Cost Comparison of Catheter Ablation and Medical Therapy in Atrial ...

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Cost Comparison of Catheter Ablation and Medical Therapy in Atrial Fibrillation ∗

YAARIV KHAYKIN, M.D., F.R.C.P.C., CARLOS A. MORILLO, M.D., F.R.C.P.C.,† ALLAN C. SKANES, M.D., F.R.C.P.C.,‡ AARON MCCRACKEN, M.B.A.,§ KARIN HUMPHRIES, SC.D.,¶ and CHARLES R. KERR, M.D., F.R.C.P.C.¶ ∗

From the Southlake Regional Health Center, Newmarket, Ontario, Canada; †Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada; ‡London Health Science Centre, London, Ontario, Canada; §Johnson & Johnson Medical Products, Markham, Ontario, Canada; and ¶St. Paul’s Hospital, Vancouver, British Columbia, Canada

Catheter Ablation and Medical Therapy. Introduction: There is emerging evidence for clinical superiority of catheter ablation over rate and rhythm control strategies in paroxysmal atrial fibrillation (PAF). The objective of this study was to compare costs related to medical therapy versus catheter ablation for PAF in Ontario (Canada). Methods: Costs related to medical therapy in the analysis included the cost of anticoagulation, rate and rhythm control medications, noninvasive testing, physician follow-up visits, and hospital admissions, as well as the cost of complications related to this management strategy. Costs related to catheter ablation were assumed to include the cost of the ablation tools (electroanatomic mapping or intracardiac echocardiography-guided pulmonary vein ablation), hospital and physician billings, and costs related to periprocedural medical care and complications. Costs related to these various elements were obtained from the Canadian Registry of Atrial Fibrillation (CARAF), government fee schedules, and published data. Sensitivity analyses looking at a range of initial success rates (50–75%) and late attrition rates (1–5%), prevalence of congestive heart failure (CHF) (20–60%), as well as discounting varying from 3% to 5% per year were performed. Results: The cost of catheter ablation ranged from $16,278 to $21,294, with an annual cost of $1,597 to $2,132. The annual cost of medical therapy ranged from $4,176 to $5,060. Costs of ongoing medical therapy and catheter ablation for PAF equalized at 3.2–8.4 years of follow-up. Conclusion: Catheter ablation is a fiscally sensible alternative to medical therapy in PAF with cost equivalence after 4 years. (J Cardiovasc Electrophysiol, Vol. 18, pp. 907-913, September 2007) atrial fibrillation, catheter ablation, pulmonary veins, health economics Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia.1 It increases mortality, causes considerable disability, impairs quality of life, and is difficult to treat.2-4 Medical therapy for AF aimed at either rate or rhythm control has been disappointing.5 There is emerging evidence implicating triggered activity arising in the pulmonary veins (PV) in initiating and maintaining paroxysmal atrial fibrillation (PAF).6,7 Elimination of such focal ectopic electrical activity using catheter ablation therapy has been shown to prevent AF recurrences and in some cases terminate chronic AF.8-12 Two of the mainstream approaches to ablation in patients with AF include electroanatomically guided circumferential pulmonary vein Aaron McCracken is an employee of Biosense Webster.

ablation10,12 and electrical isolation of the PV using a circular mapping catheter with or without real-time intracardiac echocardiography.13 Both strategies have been shown to be successful in 60–90% of patients treated, with success defined as freedom from AF ranging from 6 months to 2 years. While only a single retrospective study supports association between freedom from AF as a result of ablation and improvement in long-term morbidity and mortality,14 large randomized studies of medical therapy in AF showed benefit of sinus rhythm achieved medically with respect to both measures of quality of life and survival.15-17 We performed this analysis to compare costs related to medical therapy versus catheter ablation for AF in Ontario (Canada).

Methods

Dr. Allan C. Skanes received a speaker’s honoraria from Biosense Webster.

