with
Total cohort pmpm costs pre- and post-event increased 24% other potential scenarios of care. According to this model,
from $3447 to $4262 ($4132–$5109 2011 USD).42 stroke rates and associated costs could decrease dramatically
if 50% of warfarin-eligible patients were ­optimally coagu-
Cost benefits of optimal lated. Approximately 1.265  million patients currently not
anticoagulation receiving prophylaxis suffer over 58,000 strokes annually. If
In the US, increasing rates of AF-related stroke due to the half of those not receiving warfarin were optimally anticoagu-
aging population will come at a high cost to society given lated, approximately 19,000 strokes would be prevented.43

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Dovepress Clinical consequences and costs of AF

A states representing temporary discontinuation of therapy) was

1,400,000 designed due to the chronic nature of AF and its treatment
1,200,000 and the varying but continuous risk of stroke and hemorrhage.
1,000,000
The scenarios included in the model were: (1) perfect ­warfarin
­control (100% of patients within target INR and following
AF patients

800,000 AF patients

Strokes
guideline recommendations19,54 for ideal treatment goal);
600,000
(2) trial-like warfarin control (clinical trial conditions; INRs
400,000
within target 68% of the time as reported in the Stroke
200,000
58.392
P­revention by ORal Thrombin Inhibitor in atrial Fibrillation
39.012
0 ­[SPORTIF] V trial);55 (3) “real-world” warfarin control (r­outine
Not receiving If half of
oral
anticoagulant
untreated pop
received
clinical practice conditions; INRs within ­target 48% of the
warfarin
time based on data from a retrospective study of US outpatient
B physician practices);56 and (4) real-world ­prescription (and
5.000 control) of warfarin, aspirin, or neither for warfarin-­eligible
4.500 4.586 patients at moderate-to-high risk of stroke (routine clinical
Cost of stroke ($USD billion)

(5.643)
4.000 practice conditions, in which a proportion of warfarin-eligible
3.500
3.446
patients were prescribed either aspirin [12%] or neither war-
3.000 (4.240)
farin nor aspirin [23%]).56 The total number of primary and
2.500 recurrent ischemic strokes in a cohort of 1000 patients (age 70
2.000
years) was assessed, and the model showed increased numbers
1.500
of strokes as real-world conditions increased and trial-like
1.000
management declined. Both clinical and cost outcomes were
0.500
found to be dependent on the quality of anticoagulation
0.000
Not receiving oral
anticoagulant
If half of untreated
population received
(Table 3).
warfarin In another cost-effectiveness semi-Markov decision
Figure 3 Model results: (A) reductions in AF-related stroke based upon half of
analysis model of patients with AF, the lifetime cost per
untreated patients receiving warfarin and (B) cost of stroke.43 The economic model patient for anticoagulation using a monitoring service was
considers a stable population of patients with AF, such as that which might be found
in a managed care organization or a state’s Medicare group. found to be $8661 versus $10,746 for usual care (2004 USD;
Notes: Cost estimates were based on published epidemiologic data and 2003 $10,381 vs $12,880 2011 USD).57 The model predicted
Medicare cost data. Values in parentheses are inflation-adjusted costs to 2011 US
dollars using the Bureau of Labor Statistics CPI inflation calculator. that anticoagulation services improved the effectiveness
Abbreviation: AF, atrial fibrillation. (measured in quality-adjusted life-years [QALYs]) and
reduced costs (estimated at $2100; $2517 2011 USD), and
Warfarin therapy is monitored to ensure that patients was therefore superior to usual care.
remain within the target international normalized ratio (INR) In terms of the cost of MB events with warfarin use,
range of 2.0 to 3.0. Studies of the quality of anticoagulation a recent database study of warfarin-treated patients with
management in patients with AF found that up to 60% of AF found that MB events associated with warfarin therapy,
patients receiving warfarin have INR outside the recommended although nearly twice as costly compared with patients
therapeutic target range.50–52 It is likely that these studies can without MB events, were relatively rare; among 47,437 total
be generalized to the US population as they included AF patients, only 194 (0.4%) had intracranial MB events and
patients in a range of settings (emergency department, long- 919 (1.9%) experienced gastrointestinal MB events.58
term care, and community); one can therefore conclude that In addition to warfarin and other anticoagulants (eg,
the majority of patients with an AF diagnosis in the US are unfractionated heparin and low-molecular-weight ­heparin),
not optimally treated with anticoagulant therapies. Such direct thrombin inhibitors represent a newer class of
suboptimal therapy places patients at risk for complications anticoagulants. 59 Newer antithrombotic agents include
and further management expenditures.53 rivaroxaban, apixaban, and dabigatran, which are ­selective
One real-world study estimated the cost effectiveness for specific coagulation factors such as factor Xa and throm-
of different warfarin treatment scenarios.53 A semi-Markov bin.60–62 Advantages shared by these newer ­anticoagulants
transition model (11 primary health states with four additional over existing antithrombotic agents consist of selective

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Table 3 Results of a cost-effectiveness model predicting clinical trial versus “real-world” warfarin usage for AF-related stroke
prevention53
Base casea: Base case: Modelc:
total medical costs/patient total # primary and total # primary
(2006 USD/2011 USDb) recurrent IS and recurrent IS
Scenario 1: perfect warfarin control $68,039/$76,416 626 503
Scenario 2: clinical trial-like warfarin control $77,764/$87,338 832 737
Scenario 3: real-world warfarin control $84,518/$94,924 984 909
Scenario 4: real-world warfarin, aspirin, or neither $87,248/$97,990 1171 1120
Notes: aBase case: N = 1000, age 70, moderate-to-high risk of stroke, followed for remaining lifetime; bcosts inflation-adjusted to 2011 USD using the Bureau of Labor
Statistics CPI inflation calculator; cperfect warfarin adherence.
Abbreviations: IS, ischemic stroke; USD, United States dollars.

