Cost-effectiveness of catheter
ablation treatment for patients with symptomatic atrial fibrillation
Credits:Nathalie Eckard1 , Thomas Davidson1 , Hakan Walfridsson2
, Lars-Ake Levin1
for Medical Technology Assessment (CMT), Department of Medical and Health
Sciences, Linköping University, Sweden.2Department
of Cardiology, Linköping University Hospital, Sweden.
This paper has in part been orally
presented at: The Society for Medical Decision-Making (SMDM) Europe, Engelberg, Switzerland, June1-4, 2008.
Address for Correspondence: Nathalie Eckard, Center for Medical Technology Assessment (CMT), Department of Medical and Health Sciences, Linköping University, SE – 581 83 Linköping, Sweden.
Background: Atrial Fibrillation is the most common cardiac arrhythmia. It
increases the risk of thromboembolic events and many atrial fibrillation
patients suffer quality of life impairment due to disturbed heart rhythm.
Pulmonary vein isolation using radiofrequency catheter ablation treatment is
aimed at maintaining sinus rhythm ultimately improving quality of life. Randomized
clinical trial have shown that catheter ablation is more effective than antiarrhythmic
drugs for the treatment of atrial fibrillation, but its impact on quality of
life and cost-effectiveness has not been widely studied.
assess the cost-effectiveness of radiofrequency ablation (RFA) vs. antiarrhythmic
drug (AAD) treatment, among symptomatic atrial fibrillation patients not
previously responding to AAD.
Methods: A decision-analytic Markov model was
developed to assess costs and health outcomes in terms of quality adjusted life
years (QALYs) of RFA and AAD over a lifetime time horizon. We conducted a literature search and used
data from several sources as input variables of the model. One-year rates of
atrial fibrillation with RFA and AAD, respectively, were available from
published randomized clinical trials. Other data sources were published papers and register data.
The RFA treatment strategy was associated with reduced costs and an incremental
gain in QALYs compared to the AAD treatment strategy. The results were
sensitive to whether long-term quality of life improvement is maintained for
the RFA treatment strategy and the risk of stroke in the different atrial
fibrillation health states.
Conclusion: This study shows that the short-term
improvement in atrial fibrillation associated with RFA is likely to lead to long-term
quality of life improvement and lower costs indicating that RFA is
cost-effective compared to AAD.
Key words: Cost,
cost-effectiveness, decision-analytic model, ablation, atrial fibrillation, cardiovascular
fibrillation (AF) is the most common cardiac arrhythmia and occurs in 2 % of
adults aged 65 to 75 years. Its prevalence increases with age; 5 % of adults
above 75 years old and 14 % of adults above 85 years old .
Furthermore, AF increases the risk of thromboembolic events and many AF
patients perceive/suffer quality of life (QoL) impairment in the form of
palpitations and shortness of breath due to the disturbed heart rhythm. Pulmonary
vein isolation using radiofrequency catheter ablation (RFA) is aimed at
maintaining sinus rhythm. Randomized clinical trials have shown that RFA is
more effective than antiarrhythmic drug treatment (AAD) in maintaining sinus
rhythm, but its cost-effectiveness has not been widely studied. Cost comparison studies of RFA versus AAD were identified [2 - 3]. Though, we could only identify two studies
assessing both costs and benefits (effects) of RFA treatment [4-5].
for AF involves the use of a combination of different medications. Rhythm
control management often involves the use of AAD, foremost amiodarone or
flecainide, aimed at maintaining sinus rhythm and at avoiding relapses. Sotalol and propafenone are less commonly used for rhythm
control management in Sweden. Many AF patients do not tolerate
long-term AAD treatment, particularly with amiodarone, without side effects. In
the event of side effects or lack of efficacy the use of a non-pharmaceutical
treatment, such as pacemaker implantation followed by AV-node ablation or RFA might
be considered. RFA is already an established treatment strategy for different
types of arrhythmias including WPW-syndrome, AV-nodal reentrytachycardia,
atrial flutter and focal atrial tachycardia. However, RFA, aiming at pulmonary
vein isolation, for AF patients has only been used during the last decade and
is usually considered as an alternative treatment strategy only after medical
management has caused side effects or had no or insufficient effect.
