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The cost comparison of rhythm and rate control strategies in persistent atrial fibrillation
International Journal of Cardiology 118 (2007) 21 – 27 www.elsevier.com/locate/ijcard
The cost comparison of rhythm and rate control strategies in persistent atrial fibrillation☆ Arkadiusz Pietrasik a , Dariusz A. Kosior a,⁎, Maciej Niewada b , Grzegorz Opolski a , Maciej Latek c , Bogumil Kamiñski c b
a I Chair and Department of Cardiology, Medical University of Warsaw, Poland Department of Clinical and Experimental Pharmacology, Medical University of Warsaw, Poland c Division of Decision Analysis and Support, Warsaw School of Economics, Poland
Received 27 November 2005; received in revised form 8 March 2006; accepted 24 March 2006 Available online 19 October 2006
Abstract Our sub study was designed to analyze the cost effectiveness of two alternative treatment strategies with a view to improved allocation of the limited therapeutic resources. To that effect we conducted detailed analysis of the related costs and other relevant data collected in the course of the HOT CAFE study. Methods: The prospective costs related to 205 patients randomly assigned to rhythm or rate control were traced over a 12 month period. Since, both strategies produced similar clinical outcomes a cost minimization analysis was undertaken. The cost of diagnostic and treatment procedures, including hospitalization, outpatient visits, drugs and physicians consultations were estimated for both groups. Results: The study population comprised 205 patients (mean age 60.8 year; 35% females). A hundred and one patients were randomly assigned to the rate control group with the pharmacological heart rate frequency optimization treatment combined with Holter monitoring. A hundred and four patients were randomized to sinus rhythm (SR) restoration with its subsequent maintenance with sequential antiarrhythmic drug treatment. There was no significant difference in the composite primary end-point (all-cause mortality, number of thromboembolic and major bleeding events). The hospital admissions rate was significantly higher in the rhythm control than the rate control arm (202 vs. 5, respectively). The conservative strategy involving pharmacological ventricular rate control proved to be less costly than rhythm control (€1225 vs. €2526; p < 0.001). The main cost driver behind the established difference was the cardioversion related hospitalization. Conclusions: The cost effectiveness appraisal seems to have supported the rate control strategy as less costly due to the lower hospitalization rate as a major cost carrier. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Atrial fibrillation; Rhythm control strategy; Rate control strategy; Electrocardioversion; Antiarrhythmic therapy; Cost minimization analysis
1. Introduction Atrial fibrillation (AF) is accountable for approximately one-third of hospitalizations for cardiac arrhythmias which represents significant costs to the health care system [1,2]. Additionally, the direct cost of managing patients with other cardiovascular diseases is significantly higher where AF is ☆
The study was supported by a governmental research grant (Grant Number PO5B06012). ⁎ Corresponding author. E-mail address: [email protected] (D.A. Kosior). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.03.085
involved as co-morbidity [3,4]. The therapeutic goal in patients with AF may be defined as either restoration and maintenance of sinus rhythm (SR) through mainly antiarrhythmic therapy or allowing AF to persist and develop into permanent arrhythmia with controlled ventricular rate [5,6]. In standard practice antiarrhythmic drugs and electrical cardioversion are used to control SR, relieve symptoms and, where possible, prevent disease progression. However rhythm control, with antiarrhythmic drugs may lead to arrhythmias and negative innotropic effect [7–10]. On the other hand, rate control eliminates drug proarrhythmic risks and results in hemodynamic improvement, while also
22
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27
affecting, to a limited degree, such AF symptoms, as palpitations, dyspnea, chest pain, fatigue and dizziness [8,9]. The HOT CAFE (How To Treat Chronic Atrial Fibrillation) trial was designed to compare the strategy of SR restoration and maintenance with ventricular rate control supported by thromboembolic prophylaxis [10]. The total treatment costs of the two strategies were compared to enable selection of a more cost effective option. 2. Materials and methods The HOT CAFE trial was an open and randomized, multicenter study designed to evaluate, in a prospective manner, the risks, benefits and costs of rhythm vs. rate control strategies in persistent AF, whose protocol has been already reported [10]. The present analysis attempted to evaluate the annual cost of both alternative treatment strategies based on the data gathered for both groups during the initial period of 12 months of follow-up. The study group comprised patients with the first clinically overt persistent episode of AF. We enrolled patients no older than 75 years of age with AF known to be present for no longer than 2 years. The detailed inclusion and exclusion criteria have already been presented in earlier publications [10,11]. Fig. 1 presents the trial design. 2.1. Resource use and unit costs All costs related to the study design and directly associated with each strategy, were assessed from the payer's perspective and included such costs items as cardioversion,
hospitalizations non-related to cardioversion, outpatients visits and medications. The cardioversion cost corresponds to a fee per procedure as contracted by the National Health Care Fund and comprises such items as hospital stay, drugs, labor of medical personnel, and any supplies used. During follow-up visits information on every hospitalization was gathered. The length of each hospital stay was represented as the time span between the date of admission and discharge plus 1 day. The daily unit costs of hospital stay were retrieved from the hospital cost-accounting system and represented as mean value for each medical ward. The costs of each therapeutic procedure, diagnostic tests and physicians' fees were also derived from the same source and expressed as mean values. Outpatient resources used were also identified. Unit costs of specific treatment components were determined based on the price lists of medical procedures as contracted by National Health Care Fund. The costs of drugs were represented as the retail prices quoted by a large Polish pharmaceuticals wholesaler (Prosper S.A.; www.prosper.pl). Because of the 12 month study time perspective costs and benefits were not discounted. The results are translated into Euros (PLNs were translated at the 2002 PPP value) (Table 1). 2.2. Statistical analysis Summary data are expressed as means ± S.D. or numbers and percentages of patients. Analyses were performed based on intention-to-treat principle. Continuous variables were tested by ANOVA for between-group comparisons. Where ANOVA outcomes called for it Student t-test was used to
Fig. 1. HOT CAFE trial design.
