Abstract

The costs of atrial fibrillation (AF) are linked to the general cost of managing AF patients in different health-care systems, as well as the cost of managing AF-related complications (e.g. hospitalizations and long-term complications, such as stroke). In addition, indirect medical costs, such as care for patients who do not recuperate fully from a vascular event, and non-medical costs such as loss of work force add to the costs of AF. All estimations for cost of AF and cost of AF therapy are based on assumptions and markedly influenced by these cost determinants. This urges for extreme caution not to take cost estimates at their absolute values. In fact, even relative comparisons between interventions may have different consequences in terms of direct and indirect costs in different health-care settings. While newer therapeutic options appear to increase the cost of AF management, newer antithrombotic substances and adequate rhythm control therapy also carry the promise of preventing the two major drivers of AF-related cost, hospitalizations and AF-related complications. Formal assessment of the cost of AF requires adjustment to local practice, and more data are clearly needed especially from primary care to better estimate the ‘real’ cost impact of AF.

Introduction

The increasing prevalence of atrial fibrillation (AF) is age related, with few (∼1%) affected younger than 60 years and a higher prevalence of up to 12% of those aged 75–84 years.1 Patients with AF commonly have underlying cardiovascular or metabolic disorders, such as heart failure, stroke, valvular disease, hypertension, obstructive sleep apnoea, and diabetes mellitus.2–6 Partly related to the increasing mean age of the general population as well as to the improved management and increased survival associated with concomitant diseases such as stroke, heart failure, and myocardial infarction, the prevalence of AF is likely to increase in forthcoming years.2–6

Consequences of atrial fibrillation

Death

Even after adjusting for co-morbid conditions, AF is associated with a two-fold increase in death rates compared to those without the condition.7–9 So far, the medical means to prevent AF-related deaths are not sufficiently effective: indeed, no single therapeutic intervention has reduced death rates in AF patients. Even oral anticoagulation, which is highly effective for stroke prevention in AF, only reduces death in a pooled meta analysis,10 and in the largest published trial (RE-LY), dabigatran reduced cardiovascular death as a secondary outcome parameter.11 Other therapies, such as dronedarone, reduced a composite endpoint of cardiovascular hospitalizations and death in the ATHENA study, which was largely driven by a significant reduction in hospitalizations, although there was a positive effect on cardiovascular death in a non-hierarchical secondary analysis.12 Nonetheless, there is a remarkable residual death rate in AF trials (3–4% per year depending on the patient risk profile).

Stroke

Even within large controlled trials, rates of major cardiovascular events remain high. In the general population, approximately every fourth stroke is attributable to AF.13–15 Indeed, strokes related to AF are associated with a poorer outcome than those that are not related to AF15–18 and stroke patients with AF have higher levels of morbidity and create higher in-patient costs than other non-AF stroke patients.18–20 Furthermore, AF-related strokes more often result in permanent disability with severe consequences for patients and their families, and lower rates of patient discharge to their own homes.

Heart failure and acute coronary syndromes

Independently of strokes, AF is commonly associated with heart failure, acute coronary syndromes, and—the most common interruption of normal life in AF patients—with frequent hospitalizations (25% per year in recent controlled trials).12,21 In one cohort of almost 1000 patients, the annual medical cost of AF management was high, and that analysis found clear cost increments in patients with persistent or permanent AF compared with paroxysmal AF, as well as in patients with frequent AF recurrences, and the cost increase was largely attributable to hospitalizations.22 Thus, it is not surprising that AF is an increasing public health burden,23–26 given the progressive nature of the arrhythmia in almost all patients27,28 and the age-dependent increase in AF prevalence (see above).