traditionally been divided into paroxysmal, persistent and permanent AF. According
to international ACC/AHA/ESC 2006 guidelines patients with severe symptomatic
paroxysmal and persistent AF are eligible for RFA treatment. The RFA treatment
strategy for the treatment of symptomatic AF has been debated in the current Swedish
National Guidelines for Heart Disease and is now recommended for symptomatic AF
patients with paroxysmal or persistent AF not responding well to AAD treatment . Patients with permanent AF, on the other hand are not
eligible for RFA and are excluded in the analysis.
In this analysis,
we assess the lifetime costs and health outcomes of radiofrequency ablation (RFA)
treatment compared to antiarrhythmic drug treatment (AAD) alone. The population
used in our analysis consists of symptomatic patients with paroxysmal or
persistent AF, not responding well to AAD treatment and eligible for RFA i.e. as a second-line treatment strategy.
decision-analytic model was developed to estimate costs, health outcomes and
incremental cost-effectiveness of RFA compared to AAD treatment for AF for a
lifetime time horizon. In the absence of long-term data, decision-analytic
models can be used to estimate costs and health outcomes of health
interventions beyond the follow-up of clinical trials. Data from several sources were used to populate
the model with best available evidence. The outcome measure used in the
analysis was quality-adjusted life years (QALYs). Probability distributions
were defined for the model parameters reflecting the uncertainty in evidence/of
the information available. A Swedish societal perspective was taken, and both
costs and health outcomes were discounted at 3 % per annum, respectively. All
costs are in 2006 prices and have been converted to USD
using purchasing power parities (PPPs).
and underlying assumptions
A two-part model
structure was used, a decision tree for the initial year in which the RFA
procedure is assumed to take place, and a long-term Markov structure for
subsequent years (see Figures 1a and 1b).
The short-term model provides the proportion of patients entering the
long-term model health states after accounting for non-stroke mortality and
stroke risk. Short-term clinical end-points i.e. freedom of AF at 12 months
were used in the model. If the patient suffers a clinically significant
relapse into AF, a second RFA procedure is usually offered as a standard in Sweden and was assumed to take place during the initial year.
A Markov model
structure was developed to extrapolate the lifetime costs and QALYs of the two
intervention strategies. In a Markov structure a hypothetical cohort of
patients reside in mutually exclusive health states during intervals of equal
length referred to as Markov cycles. The model consists of health states for
controlled AF, uncontrolled AF, stroke and death. Separate health states for
death were used; whether caused by stroke or other cause mortality. Annual
Markov cycles were applied.
implies that the hypothetical patients enter the controlled AF health state. If
the treatment strategy is not successful, the cohort of patients enters the
uncontrolled AF health state. In case of a stroke event, the cohort may enter the
stroke dead or post stroke health states. The ´post stroke´ health state
implying an elevated mortality risk and reduced QoL. Patients face a risk of
non-stroke mortality and may at any stage make the transition to the non-stroke
dead health state.
A summary of
base-case model inputs are given in Table 1.
Table 1:Summary of model inputs.
* Average cost for RFA procedure includes; 3-4 hospitalization days, diagnostic examinations e.g. ultrasound and/or CT and MR and catheters.
§ Anticoagulation treatment (warfarin) consists of; monitoring at specialist dept. (58 %), average cost per unit, 200SEK (22USD); number of visits per annum, 16.25; monitoring at primary care unit average cost per unit 545SEK (60USD) (42 % average cost 509SEK (56USD) of which 10 % at home, average cost 861SEK (94USD), number of visits, 13.75; travel, 42SEK (5USD); loss of production, 26SEK (3USD) and medication 576SEK (63USD).
We conducted a
literature search to find data to populate our model. Clinical studies have
shown a success rate for RFA, measured as freedom from AF relapses at 12
months, between 70 to 80 %, assuming that the intervention is repeated within a
year in case of clinically significant relapse into AF or atrial tachycardia [7-8]. Five randomized controlled clinical trials reporting
efficacy of RFA compared with AAD were identified [9-13].