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27 Table 1 Unit costs in Euros Cost item
Unit cost
Electrical cardioversion Intensive cardiology care unit (cost per day) Intensive care unit (cost per day) Cardiology unit (cost per day) Stroke unit/neurology ward (cost per day) Endocrinology ward (cost per day) General ward (cost per day) VVI pacemaker implantation DDD pacemaker implantation Holter ECG 12-leads ECG Exercise test Echocardiography Abdominal ultrasound Chest X-ray Carotid ultrasound Doppler Doppler flow examination Thyroid ultrasound Thoracic computer tomography Brain computer tomography (with contrast) Brain computer tomography (without contrast) Lungs scyntygraphy Thyroid biopsy Specialist consultations
591 247 255 201 178 174 157 875 1280 46 17 58 42 21 28 39 51 23 117 183 111 138 71 45
compare mean value of parameters in each group. Where the parameter values did not correspond to T-Student assumptions Kruskal–Wallis test was applied to compare medians. Because the costs curve was tilted bootstrapping (with 10,000 iterations) was applied to estimate 95% CI for mean total costs in compared groups. The p value of <0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics Two hundred and five patients (M/F 134/71; average age 60.8 ± 11.2 years) with non-valvular persistent AF were eligible for the study. The mean arrhythmia duration prior to enrolment was 273.7 ± 112.4 days. In 104 patients, restoration and maintenance of SR for a period of at least 12 months was attempted. There were no significant differences in duration of follow-up between the two study groups. The characteristics of study patients were typical of a population affected by persistent AF. There were no significant differences in terms of baseline characteristics between the rate and rhythm control groups. Clinical characteristics of the study patients at baseline are presented in Table 2. 3.2. Clinical outcome None of the patients followed up was lost from observation. One patient (1.0%) assigned to the rate control limb died from leukemia diagnosed 6 months after the
23
enrolment. Three patients (2.9%) died in the rhythm control group, two of them (1.9%) from strokes. One female patient (1.0%) from the rhythm control arm died as a passenger in a motor vehicle accident in the 10th month of observation. Three patients (2.9%) assigned to the rhythm control group developed massive cerebral strokes. Two of them (1.9%), both, lethal, were observed on the third day following successful cardioversion despite appropriate anticoagulant therapy (INR value 2.8 ± 0.7) administered for a sufficient period of time (35.3 ± 11.2 days) prior to the procedure. In both cases, a cardiogenic etiology was supported through exclusion of any other possible causes. The third (0.9%), not disabling stroke, affected a patient with AF recurrence during amiodarone therapy. The patient was on chronic aspirin therapy. Despite oral anticoagulation, pulmonary embolism occurred in one patient (1.0%) in the rate control group. One patient from the rhythm control arm withdrew his consent after 6 months of observation. Table 2 The study group baseline characteristics Parameter
Rate control
Number of patients 101 Age (years) 61.4 ± 17.6 Tender Female 38 (37.6%) Male 63 (62.4%) AF duration 7 days–1 month 17 (16.8%) 1 month–2 years 84 (83.2%) Mean AF duration (days) 243.2 ± 137.3 AF etiology: Ischemic heart disease 38 (37.6%) Myocardial infarction 7 (6.9%) CABG 0 (0.0%) Hypertension 60 (59.4%) Valvular heart disease 15 (14.8%) Lone AF 25 (24.8%) Diabetes 18 (17.8%) Congestive heart failure (NYHA scale) I 48 (47.5%) II 48 (47.5%) III 5 (5.0%) Echocardiographic parameters LAsax (mm) 48.0 ± 4.7 LAlax (mm) 64.0 ± 6.8 LVEDD (mm) 50.8 ± 5.9 FS (%) 32.8 ± 6.6 Pharmacological therapy Beta-adrenolitics 49.5% Verapamil/diltiazem 7.9% Digoxin 3.0% Beta-adrenolitics + digoxin 39.6% ACE-I 71.2% Amlodipine 12.1% Nitrates 9.1% Diuretics 16.1%
Rhythm control
Significance
104 60.4 ± 7.9
NS NS
33 (31.7%) 71 (68.3%)
NS NS
16 (15.4%) NS 88 (84.6%) NS 220.4 ± 148.6 NS 52 (50.0%) 7 (6.7%) 1 (1.0%) 72 (69.2%) 16 (15.4%) 18 (17.3%) 15 (14.4%)
NS NS NS NS NS NS NS
30 (28.8%) 59 (56.7%) 15 (14.4%)
NS NS NS
47.4 ± 5.3 62.5 ± 7.9 52.2 ± 6.8 29.9 ± 6.9
NS NS NS NS
52.1% 7.7% 6.5% 31.7% 69.2% 14.4% 8.7% 14.4%
NS NS NS NS NS NS NS NS
Abbreviations: LAsax, left atrial antero-posterior axis; LAlax, left atrial longitudinal axis; LVEDD, left ventricular end diastolic diameter; FS, left ventricular fractional shortening.
