Abstract
Radiofrequency catheter ablation has become an established treatment option for the management of patients with atrial fibrillation (AF). Although the concept of a rhythm control strategy devoid of the adverse events related to antiarrhythmic treatment seems highly attractive, further steps are needed in order to improve our understanding of the underlying pathophysiology, refine our ablative techniques, and increase our therapeutic efficacy. Furthermore, the increased cost of AF catheter ablation combined with the substantial number of potential candidates also mandates the evaluation of this invasive treatment through a cost-effectiveness prism. In the present review, we recapitulate the existing evidence pertaining to cost-effectiveness of AF catheter ablation as well as the shortcomings, peculiarities, and distinctive aspects of such a cost-to-benefit analysis.
Rising health care costs have emphasized the need for evaluating modern therapies through a cost-effectiveness prism. More specifically, health care expenditure has been rising faster than Gross Domestic Product in most western countries and, if the escalation rate in health care costs is maintained at current levels, the consequent socioeconomic impact is anticipated to be insupportable. 1 In this context, to maximize efficiency and value for the money spent, it is a prerequisite to evaluate whether the benefits of new innovative and costly therapies outweigh the associated risks and are obtained at an acceptable price.
Such a perspective is crucial for therapies available for the management of atrial fibrillation (AF). The latter represents the most prevalent rhythm abnormality in everyday clinical practice and its prevalence is expected to reach alarming proportions in the future, as it has been forecast to increase 2.5-fold during the next 50 years. 2 , 3 This trend is mainly attributable to the significant shift in the population age distribution towards older ages. The aging of the population is associated with an increased risk of AF development and an increased incidence of predisposing or related heart diseases and conditions, such as coronary artery disease, hypertension, valvular heart disease, heart failure, and diabetes. 4 , 5
The management of AF imposes a considerable financial burden upon health care systems. Specifically, the total annual cost for the treatment of AF was estimated at $6.65 billion in the United States in 2005, and more recently at €6.2 billion in five European countries, including Greece, Italy, Poland, Spain, and the Netherlands. 6 , 7 Similarly, the annual direct cost of AF in the UK has been reported to reach €655 million in 2000, which is equivalent to 0.97% of the total NHS budget. 8
The well-established increasing trend in the prevalence of AF is anticipated to augment the associated socioeconomic burden further in the coming years. Hence, the criterion of cost-effectiveness should be integrated into the evaluation process of all available therapeutic strategies in order to allow for disparities in related operational, clinical, and economic aspects.
Pharmacological management of atrial fibrillation
The pharmacological management of AF is mainly separated into two treatment strategies: rhythm and rate control. Evidence derived from randomized trials has lent credence to the notion that both strategies have a similar effect on symptoms, quality of life, hospitalization rates and mortality. 9–13 However, the similar efficacy of the compared treatment strategies is largely attributable to the detrimental effect of antiarrhythmic agents, which offsets the well-validated benefit reaped from sinus rhythm maintenance. 14 The on-treatment analysis of the AFFIRM trial reached the conclusion that the presence of sinus rhythm was associated with a decreased risk of death, while the use of rhythm control agents was associated with increased mortality after adjustment for other covariates. 15 Thus, the efficacy equivalence of rate and rhythm control strategies mainly reflects the paucity of our pharmacological armamentarium as regards safe and effective antiarrhythmic drugs and should definitely not restrain us from striving for sinus rhythm maintenance. In this context, a non-pharmacological therapeutic approach, which would retain the benefits associated with sinus rhythm maintenance while being free of the adverse effects of antiarrhythmic medications, would represent an attractive treatment paradigm.
Catheter ablation of atrial fibrillation
Despite a number of unresolved issues, catheter ablation has gained acceptance over the past few years. Pulmonary vein isolation was introduced almost a decade ago as a novel approach to AF treatment. 16 Since then, the ablation strategy has been redirected, from targeting the ectopic arrhythmogenic foci, to a practice of anatomic and/or electrical pulmonary vein isolation. 17–19 On the basis of the highly encouraging results of ablation in patients with paroxysmal AF, there is a tendency to expand the existing indications to patient subgroups with persistent as well as longstanding persistent AF. In the latter cases, the implemented ablative techniques are even more complex, aiming not only to abolish AF initiators, but also to modify the electrical substrate. 20 , 21 Therefore, a potential enlargement of the pool of patients considered as candidates for this expensive therapy will increase the relevant treatment expenses further, thus stressing the need for thorough cost-effectiveness evaluation of available alternatives in different patient subgroups.