One study was excluded as it only consider RFA as first-line treatment i.e. the
patients did not receive AAD treatment prior to RFA . One
of the randomized clinical trial found showing 56 % free from AF relapses
during a follow-up period of 12 months of RFA treatment after a single procedure
i.e. not repeated if failed . After a follow-up period
of 12 months, 91 % (63/69) patients still using AAD had at least one AF
recurrence with the AAD treatment strategy .
used for the decision-tree was based on the assumption that the intervention is
repeated within the first year in case of relapse into AF, the standard
procedure in Sweden. The yearly rate of AF and relative risk ratios for both a
first and a second RFA procedure were estimated using randomized controlled
clinical trial data. An average of 1.4 procedures per patient is needed to
successfully isolate the pulmonary veins based on Swedish clinical data .
All AF patients
with at least one risk factor for stroke (CHADS2) benefit from
anticoagulation treatment to reduce thromboembolic events. No evidence was
found to indicate different stroke risks in the controlled AF and uncontrolled
AF health states. The baseline risk of stroke was assumed to be 1.5 % for AF
and non-AF on anticoagulation treatment using a conservative assumption . The age-dependant standard mortality rates were based on
the Swedish national data .
decision tree considered the costs associated with the RFA procedure. It was
assumed that the RFA procedure was repeated within a year if not successful
implying an additional cost for the repeated procedure in the short-term decision
tree. A single RFA procedure was costed at 90 000 SEK (9 860 USD) [16-17].
This cost includes 3 to 4 hospitalization days and diagnostic examinations e.g.
ultrasound, CT /or MR and disposables such as catheters. This cost was thus multiplied by 1.4 procedures in the Markov
complications associated with the RFA procedure include; tamponade, bleeding,
pulmonary vein stenosis, stroke and oesophageal fistulas .
Deaths have been reported in some cases in connection with pulmonary vein
stenosis and oesophageal fistulas. In the Swedish national catheter ablation register
information on complications associated with RFA treatment was available. The
probability of a major complication was assumed to be 3 % using Swedish register
data, no deaths were reported . All complications used
in our model were treated as costs.
for AF often involves the use of a combination of different medications. Both
the RFA and AAD treatment strategy involves the use of AAD. The annual cost of
AAD treatment has been estimated to 15 000 SEK (1 640
USD). This cost includes hospitalisation, AAD medication and
consultation; hospitalisation being the major cost driver for AAD .
In the long-term model, continued use of AAD after the initial year, was
assumed in the case RFA did not eliminate AF i.e. not free from AF.
The average cost
of monitoring AF patients using warfarin (anticoagulation) was 375 SEK (41 USD) per visit and 15 times a year,
totalling to 6 052 SEK (663 USD) per annum . This cost includes the cost for monitoring at either a
specialist department or primary care unit and actual medication. The cost of
medication was estimated to 575 SEK (63 USD) per
annum. The post stroke health state is associated with increased cost and the annual
cost of stroke was assumed to be greater during the first year, based on the incidence
of first-time stroke .
Quality-adjusted life years
No studies were
found measuring QoL improvement on AF patients in a way that could readily be
used for QALY weights. However, several studies have shown improved quality of
life (QoL) after RFA treatment . For
instance, QoL, measured by the SF-36 instrument, improved significantly in all
eight health dimensions after RFA treatment . In order
to estimate QALY weights for different health states, age-adjusted QALY weights
based on a Swedish general population were applied for patients in the
controlled AF state, and used as reference points. The QALY weights used in
the model was 0.83, 0.81 and 0.74 for individuals aged >69, 70-79 and >80
. Decrements were applied to the general population utility
weight for the uncontrolled AF state and the post stroke state. A decrement of
0.1 for uncontrolled AF and 0.25 for stroke was applied to the baseline utility
in the controlled AF state.