Medical costs in atrial fibrillation

In addition to the general cost for managing AF patients in different health-care systems,29–31 the management of AF-related complications contributes markedly to the medical costs of AF, e.g. through costs for hospitalizations and long-term complications, such as stroke.32 In addition, indirect medical costs, such as care for patients who do not recuperate fully from a vascular event, and non-medical costs such as loss of work force add to the cost of AF (Table 1). All estimations for cost of AF and cost of AF therapy are based on assumptions and markedly influenced by these cost determinants.33 This urges for extreme caution not to take cost estimates at their absolute values. In fact, even relative comparisons between interventions may have different consequences in terms of direct and indirect costs in different health-care settings (Table 1).

Table 1

Direct (medical and non-medical) and indirect costs of atrial fibrillation and of complications

Direct medical costs of AF 
 Hospitalization (inpatient care) 
  Electrical cardioversion 
  AF ablation 
  Atrioventricular node-ablation including pacemaker therapy 
  Maze surgery 
  Other surgery for AF 
 Hospital-based ambulatory and outpatient care 
  Visit to a specialist 
  Electrical cardioversion 
  Pacemaker interrogation and monitoring 
  Visit to a general practitioner 
 AF as secondary diagnosis 
  Pharmaceuticals 
  Anticoagulation monitoring 
Direct costs of complications (stroke, heart failure, and acute coronary syndromes) 
Indirect costs of AF 
 Production loss 
Indirect costs of complications (stroke, heart failure, and acute coronary syndromes) 
 Production loss 
Direct medical costs of AF 
 Hospitalization (inpatient care) 
  Electrical cardioversion 
  AF ablation 
  Atrioventricular node-ablation including pacemaker therapy 
  Maze surgery 
  Other surgery for AF 
 Hospital-based ambulatory and outpatient care 
  Visit to a specialist 
  Electrical cardioversion 
  Pacemaker interrogation and monitoring 
  Visit to a general practitioner 
 AF as secondary diagnosis 
  Pharmaceuticals 
  Anticoagulation monitoring 
Direct costs of complications (stroke, heart failure, and acute coronary syndromes) 
Indirect costs of AF 
 Production loss 
Indirect costs of complications (stroke, heart failure, and acute coronary syndromes) 
 Production loss 

Hospital admissions were reported to cause between 40 and 60% of the direct medical cost in AF patients in different European countries.29,30,33–37 In a medium-sized prospective French survey (671 patients), hospitalizations were more frequent in patients with persistent AF than in those with paroxysmal AF (127 vs. 83, P< 0.05).34 The first cost driver was hospitalizations (52%), followed by drugs (23%), consultations (9%), further investigations (8%), loss of work (6%), and paramedical procedures (2%). According to the multivariate analysis, heart failure (P< 0.04), coronary artery disease (P< 0.001), use of potassium channel blockers (P< 0.002), hypertension (P< 0.002), and metabolic disease (P< 0.001) were significantly associated with higher costs.34 In the EuroHeartSurvey on AF, more than half of the estimated direct medical cost were due to hospitalizations and interventions for AF.29,35

Cost and cost effectiveness of atrial fibrillation management

The main goals with treatment in AF patients are to prevent thromboembolic complications and to alleviate symptoms.38 Treatment of AF thus includes anti-thrombotic therapy, management of concomitant, disease-modifying conditions, and various strategies for symptom relief including rate control, electrical cardioversion, antiarrhythmic drugs for conversion or rhythm control, and left atrial ablation. Consequently, there is increasing attention on the demand of resources for patients with AF and its related diseases. However, there is limited information on cost effectiveness for managing patients with AF in their different clinical settings and on a long-term basis.