targeting for a single coagulation factor, rapid onset of action, both comparisons). This decrease in the number of strokes
fewer drug interactions, and no required dosage adjustment with dabigatran may decrease the costs and economic burden
according to patient age, gender, body weight, or mild renal associated with stroke. The 2011 ACCF/AHA/HRS guide-
impairment.62 Clinical trials with these new ­anticoagulants lines recommend dabigatran as an alternative to warfarin
in patients with AF include ROCKET-AF (rivaroxaban vs for the prevention of stroke and systemic thromboembolism
­warfarin), ARISTOTLE (apixaban vs warfarin) and AVER- in patients who have paroxysmal to permanent AF and risk
ROES (apixaban vs aspirin in patients unsuitable for war- factors for stroke/systemic embolization and who do not have
farin). The ROCKET-AF trial showed that rivaroxaban was a prosthetic heart valve, hemodynamically significant valve
noninferior to warfarin with regard to stroke or systemic disease, severe renal failure, or advanced liver disease.70
embolism in patients with nonvalvular AF.63 Rivaroxaban is
approved by the FDA for the prevention of stroke in patients Cost effectiveness of treatment
with nonvalvular AF.64 In the ­AVERROES study, apixaban strategies for AF
reduced the risk of stroke or systemic embolism without The Fibrillation Registry Assessing Costs, Therapies,
significantly increasing major bleeding or intracranial hem- Adverse Events, and Lifestyle (FRACTAL) study showed
orrhage,65 while the ARISTOTLE study demonstrated that that patients with AF who are managed with cardioversion
apixaban was superior to warfarin in preventing stroke or and pharmacotherapy incur AF- and cardiovascular-
systemic embolism.66 An important limitation to the use of related health care costs of $4000 to $5000 per year (2002
these agents is the lack of readily available reversal agents USD; $5034–$6293 2011 USD).71 AF-related health care
or antidotes. costs averaged $4700 ($5915 2011 USD) per patient per
Dabigatran is a novel oral direct thrombin inhibitor that year during the first few years following diagnosis,71 but
is approved in the US (October 2010) to reduce the risk of subsequent annual costs varied greatly according to the
stroke and systemic embolism in patients with AF.67 In the AF clinical course, with hospital care contributing the
Randomized Evaluation of Long-Term Anticoagulation largest and most variable component of total cost. Among
Therapy (RE-LY) trial, two fixed doses of dabigatran patients with recurrent AF, the frequency of recurrence
(110 and 150 mg, administered in a blinded fashion) were was strongly associated with higher resource utilization,
compared with open-label use of warfarin in patients with with each recurrence increasing annual costs by an average
AF and an increased risk for stroke.68,69 After a follow-up of of $1600 (2002 USD; $2014 2011 USD).71 Several recent
2 years, the primary endpoint of stroke or systemic embolism studies comparing rate and rhythm control strategies have
occurred in 182 patients in the dabigatran 110  mg group found no meaningful differences in terms of mortality from
(1.53%/year), 134 patients in the dabigatran 150 mg group cardiovascular causes and stroke.8,21,72–75 Additionally, drivers
(1.11%/year), and 199 patients in the warfarin group (1.69%/ of cost in patients with AF are not fully elucidated.
year). Both dabigatran doses were found to be noninferior to A post-hoc cost-effectiveness analysis from the Atrial
warfarin (P , 0.001), and the dabigatran 150-mg dose was Fibrillation Follow-Up Investigation of Rhythm Management
found to be superior to warfarin (P , 0.001). Hemorrhagic (AFFIRM) study was published shortly after the FRACTAL
stroke rates were 0.38% per year in the warfarin group study and demonstrated that patients randomized to
versus 0.12% per year in the dabigatran 110 mg group and pharmacologic rate control had less resource utilization
0.10% per year in the dabigatran 150 mg group (P , 0.001, and lower costs than patients randomized to rhythm control

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Dovepress Clinical consequences and costs of AF