The model was
evaluated using second-order Monte Carlo simulation. The cohort was simulated
during Markov cycles until all hypothetical patients were assumed to be in the
‘dead’ health state during sixty-one Markov cycles. The total accumulated
costs and health outcomes for each Markov cycle were summarized for the
hypothetical cohort of symptomatic AF patients. The results were presented in
two ways. First, mean lifetime costs and QALYs showing the incremental
cost-effectiveness ratios (ICERs) of the compared treatment strategies are
shown in Table 2 illustrating the additional costs needed
per additional gained QALY. Second, decision uncertainty of the probabilistic
analysis is plotted in the cost-effectiveness plane. The model was programmed
and analyzed using Microsoft Office Excel.
The base-case results show that the
RFA treatment strategy was associated with an incremental gain in QALYs and
reduced costs compared to the AAD strategy in the lifetime analysis. The model
was run probabilistically and the results of the 1000 simulations are shown in Figure 2. The vertical axis represents the
difference in costs and the horizontal axis the difference in health outcomes
for the two treatment strategies. The plotted results imply that most of the
ICERs are more effective and less costly in the SE quadrant and more costly in
the NE quadrant. If the benefits of the RFA treatment strategy are
sustained during a lifetime, the RFA treatment strategy would be the optimal one.
Figure 2:Cost-effectiveness plane of probabilistic base-case analysis of RFA vs. AAD.
Scatterplot diagram to illustrate uncertainty in the results of the analysis. Each point represents the result from one simulation run based on parameter values drawn from prespecified statistical distributions. Results measured in additional (incremental) costs and QALYs gained (incremental effects) by replacing AAD with RFA in the lifetime analysis. The SE quadrant implies a treatment strategy associated reduced costs and incremental gain in QALYs i.e. is considered a dominant treatment strategy.
sensitivity analysis was preformed to assess whether the results were affected
by changes in the model assumptions. The results of the analysis are dependant
whether the long-term positive effect of RFA is maintained over a lifetime
period i.e. patients remaining free from AF. In the absence of data beyond a
12 month follow-up period, we considered annual reversion rates back to
uncontrolled AF after RFA of 5 %, 10 % and 15 % annually, in the alternative
scenarios (Table 2). The results of the analyses were
sensitive to reversion back into AF, implying both decreasing QALYs and higher
costs for the RFA treatment strategy. Even though the
results were sensitive to reversion back into AF, the costs of RFA are only slightly
higher compared to the AAD treatment strategy. The benefits (QALYs) of RFA are
always higher than that of the AAD strategy in the alternative scenarios. In spite
of higher costs and decreasing QALYs for the RFA strategy, Table
2 is to be interpreted, by combining both costs and benefits in the ICER
column. For all values tested, the ICERs
were below the so called threshold value for what is considered cost-effective (ranging
from dominant to 440 800 SEK (48 310 USD).
Table 2:Quality adjusted life years and incremental cost effectiveness ratios for RFA compared with AAD treatment.
ICER, Incremental cost-effectiveness ratio; QALY, quality adjusted life years; RFA, radiofrequency ablation treatment; AAD, antiarrhythmic drug treatment. Dom, dominant.
Little is known
whether the elevated stroke risk in the AF health state is eliminated with the
RFA treatment strategy. In the base-case analysis an estimate of 1.5 % was
used for both controlled and uncontrolled AF. In the sensitivity analysis the
stroke risk was varied in the uncontrolled AF health state. There are more
patients in the AF state in the AAD treatment strategy. An elevated stroke
risk for the AF state will decrease health outcomes in the AAD treatment
strategy. As there are more AF patients in the AAD strategy, the AAD treatment
strategy is disfavoured.
Our results, based
on a modelling approach, indicate that the RFA treatment strategy is
cost-effective. We assessed lifetime costs and effects using relevant
randomized controlled trials, different published papers and Swedish
register data as input variables for both treatment
strategies. Using probabilistic analysis allows uncertain parameters to vary
randomly within predefined distributions reflecting the overall level of
uncertainty of model parameters.