Medical Treatment Related Costs

Address for correspondence: Yaariv Khaykin, M.D., F.R.C.P.C., Heart Rhythm Program, Division of Cardiology, Southlake Regional Health Center, 105-712 Davis Drive, Newmarket, L3Y 8C3 Ontario, Canada. Fax: (416) 848-0050; E-mail: [email protected]

Medical management of AF involves anticoagulation to prevent stroke and other embolic sequelae of this condition, rate control for patients who stay in AF permanently, and rhythm control for patients who cannot tolerate their AF. Multiple comparative studies looking at the risks and benefits of rate versus rhythm control demonstrated that both strategies are equally poor at reducing the risk of stroke and at improving the quality of life and survival of the patients

Manuscript received 5 March 2007; Revised manuscript received 19 April 2007; Accepted for publication 15 May 2007. doi: 10.1111/j.1540-8167.2007.00902.x

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Journal of Cardiovascular Electrophysiology

Vol. 18, No. 9, September 2007

with AF.5,18 Mortality in these patients remains greater than in the general population, even with appropriate therapy.14 Anticoagulation To estimate the cost of anticoagulation therapy for AF, we used a recently published Canadian analysis19 that evaluated the costs associated with anticoagulation and its hemorrhagic complications and embolic events in patients with AF in 1998 Canadian dollars. Our calculations included an inflationary adjustment of 16.5%, based on the Statistics Canada consumer price index. The Canadian Registry of Atrial Fibrillation (CARAF) prospectively collects information on treatment of AF patients across the country. CARAF began enrollment of patients with newly diagnosed AF in 1990 in six cities across Canada (Vancouver, Calgary, London, Hamilton, Ottawa, and Montreal). Patients were recruited from physicians’ offices and emergency departments and during hospital admission for other diagnoses. Enrollees were obtained through routine, consistent screening of patients in emergency departments and of in-hospital patients, and from consistent referrals from general practitioners.20 We assumed the proportion of Ontario patients taking warfarin, based on CARAF findings, at 56% in 2005, and used this to estimate the economic burden of anticoagulation. Rate and Rhythm Control We utilized the data for medication use collected in the CARAF registry for Ontario, the typical clinically prescribed dose for each medicine, and the Ontario Drug Benefit Formulary unit price21 to project the cost associated with rhythm or rate control in AF patients. The average annual cost per category was multiplied by the percentage of patients receiving drugs from that category (from CARAF) to determine the total annual cost of additional drugs per patient. Costs Related to Patient Follow-Up AF requires close patient follow-up for several reasons. Many patients with this condition are anticoagulated and need monitoring of their international normalized ratio (INR). Others feel unwell with symptoms related to heart rate irregularity and rapid ventricular rates. Still others experience congestive heart failure (CHF) related to tachycardia mediated cardiomyopathy and/or loss of atrial contribution to cardiac output. While the bulk of patient visits take place on an outpatient basis, many patients do present to emergency rooms and are admitted to the hospital for initiation of rate or rhythm control medications, cardioversion, or for treatment of AF complications. Unfortunately, neither CARAF nor any other registry tracks this information for Canadian patients. Treatment costs associated with follow-up of AF patients, including hospital admissions, emergency room visits, testing, and follow-up with cardiologists, internists, and family physicians were analyzed in France.22 This analysis stratified patients according to therapeutic strategy—rate or rhythm control—as well as according to concomitant CHF symptoms. We adopted the data for the number of visits to each physician category, frequency of testing, and hospital admissions from this analysis, and assigned a cost to each patient interaction with the healthcare system. Rather than accept proportions of patients in each therapeutic category based on the French model,22 we substituted Ontario data from the CARAF registry. A sensitivity analysis looking at