(cost savings range, $2189–$5481 per patient, 2002 USD; Double-Blind, Parallel Arm Trial to Assess the Efficacy of
$2755–$6898 2011 USD).76 Another post-hoc analysis of Dronedarone 400 mg bid for the Prevention of Cardiovascular
AFFIRM clinical treatment data suggested that the benefits Hospitalization or Death from any Cause in Patients with Atrial
of rhythm control may have been offset by the adverse Fibrillation/Atrial Flutter (ATHENA) trial,82 this agent has the
effects of antiarrhythmic therapy, specifically amiodarone, potential to reduce costs in patients with AF. One retrospective
which was used for rhythm control in the study.77 Whether study analyzed the incidence and direct costs of ATHENA-
these AFFIRM cost data would be affected if different type outcomes in 15,552 patients with AF who were covered
antiarrhythmic agents (with better adverse-effect profiles by Medicare supplemental insurance from 2004 to 2007.83
than amiodarone) were analyzed in the model is unknown; Mean hospitalization cost per patient was $11,085 (2006
however, as the adverse effects had considerable influence USD; $12,450 2011 USD). Mean costs per patient varied from
over the cost model, cost data can be expected to be $7476 (mean cost per hospitalization for AF/supraventricular
affected.77 rhythm disorder [primary diagnosis, nonfatal]) to $37,067
Newer anticoagulants and antiarrhythmic agents may (mean hospitalization cost per death, cardiovascular
present cost savings compared with older treatments. In an transcutaneous intervention procedure, or cardiovascular
analysis including patients aged $65 years with AF who surgical intervention) ($8396 to $41,631, respectively, 2011
were at increased risk of stroke, dabigatran was shown to USD).83 Novel antiarrhythmic therapies such as dronedarone,
be a cost-effective alternative to warfarin.78 The analysis with the potential to reduce cardiovascular hospitalizations
estimated a cost of $45,372 per QALY (2008 USD; $47,715 and mortality in similar patients, could decrease health
2011 USD) gained with high-dose dabigatran (150 mg twice care costs.
daily) compared with warfarin.78 Another study compared
the cost-effectiveness of dabigatran 150  mg twice daily
New antiarrhythmic agents
with warfarin, employing a Markov decision-analysis
model in a hypothetical cohort of 70-year-old patients with
for the treatment of AF
Data demonstrate limited efficacy and partially deleterious
AF and a cost-effectiveness threshold of $50,000/QALY.79
adverse-effect profiles for conventional antiarrhythmic agents
The analysis found dabigatran to be cost-effective in AF
for AF.84 Antiarrhythmic agents that have atrial-selective
populations at high risk of hemorrhage or stroke (CHADS2
actions and target multiple ion channels may be more
score $ 3) and warfarin to be cost-effective in moderate-risk
tolerable and free of proarrhythmic effects.85 New agents
AF populations (CHADS2 score 1 or 2). Dabigatran was
(ie, dronedarone and vernakalant) offer promise in optimizing
cost-effective for patients with a CHADS2 score of 2 only
the management of AF by potentially reducing AF burden
if they were at a high risk of major hemorrhage or had poor
and costs through more favorable tolerability profiles.
INR control with warfarin.79 In a separate cost-effectiveness
analysis employing a Markov decision-analysis model in a
hypothetical cohort of 70-year-old patients with AF and a Dronedarone
history of stroke or transient ischemic attack, dabigatran Dronedarone, a noniodinated benzofuran derivative, is
provided 0.36 additional QALYs versus warfarin at a cost a recently (2009) approved multichannel antiarrhythmic
of $9000 (2010 USD; $9314 2011 USD), yielding an agent. Dronedarone is indicated in the US to reduce the
incremental cost-effectiveness ratio of $25,000 ($25,873 risk of hospitalization for AF in patients in sinus rhythm
2011 USD). However, dabigatran was not cost-effective if with a history of paroxysmal or persistent AF.86 According
its relative risk of stroke compared with warfarin exceeded to the 2011 ACCF/AHA/HRS guidelines, dronedarone is
0.92.80 Lastly, in a cost-effectiveness analysis in the United recommended as first-line therapy in patients with AF who
Kingdom of simulated patients at moderate-to-high risk of have no or minimal heart disease, hypertension without left
stroke with a mean baseline CHADS2 score of 2, dabigatran ventricular hypertrophy, or coronary heart disease (class
150 mg twice daily was associated with positive incremental IIa recommendation).70 In the ATHENA trial, dronedarone
net benefits versus warfarin, but was unlikely to be cost- demonstrated a significant risk reduction (24%, P , 0.001)
effective in clinics able to achieve good INR control with in hospitalizations due to cardiovascular events or deaths
warfarin.81 from any cause compared with placebo in patients with
Given the 24% relative reduction in hospitalizations paroxysmal or persistent AF/AFL.82 In an analysis of stroke
demonstrated with dronedarone use in the A Placebo-Controlled, in the ATHENA trial, dronedarone reduced the risk of