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Table 3 Annual cost per patient in Euros Item
Rate control
Rhythm control
statistical significance
Cardioversion Other hospitalizations Hospital stay and physicians consultations Diagnostic procedures Pacemaker implantation Drugs Out patient visits Physicians consultations Diagnostic procedures Total annual cost
0 235 (0; 477) 199
1020 (938;1102) <0.001 501 (174; 822) 0.186 438
13 23 135 (121; 238) 854 (842; 866) 269 584 1225
24 181 (155; 207) 823 (805; 838) 271 551 2526
0.0002 0.016
<0.001
The treatment's goal in the rate control group was to optimize the heart rate based on 24-h Holter monitoring readings. Calcium antagonists (7.9%), beta-blockers (49.5%), beta-blockers + digoxin (39.6%) or digoxin alone (3.0%) were in administered. Two patients (2.0%) developed symptomatic, sustained tachycardia despite pharmacological therapy, and ultimately underwent atrioventricular node ablation with pacemaker implantation. Another patient (1.0%) required a pacemaker due to a symptomatic bradycardia and pauses >3.5 s. In all the study subjects assigned to the rate control arm AF was presented at 1 year of follow-up. Planned electrical cardioversion was performed in all 104 patients assigned to rhythm control strategy. SR was restored in 56 patients (53.8%) after the first procedure. Forty-eight patients failed to convert and continued to receive loading doses of amiodarone, prior to the next cardioversion attempt. SR was recovered in 10 patients (20.8%) during amiodarone loading. The second electrical cardioversion, preceded by amiodarone loading, restored SR in 24 out of 38 patients
(63.2%). The first and second cardioversions, the latter preceded by amiodarone loading, resulted in SR restoration in 90 patients (86.5%). Sixty-six patients, accounting for 63.5% of the total rhythm control population, demonstrated SR at the end of the study. In 27 patients SR was successfully maintained with the first antiarrhythmic compound following the initial effective cardioversion. Sequential electrical cardioversions and antiarrhythmic treatment resulted in SR maintenance in additional 15 patients previously subject to a successful initial procedure. Amiodarone in loading doses prior to the second cardioversion and maintenance therapy following the successful procedure prevented AF recurrence in the remaining 24 subjects whose initial cardioversion had failed. Two bradycardiac subjects (1.9%) in the rhythm control arm required pacemaker placement. In both cases antiarrhythmic therapy was continued. 3.3. Hospitalization The overall hospitalization rate was significantly higher in the rhythm than the rate control group (p < 0.001). Five patients (4.8%; 0.05/per person) assigned to ventricular rate control strategy required hospitalization because of adverse effects directly associated with the study treatment or comorbidities (average stay 12.3 ± 4.2 days). There were 211 hospitalizations in the group where SR restoration was attempted. Given 104 hospitalizations required by the cardioversion protocol, on average, there were 1.03 hospitalizations per person in rhythm control arm. The mean hospital stay duration of 2.5 days (average stay 2.5 ± 1.1 days) resulted from re-cardioversion as the most frequent cause of hospital readmission (94 cases; 95.5%). Seven patients (4.5%) required inpatient care due to treatment side effects and/or new or worsening concomitant diseases. The average hospital stay duration in this subgroup was 10.5 ± 4.1 days (statistically insignificant difference between the
Fig. 2. Annual mean drug cost per patient.
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27
study groups). When compared to the rate control group, the incidence of hospital admission in rhythm control limb was strikingly higher (1.03 vs. 0.05/per person; p < 0.001). 3.4. Cost analysis The conservative strategy involving pharmacological ventricular rate control turned out to be less costly than cardioversion and subsequent SR maintenance, with costs standing at €1225.00 and €2526.00, respectively (p < 0.001). The structure of total costs for both therapeutic groups is presented in Table 3. The bootstrapped results, as shown in Fig. 2, prove the rate control strategy to be more cost effective than rhythm control treatments. The cost of cardioversion related hospitalization was found to be responsible for the observed variance. All patients in the rhythm control group required an initial 2-day hospitalization in connection with the first electrical cardioversion and study protocol. The first cardioversion performed to maintain SR, as required by the study protocol, represented a significant part of the total costs in the rhythm control group (Table 3). Due to a low antiarrhythmic drugs efficacy and AF recurrence most patients required a repeat cardioversion. Although, cardioversions were performed mostly in an outpatient mode, all the SR restoration related procedures resulted in an additional mean annual cost of €1020.00 per patient. Patients who received cardioversion generated not only direct procedure related costs but also anesthesiological and cardiological consultation fees. Costs related to other hospitalizations due to worsening of concomitant diseases or/and side effects of standard therapies were two times higher in rhythm control group. However, the recorded difference was not statistically significant due to a small number of hospitalizations (€199.00 vs. €438.00; p < 0.19). Catheter ablation and pacemaker implantation were relatively infrequent in both arms and there was basically no difference between the two study groups in terms of costs of invasive strategies (€23.00 vs. €37.00). On the other hand, slight and negligible difference in outpatient visits cost levels related to close monitoring of safety and efficacy of antiarrhythmic therapy,
Table 4 Drugs consumption in the rhythm and rate control groups Drug
Rate control %
Rhythm control %
Statistical significance
Propafenone Sotalol Amiodaron Atenolol Verapamil Digoxin Dizopyramide Aspirine Ticlopidine⁎ Acenocoumarol
0.00 0.00 0.99 88.12 11.88 40.59 0.00 21.78 0.00 77.23
36.54 33.65 70.19 79.81 11.54 18.27 9.61 43.27 1.92 100.00
0.00001 0.00001 0.00001 0.08 0.99 0.005 0.0022 0.008 0.16 0.00001
25
and though statistically insignificant, the costs were slightly higher in the rate control group (€854 and €823, respectively). Drug costs were also significantly higher in the rhythm control group than the rate control group, €135,00 and €181,00, respectively. The recorded difference was caused by the consumption of antiarrhythmics (i.e. amiodarone, propafenone and sotalol), antiplatelates and anticoagulation agents in the rhythm control group, as shown in Fig. 2 and Table 4. 