Methodology in cost-effectiveness analysis
The core of cost-effectiveness analysis is the estimation of the difference in relative cost and efficacy (or effectiveness, that is real world efficacy) of two compared therapeutic interventions. The ratio of the estimated difference in cost to the difference in efficacy measure defines the incremental cost-effectiveness ratio (ICER), which is considered a reliable index of cost-effectiveness. Thus, the evaluation of catheter ablation’s cost-effectiveness is a two-arm procedure, requiring first the appraisal of relative efficacy and secondly the assessment of relative cost in relation to pharmacological rhythm or rate control. An important factor that should be taken into account in cost-effectiveness analysis is that the calculated ICER is expected to vary according to the selected efficacy measure. Thus, the relative economic attractiveness of AF ablation may be overestimated if we select a rather ‘soft’ efficacy endpoint, such as hospitalization rate, recurrence rate, or quality of life, in comparison to a rather ‘hard’ endpoint such as mortality.
The most frequently used approach in cost-effectiveness analysis is to calculate the incremental cost per quality adjusted life year (QALY) associated with a new therapeutic intervention (e.g. ablation) in relation to an existing reference comparator (e.g. drug therapy). In the context of quantifying the impact of evaluated treatment on both the quality and quantity of life, the preferred efficacy endpoint is survival adjusted by a measure of health-related quality of life, such as EQ-5D. 22 , 23 This approach can be graphically illustrated with the so called cost-effectiveness plane depicted in Figure 1 . The horizontal axis represents the difference in QALYs between an existing reference therapy and the therapy under consideration (e.g. catheter ablation), while the vertical axis represents the difference in total treatment cost. When appraising new technologies in relation to existing ones there are four situations that may arise, and these relate to the corresponding quadrants in the plane. The lower right corresponds to situations where the new technology is associated with higher QALYs and lower total treatment cost and implies that the existing approach should be immediately abandoned in favour of the new. The opposite situation is depicted in the upper left quadrant, which relates to new technologies associated with higher cost and lower QALYs, which should not be used at all. The most common case, however, relates to the right-upper quadrant where the new technology is associated with both higher QALYs and higher cost. Mathematically, the incremental cost per QALY saved with the new technology is represented by the slope of the line that intersects the origin of the axes. The steeper the line, the higher the slope, the higher the incremental cost per QALY gained, in other words the money spent for every QALY attained with use of the new technology. The critical issue is the threshold which will be used as a benchmark to define whether a new technology is deemed good value for money (i.e. cost-effective) or not, relative to an existing one. There is a lot of debate among experts about the estimation and the level of this threshold. In general, technologies with an incremental cost per QALY gained up to €20 000 are deemed very good value for money, those between €20 000 and €40 000 are still attractive, while up to €60 000 represents the borderline. Treatments with an incremental cost per QALY gained above €60 000 are deemed expensive and if it exceeds €100 000 they are then deemed not good value at all. 22 , 23
The cost-effectiveness plane.
Cost evaluation of atrial fibrillation ablation vs. pharmacological treatment
Khaykin et al . 24 compared treatment expenses of catheter ablation vs. medical management in patients with paroxysmal AF and reached the conclusion that AF ablation is a cost-comparable strategy to the medical treatment of AF in this subgroup of patients. Specifically, the estimated median total treatment cost with catheter ablation ranged in Canada from $16 278 to $21 294, with an annual follow-up cost of $1597 to $2132, while the annual cost of medical therapy ranged from $4176 to $5060. Thus, the cost of ongoing chronic medical therapy for AF equalled that of AF ablation between 3.2 and 8.4 years of follow-up, with cost-equivalence after 4 years on average. 24
This finding is in line with the results of a retrospective cost comparison of the two treatment strategies in patients with paroxysmal AF, according to which the cost of catheter ablation equated to that of pharmacological treatment after a 5 year time interval with a continuously diverging trend thereafter. 25 In this study, the mean cost of pharmacological treatment in 2001 in France was €1590 per patient per year and the cost of ablation was €4715 in the first year and €445 each year thereafter, thus supporting the view that ablation represents a sensible alternative to pharmacological treatment from an economic perspective.