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85
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stroke from 1.8% per year to 1.2% per year (P = 0.027).87 In This review showed that dronedarone increased the risk of
the Efficacy and Safety of Dronedarone for the Control of serious cardiovascular events, including death, when used by
Ventricular Rate During Atrial Fibrillation (ERATO) study, patients with permanent AF.96 The prescribing information
dronedarone was found to control ventricular rate in patients for dronedarone has been revised to include recommenda-
diagnosed with permanent AF already treated with standard tions from the FDA regarding the use of dronedarone to
therapies.88 manage the potential serious cardiovascular risks with the
Dronedarone was demonstrated to be effective in drug.86,96 These recommendations include: dronedarone
maintaining sinus rhythm in The European Trial in Atrial should not be used in patients with AF who cannot or will
­Fibrillation or Flutter Patients Receiving Dronedarone for not be converted into normal sinus rhythm (permanent AF);
the Maintenance of Sinus Rhythm (EURIDIS) study and heart rate should be monitored by electrocardiogram at least
the American–­Australian–African Trial with Dronedarone once every 3 months, and if the patient is in AF, dronedarone
in Atrial Fibrillation or Flutter Patients for the Maintenance should be stopped or, if clinically indicated, the patient should
of Sinus Rhythm (ADONIS) study.89 The most common be cardioverted; dronedarone is indicated to reduce hospital-
adverse events seen with dronedarone include gastrointestinal ization for AF in patients in sinus rhythm with a history of
problems including diarrhea, nausea, and abdominal pain.82,88– nonpermanent AF (known as paroxysmal or persistent AF);
91
­Dronedarone is contraindicated in patients with symp- and patients taking dronedarone should receive appropriate
tomatic heart failure with recent decompensation requiring antithrombotic therapy.86,96
hospitalization or New York Heart Association (NYHA) class
IV heart failure and in patients with AF who will not or can- Vernakalant
not be cardioverted into normal sinus rhythm.86 Intravenous vernakalant, a sodium and potassium ­channel
The PALLAS study, a trial assessing potential ­cardiovascular blocker with atrial-selective action, is approved in the
outcomes in patients with permanent AF, was ­prematurely European Union, Iceland, and Norway for the rapid
terminated due to increased adverse ­cardiovascular events in ­conversion of recent-onset AF to sinus rhythm in adult
the dronedarone arm.92 There were 25 deaths in the drone- ­nonsurgery patients with AF of #7  days duration and for
darone group (21 from cardiovascular causes) and 13 in the adult post-cardiac surgery patients with AF of #3  days
placebo group (10 from cardiovascular causes) (P = 0.046). duration.97 In the AVRO study, intravenous vernakalant
The coprimary outcome, a composite of stroke, myocardial was more effective than amiodarone for acute conversion of
infarction, systemic embolism, or death from cardiovascular ­recent-onset AF.98 For the oral formulation, early phase II
causes, occurred in 43 patients receiving dronedarone and ­studies demonstrated that oral vernakalant successfully main-
19 patients receiving placebo (P = 0.002). These data indicate tained sinus rhythm compared with placebo, and no proar-
that dronedarone should not be used in patients with permanent rhythmias relating to vernakalant have been reported to date.99
AF who are at risk for major vascular events.92 There were also no serious adverse events related to vernakal-
There have been several postmarketing reports of ant in phase II trials.100 Vernakalant was found to be an effec-
hepatocellular liver injury and hepatic failure in patients tive agent for conversion to normal sinus rhythm in patients
receiving dronedarone, including two reports of acute with recent-onset AF.99 In a review of six early-phase clinical
hepatic failure that required transplantation and new-onset or trials, vernakalant rapidly and effectively terminated recent-
worsening heart failure.93,94 Obtaining periodic hepatic serum onset AF and was found to be well tolerated and efficacious
enzymes, especially during the first 6 months of treatment at AF conversion in patients with postoperative AF.99 Further
with dronedarone, is recommended.86 Postmarketing cases studies are warranted to better define the role of vernakalant
of increased INR with or without bleeding events have in the management of AF in order to determine whether its
also been reported in patients on warfarin initiated on benefits translate into a decreased cost burden.
dronedarone.86,95 Postmarketing cases of interstitial lung
disease including pneumonitis and pulmonary fibrosis have Catheter ablation
also been reported.86 Exposure to dabigatran is also higher For AF patients whose symptoms are not well controlled
when it is administered with dronedarone than when it is with pharmacologic therapy, catheter ablation is an
administered alone.86 increasingly used treatment option. According to the
The US FDA recently completed a safety review of drone- 2011ACCF/AHA/HRS guideline update, catheter ablation
darone based on data from the PALLAS and ATHENA trials. may be useful to maintain sinus rhythm in selected patients

86 submit your manuscript | www.dovepress.com Clinico Economics and Outcomes Research 2012:4
Dovepress
Dovepress Clinical consequences and costs of AF

with signif icantly symptomatic, paroxysmal AF who Acknowledgments/Disclosure

have failed treatment with an antiarrhythmic agent and Editorial support for this article was provided by Vrinda
have normal or mildly dilated left atria, normal or mildly Mahajan, PharmD, of Peloton Advantage, LLC. Editorial
reduced left ventricular function, and no severe pulmonary ­support for this article was funded by sanofi-aventis US. The
disease (class I recommendation upgraded from class IIa, opinions expressed in the current article are those of the author.
but remaining a class IIa recommendation in both Europe The author received no honoraria or other form of financial
and Canada); to treat symptomatic persistent AF (class IIa support related to the development of this manuscript.
recommendation); and to treat symptomatic paroxysmal
AF in patients with significant left atrial dilatation or
References
with significant left ventricular dysfunction (class IIb 1. Bajpai A, Savelieva I, Camm AJ. Epidemiology and economic burden
recommendation). 70 Recent studies have reported that of atrial fibrillation. Touch Briefings. 2007:14–17.
2. Dorian P, Mangat I, Pinter A, Korley V. The burden of atrial fibrillation:
catheter ablation successfully treats paroxysmal AF in .80% should we abandon antiarrhythmic drug therapy? J Cardiovasc
of cases and persistent AF in .70% of cases.101 However, ­Pharmacol Ther. 2004;9(4):257–262.
3. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence
catheter ablation is associated with major complications
of atrial fibrillation and flutter in the United States. Am J Cardiol. 2009;
(reported in about 6% of procedures) such as pulmonary 104(11):1534–1539.
vein stenosis, thromboembolism, atrioesophageal fistula, 4. Wattigney WA, Mensah GA, Croft JB. Increasing trends in hospitalization
for atrial fibrillation in the United States, 1985 through 1999: implications
and left atrial flutter.19,102 for primary prevention. Circulation. 2003;108(6):711–716.
The cost-effectiveness of catheter ablation is difficult to 5. Bialy D. Hospitalization for arrhythmias in the United States:
Importance of atrial fibrillation [abstract 716–714]. J Am Coll Cardiol.
determine due to a number of factors, including differences in
1992;19(3):41A.
the experience levels of centers, use of technology, and rates 6. Wyse DG, Gersh BJ. Atrial fibrillation: a perspective: thinking inside
of reimbursement, which affect cost calculations.101 Studies and outside the box. Circulation. 2004;109(25):3089–3095.
7. Chatap G, Giraud K, Vincent JP. Atrial fibrillation in the elderly: facts
evaluating the cost-effectiveness of AF ablation compared and management. Drugs Aging. 2002;19(11):819–846.
with rhythm control or antiarrhythmic agents have shown 8. Hagens VE, Ranchor AV, Van Sonderen E, et  al. Effect of rate or
rhythm control on quality of life in persistent atrial fibrillation. Results
that ablation treatment results in improved quality-adjusted
from the Rate Control Versus Electrical Cardioversion (RACE) Study.
life expectancy, but at a higher cost.103–105 J Am Coll Cardiol. 2004;43(2):241–247.
9. Dorian P, Jung W, Newman D, et al. The impairment of health-related