4. Discussion The outcomes of HOT CAFE Polish trial seem to have suggested that rate control, as management strategy, may be considered an acceptable therapy for patients with persistent AF presenting no or mild arrhythmia related symptoms. Our trial findings support the results of the recently published studies such as PIAF, AFFIRM, RACE, and STAF which offer a prospective comparison of long-term outcomes of both alternative treatment strategies [12–15]. A slightly higher incidence of strokes or systemic embolus in the rhythm control vs. the rate control strategy, as observed in HOT CAFE, was also recorded in other trials [10]. However, none of the recently published studies have shown that SR restoration and maintenance mitigate the risk of thromboembolic complications [12–16]. In our study strokes tended to affect patients assigned to SR restoration, while thromboembolic prophylaxis seemed to effectively protect patients in rate control group. The advantage of the rate over rhythm control is further supported by the lower rate of hospitalization and AF recurrence. Given comparable clinical benefits offered by the rhythm and rate control management strategies in AF, it is the economic appraisal that carries extra information on the costeffectiveness of the two treatments. All the four trials published so far, have proven that the rhythm control strategy required significantly more hospitalizations. In the AFFIRM trial 73% patients assigned to the rate control were hospitalized after baseline, while the corresponding percentage in the rhythm control arm amounted to 80.1% [13]. The mean number of hospitalizations per patient was not explicitly reported. In the PIAF trial population, 24% of the rate control patients were admitted to hospital at least once compared with 69% of rhythm control individuals [12]. The most frequent cause for hospital admissions in the rhythm control group was electrical cardioversion. This trend seems to match the STAF trial findings, where the number of hospital admissions in rhythm control group was reported significantly higher than among the rate control patients [15]. In the rhythm control group a total of 54 cardiovascular related hospitalizations were recorded (449 hospital days) versus 26 hospitalizations in the rate control group (314 days). Although not explicitly stated, the number of hospitalization in the RACE trial was presumably lower in the rate control group [14]. The
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revealed variance in the hospitalization rate does not seem to result from modifications to a largely standardized medical practice. Hence, this cost item may be responsible for a substantial difference in everyday practice applicable in various countries. Our economic analysis demonstrates that given the standard decision making criteria, rhythm control is not as cost effective as rate control. The cost analysis revealed that rate control is a less costly strategy, mainly due to the absence of cardioversion associated hospitalization costs typical of the rhythm control group. Economic analyses based on AFFIRM, COCAF, and RACE trials revealed, that hospitalizations represent a major cost driver in the treatment of AF patients [13,14,17]. Over the 3.5 years of the AFFIRM study follow-up, the incremental cost of rhythm control compared with rate control exceeded $5000 per patient and rhythm control strategy was less cost effective given a wide range of cost assumptions. The difference in outpatient visits cost level resulted from the study design, as patients assigned to the rhythm control group required additional outpatient visits after a successful cardioversion and/or prior to the procedure pretreated with amiodarone. Finally, the major cost item accounting for the difference in the total treatment costs was drug utilization. In the rate control group drugs controlling heart rate frequency and anticoagulation agents were used more frequently, while antiarrhythmics and antiplatelates were the case in the rhythm control group. The difference in drug management resulted from different treatment goals and study designs. The absence in the rate control arm of such drugs as expensive antiarrhythmics used almost exclusively in the rhythm control group resulted in lower treatment cost of the former. Pharmacological therapy applied in the HOT CAFE study corresponds to that of the AFFIRM trial. The difference in drug costs is strongly affected by higher utilization of antiarrhythmics in the rhythm control group. Additionally, both the AFFIRM and RACE trials reported more frequent adverse drug effects in the rhythm control arm. 5. Study limitations The costs of resources were analyzed based on scarce pricing information available through the hospital accounting system. Although many analysts may encounter problems relative to reliability of data, our findings may be additionally biased by limited availability of information on costs and strong volatility of prices for health care services caused by the ongoing transformation of the Polish health care system. Substantial portion of the total treatment costs in both groups is attributable to study design and as such might not reflect the everyday clinical practice. The costs of managing patients with AF in other countries may differ from our findings due to varied costs of resources, incompatibility of drug reimbursement
schemes, or practice patterns, thus making our findings difficult to generalize. 6. Conclusions Like other large scale trials, the HOT CAFE has shown no significant differences between strategies of rhythm and rate control in persistent AF. The findings of economic appraisal supported the rate control strategy as less costly, mainly due to a lower hospitalization rate. Meta-analysis of all randomized trials, as supported by pharmacoeconomic appraisal, might offer a new potential for subgroup analyses, thus contributing to improved treatment choice decisions in everyday clinical practice. References [1] Bialy D, Lehman MH, Schumacher DN, et al. Hospitalization for arrhythmias in the United States. Importance of atrial fibrillation. J Am Coll Cardiol 1992;19(suppl A):41A–8A. [2] Chugh SS, Blackshear JL, Shen WK, et al. Epidemiology and natural history of atrial fibrillation—clinical implications. J Am Coll Cardiol 2001;37:371–8. [3] Catherwood E, Fitzpatrick D, Greenberg ML, et al. Cost-effectiveness of cardioversion and antiarrhythmic therapy in nonvalvular atrial fibrillation. Ann Intern Med 1999;130:625–36. [4] Eckman MH, Falk RH, Pauker SG. Cost-effectiveness of therapies for patients with nonvalvular atrial fibrillation. Arch Intern Med 1998;158:1669–77. [5] Stafford RS, Robson DC, Misra B, et al. Rate control and sinus rhythm maintenance in atrial fibrillation. Arch Intern Med 1998;158:2144–8. [6] Falk RH. Atrial fibrillation. N Engl J Med 2001;344:1067–78. [7] Stanton MS, Prystowsky EN, Fineberg NS, et al. Arrhythmogenic drugs effects: a study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol 1989;14:200–15. [8] Grogan M, Smith HC, Gersh BJ, et al. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Eur Heart J 1992;13:1290–5. [9] Nichol G, McAlister F, Pham B, et al. Meta-analysis of randomized controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation. Heart 2002;87:535–43. [10] Opolski G, et al, for Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study. Rate control vs. rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. CHEST 2004;126:476–86. [11] Kosior DA, et al, for the Investigators of HOT CAFE Polish Trial. Serial antiarrhythmic therapy: role of amiodarone in prevention of atrial fibrillation recurrence—a lesson from HOT CAFE Polish study. Cardiology 2005;104:35–44. [12] Hohnloser SH, et al, for the PIAF Investigators. Rhythm or rate-control in atrial fibrillation: Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomized trial. Lancet 2000;356:1789–94. [13] The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33. [14] Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–40. [15] Carlsson J, Miketic S, Windeler J, et al. Randomized trial of ratecontrol versus rhythm-control in persistent atrial fibrillation: the
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27 Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690–6. [16] Van Gelder IC, Crijns HJGM, Hillege HI, et al. Electrical cardioversion strategy does not reduce risk of thromboembolism in atrial fibrillation. Eur Heart J 1995;16:282 [abstract].
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[17] Le Heuzey J, Paziaud O, Piot O, et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J 2004;147 (1):121–6.