the prevalence of CHF symptoms in this population ranging from 20% to 60% was performed. While this may be perceived as an overestimate of CHF in this population, it was based on data from the CARAF registry where 20% of the patients had a concomitant CHF diagnosis and the Framingham study in which 50% of the AF patients also suffered from CHF.23 There are no data for prevalence of CHF among ablated AF patients, but several important studies support the clinical benefit of ablation in patients with CHF and structural heart disease.24-26 Because the published economic data were reflective of the French healthcare system, a cost was assigned to each event (clinical test, physician visit, overnight stay in hospital, etc.) using Canadian data, generally from the Ontario Physician Schedule of Benefits.27 INR, digoxin, and thyroid function test costs have been estimated by authors in the absence of publicly available data. Finally, a weighted average total cost was determined, based on the prevalence of each of the eight patient categories and their respective follow-up characteristics. Catheter Ablation Related Costs Catheter ablation procedure The techniques of catheter ablation for AF are presented elsewhere.12,28 It is important to stress that both ablation strategies for AF utilize several catheters simultaneously with the procedure guided by such nonfluoroscopic modalities as virtual electroanatomical imaging of the heart or real-time intracardiac echocardiography. Advanced mapping techniques significantly boost success of this ablation procedure: comparable in its extent to an open heart maze procedure, but without the significant morbidity, mortality, and length of hospital stay that is associated with open heart surgery. Unfortunately, this comes with a hefty price tag, with catheter ablation for AF generally 2–4 times more expensive in equipment costs compared with ablation for other supraventricular tachyarrhythmias. Analysis of the procedural cost of pulmonary vein ablation/isolation accounted for an overnight admission to the hospital, based on standard clinical practice at all major Ontario centers performing this procedure. A transesophageal echocardiogram27,29 to rule out left atrial thrombus prior to ablation, as well as costs associated with a 4-hour utilization of the electrophysiology laboratory and various supplies,30 were accounted for. Special attention was focused on analyzing costs related to AF ablation using two of the most prevalent modalities—pulmonary vein isolation using intracardiac echocardiography and circular mapping as well as circumferential pulmonary vein ablation using electroanatomic mapping. Physician fees related to the procedure27 and the cost of various procedural complications29,31 were also accounted for. We assumed that 100% of the patients would be treated with warfarin for 1 month pre-ablation. Follow-up of the successfully treated patients was assumed to include 3 months of standard medical care at the same cost as that for patients with AF not undergoing ablation, because most centers performing catheter ablation for AF do not claim definitive success until after a 3-month “blanking” period following the procedure. Thereafter, successful patients were assumed to have one specialist visit per year related to AF, as well as ongoing follow-up care related to anticoagulation in patients

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who would otherwise warrant anticoagulation based on established guidelines. This assumption had to be made based on paucity of data regarding our ability to prevent stroke with catheter ablation strategy alone. Because 56% of Ontario patients were anticoagulated in 2005, based on the CARAF data, we assumed that 56% of the successfully ablated patients would continue to take warfarin following ablation. Patients undergoing ablation, who would otherwise not require anticoagulation based on existing guidelines, would receive anticoagulation for 1 month before and 3 months following ablation as per standard practice at all Ontario electrophysiology laboratories performing this procedure. Forty-four percent of the successfully ablated patients were assumed to fall into this category. Patients with recurrent AF following ablation were assumed to continue incurring the same ongoing medical treatment costs as patients who had never been ablated, with 56% of these patients incurring the costs associated with anticoagulation. As it is the current practice at most Ontario centers to perform a CT scan at 3 months following pulmonary vein isolation to screen for pulmonary vein stenosis, an infrequent but serious complication of catheter ablation therapy,32 the cost of CT was included in the model. A sensitivity analysis addressing the anticipated range of ablation success rates, off antiarrhythmic medications, ranging from 50% to 75% after the initial ablation, 60% to 85% after two procedures, and 70% to 90% after three procedures, as well as accounting for late success attrition rates ranging from 1% to 5% per year projected for 5 years following the first procedure and a range of catheter costs based on different ablation techniques was performed.14,29,33-35 A sensitivity analysis based on discount rates of 3–5% per year starting with 2005 values was performed as well. Results Medical Strategy We estimated the annual cost of anticoagulation and related complications adjusted for inflation at $1,586 in 2005.19 Assuming that 56% of the Ontario patients were anticoagulated in 2005, based on the CARAF data, the cost related to anticoagulation contributed $891 per year to the overall cost of medical therapy. The expense associated with the use of antiarrhythmic medications and rate control drugs amounted to an additional $410 (range $265–$556) per year (Table 1). Utilization of the healthcare services including testing, hospital visits, cardioversions, and assessments by specialists and general practitioners added another $3,539 per year (range $3,021–$3,613 adjusting CHF prevalence from 20% to 60%) to the overall cost of medical therapy in AF patients (Table 2). Total costs associated with medical therapy for AF amounted to $4,840 (range $4,176–$5,060) per patient per year in Ontario. Catheter Ablation Strategy Incorporating the physician fees,27 the costs of ablation tools (Table 3), periprocedural complications (Table 4), medical care around the time of AF ablation, pre-procedural and post-procedural testing, and the cost of utilizing the hospital infrastructure (Table 5) arrived at the total cost estimate for AF ablation ranging from $16,278 to $21,294, with the me-