There are several
sources of uncertainty to be considered when interpreting the results
associated with methodological aspects and model assumptions. We used a
lifetime time horizon to analyse the model. A lifetime time horizon is
relevant, as benefits are likely to accrue well beyond the duration of a
clinical trial and costs are largely the result of the initial intervention. The main costs for RFA treatment occurs during the first year due to
considerably higher intervention costs compared to AAD treatment.
The RFA treatment
strategy, when used as a second-line strategy, is the standard procedure in Sweden and in accordance with international guidelines. AAD treatment involves the daily
use of medications and is not always well tolerated by the patient. This is
also a reason why the RFA might be considered cost-effective compared to AAD. The
AAD strategy has often proven non successful and the low efficacy AAD therefore
favours the RFA treatment strategy. One could argue that the AAD treatment
strategy might be associated with a higher disutility compared to the RFA
treatment strategy. We chose to use conservative estimates as not to disfavour
the AAD treatment strategy in the base-case scenario.
The two key parameters
we found to be most important to examine were the reversion rates of the RFA
procedure back to AF and variations in stroke risks in the different AF health
states. We found no long-term studies of the sustainability of the RFA
treatment strategy i.e. if the QoL benefits are maintained over a lifetime
period. We considered different annual reversion rates back to AF in the
alternative scenarios, implying both decreasing QALYs and higher costs for the RFA
strategy. We used a conservative estimate for the stroke risk in the base-case
analysis for the controlled and uncontrolled AF health states. There are more
patients in the AF health state in the AAD strategy; therefore the AAD strategy
was more sensitive to variations in stroke risk.
Only two studies
were found assessing cost-effectiveness of the RFA treatment strategy [4-5]. The US study concludes that RFA treatment is potentially
cost-effective for symptomatic AF patients compared to medical management. The
benefit of each treatment strategy was driven primarily by stroke risk
reduction. A wide range of efficacy rates were explored and there is a risk that
the effects of the RFA treatment strategy have been overestimated. Early
studies have indicated that RFA is a curative treatment strategy and the US study also refers to the restoration of sinus rhythm. We found no evidence to indicate
stroke risk reduction in the controlled AF health state after an RFA procedure.
The second study was based on a UK population using a similar model structure to
ours . The UK study has considerably higher probabilities
for the success rates for both the RFA and AAD treatment strategies compared to
our study. The clinical effectiveness input variables in the UK study were based on a meta-analysis. It is unclear whether the high efficacy refers to a mix of
first- and second-line treatment . There is also the
possibility of bias toward one study with higher efficacy compared to other
clinical studies . However, both previous
cost-effectiveness studies are in line with our results, indicating a
cost-effective treatment strategy for RFA if QoL improvement is maintained. Other studies were found comparing catheter ablation
treatment with medical management but not in relation to effects. The cost comparison
analyses by Khaykin et al. [2-3] studied RFA versus AAD both
as a second-line and first-line treatment strategy. They conclude that the RFA
treatment strategy was considered cost-equivalent at 4 years when used as
second-line treatment strategy and was cost neutral at 2 years when used as a
first-line treatment strategy.
The results were
sensitive to whether the long-term QoL benefits are maintained after the initial
RFA procedure. Follow-up studies would be important when confirming the
sustainability of the RFA treatment strategy. Our modelling
approach provides an analytic framework and new parameter estimates can readily
be incorporated into the model once more evidence becomes available.
In conclusion, the
RFA treatment strategy was associated with reduced cost and an incremental gain
in QALYs and was considered a cost-effective treatment strategy compared to the
AAD in a lifetime perspective, despite higher initial intervention costs.
We would like to thank Martin Henriksson for valuable modeling support during the working process.
Reynolds MW, Fahrbach K, Hauch O, Wygant G, Estok R, Cella C, et al., Warfarin anticoagulation and outcomes in patients with atrial fibrillation: A systematic review and metaanalysis. Chest, 2004, 126: 1938-1945.
Khaykin Y, Morillo CA, Skanes AC, McCracken A, Humphries K, Kerr CR, Cost Comparison of Catheter Ablation and Medical Therapy in Atrial Fibrillation, J Cardiovasc Electrophysiol, 2007, 18: 907-913.