The cost comparison of rhythm and rate control strategies in persistent atrial fibrillation☆ Arkadiusz Pietrasik a , Dariusz A. Kosior a,⁎, Maciej Niewada b , Grzegorz Opolski a , Maciej Latek c , Bogumil Kamiñski c b
a I Chair and Department of Cardiology, Medical University of Warsaw, Poland Department of Clinical and Experimental Pharmacology, Medical University of Warsaw, Poland c Division of Decision Analysis and Support, Warsaw School of Economics, Poland
Received 27 November 2005; received in revised form 8 March 2006; accepted 24 March 2006 Available online 19 October 2006
Abstract Our sub study was designed to analyze the cost effectiveness of two alternative treatment strategies with a view to improved allocation of the limited therapeutic resources. To that effect we conducted detailed analysis of the related costs and other relevant data collected in the course of the HOT CAFE study. Methods: The prospective costs related to 205 patients randomly assigned to rhythm or rate control were traced over a 12 month period. Since, both strategies produced similar clinical outcomes a cost minimization analysis was undertaken. The cost of diagnostic and treatment procedures, including hospitalization, outpatient visits, drugs and physicians consultations were estimated for both groups. Results: The study population comprised 205 patients (mean age 60.8 year; 35% females). A hundred and one patients were randomly assigned to the rate control group with the pharmacological heart rate frequency optimization treatment combined with Holter monitoring. A hundred and four patients were randomized to sinus rhythm (SR) restoration with its subsequent maintenance with sequential antiarrhythmic drug treatment. There was no significant difference in the composite primary end-point (all-cause mortality, number of thromboembolic and major bleeding events). The hospital admissions rate was significantly higher in the rhythm control than the rate control arm (202 vs. 5, respectively). The conservative strategy involving pharmacological ventricular rate control proved to be less costly than rhythm control (€1225 vs. €2526; p < 0.001). The main cost driver behind the established difference was the cardioversion related hospitalization. Conclusions: The cost effectiveness appraisal seems to have supported the rate control strategy as less costly due to the lower hospitalization rate as a major cost carrier. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Atrial fibrillation; Rhythm control strategy; Rate control strategy; Electrocardioversion; Antiarrhythmic therapy; Cost minimization analysis
1. Introduction Atrial fibrillation (AF) is accountable for approximately one-third of hospitalizations for cardiac arrhythmias which represents significant costs to the health care system [1,2]. Additionally, the direct cost of managing patients with other cardiovascular diseases is significantly higher where AF is ☆
The study was supported by a governmental research grant (Grant Number PO5B06012). ⁎ Corresponding author. E-mail address: [email protected] (D.A. Kosior). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.03.085
involved as co-morbidity [3,4]. The therapeutic goal in patients with AF may be defined as either restoration and maintenance of sinus rhythm (SR) through mainly antiarrhythmic therapy or allowing AF to persist and develop into permanent arrhythmia with controlled ventricular rate [5,6]. In standard practice antiarrhythmic drugs and electrical cardioversion are used to control SR, relieve symptoms and, where possible, prevent disease progression. However rhythm control, with antiarrhythmic drugs may lead to arrhythmias and negative innotropic effect [7–10]. On the other hand, rate control eliminates drug proarrhythmic risks and results in hemodynamic improvement, while also
22
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27
affecting, to a limited degree, such AF symptoms, as palpitations, dyspnea, chest pain, fatigue and dizziness [8,9]. The HOT CAFE (How To Treat Chronic Atrial Fibrillation) trial was designed to compare the strategy of SR restoration and maintenance with ventricular rate control supported by thromboembolic prophylaxis [10]. The total treatment costs of the two strategies were compared to enable selection of a more cost effective option. 2. Materials and methods The HOT CAFE trial was an open and randomized, multicenter study designed to evaluate, in a prospective manner, the risks, benefits and costs of rhythm vs. rate control strategies in persistent AF, whose protocol has been already reported [10]. The present analysis attempted to evaluate the annual cost of both alternative treatment strategies based on the data gathered for both groups during the initial period of 12 months of follow-up. The study group comprised patients with the first clinically overt persistent episode of AF. We enrolled patients no older than 75 years of age with AF known to be present for no longer than 2 years. The detailed inclusion and exclusion criteria have already been presented in earlier publications [10,11]. Fig. 1 presents the trial design. 2.1. Resource use and unit costs All costs related to the study design and directly associated with each strategy, were assessed from the payer's perspective and included such costs items as cardioversion,
hospitalizations non-related to cardioversion, outpatients visits and medications. The cardioversion cost corresponds to a fee per procedure as contracted by the National Health Care Fund and comprises such items as hospital stay, drugs, labor of medical personnel, and any supplies used. During follow-up visits information on every hospitalization was gathered. The length of each hospital stay was represented as the time span between the date of admission and discharge plus 1 day. The daily unit costs of hospital stay were retrieved from the hospital cost-accounting system and represented as mean value for each medical ward. The costs of each therapeutic procedure, diagnostic tests and physicians' fees were also derived from the same source and expressed as mean values. Outpatient resources used were also identified. Unit costs of specific treatment components were determined based on the price lists of medical procedures as contracted by National Health Care Fund. The costs of drugs were represented as the retail prices quoted by a large Polish pharmaceuticals wholesaler (Prosper S.A.; www.prosper.pl). Because of the 12 month study time perspective costs and benefits were not discounted. The results are translated into Euros (PLNs were translated at the 2002 PPP value) (Table 1). 2.2. Statistical analysis Summary data are expressed as means ± S.D. or numbers and percentages of patients. Analyses were performed based on intention-to-treat principle. Continuous variables were tested by ANOVA for between-group comparisons. Where ANOVA outcomes called for it Student t-test was used to
Fig. 1. HOT CAFE trial design.