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TABLE 1 Average Annual Cost of Rate and Rhythm Control Medications Based on the Ontario Drug Benefit Formulary21 and Weighted According to Canadian Registry of Atrial Fibrillation (CARAF) Reported Use Frequencies Average Annual Cost Drug Type Antiarrhythmic Beta-blocker Calcium channel blocker Digoxin Total estimated cost of additional drugs (range) Total estimated cost of additional drugs (midpoint)

Low

High

$453.67 $48.77 $206.56 $313.38 $264.57

$759.25 195.08 $464.44 $626.77 $555.83

Ontario Usage (%) 26.15 54.42 24.03 22.26

$410.20

dian estimate of $18,151 and follow-up costs ranging from $1,597 to $2,132 per year (Table 6). Summary of Results Using the estimates, costs for ongoing chronic medical therapy for AF and catheter ablation would meet at 3.2– 8.4 years, a finding favoring ablation as a fiscally reasonable alternative to ongoing medical therapy (Fig. 1). Sensitivity analysis of discounting, varying the rate from 3% to 5% per year, yielded crossover between the cost estimates from 4.5 to 10.8 years at 3% and 4.6 to 12.1 years at 5% discounting. Additional Costs and Limitations A number of patients with AF, particularly those younger than 65 years of age, may be completely disabled by their AF. This societal impact of AF would include missed workdays because of AF, a phenomenon very common, especially in younger people. For typical 40-year-old patients with lone AF, ablation may be very attractive because they are young and may derive higher productivity over the longer term. We have not been able to arrive at the data for frequency or duration of such disabling symptoms in AF and have not accounted for this substantial burden in our analysis. Some centers may perform catheter ablation for AF using catheters from other manufacturers, which may be cheaper than quoted in this study, further improving the value of this procedure. Clinical practice guidelines recommend anticoagulation in AF patients at moderate and high risk of embolism based on the available evidence.36 It is unknown to what extent these guidelines have penetrated into the clinical practice in Ontario and little information is available on the prevalence of the risk factors for embolism in the Ontario patients suffering from AF. Specifically, while the current AF guidelines36 recommend chronic anticoagulation only in patients with two or more CHADS-237 risk factors for stroke, the prevalence of this in the Ontario population is unknown. Furthermore, prevalence of the risk factors for embolism and specifically prevalence of moderate to high CHADS-2 score among patients actually undergoing AF ablation in Ontario is unknown. While evidence supports superiority of AF ablation as a means to restore and maintain sinus rhythm, there is little data to suggest that sinus rhythm achieved as a result of ablation would improve “hard” outcomes of morbidity and

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TABLE 2 Annual Follow-Up Costs for Atrial Fibrillation22,27 Rhythm Control

Percentage of patients (in Ontario) Clinical tests (number/year) INR ECG Holter monitoring Echocardiography Exercise testing Thyroid function Digoxin levels Weighted annual cost Physician visits no CHF (per year, 45% patients without CHF) GP Specialist Hospital days Weighted cost Physician visits CHF (per year, 55% CHF prevalence) GP Specialist Hospital days Weighted cost Unscheduled visits (per year) Cardiologist Hospital days (assumed ICU) Weighted cost Annual weighted cost of clinical tests and visits

Rate Control

Warfarin

ASA

Warfarin

ASA

Total

26.39

10.77

43.64

19.20

14 3.11 1.06 0.67 0.05 0.03 0 $176.95

0 2.63 0.69 0.73 0.1 0 0 $31.46

14 3.11 0.15 0.67 0.05 0.03 0.28 $254.18

0 2.63 0.3 0.73 0.1 0 0.28 $49.60

$512.18

6.6 2.6 1.4 $123.02

5.56 2.11 0.5 $29.91

7.44 2 0.69 $146.54

5.67 1.67 0.76 $58.14

$357.61

11.22 3.89 5 $388.79

10.14 3.5 4.14 $134.41

10.89 3 4.13 $530.59

8.13 2.75 3.57 $197.47

$1,251.26

0.99 2.01 $707.38

0.99 2.01 $288.69

0.39 0.49 $293.27

0.39 0.49 $129.03

$1,418.37 $3,539.42

Proportions of patients in each therapeutic strategy was derived from the CARAF registry.