Conclusion quality of life in patients with intermittent atrial fibrillation: implications

for the assessment of investigational therapy. J Am Coll Cardiol. 2000;
Recent data present a compelling picture of the burden of 36(4):1303–1309.
10. Paquette M, Roy D, Talajic M, et al. Role of gender and personality
AF on the US health care system and society. As the US
on quality-of-life impairment in intermittent atrial fibrillation. Am J
population ages and the prevalence of AF increases, it is Cardiol. 2000;86(7):764–768.
clear that AF management strategies need to be optimal. 11. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic
features of chronic atrial fibrillation: the Framingham study. N Engl J
Suboptimal management of AF places patients at risk for Med. 1982;306(17):1018–1022.
AF-associated stroke, the most costly AF-associated event. 12. Wattigney WA, Mensah GA, Croft JB. Increased atrial fibrillation
mortality: United States, 1980–1998. Am J Epidemiol. 2002;155(9):
Numerous studies demonstrate the efficacy of anticoagulation
819–826.
in reducing the risk of AF-related embolic events and 13. Atrial fibrillation as a contributing cause of death and Medicare
preventing hospitalizations, but efficacy is compromised by hospitalization – United States, 1999. MMWR Morb Mortal Wkly Rep.
2003;52(7):128, 130–128, 131.
inadequate and suboptimal treatment patterns. Therapeutic 14. Singh SN, Tang XC, Singh BN, et  al. Quality of life and exercise
strategies such as rate control, rhythm control, and ­performance in patients in sinus rhythm versus persistent atrial
fibrillation: a Veterans Affairs Cooperative Studies Program Substudy.
anticoagulation provide cost-effective means to optimally
J Am Coll Cardiol. 2006;48(4):721–730.
manage the patient with AF, as do treatment options such as 15. Coyne KS, Paramore C, Grandy S, Mercader M, Reynolds M,
new antiarrhythmic agents or catheter ablation. Given that Zimetbaum P. Assessing the direct costs of treating nonvalvular atrial
fibrillation in the United States. Value Health. 2006;9(5):348–356.
nearly 75% of the total costs associated with AF are attributed 16. Wu EQ, Birnbaum HG, Mareva M, et  al. Economic burden and
to direct and indirect hospitalization costs,15 clinical strategies ­co-morbidities of atrial fibrillation in a privately insured population.
Curr Med Res Opin. 2005;21(10):1693–1699.
that can reduce AF-related hospitalizations may optimize
17. Lee WC, Lamas GA, Balu S, Spalding J, Wang Q, Pashos CL. Direct
care by improving clinical outcomes and reducing costs. treatment cost of atrial fibrillation in the elderly American population:
Further research is necessary to compare new antiarrhythmic a Medicare perspective. J Med Econ. 2008;11(2):281–298.
18. Anis RR. Role of angiotensin-converting enzyme inhibitors and
agents with existing therapies to assess clinical and economic angiotensin receptor blockers in the management of atrial fibrillation.
differences in real-world settings. Exp Clin Cardiol. 2009;14(1):e1–e7.

Clinico Economics and Outcomes Research 2012:4 submit your manuscript | www.dovepress.com
87
Dovepress
Singh Dovepress