Therapy of concomitant conditions

A number of economic analyses have focused on AF-related costs, the majority of which have evaluated the costs of specific interventions or pharmacologic treatments.39–41 Treatment of hypertension, a common co-morbid condition in AF patients, has been shown to be cost effective in virtually all patient populations (and circumstances) studied and for a wide variety of drugs, more so with coexisting risk factors.39 In the same study, the cost effectiveness of anticoagulants was favourable for prosthetic valves, although sensitive to imprecision in monitoring, and it was also favourable for mitral stenosis in the presence of AF but not normal sinus rhythm.39

Anticoagulation

In a more recent analysis, anticoagulation is cost effective in patients at high risk of stroke, but not for those with a low risk of stroke.42 Furthermore, the additional benefit of newer anticoagulants such as dabigatran may be cost effective according to modelling estimations.43 With the evidence available for stroke risk factors and the various stroke risk stratification models, a review of these models regarding their validity and their performance in representative AF populations would be highly desirable:42 The recent guidelines of the European Society of Cardiology have slightly broadened the range of patients in whom oral anticoagulation is recommended, resulting in a recommendation for oral anticoagulation in patients at moderate risk for stroke.38 Although this recommendation is based on a net benefit between bleeding and ischaemic events in such patients, and supported by the more recent anticoagulation trials in AF patients, formal cost analyses of these recommendations may be of economic interest.

Rate and rhythm control therapy

Cost-effectiveness analyses of ‘pure’ rate control therapy without a rhythm control comparator are scarce. In combination with antithrombotic therapy, cardioversion followed by the use of amiodarone may be cost effective, at least in patients at moderate or high risk for stroke and according to older analyses.40,41 So far, however, most cost analyses suggest that adding rhythm control (albeit using partially ineffective antiarrhythmic drugs and cardioversions) adds cost to the medical management of AF patients rather than avoiding complication-related cost.27,44,45 There is a clear need to better delineate which patients may benefit from rhythm control therapy, and when and to what extent such therapy should be pursued.

Limitations of current atrial fibrillation management

The observations discussed so far were made in relatively small patient samples, and extrapolated to the general AF population. Importantly, the majority of patients were enrolled through cardiologists and hospital physicians, while many AF patients are managed in primary care as outpatients,38 with potential implications for the type and quality of management as well as for medical cost. A large recent analysis of health-care provider data, however, confirms that the cost of managing AF-related complications and cost of hospitalizations are the main drivers of direct medical cost in AF patients.46 In this survey of over 100 000 patients with AF, major cost drivers were the direct cost of complications (54%) and hospitalization due to AF, including AF as secondary diagnosis (18%), followed by loss of productivity (12%).46 Notably, cost of primary care management was not well assessed in this survey, reinforcing the need for data on AF management in primary care. Another indirect confirmation of hospitalizations as a major driver for AF-related medical cost stems from an analysis that demonstrated reduced AF-related cost when management guidelines with a focus on avoiding unnecessary hospitalizations were implemented.47

Even though effective treatments are available for the prevention of thromboembolic complications and for rhythm and rate control in AF patients,38 there is not only marked residual stroke and death, but the interventions also have a limited impact on hospitalization rates that may even increase on progression of AF.25,48,49 These observations have important implications because estimates of the health-care costs of AF have identified direct costs and hospitalizations as the major cost drivers.22,29,30,33–37

Quo vadis?

In principle, prevention of AF appears an attractive road to preventing the cost of AF-related complications and AF-related hospitalizations. It is conceivable that limiting the duration of antiarrhthmic drug therapy,50–52 the use of newer, potentially safer antiarrhythmic drugs,53 or a wider-spread use of catheter ablation of AF54,55 including an earlier rhythm control intervention56,57 could help to improve the cost effectiveness of rhythm control therapy in AF patients. This assumption requires formal assessment including a formal demonstration that rhythm control therapy conveys additional benefits for AF patients in addition to improving symptoms.38

Conclusion

The costs of AF are high and are likely to be driven by the consequences of AF-related complications such as strokes, cost of hospitalizations in AF patients, and loss of productivity. While newer therapeutic options appear to increase the cost of AF management, newer antithrombotic substances and adequate rhythm control therapy also carry the promise of preventing the two major drivers of AF-related cost, hospitalizations and AF-related complications. Formal assessment of the cost of AF requires adjustment to local practice, and more data are clearly needed, especially from primary care, to better estimate the ‘real’ cost impact of AF.