In trying to explain these findings, it should be pointed that hospitalizations have been consistently demonstrated to constitute the major contributor to the total treatment cost of AF patients. In the COCAF survey, hospitalizations were the primary cost driver, accounting for 52% of total treatment cost, while in the FRACTAL registry 47% of AF-related healthcare cost corresponded to inpatient care. 26 , 27 Atrial fibrillation recurrences increase the utilization of healthcare resources while each one has been found to be responsible for an annual cost of $1600 on average. 27 In another study, 44% of the cost of AF was attributed to direct and 29% to indirect hospital care. 6 Thus, treatments which reduce recurrences are expected to decrease the total treatment cost in the long run. Thus, catheter ablation is expected to be cost-effective, since its initial upfront cost could be offset in the long run by the afforded reduction in the AF recurrence rate. 21 , 27–31
Therefore, on the basis of the evidence presented above, it can be argued that catheter ablation can be a cost-attractive alternative to pharmacotherapy in the long run, by decreasing subsequent long-term healthcare expenses, despite the initial high procedural cost. 27 , 32–36 However, this argument is limited by the lack of robust long-term data pertaining to the efficacy of AF ablation. The majority of published studies have reported follow-up data that do not extend beyond a 6–12 month period, while in the worldwide survey only six centres had a follow-up longer than 24 months. 34 Thus, the possibility of very late recurrences and associated health care expenditures remains open, especially in light of previous evidence demonstrating an increased late conduction recurrence across acutely electrically disconnected pulmonary veins. 35 Shah et al . 36 recently reported an AF recurrence rate of 8.7% in a follow-up period of 28 ± 12 months while the calculated actuarial recurrence rate increased from 5.8% at 2 years post-ablation to 25.5% at 5 years. Furthermore, late recurrence seems to be rather unpredictable, since it can occur even when early post-procedural arrhythmias are absent, as well as after long-lasting (>1 year) episode-free intervals. 36–40 Through this prism, it seems imperative to establish credibly the long-term effects of AF ablation in order to be sure about its true cost-effectiveness.
Is atrial fibrillation ablation cost-effective?
The existing evidence concerning the cost-effectiveness of AF catheter ablation is rather sparse. Chan et al . 41 have presented data from a decision-analytic model which evaluated the cost-effectiveness of left atrial catheter ablation (LACA) in comparison with medical rate control therapy and medical rhythm control therapy with amiodarone. Left atrial catheter ablation was considered unlikely to be cost-effective in patients at low risk of stroke (ICER of $98 900 per QALY gained when compared with rate control). In patients at moderate risk of stroke (presence of one risk factor), the cost-effectiveness of LACA was dependent on the achieved relative reduction in stroke risk and on the AF recurrence rate. In 65-year-old patients at moderate risk of stroke, with an estimated 1 year LACA efficacy for sinus rhythm restoration of 80%, the relative risk in stroke reduction should be below 42 and 11% in order to achieve cost-effectiveness at the levels of $50 000 and $100 000 per QALY, respectively. The incremental cost per QALY gained with LACA over rate control therapy in 2004 prices was $51 800 in the 65-year-old group at moderate risk, $28 700 in the 55-year-old group at moderate risk, and $98 900 in the 65-year-old group at low risk. Thus, LACA was not cost-effective in patients at low risk for stroke but could be cost-effective in moderate risk patients. The most significant parameters impacting the results included the risk of stroke, the cost of ablation, the rate of recurrence of AF after ablation, and the risk of haemorrhage after warfarin therapy. It should also be acknowledged that although this decision analysis model focused on the cost-effectiveness of AF ablation through the prism of stroke risk reduction, the latter association needs to be validated by prospective randomized clinical trials.