19. Fuster V, Ryden LE, Cannom DS, et al. 2011ACCF/AHA/HRS Focused 39. Ryder KM, Benjamin EJ. Epidemiology and significance of atrial
Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for fibrillation. Am J Cardiol. 1999;84(9A):131R–138R.
the Management of Patients With Atrial Fibrillation A Report of 40. Miller PS, Andersson FL, Kalra L. Are cost benefits of anticoagulation
the American College of Cardiology Foundation/American Heart for stroke prevention in atrial fibrillation underestimated? Stroke. 2005;
­Association Task Force on Practice Guidelines Developed in partnership 36(2):360–366.
with the European Society of Cardiology and in collaboration with the 41. Dulli DA, Stanko H, Levine RL. Atrial fibrillation is associated
European Heart Rhythm Association and the Heart Rhythm Society. with severe acute ischemic stroke. Neuroepidemiology. 2003;22(2):
J Am Coll Cardiol. 2011;57(11):e101–e198. 118–123.
20. Teng MP, Catherwood LE, Melby DP. Cost effectiveness of therapies 42. Boccuzzi SJ, Martin J, Stephenson J, et al. Retrospective study of total
for atrial fibrillation. A review. Pharmacoeconomics. 2000;18(4): healthcare costs associated with chronic nonvalvular atrial fibrillation
317–333. and the occurrence of a first transient ischemic attack, stroke or major
21. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control bleed. Curr Med Res Opin. 2009;25(12):2853–2864.
and rhythm control in patients with atrial fibrillation. N Engl J Med. 43. Caro JJ. An economic model of stroke in atrial fibrillation: the
2002;347(23):1825–1833. cost of suboptimal oral anticoagulation. Am J Manag Care.
22. Bushnell CD, Matchar DB. Pharmacoeconomics of atrial fibrillation and 2004;10(Suppl 14):S451–S458.
stroke prevention. Am J Manag Care. 2004;10(Suppl 3):S66–S71. 44. Ezekowitz MD, Falk RH. The increasing need for anticoagulant therapy
23. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, to prevent stroke in patients with atrial fibrillation. Mayo Clin Proc.
Radford MJ. Validation of clinical classification schemes for predicting 2004;79(7):904–913.
stroke: results from the National Registry of Atrial Fibrillation. JAMA. 45. Wittkowsky AK. Effective anticoagulation therapy: defining the gap
2001;285(22):2864–2870. between clinical studies and clinical practice. Am J Manag Care. 2004;
24. Ishak KJ, Proskorovsky I, Guo S, Lin J. Persistence with antiarrhythmics 10(Suppl 10):S297–S306.
and the impact on atrial fibrillation-related outcomes. Am J Pharm 46. Thosani AJ, Xiong Y, Lin J, Kothawala P, Zimetbaum PJ. Are atrial
Benefits. 2009;1(4):193–200. fibrillation patients receiving anticoagulation in accordance with their
25. Naccarelli GV, Dell’Orfano JT, Wolbrette DL, Patel HM, Luck JC. stroke risk? [abstract PO06-60]. Presented at: Heart Rhythm 2009;
­Cost-effective management of acute atrial fibrillation: role of rate ­control, May 13–16, 2009; Boston, MA.
spontaneous conversion, medical and direct current cardioversion, 47. Damaske DL, Baird RW. Development and implementation of a
transesophageal echocardiography, and antiembolic therapy. Am J pharmacist-managed inpatient warfarin protocol. Proc (Bayl Univ Med
Cardiol. 2000;85(10A):36D–45D. Cent). 2005;18(4):397–400.
26. Kim MH, Johnston SS, Chu BC, Dalal MR, Schulman KL. Estimation of 48. NYSED.gov. Practice Aler ts and Guidelines: Coumadin
total incremental health care costs in patients with atrial fibrillation in the (Warfarin) Managed Dosing by Nurses. June 25, 2009. New York
United States. Circ Cardiovasc Qual Outcomes. 2011;4(3):313–320. State Education Department Office of the Professions. Available
27. Kim MH, Lin J, Hussein M, Battleman D. Incidence and temporal from: http://www.op.nysed.gov/prof/nurse/nurse-coumadin.htm.
­pattern of hospital readmissions for patients with atrial fibrillation. Accessed December 12, 2011.
Curr Med Res Opin. 2009;25(5):1215–1220. 49. Chiquette E, Amato MG, Bussey HI. Comparison of an anticoagulation
28. Kim MH, Lin J, Hussein M, Kreilick C, Battleman D. Cost of atrial clinic with usual medical care: anticoagulation control, patient outcomes,
fibrillation in United States managed care organizations. Adv Ther. and health care costs. Arch Intern Med. 1998;158(15):1641–1647.
2009;26(9):1–11. 50. Scott PA, Pancioli AM, Davis LA, Frederiksen SM, Eckman J.
29. Patel PP, Johnston SJ, Lin J, Schulman KL, Naccarelli GV. Cost burden Prevalence of atrial fibrillation and antithrombotic prophylaxis in
of hospitalization and mortality in United States atrial fibrillation/flutter emergency department patients. Stroke. 2002;33(11):2664–2669.
patients [abstract PO03-53]. Presented at: Heart Rhythm 2009; May 51. McCormick D, Gurwitz JH, Goldberg RJ, et al. Prevalence and quality
13–16, 2009; Boston, MA. of warfarin use for patients with atrial fibrillation in the long-term care
30. Kim MH, Klingman D, Lin J, Battleman DS. Patterns and predictors setting. Arch Intern Med. 2001;161(20):2458–2463.
of discontinuation of rhythm-control drug therapy in patients with 52. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation
newly diagnosed atrial fibrillation. Pharmacotherapy. 2009;29(12): management among patients with atrial fibrillation: results of a review
1417–1426. of medical records from 2 communities. Arch Intern Med. 2000;160(7):
31. Kim MH, Klingman D, Lin J, Pathak P, Battleman DS. Cost of hospital 967–973.
admission for antiarrhythmic drug initiation in atrial fibrillation. Ann 53. Sorensen SV, Dewilde S, Singer DE, Goldhaber SZ, Monz BU,
Pharmacother. 2009;43(5):840–848. Plumb JM. Cost-effectiveness of warfarin: trial versus “real-world” stroke
32. Berlex Laboratories. Betapace [package insert]. Wayne, NJ: Berlex prevention in atrial fibrillation. Am Heart J. 2009;157(6):1064–1073.
Laboratories, Inc; 2010. 54. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ.
33. Pfizer. Tikosyn [package insert]. New York, NY: Pfizer Labs; 2006. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP
34. Kim MH, Lin J, Hussein M, Battleman D. Incidence and economic Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;
burden of suspected adverse events and adverse event monitoring ­during 126(Suppl 3):429S–456S.
AF therapy. Curr Med Res Opin. 2009;25(12):3037–3047. 55. Albers GW, Diener HC, Frison L, et  al. Ximelagatran vs warfarin
35. World Health Organization. Shaping the Future. The World Health for stroke prevention in patients with nonvalvular atrial fibrillation:
Report 2003. Geneva, Switzerland: World Health Organization; 2003: a randomized trial. JAMA. 2005;293(6):690–698.
1–204. 56. Boulanger L, Kim J, Friedman M, Hauch O, Foster T, Menzin J. ­Patterns
36. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent of use of antithrombotic therapy and quality of anticoagulation among
risk factor for stroke: the Framingham Study. Stroke. 1991;22(8): patients with non-valvular atrial fibrillation in clinical practice. Int J
983–988. Clin Pract. 2006;60(3):258–264.
37. The Atrial Fibrillation Investigators. Risk factors for stroke and efficacy 57. Sullivan PW, Arant TW, Ellis SL, Ulrich H. The cost effectiveness of
of antithrombotic therapy in atrial fibrillation. Analysis of pooled data anticoagulation management services for patients with atrial fibrillation
from five randomized controlled trials. Arch Intern Med. 1994;154(13): and at high risk of stroke in the US. Pharmacoeconomics. 2006;24(10):
1449–1457. 1021–1033.
38. Szucs TD, Bramkamp M. Pharmacoeconomics of anticoagulation 58. Ghate SR, Biskupiak J, Ye X, Kwong WJ, Brixner DI. All-cause and
therapy for stroke prevention in atrial fibrillation: a review. J Thromb bleeding-related health care costs in warfarin-treated patients with atrial
Haemost. 2006;4(6):1180–1185. fibrillation. J Manag Care Pharm. 2011;17(9):672–684.