Conflict of interest: A full list of financial disclosures for G.Y.H.L. and P.K. is available on the web site of the European Society of Cardiology (ESC).

References

1
Wolf
PA
Benhamin
EJ
Belanger
AJ
Kannel
WB
Levy
D
D'Agostino
RB
Secular trends in the prevalence of atrial fibrillation: The Framingham study
Am Heart J
 , 
1996
, vol. 
131
 (pg. 
790
-
5
)
2
Go
AS
Hylek
EM
Phillips
KA
Chang
Y
Henault
LE
Selby
JV
, et al.  . 
Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study
JAMA
 , 
2001
, vol. 
285
 (pg. 
2370
-
5
)
3
Naccarelli
GV
Varker
H
Lin
J
Schulman
KL
Increasing prevalence of atrial fibrillation and flutter in the United States
Am J Cardiol
 , 
2009
, vol. 
104
 (pg. 
1534
-
9
)
4
MacIntyre
K
Capewell
S
Stewart
S
Chalmers
JWT
Boyd
J
Finlayson
A
, et al.  . 
Evidence of improving prognosis in heart failure : trends in case fatality in 66 547 patients hospitalized between 1986 and 1995
Circulation
 , 
2000
, vol. 
102
 (pg. 
1126
-
31
)
5
Peltonen
M
Stegmayr
B
Asplund
K
Time trends in long-term survival after stroke: The Northern Sweden Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Study, 1985–1994
Stroke
 , 
1998
, vol. 
29
 (pg. 
1358
-
65
)
6
Rosamond
WD
Chambless
LE
Folsom
AR
Cooper
LS
Conwill
DE
Clegg
L
, et al.  . 
Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994
N Engl J Med
 , 
1998
, vol. 
339
 (pg. 
861
-
7
)
7
Friberg
L
Hammar
N
Pettersson
H
Rosenqvist
M
Increased mortality in paroxysmal atrial fibrillation: report from the Stockholm Cohort-Study of Atrial Fibrillation (SCAF)
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
2346
-
53
)
8
Stewart
S
Hart
CL
Hole
DJ
McMurray
JJ
A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study
Am J Med
 , 
2002
, vol. 
113
 (pg. 
359
-
64
)
9
Benjamin
EJ
Wolf
PA
D'Agostino
RB
Silbershatz
H
Kannel
WB
Levy
D
Impact of atrial fibrillation on the risk of death: the Framingham Heart Study
Circulation
 , 
1998
, vol. 
98
 (pg. 
946
-
52
)
10
Hart
RG
Pearce
LA
Aguilar
MI
Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation
Ann Intern Med
 , 
2007
, vol. 
147
 (pg. 
590
-
2
)
11
Connolly
SJ
Ezekowitz
MD
Yusuf
S
Eikelboom
J
Oldgren
J
Parekh
A
, et al.  . 
Dabigatran versus warfarin in patients with atrial fibrillation
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
1139
-
51
)
12
Hohnloser
SH
Crijns
HJ
van Eickels
M
Gaudin
C
Page
RL
Torp-Pedersen
C
, et al.  . 
Effect of dronedarone on cardiovascular events in atrial fibrillation
N Engl J Med
 , 
2009
, vol. 
360
 (pg. 
668
-
78
)
13
Kannel
WB
Wolf
PA
Benjamin
EJ
Levy
D
Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates
Am J Cardiol
 , 
1998
, vol. 
82
 