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27 Table 1 Unit costs in Euros Cost item
Unit cost
Electrical cardioversion Intensive cardiology care unit (cost per day) Intensive care unit (cost per day) Cardiology unit (cost per day) Stroke unit/neurology ward (cost per day) Endocrinology ward (cost per day) General ward (cost per day) VVI pacemaker implantation DDD pacemaker implantation Holter ECG 12-leads ECG Exercise test Echocardiography Abdominal ultrasound Chest X-ray Carotid ultrasound Doppler Doppler flow examination Thyroid ultrasound Thoracic computer tomography Brain computer tomography (with contrast) Brain computer tomography (without contrast) Lungs scyntygraphy Thyroid biopsy Specialist consultations
591 247 255 201 178 174 157 875 1280 46 17 58 42 21 28 39 51 23 117 183 111 138 71 45
compare mean value of parameters in each group. Where the parameter values did not correspond to T-Student assumptions Kruskal–Wallis test was applied to compare medians. Because the costs curve was tilted bootstrapping (with 10,000 iterations) was applied to estimate 95% CI for mean total costs in compared groups. The p value of <0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics Two hundred and five patients (M/F 134/71; average age 60.8 ± 11.2 years) with non-valvular persistent AF were eligible for the study. The mean arrhythmia duration prior to enrolment was 273.7 ± 112.4 days. In 104 patients, restoration and maintenance of SR for a period of at least 12 months was attempted. There were no significant differences in duration of follow-up between the two study groups. The characteristics of study patients were typical of a population affected by persistent AF. There were no significant differences in terms of baseline characteristics between the rate and rhythm control groups. Clinical characteristics of the study patients at baseline are presented in Table 2. 3.2. Clinical outcome None of the patients followed up was lost from observation. One patient (1.0%) assigned to the rate control limb died from leukemia diagnosed 6 months after the
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enrolment. Three patients (2.9%) died in the rhythm control group, two of them (1.9%) from strokes. One female patient (1.0%) from the rhythm control arm died as a passenger in a motor vehicle accident in the 10th month of observation. Three patients (2.9%) assigned to the rhythm control group developed massive cerebral strokes. Two of them (1.9%), both, lethal, were observed on the third day following successful cardioversion despite appropriate anticoagulant therapy (INR value 2.8 ± 0.7) administered for a sufficient period of time (35.3 ± 11.2 days) prior to the procedure. In both cases, a cardiogenic etiology was supported through exclusion of any other possible causes. The third (0.9%), not disabling stroke, affected a patient with AF recurrence during amiodarone therapy. The patient was on chronic aspirin therapy. Despite oral anticoagulation, pulmonary embolism occurred in one patient (1.0%) in the rate control group. One patient from the rhythm control arm withdrew his consent after 6 months of observation. Table 2 The study group baseline characteristics Parameter
Rate control
Number of patients 101 Age (years) 61.4 ± 17.6 Tender Female 38 (37.6%) Male 63 (62.4%) AF duration 7 days–1 month 17 (16.8%) 1 month–2 years 84 (83.2%) Mean AF duration (days) 243.2 ± 137.3 AF etiology: Ischemic heart disease 38 (37.6%) Myocardial infarction 7 (6.9%) CABG 0 (0.0%) Hypertension 60 (59.4%) Valvular heart disease 15 (14.8%) Lone AF 25 (24.8%) Diabetes 18 (17.8%) Congestive heart failure (NYHA scale) I 48 (47.5%) II 48 (47.5%) III 5 (5.0%) Echocardiographic parameters LAsax (mm) 48.0 ± 4.7 LAlax (mm) 64.0 ± 6.8 LVEDD (mm) 50.8 ± 5.9 FS (%) 32.8 ± 6.6 Pharmacological therapy Beta-adrenolitics 49.5% Verapamil/diltiazem 7.9% Digoxin 3.0% Beta-adrenolitics + digoxin 39.6% ACE-I 71.2% Amlodipine 12.1% Nitrates 9.1% Diuretics 16.1%
Rhythm control
Significance
104 60.4 ± 7.9
NS NS
33 (31.7%) 71 (68.3%)
NS NS
16 (15.4%) NS 88 (84.6%) NS 220.4 ± 148.6 NS 52 (50.0%) 7 (6.7%) 1 (1.0%) 72 (69.2%) 16 (15.4%) 18 (17.3%) 15 (14.4%)
NS NS NS NS NS NS NS
30 (28.8%) 59 (56.7%) 15 (14.4%)
NS NS NS
47.4 ± 5.3 62.5 ± 7.9 52.2 ± 6.8 29.9 ± 6.9
NS NS NS NS
52.1% 7.7% 6.5% 31.7% 69.2% 14.4% 8.7% 14.4%
NS NS NS NS NS NS NS NS
Abbreviations: LAsax, left atrial antero-posterior axis; LAlax, left atrial longitudinal axis; LVEDD, left ventricular end diastolic diameter; FS, left ventricular fractional shortening.