88 submit your manuscript | www.dovepress.com Clinico Economics and Outcomes Research 2012:4
Dovepress
Dovepress Clinical consequences and costs of AF

59. Baetz BE, Spinler SA. Dabigatran etexilate: an oral direct thrombin 80. Kamel H, Johnston SC, Easton JD, Kim AS. Cost-effectiveness of
inhibitor for prophylaxis and treatment of thromboembolic diseases. dabigatran compared with warfarin for stroke prevention in patients
Pharmacotherapy. 2008;28(11):1354–1373. with atrial fibrillation and prior stroke or transient ischemic attack.
60. Franchini M, Mannucci PM. A new era for anticoagulants. Eur J Intern Stroke. 2012;43(3):881–883.
Med. 2009;20(6):562–568. 81. Pink J, Lane S, Pirmohamed M, Hughes DA. Dabigatran etexilate
61. De Caterina R, Kristensen SD, Renda G. New anticoagulants for atrial versus warfarin in management of non-valvular atrial fibrillation in UK
fibrillation. J Cardiovasc Med (Hagerstown). 2009;10(6):446–453. context: quantitative benefit-harm and economic analyses. BMJ. 2011;
62. Samama MM, Gerotziafas GT. Newer anticoagulants in 2009. J Thromb 343:d6333.
Thrombolysis. 2010;29(1):92–104. 82. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on
63. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):
nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891. 668–678.
64. US Food and Drug Administration. FDA approves Xarelto to ­prevent 83. Naccarelli GV, Johnston SS, Lin J, Patel PP, Schulman KL. Cost
stroke in people with common type of abnormal heart rhythm [press ­burden of cardiovascular hospitalization and mortality in ATHENA-like
release]. November 4, 2011. Available from: http://www.fda.gov/News patients with atrial fibrillation/atrial flutter in the United States. Clin
Events/Newsroom/PressAnnouncements/ucm278646.htm. Accessed Cardiol. 2010;33(5):270–279.
­November 7, 2011. 84. Ehrlich JR, Nattel S. Atrial-selective pharmacological therapy for atrial
65. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with fibrillation: hype or hope? Curr Opin Cardiol. 2009;24(1):50–55.
atrial fibrillation. N Engl J Med. 2011;364(9):806–817. 85. Bajpai A, Savelieva I, Camm AJ. Treatment of atrial fibrillation. Br
66. Granger CB, Alexander JH, McMurray JJ, et  al. Apixaban versus Med Bull. 2008;88(1):75–94.
­warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11): 86. sanofi-aventis. Multaq [package insert]. Bridgewater, NJ: sanofi-aventis
981–992. US LLC; 2012.
67. US Food and Drug Administration. FDA approves Pradaxa to prevent 87. Connolly SJ, Crijns HJ, Torp-Pedersen C, et al. Analysis of stroke in
stroke in people with atrial fibrillation. October 19, 2010. Available from: ATHENA: a placebo-controlled, double-blind, parallel-arm trial to
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ assess the efficacy of dronedarone 400 mg BID for the prevention of
ucm230241.htm. Accessed July 13, 2011. cardiovascular hospitalization or death from any cause in patients with
68. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of atrial fibrillation/atrial flutter. Circulation. 2009;120:1174–1180.
RE-LY: randomized evaluation of long-term anticoagulant therapy, 88. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of
­warfarin, compared with dabigatran. Am Heart J. 2009;157(5): ventricular rate in permanent atrial fibrillation: the Efficacy and safety of
805–810. dRonedArone for The cOntrol of ventricular rate during atrial fibrillation
69. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus ­warfarin (ERATO) study. Am Heart J. 2008;156(3):527–529.
in patients with atrial fibrillation. N Engl J Med. 2009;361(12): 89. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of
1139–1151. sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):
70. Wann LS, Curtis AB, January CT, et  al. 2011 ACCF/AHA/HRS 987–999.
focused update on the management of patients with atrial fibrillation 90. Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH.
(updating the 2006  guideline): a report of the American College of Dronedarone for prevention of atrial fibrillation: a dose-ranging study.
Cardiology Foundation/American Heart Association Task Force on Eur Heart J. 2003;24(16):1481–1487.
practice guidelines. Circulation. 2011;123:104–123. 91. Kober L, Torp-Pedersen C, McMurray JJ, et  al. Increased mortality
71. Reynolds MR, Essebag V, Zimetbaum P, Cohen DJ. Healthcare after dronedarone therapy for severe heart failure. N Engl J Med. 2008;
resource utilization and costs associated with recurrent episodes of 358(25):2678–2687.
atrial ­fibrillation: the FRACTAL registry. J Cardiovasc Electrophysiol. 92. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk
2007;18(6):628–633. permanent atrial fibrillation. N Engl J Med. 2011;365(24):2268–2276.
72. Gronefeld GC, Lilienthal J, Kuck KH, Hohnloser SH. Impact of rate 93. US Food and Drug Administration. FDA Drug Safety Communication:
versus rhythm control on quality of life in patients with persistent atrial Severe liver injury associated with the use of dronedarone (marketed as
fibrillation. Results from a prospective randomized study. Eur Heart J. Multaq). January 14, 2011. Available from: http://www.fda.gov/Drugs/
2003;24(15):1430–1436. DrugSafety/ucm240011.htm. Accessed July 13, 2011.
73. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control 94. US Food and Drug Administration. Potential signals of serious risks/new
versus rhythm-control in persistent atrial fibrillation: the Strategies of safety information identified by the adverse event reporting system (AERS)
Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol. 2003; between July–September 2010. January 11, 2011. Available from: http://www.
41(10):1690–1696. fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/
74. van Gelder I, Hagens VE, Bosker HA, et  al. A comparison of rate AdverseDrugEffects/ucm237585.htm. Accessed March 21, 2011.
control and rhythm control in patients with recurrent persistent atrial 95. QuarterWatch. QuarterWatch: 2010 Quarter 1. Monitoring MedWatch
fibrillation. N Engl J Med. 2002;347(23):1834–1840. Reports. Signals for acetaminophen, dronedarone and botulinum toxin
75. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control products [executive summary]. November 4, 2010. Available from:
for atrial fibrillation and heart failure. N Engl J Med. 2008;358(25): http://freepdfhosting.com/078147c86d.pdf. Accessed March 21, 2011.
2667–2677. 96. US Food and Drug Administration. FDA Drug Safety Communication:
76. Marshall DA, Levy AR, Vidaillet H, et al. Cost-effectiveness of rhythm review update of multaq (dronedarone) and increased risk of death
versus rate control in atrial fibrillation. Ann Intern Med. 2004;141(9): and serious cardiovascular adverse events. December 21, 2011.
653–661. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm283933.
77. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus htm. Accessed January 3, 2012.
rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up 97. Merck. Merck to Acquire Rights to Vernakalant i.v. in Canada, Mexico
Investigation of Rhythm Management (AFFIRM) Study. Circulation. and the United States from Astellas. Jul 26, 2011. Available from:
2004;109(12):1509–1513. http://www.merck.com/newsroom/news-release-archive/research-and-
78. Freeman JV, Zhu RP, Owens DK, et al. Cost-effectiveness of dabigatran development/2011_0726.html. Accessed November 1, 2011.
compared with warfarin for stroke prevention in atrial fibrillation. Ann 98. Camm AJ, Capucci A, Hohnloser SH, et  al. A randomized active-
Intern Med. 2011;154(1):1–11. controlled study comparing the efficacy and safety of vernakalant to
79. Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke ­prophylaxis amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol. 2011;
in atrial fibrillation. Circulation. 2011;123(22):2562–2570. 57(3):313–321.

Clinico Economics and Outcomes Research 2012:4 submit your manuscript | www.dovepress.com
89
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Singh Dovepress

99. Cheng JW. Vernakalant in the management of atrial fibrillation. Ann 103. Chan PS, Vijan S, Morady F, Oral H. Cost-effectiveness of radio
Pharmacother. 2008;42(4):533–542. frequency catheter ablation for atrial fibrillation. J Am Coll Cardiol.
100. Ehrlich JR, Nattel S. Novel approaches for pharmacological 2006;47(12):2513–2520.
management of atrial fibrillation. Drugs. 2009;69(7):757–774. 104. Reynolds MR, Zimetbaum P, Josephson ME, Ellis E, Danilov T,
101. Nault I, Miyazaki S, Forclaz A, et al. Drugs vs ablation for the ­treatment Cohen DJ. Cost-effectiveness of radiofrequency catheter ablation
of atrial fibrillation: the evidence supporting catheter ablation. Eur compared with antiarrhythmic drug therapy for paroxysmal atrial
Heart J. 2010;31(9):1046–1054. fibrillation. Circ Arrhythm Electrophysiol. 2009;2(4):362–369.
102. Cappato R, Calkins H, Chen SA, et  al. Worldwide survey on the 105. Rodgers M, McKenna C, Palmer S, et al. Curative catheter ablation
methods, efficacy, and safety of catheter ablation for human atrial in atrial fibrillation and typical atrial flutter: systematic review and
fibrillation. Circulation. 2005;111(9):1100–1105. ­economic evaluation. Health Technol Assess. 2008;12(34):iii–xiii, 1.

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