Suppl. 1
(pg. 
2N
-
9N
)
14
Atrial Fibrillation Investigators: Atrial Fibrillation AAS, Boston Area Anticoagulation Trial for Atrial Fibrillation S, Canadian Atrial Fibrillation Anticoagulation S, Stroke Prevention in Atrial Fibrillation S, Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation S
Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials
Arch Intern Med
 , 
1994
, vol. 
154
 (pg. 
1449
-
57
)
15
Michel
P
Odier
C
Rutgers
M
Reichhart
M
Maeder
P
Meuli
R
, et al.  . 
The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging
Stroke
 , 
2010
, vol. 
41
 (pg. 
2491
-
8
)
16
Jorgensen
HS
Nakayama
H
Reith
J
Raaschou
HO
Olsen
TS
Acute stroke with atrial fibrillation. The Copenhagen Stroke Study
. Stroke
 , 
1996
, vol. 
27
 (pg. 
1765
-
9
)
17
Lamassa
M
Di Carlo
A
Pracucci
G
Basile
AM
Trefoloni
G
Vanni
P
, et al.  . 
Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project)
Stroke
 , 
2001
, vol. 
32
 (pg. 
392
-
8
)
18
Steger
C
Pratter
A
Martinek-Bregel
M
Avanzini
M
Valentin
A
Slany
J
, et al.  . 
Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry
Eur Heart J
 , 
2004
, vol. 
25
 (pg. 
1734
-
40
)
19
Ghatnekar
O
Glader
E-L
The effect of atrial fibrillation on stroke-related inpatient costs in Sweden: a 3-year analysis of registry incidence data from 2001
Value Health
 , 
2008
, vol. 
11
 (pg. 
862
-
8
)
20
Dulli
D
Stanko
H
Levine
R
Atrial fibrillation is associated with severe acute ischemic stroke
Neuroepidemiology
 , 
2003
, vol. 
22
 (pg. 
118
-
23
)
21
Van Gelder
IC
Groenveld
HF
Crijns
HJ
Tuininga
YS
Tijssen
JG
Alings
AM
, et al.  . 
Lenient versus strict rate control in patients with atrial fibrillation
N Engl J Med
 , 
2010
, vol. 
362
 (pg. 
1363
-
73
)
22
Reynolds
MR
Essebag
V
Zimetbaum
P
Cohen
DJ
Healthcare resource utilization and costs associated with recurrent episodes of atrial fibrillation: the FRACTAL registry
J Cardiovasc Electrophysiol
 , 
2007
, vol. 
18
 (pg. 
628
-
33
)
23
Kannel
B
Benjamin
J
Current perceptions of the epidemiology of atrial fibrillation
Cardiol Clin
 , 
2009
, vol. 
27
 (pg. 
13
-
24
)
24
Miyasaka
Y
Barnes
ME
Gersh
BJ
Cha
SS
Bailey
KR
Abhayaratna
WP
, et al.  . 
Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence
Circulation
 , 
2006
, vol. 
114
 (pg. 
119
-
25
)
25
Wattigney
WA
Mensah
GA
Croft
JB
Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention
Circulation
 , 
2003
, vol. 
108
 (pg. 
711
-
6
)
26
Yang
J
Liu
B
Liu
D
Luo
Y
Fang
F
Prevalence and risk factors of atrial fibrillation in preterminal inpatients aged 60 years and over
Chin Med J (Engl)
 , 
2008
, vol. 
121
 (pg. 
2046
-
9
)
27
Kirchhof
P
Auricchio
A
Bax
J
Crijns
H
Camm
J
Diener
HC
, et al.  . 
Outcome parameters for trials in atrial fibrillation: executive summary. Recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA)
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
2803
-
17
)
28
Jahangir
A
Lee
V
Friedman
PA
Trusty
JM
Hodge
DO
Kopecky
SL
, et al.  . 
Long-term progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year follow-up study
Circulation
 , 
2007
, vol. 
115
 (pg. 
3050
-
6
)
29
Ringborg
A
Nieuwlaat
R
Lindgren
P
Jonsson
B
Fidan
D
Maggioni
AP
, et al.  . 
Costs of atrial fibrillation in five European countries: results from the Euro Heart Survey on atrial fibrillation
Europace
 , 
2008
, vol. 
10
 (pg. 
403
-
11
)
30
Coyne
KS
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
 , 
2006
, vol. 
9
 (pg. 
348
-
56
)
31
Jowett
S
Bryan
S
Mahe
I
Brieger
D
Carlsson
J
Kartman
B
, et al.  . 
A multinational investigation of time and traveling costs in attending anticoagulation clinics
Value Health
 , 
2008
, vol. 
11
 (pg. 
207
-
12
)
32
Bruggenjurgen
B
Rossnagel
K
Roll
S
Andersson
FL
Selim
D
Muller-Nordhorn
J
, et al.  . 
The impact of atrial fibrillation on the cost of stroke: the Berlin acute stroke study
Value Health
 , 
2007
, vol. 
10
 (pg. 
137
-
43
)
33
Fenwick
E
Marshall
DA
Blackhouse
G
Vidaillet
H
Slee
A
Shemanski
L
, et al.  . 
Assessing the impact of censoring of costs and effects on health-care decision-making: an example using the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study
Value Health
 , 
2008
, vol. 
11
 (pg. 
365
-
75
)
34
Le Heuzey
J-Y
Paziaud
O
Piot
O
Ait Said
M
Copie
X
Lavergne
T
, et al.  . 
Cost of care distribution in atrial fibrillation patients: the COCAF study
Am Heart J
 , 
2004
, vol. 
147
 (pg. 
121
-
6
)
35
Holstenson
E
Ringborg
A
Lindgren
P
Coste
F
Diamand
F
Nieuwlaat
R
, et al.  . 
Predictors of costs related to cardiovascular disease among patients with atrial fibrillation in five European countries
Europace
 , 
2011
, vol. 
13
 (pg. 
23
-
30
)
36
McBride
D
Mattenklotz
AM
Willich
SN
Brüggenjürgen
B
The costs of care in atrial fibrillation and the effect of treatment modalities in Germany
Value Health
 , 
2009
, vol. 
12
 (pg. 
293
-
301
)
37
Stewart
S
Murphy
N
Walker
A
McGuire
A
McMurray
JJV
Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK
Heart
 , 
2004
, vol. 
90
 (pg. 
286
-
92
)
38
Camm
AJ
Kirchhof
P
Lip
GYH
Schotten
U
Savelieva
I
Ernst
S
, et al.  . 
Guidelines for the management of atrial fibrillation
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
2369
-
429
)
39
Kupersmith
J
Holmes-Rovner
M
Hogan
A
Rovner
D
Gardiner
J
Cost-effectiveness analysis in heart disease, part III: Ischemia, congestive heart failure, and arrhythmias
Prog Cardiovasc Dis
 , 
1995
, vol. 
37
 (pg. 
307
-
46
)
40
Catherwood
E
Fitzpatrick
WD
Greenberg
ML
Holzberger
PT
Malenka
DJ
Gerling
BR
, et al.  . 
Cost-effectiveness of cardioversion and antiarrhythmic therapy in nonvalvular atrial fibrillation
Ann Intern Med
 , 
1999
, vol. 
130
 (pg. 
625
-
36
)
41
Eckman
MH
Falk
RH
Pauker
SG
Cost-effectiveness of therapies for patients with nonvalvular atrial fibrillation
Arch Intern Med
 , 
1998
, vol. 
158
 (pg. 
1669
-
77
)
42
Hughes
M
Lip
GYH
Guideline Development Group NCGfMoAFiPaSC, National Institute for Health and Clinical Excellence
Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data
Thromb Haemost
 , 
2008
, vol. 
99
 (pg. 
295
-
304
)
43
Freeman
JV
Zhu
RP
Owens
DK
Garber
AM
Hutton
DW
Go
AS
, et al.  . 
Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation
Ann Intern Med
 , 
2011
, vol. 
154
 (pg. 
1
-
11
)
44
Marshall
DA
Levy
AR
Vidaillet
H
Fenwick
E
Slee
A
Blackhouse
G
, et al.  . 
Cost-effectiveness of rhythm versus rate control in atrial fibrillation
Ann Intern Med
 , 
2004
, vol. 
141
 (pg. 
653
-
61
)
45
Hagens
VE
Vermeulen
KM
TenVergert
EM
Van Veldhuisen
DJ
Bosker
HA
Kamp
O
, et al.  . 
Rate control is more cost-effective than rhythm control for patients with persistent atrial fibrillation—results from the RAte Control versus Electrical cardioversion (RACE) study
Eur Heart J
 , 
2004
, vol. 
25
 (pg. 
1542
-
9
)
46
Ericson
L
Bergfeldt
L
Björholt
I
Atrial fibrillation: the cost of illness in Sweden
Eur J Health Econ
 , 
2010
 