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A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27
Table 3 Annual cost per patient in Euros Item
Rate control
Rhythm control
statistical significance
Cardioversion Other hospitalizations Hospital stay and physicians consultations Diagnostic procedures Pacemaker implantation Drugs Out patient visits Physicians consultations Diagnostic procedures Total annual cost
0 235 (0; 477) 199
1020 (938;1102) <0.001 501 (174; 822) 0.186 438
13 23 135 (121; 238) 854 (842; 866) 269 584 1225
24 181 (155; 207) 823 (805; 838) 271 551 2526
0.0002 0.016
<0.001
The treatment's goal in the rate control group was to optimize the heart rate based on 24-h Holter monitoring readings. Calcium antagonists (7.9%), beta-blockers (49.5%), beta-blockers + digoxin (39.6%) or digoxin alone (3.0%) were in administered. Two patients (2.0%) developed symptomatic, sustained tachycardia despite pharmacological therapy, and ultimately underwent atrioventricular node ablation with pacemaker implantation. Another patient (1.0%) required a pacemaker due to a symptomatic bradycardia and pauses >3.5 s. In all the study subjects assigned to the rate control arm AF was presented at 1 year of follow-up. Planned electrical cardioversion was performed in all 104 patients assigned to rhythm control strategy. SR was restored in 56 patients (53.8%) after the first procedure. Forty-eight patients failed to convert and continued to receive loading doses of amiodarone, prior to the next cardioversion attempt. SR was recovered in 10 patients (20.8%) during amiodarone loading. The second electrical cardioversion, preceded by amiodarone loading, restored SR in 24 out of 38 patients
(63.2%). The first and second cardioversions, the latter preceded by amiodarone loading, resulted in SR restoration in 90 patients (86.5%). Sixty-six patients, accounting for 63.5% of the total rhythm control population, demonstrated SR at the end of the study. In 27 patients SR was successfully maintained with the first antiarrhythmic compound following the initial effective cardioversion. Sequential electrical cardioversions and antiarrhythmic treatment resulted in SR maintenance in additional 15 patients previously subject to a successful initial procedure. Amiodarone in loading doses prior to the second cardioversion and maintenance therapy following the successful procedure prevented AF recurrence in the remaining 24 subjects whose initial cardioversion had failed. Two bradycardiac subjects (1.9%) in the rhythm control arm required pacemaker placement. In both cases antiarrhythmic therapy was continued. 3.3. Hospitalization The overall hospitalization rate was significantly higher in the rhythm than the rate control group (p < 0.001). Five patients (4.8%; 0.05/per person) assigned to ventricular rate control strategy required hospitalization because of adverse effects directly associated with the study treatment or comorbidities (average stay 12.3 ± 4.2 days). There were 211 hospitalizations in the group where SR restoration was attempted. Given 104 hospitalizations required by the cardioversion protocol, on average, there were 1.03 hospitalizations per person in rhythm control arm. The mean hospital stay duration of 2.5 days (average stay 2.5 ± 1.1 days) resulted from re-cardioversion as the most frequent cause of hospital readmission (94 cases; 95.5%). Seven patients (4.5%) required inpatient care due to treatment side effects and/or new or worsening concomitant diseases. The average hospital stay duration in this subgroup was 10.5 ± 4.1 days (statistically insignificant difference between the
Fig. 2. Annual mean drug cost per patient.
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27
study groups). When compared to the rate control group, the incidence of hospital admission in rhythm control limb was strikingly higher (1.03 vs. 0.05/per person; p < 0.001). 3.4. Cost analysis The conservative strategy involving pharmacological ventricular rate control turned out to be less costly than cardioversion and subsequent SR maintenance, with costs standing at €1225.00 and €2526.00, respectively (p < 0.001). The structure of total costs for both therapeutic groups is presented in Table 3. The bootstrapped results, as shown in Fig. 2, prove the rate control strategy to be more cost effective than rhythm control treatments. The cost of cardioversion related hospitalization was found to be responsible for the observed variance. All patients in the rhythm control group required an initial 2-day hospitalization in connection with the first electrical cardioversion and study protocol. The first cardioversion performed to maintain SR, as required by the study protocol, represented a significant part of the total costs in the rhythm control group (Table 3). Due to a low antiarrhythmic drugs efficacy and AF recurrence most patients required a repeat cardioversion. Although, cardioversions were performed mostly in an outpatient mode, all the SR restoration related procedures resulted in an additional mean annual cost of €1020.00 per patient. Patients who received cardioversion generated not only direct procedure related costs but also anesthesiological and cardiological consultation fees. Costs related to other hospitalizations due to worsening of concomitant diseases or/and side effects of standard therapies were two times higher in rhythm control group. However, the recorded difference was not statistically significant due to a small number of hospitalizations (€199.00 vs. €438.00; p < 0.19). Catheter ablation and pacemaker implantation were relatively infrequent in both arms and there was basically no difference between the two study groups in terms of costs of invasive strategies (€23.00 vs. €37.00). On the other hand, slight and negligible difference in outpatient visits cost levels related to close monitoring of safety and efficacy of antiarrhythmic therapy,
Table 4 Drugs consumption in the rhythm and rate control groups Drug
Rate control %
Rhythm control %
Statistical significance
Propafenone Sotalol Amiodaron Atenolol Verapamil Digoxin Dizopyramide Aspirine Ticlopidine⁎ Acenocoumarol
0.00 0.00 0.99 88.12 11.88 40.59 0.00 21.78 0.00 77.23
36.54 33.65 70.19 79.81 11.54 18.27 9.61 43.27 1.92 100.00
0.00001 0.00001 0.00001 0.08 0.99 0.005 0.0022 0.008 0.16 0.00001
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and though statistically insignificant, the costs were slightly higher in the rate control group (€854 and €823, respectively). Drug costs were also significantly higher in the rhythm control group than the rate control group, €135,00 and €181,00, respectively. The recorded difference was caused by the consumption of antiarrhythmics (i.e. amiodarone, propafenone and sotalol), antiplatelates and anticoagulation agents in the rhythm control group, as shown in Fig. 2 and Table 4. 