Comments
The economic analysis of catheter ablation needs to account for age, stroke risk level, and other important baseline patient characteristics. In addition, the evaluation of AF ablation is further complicated by the presence of several coexisting confounding factors that also need to be taken into consideration. First, the exact type of implemented ablative method is of primary importance, since the procedure of AF ablation encompasses a diverse array of ablative techniques associated with variable costs and different efficacy rates. In the worldwide registry five different ablative strategies were reported, while in a minority of patients a combined approach with two or more strategies was followed. 34 Learning curve and centre experience are also decisive factors that exert a significant influence on success rate and consequently on cost-effectiveness. Indeed, the success rate is significantly increased in higher-volume compared with lower-volume centres. 34
Another well-acknowledged caveat is the underestimation of arrhythmia recurrence when asymptomatic bouts of AF fail to be recognized, mainly because of inadequately strict and rigorous rhythm monitoring. A pivotal factor that also modifies the cost-effectiveness of the procedure is the occurrence of complications. In the worldwide survey, the complication rate was 6% with four early deaths, while in a recent study of 1101 consecutive patients the respective percentage was 3.9%. 34 , 42 These complications significantly increase the procedure-related costs while they are more likely to occur in low-volume centres mainly as a result of the learning curve effect. 24 Thus, in experienced centres, the overall success rate is higher while the recurrence and the complication rates are lower, thus improving the cost-effectiveness of the procedure.
Another shortcoming in evaluating the cost-effectiveness of AF ablation is the heterogeneity of the patient population as well as the limited generalizability of the patient subgroups included in clinical trials and treated in high-volume centres. These patients do not constitute a representative sample of the general patient population, while the advanced level of healthcare provided in the specialized centres may improve efficacy and safety but may also increase the related treatment cost. Thus, any attempt at extrapolation of the calculated cost and cost-effectiveness measures is prone to biases. Furthermore, considerable differences in unit prices and resource utilization among different centres and, importantly, among different countries, impair a cost calculation that could be representative of all European countries. 7
Keeping in mind the above-mentioned pitfalls, some further comments regarding the evidence on cost-effectiveness of AF ablation could be noted. The cost-effectiveness is expected to wane in older patients, since old age is inherently associated with enhanced stroke risk, irrespectively of underlying rhythm. Furthermore, from a statistical point of view, the higher the patient’s age the lower the likelihood of 5 year event-free survival, which is needed to equate ablation costs with chronic medical therapy expenses. On the other hand, catheter ablation is anticipated to be more cost-effective in younger patients at medium stroke risk, as long as a high late recurrence rate can be avoided. If this is the case, the cost spared by preventing an increased number of AF recurrences during the prolonged lifespan of younger patients is expected to counterbalance the initial cost of the procedure. 41
Regardless of the apparent lack of long-term efficacy data that could provide a solid background for a cost-effectiveness analysis of AF ablation, there is little doubt that this therapeutic modality is widely accepted and practiced. It is also true that electrophysiologists who have performed a large number of AF ablation procedures have obtained valuable clinical experience and expertise. In this context, they may have improved their competence in trans-septal access to the left atrium, electro-anatomic mapping techniques, catheter manipulation, and navigation in the left atrium and ablation of left-sided tachyarrhythmias. Should we include these gains in a critical cost-effectiveness analysis of AF ablation? Even if we decided to do so, there is no definite way to quantify and include in a similar analysis the progress in electrophysiology associated with the development of this treatment approach. Thus, even with several assumptions and modelling, uncertainty will inevitably hamper a balanced appraisal of this therapy.
Indeed, the value of innovation is priceless, but on the other hand the cost of uncertainty that shadows the currently available long-term efficacy and cost-effectiveness results of AF ablation could be enormous. Being in agreement with Dr Mark Estes, 43 we would also like to underline the fact that clinical electrophysiology has earned its credentials by driving through careful, evidence-based steps during the last decades. Many electrophysiologists who are afraid that enthusiasm should have been tempered by reality, especially in the case of persistent AF, would argue that a critical appraisal of AF ablation’s cost-effectiveness should have to challenge effectiveness before addressing the cost issue.
In conclusion, catheter ablation of AF is a constantly evolving therapy that targets a heterogeneous patient population. The continuously improving ablative techniques, complemented by advanced mapping modalities, have enabled the achievement of reproducible efficacy, at least in certain patient subgroups. There is early evidence that ablation may be a cost-effective treatment option compared with medical therapy. However, several pieces are still missing from the cost-effectiveness puzzle. The completion of properly designed prospective, randomized trials or (medical, economic, quality of life) outcome observational studies which would quantify the long-term effects of this therapy will delineate in which patients catheter ablation can exert tangible beneficial effects at an acceptable cost and will provide valuable evidence to optimize the organization of modern laboratories and maximize efficiency in health-care provision.
Conflict of interest: none declared.
Funding
S.T. is supported by a training fellowship provided by the European Heart Rhythm Association. This work was undertaken and supported by the Hellenic Cardiovascular Research Society.