Published online ahead of print 1 July 2010, doi:10.1007/s10198-010-0261-3
47
Zimetbaum
P
Reynolds
MR
Ho
KK
Gaziano
T
McDonald
MJ
McClennen
S
, et al.  . 
Impact of a practice guideline for patients with atrial fibrillation on medical resource utilization and costs
Am J Cardiol
 , 
2003
, vol. 
92
 (pg. 
677
-
81
)
48
Miyasaka
Y
Barnes
ME
Gersh
BJ
Cha
SS
Bailey
KR
Seward
JB
, et al.  . 
Changing trends of hospital utilization in patients after their first episode of atrial fibrillation
Am J Cardiol
 , 
2008
, vol. 
102
 (pg. 
568
-
72
)
49
Friberg
J
Buch
P
Scharling
H
Gadsbphioll
N
Jensen
GB
Rising rates of hospital admissions for atrial fibrillation
Epidemiology
 , 
2003
, vol. 
14
 (pg. 
666
-
72
)
50
Saborido
CM
Hockenhull
J
Bagust
A
Boland
A
Dickson
R
Todd
D
Systematic review and cost-effectiveness evaluation of ‘pill-in-the-pocket’ strategy for paroxysmal atrial fibrillation compared to episodic in-hospital treatment or continuous antiarrhythmic drug therapy
Health Technol Assess
 , 
2010
, vol. 
14
 (pg. 
1
-
104
)
51
Kirchhof
P
Fetsch
T
Hanrath
P
Meinertz
T
Steinbeck
G
Lehmacher
W
, et al.  . 
Targeted pharmacological reversal of electrical remodeling after cardioversion—rationale and design of the Flecainide Short-Long (Flec-SL) trial
Am Heart J
 , 
2005
, vol. 
150
 pg. 
899
  