4. Discussion The outcomes of HOT CAFE Polish trial seem to have suggested that rate control, as management strategy, may be considered an acceptable therapy for patients with persistent AF presenting no or mild arrhythmia related symptoms. Our trial findings support the results of the recently published studies such as PIAF, AFFIRM, RACE, and STAF which offer a prospective comparison of long-term outcomes of both alternative treatment strategies [12–15]. A slightly higher incidence of strokes or systemic embolus in the rhythm control vs. the rate control strategy, as observed in HOT CAFE, was also recorded in other trials [10]. However, none of the recently published studies have shown that SR restoration and maintenance mitigate the risk of thromboembolic complications [12–16]. In our study strokes tended to affect patients assigned to SR restoration, while thromboembolic prophylaxis seemed to effectively protect patients in rate control group. The advantage of the rate over rhythm control is further supported by the lower rate of hospitalization and AF recurrence. Given comparable clinical benefits offered by the rhythm and rate control management strategies in AF, it is the economic appraisal that carries extra information on the costeffectiveness of the two treatments. All the four trials published so far, have proven that the rhythm control strategy required significantly more hospitalizations. In the AFFIRM trial 73% patients assigned to the rate control were hospitalized after baseline, while the corresponding percentage in the rhythm control arm amounted to 80.1% [13]. The mean number of hospitalizations per patient was not explicitly reported. In the PIAF trial population, 24% of the rate control patients were admitted to hospital at least once compared with 69% of rhythm control individuals [12]. The most frequent cause for hospital admissions in the rhythm control group was electrical cardioversion. This trend seems to match the STAF trial findings, where the number of hospital admissions in rhythm control group was reported significantly higher than among the rate control patients [15]. In the rhythm control group a total of 54 cardiovascular related hospitalizations were recorded (449 hospital days) versus 26 hospitalizations in the rate control group (314 days). Although not explicitly stated, the number of hospitalization in the RACE trial was presumably lower in the rate control group [14]. The
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revealed variance in the hospitalization rate does not seem to result from modifications to a largely standardized medical practice. Hence, this cost item may be responsible for a substantial difference in everyday practice applicable in various countries. Our economic analysis demonstrates that given the standard decision making criteria, rhythm control is not as cost effective as rate control. The cost analysis revealed that rate control is a less costly strategy, mainly due to the absence of cardioversion associated hospitalization costs typical of the rhythm control group. Economic analyses based on AFFIRM, COCAF, and RACE trials revealed, that hospitalizations represent a major cost driver in the treatment of AF patients [13,14,17]. Over the 3.5 years of the AFFIRM study follow-up, the incremental cost of rhythm control compared with rate control exceeded $5000 per patient and rhythm control strategy was less cost effective given a wide range of cost assumptions. The difference in outpatient visits cost level resulted from the study design, as patients assigned to the rhythm control group required additional outpatient visits after a successful cardioversion and/or prior to the procedure pretreated with amiodarone. Finally, the major cost item accounting for the difference in the total treatment costs was drug utilization. In the rate control group drugs controlling heart rate frequency and anticoagulation agents were used more frequently, while antiarrhythmics and antiplatelates were the case in the rhythm control group. The difference in drug management resulted from different treatment goals and study designs. The absence in the rate control arm of such drugs as expensive antiarrhythmics used almost exclusively in the rhythm control group resulted in lower treatment cost of the former. Pharmacological therapy applied in the HOT CAFE study corresponds to that of the AFFIRM trial. The difference in drug costs is strongly affected by higher utilization of antiarrhythmics in the rhythm control group. Additionally, both the AFFIRM and RACE trials reported more frequent adverse drug effects in the rhythm control arm. 5. Study limitations The costs of resources were analyzed based on scarce pricing information available through the hospital accounting system. Although many analysts may encounter problems relative to reliability of data, our findings may be additionally biased by limited availability of information on costs and strong volatility of prices for health care services caused by the ongoing transformation of the Polish health care system. Substantial portion of the total treatment costs in both groups is attributable to study design and as such might not reflect the everyday clinical practice. The costs of managing patients with AF in other countries may differ from our findings due to varied costs of resources, incompatibility of drug reimbursement
schemes, or practice patterns, thus making our findings difficult to generalize. 6. Conclusions Like other large scale trials, the HOT CAFE has shown no significant differences between strategies of rhythm and rate control in persistent AF. The findings of economic appraisal supported the rate control strategy as less costly, mainly due to a lower hospitalization rate. Meta-analysis of all randomized trials, as supported by pharmacoeconomic appraisal, might offer a new potential for subgroup analyses, thus contributing to improved treatment choice decisions in everyday clinical practice. References [1] Bialy D, Lehman MH, Schumacher DN, et al. Hospitalization for arrhythmias in the United States. Importance of atrial fibrillation. J Am Coll Cardiol 1992;19(suppl A):41A–8A. [2] Chugh SS, Blackshear JL, Shen WK, et al. Epidemiology and natural history of atrial fibrillation—clinical implications. J Am Coll Cardiol 2001;37:371–8. [3] Catherwood E, Fitzpatrick D, Greenberg ML, et al. Cost-effectiveness of cardioversion and antiarrhythmic therapy in nonvalvular atrial fibrillation. Ann Intern Med 1999;130:625–36. [4] Eckman MH, Falk RH, Pauker SG. Cost-effectiveness of therapies for patients with nonvalvular atrial fibrillation. Arch Intern Med 1998;158:1669–77. [5] Stafford RS, Robson DC, Misra B, et al. Rate control and sinus rhythm maintenance in atrial fibrillation. Arch Intern Med 1998;158:2144–8. [6] Falk RH. Atrial fibrillation. N Engl J Med 2001;344:1067–78. [7] Stanton MS, Prystowsky EN, Fineberg NS, et al. Arrhythmogenic drugs effects: a study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol 1989;14:200–15. [8] Grogan M, Smith HC, Gersh BJ, et al. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Eur Heart J 1992;13:1290–5. [9] Nichol G, McAlister F, Pham B, et al. Meta-analysis of randomized controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation. Heart 2002;87:535–43. [10] Opolski G, et al, for Investigators of the Polish How to Treat Chronic Atrial Fibrillation Study. Rate control vs. rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. CHEST 2004;126:476–86. [11] Kosior DA, et al, for the Investigators of HOT CAFE Polish Trial. Serial antiarrhythmic therapy: role of amiodarone in prevention of atrial fibrillation recurrence—a lesson from HOT CAFE Polish study. Cardiology 2005;104:35–44. [12] Hohnloser SH, et al, for the PIAF Investigators. Rhythm or rate-control in atrial fibrillation: Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomized trial. Lancet 2000;356:1789–94. [13] The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33. [14] Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–40. [15] Carlsson J, Miketic S, Windeler J, et al. Randomized trial of ratecontrol versus rhythm-control in persistent atrial fibrillation: the
A. Pietrasik et al. / International Journal of Cardiology 118 (2007) 21–27 Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690–6. [16] Van Gelder IC, Crijns HJGM, Hillege HI, et al. Electrical cardioversion strategy does not reduce risk of thromboembolism in atrial fibrillation. Eur Heart J 1995;16:282 [abstract].
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[17] Le Heuzey J, Paziaud O, Piot O, et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J 2004;147 (1):121–6.