mortality. Under the circumstances, we felt it reasonable to assume prevalence of chronic anticoagulation among the ablated patients to equal that in the overall AF population. We therefore used the proportion of Ontario patients currently anticoagulated, based on the CARAF data, to estimate the cost of anticoagulation among both medically treated patients and those undergoing ablation. If ablation does prevent stroke and patients who are in sinus rhythm as a result of ablation could discontinue their anticoagulation therapy, the cost esti-

mate for ablation would drop dramatically and make it even more appealing. Some patients with AF may also be treated with catheter ablation of the AV node and permanent pacing.38 These patients still require anticoagulation, as they run the same risk of thromboembolic complications as an AF patient who is not treated with AV node ablation. They will also face the additional risks of the ablation procedure and of chronic pacemaker therapy. Not only do they require regular pacemaker

TABLE 3 Catheter Cost Estimates

CARTO/3-D mapping case Diagnostic decapolar catheter Navistar catheters (8 mm) Thermocool catheters Average of above-listed catheters Reference patches Non-CARTO/non-3-D mapping case Diagnostic decapolar catheter Celsius catheter (8 mm) LASSO catheter ICE probe NAVx case Diagnostic decapolar catheter Celsius catheter (8 mm) LASSO catheter NAVx patch Total CARTO/3-D mapping case (33% of total volume) Total non-CARTO/non-3-D mapping case (33% of total volume) Total NAVx case (33% of total volume) Weighted average cost of catheters NA = not applicable.

Low

Medium

High

$636.00 $4,050.00 $4,450.00 $4,250.00 $764.00

$829.00 $4,324.00 $5,050.00 $4,687.00 $1,346.00

$897.00 $5,000.00 $5,900.00 $5,450.00 $2,000.00

$636.00 $786.00 $1,837.00 NA

$829.00 $916.00 $2,286.00 NA

$897.00 $1,189.00 $2,657.00 $4,000.00

$636.00 $786.00 $1,837.00 $1,200.00 $5,650.00 $3,259.00 $4,459.00 $4,455.55

$829.00 $916.00 $2,286.00 $1,200.00 $6,862.00 $4,031.00 $5,231.00 $5,374.13

$897.00 $1,189.00 $2,657.00 $1,200.00 $8,347.00 $8,743.00 $5,943.00 $7,676.90

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TABLE 4 Prevalence and Cost of Procedural Complications29,31 Complication Type

Prevalence (%)

Cost

1.22 0.28 0.66 1.62

$5,382 $13,700 $3,958 $7,818 $256.91

Tamponade Stroke Transient ischemic attack PV stenosis Total cost of complications

Figure 1. Comparison of medical versus ablative cost of therapy in atrial fibrillation (AF). Estimates in the Figure are based on 3% discounting.

TABLE 5 Total Pulmonary Vein Ablation Cost27,30,32 Item

Cost

Cost of anticoagulation for 1 month pre-procedure∗ Average cost of procedure (fixed costs, patient charges, EP lab staff costs, materials, and supplies) CT chest scan Physician fees 3 months post-procedure follow-up Cost of procedure complications Catheters Total

$57.92 $1,700.00 $356.60 $1,276.00 $1,566.65 $256.91 $5,374.13 10,588.21

∗ Cost of anticoagulation in 44% of the patients who would not otherwise be anticoagulated for 1 month pre-ablation.

follow-up and replacement in addition to standard followup of AF, recent data suggest systematic deterioration of the ventricular function in many of these patients with a resultant potential increase in the burden of CHF.39 Finally, a number of assumptions have been made in the study, including similar patient healthcare interactions in Canada to those in France, the fact that the cost of follow-up

in ablated patients would equal that in medically treated patients for 3 months following ablation (and indefinitely in those who fail ablation), and that those who are successfully ablated would have only one visit per year related to their AF beyond the first 3 months. True prevalence of CHF in patients undergoing AF ablation in Ontario is not well established. Furthermore, the analysis accounted for a pre-procedure trans-esophageal echocardiogram (TEE), an overnight hospital stay following ablation, and a single CT scan in ablated patients. These assumptions may or may not apply in all jurisdictions, but the investigators felt that they would most closely approximate current practice patterns in Ontario. Discussion This analysis supports the fact that catheter ablation is a cost-comparable alternative to medical therapy in AF. This is particularly important because AF is a chronic condition with medical care costs accruing over the entire lifetime of the patient treated. It is particularly common in the elderly