e1–e6
52
Kirchhof
P
Breithardt
G
New concepts for old drugs to maintain sinus rhythm in patients with atrial fibrillation
Heart Rhythm
 , 
2007
, vol. 
4
 (pg. 
790
-
3
)
53
Naccarelli
GV
Johnston
SS
Lin
J
Patel
PP
Schulman
KL
Cost burden of cardiovascular hospitalization and mortality in ATHENA-like patients with atrial fibrillation/atrial flutter in the United States
Clin Cardiol
 , 
2010
, vol. 
33
 (pg. 
270
-
9
)
54
Rodgers
M
McKenna
C
Palmer
S
Chambers
D
Van Hout
S
Golder
S
, et al.  . 
Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation
Health Technol Assess
 , 
2008
, vol. 
12
 (pg. 
1
-
198
iii–iv, xi–xiii
55
McKenna
C
Palmer
S
Rodgers
M
Chambers
D
Hawkins
N
Golder
S
, et al.  . 
Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom
Heart
 , 
2009
, vol. 
95
 (pg. 
542
-
9
)
56
Kirchhof
P
Can we improve outcomes in atrial fibrillation patients by early therapy?
BMC Med
 , 
2009
, vol. 
7
 pg. 
72
 
57
Kirchhof
P
Bax
J
Blomstrom-Lundquist
C
Calkins
H
Camm
AJ
Cappato
R
, et al.  . 
Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference ‘research perspectives in AF
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
2969
-
77c
)