TABLE 6 Sensitivity Analysis: Catheter Ablation Cost at Various Success Rates Successful after 1st procedure (%) Successful after 2nd procedure (%) Successful after 3rd procedure (%) Requiring a 2nd procedure (%) Requiring a 3rd procedure (%) Unsuccessful (%) Average # of procedures per patient

50 60 70 50 40 30 1.90

60 70 75 40 30 25 1.70

65 75 80 35 25 20 1.60

70 80 85 30 20 15 1.50

75 85 90 25 15∗ 10 1.40

Cost of ablation—year 1 (per patient) Annual success attrition (%) Annual follow-up cost Year 1 Year 2 Year 3 Year 4 Year 5

$20,118 5

$18,000 4

$16,941 3

$15,882 2

$14,823 1

$1,462 $2,346 $2,538 $2,730 $2,922

$1,336 $2,116 $2,259 $2,403 $2,546

$1,210 $1,886 $1,981 $2,076 $2,171

$1,084 $1,655 $1,702 $1,749 $1,795

$958 $1,425 $1,423 $1,422 $1,420

Average annual follow-up cost over 5 years Catheter costs Low Low-medium Medium Medium-high High

$2,400

$2,132

$1,865

$1,597

$1,330

$19,835 $20,707 $21,580 $23,768 $25,955

$17,775 $18,556 $19,336 $21,294 $23,251

$16,682 $17,417 $18,151 $19,994 $21,836

$15,589 $16,278 $16,967 $18,694 $20,421

$14,496 $15,139 $15,782 $17,394 $19,006

∗ Annual success attrition refers to the percentage of “successful” patients each year who become refractory to ablation after a successful procedure and thus “re-enter” the medical management stream.

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and with an aging society, the costs of AF management are only expected to escalate over the years.40,41 The study is not a prospective analysis of costs associated with AF management, but an approximation based on perceived costs associated with medical care in these patients. In particular, the data may be sensitive to the differences in the occurrence of concomitant heart failure or the frequency of physician visits and investigations in patients treated for AF between Canada and France. To account for some of that variability, we did perform a sensitivity analysis looking at a range of heart failure prevalence in this population and did not find a substantial impact of heart failure symptom frequency on the overall cost of AF management. Access to publicly funded healthcare in France may also be similar to that in Canada, making a significant difference in the frequency of physician visits or testing less likely. The strongest limitation of this analysis is the fact that the catheter ablation for AF is a relatively new procedure and little is known about the long-term outcomes beyond 3 years. On the other hand, most investigators to date find little, if any, attrition rate in the success of catheter ablation therapy for AF beyond 6 months to a year. Further randomized clinical trials are needed to help us learn more about the relative efficacy of AF ablation versus medical therapy and allow for standardization of the “best” ablation strategy for this condition. The techniques of AF ablation and advanced mapping systems used to facilitate ablation are ever evolving as we are learning more about this condition. The costs associated with ablation may diminish over time as it penetrates into the mainstream. At present, catheter ablation for AF is practiced to some extent at all centers performing ablation for other arrhythmias in Ontario. Most of these centers are performing fewer than 60 procedures per year and have 6- to 12-month waiting lists for this procedure. The barriers to increasing numbers of catheter ablation procedures for AF involve several factors, including the need for extensive operator training and lack of allocated funding to support this highly specialized procedure. At 2–4 times the cost of the “traditional” electrophysiology study/ablation procedures, in the setting of a cost per case budget, it is difficult to afford routinely performing this procedure. As a result, many physicians do not refer eligible patients for this procedure because the excessive wait list is seen as prohibitive and the procedure as unattainable. Conclusions Catheter ablation is a fiscally sensible strategy in patients with AF. Special funding to support AF ablation is necessary and should be provided to centers with the appropriate expertise. References 1. Camm AJ, Obel OA: Epidemiology and mechanism of atrial fibrillation and atrial flutter. Am J Cardiol 1996;78:3-11. 2. 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;98:946-952. 3. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB: Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229-234. 4. Connolly SJ: Preventing stroke in atrial fibrillation: Why are so many eligible patients not receiving anticoagulant therapy? CMAJ 1999; 161:533-534.

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