Khaykin Y, Wang X, Natale A, Wazni OM, Skanes AC, Humphries KH, et al., Cost Comparison of Ablation Versus Antiarrhythmic Drugs as First-Line Therapy for Atrial Fibrillation: An Economic Evaluation of the RAAFT Pilot Study, J Cardiovasc Electrophysiol, 2009, 20: 7-12.
Chan PS, Vijan S, Morady F, Oral H, Cost-Effectiveness of Radiofrequency Catheter Ablation for Atrial Fibrillation, Journal of the American College of Cardiology, 2006, 47; 12: 2513-2520.
McKenna C, Palmer S, Rodgers M, Chambers D, Hawkins N, Golder S, et al., Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom, Heart, 2009, 95: 542-549.
Swedish National Guidelines for Heart Disease 2008. The National Board of Health and Welfare. Socialstyrelsens riktlinjer för hjärtsjukvård 2008. Beslutsstöd för prioriteringar, Socialstyrelsen.
Pappone C, Oreto G, Lamberti F, Vicedomini G, Lorricchio ML, Shpun S, et al., Catheter ablation of paroxysmal atrial fibrillation using a 3D mapping system, Circulation, 1999, 100: 1203-1208.
Khaykin Y, Cost-effectiveness of catheter ablation for atrial fibrillation, Cardiology, 2007, 22: 11-17.
Krittayaphong R, Raungrattanaamporn O, Bhuripanyo K, Sriratanasathavorn C, Pooranawattanakul s, Punlee K, et al., A randomized clinical trial of the efficacy of radiofrequency catheter ablation and amiodarone in the treatment of symptomatic atrial fibrillation, J Med Assoc Thai, 2003, 86; 1: S8-16.
Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, et al., Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation. A randomized trial, JAMA 2005, 293; 21: 2634-2640.
Stabile G, Bertaglia E, Senatore G, De Simone A, Zoppo F, Donnici G, et al., Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective multi-centre, randomized, controlled study (Catheter ablation for the cure of atrial fibrillation study), European Heart Journal 2006; 27: 216-221.
Pappone C, Augello G, Sala S, Gugliotta F, Vicedomini G, Gulletta S, et al., A Randomized Trial of Circumferential Pulmonary Vein Ablation Versus Antiarrhythmic Drug Therapy in Paroxysmal Atrial Fibrillation. The APAF Study, Journal of the American College of Cardiology, 2006, 48; 11, 2340-2347.
Jais P, Cauchmez B, Macle L, Daoud E, Khairy P, Subbiah R et al., Catheter Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation: The A4 Study, Circulation, 2008, 118: 2498-2505.
Department of Cardiology, Linköping University Hospital, Sweden, 2001-2008.
Statistics Sweden. Life Tables. 2008. http://www.scb.se/statistik/BE/BE0101/2006MO2/be0101Livslängdstabeller eng.xls (accessed 28 Feb 2008).
Samverkansnämnden Sydöstra sjukvårdsregionen. Prislista år 2005. http://www.lio.se/upload/16047/Prislista 2005 (accessed 28 Aug 2008).
SBU Alert, Kateterburen ablationsbehandling vid förmaksflimmer, SBU ALERT-Rapport nr 2005-02, 2005.
Cappato R, Calkins H, Chen S-A, Davies W, Iesaka Y, Kalman J, et al., Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation, Circulation, 2005, 111: 1100-1105.
Swedish national catheter ablation register, 2007.
Weerasooriya, R, Jais P, Le Heuzy J-Y, Scavée C, Choi K-J, Macle L, et al., Cost analysis of catheter ablation for paroxysmal atrial fibrillation, PACE, 2003; 26: 292-294.
Davidson T, Levin L-Å, Kostnaden för förmaksflimmer i Östergötland, CMT-rapport, 2006:5, Linköpings universitet, 2006.
Ghatnekar O, Persson U, Glader E-L, Terént A. Cost of stroke in Sweden: An incidence estimate. International Journal of Technology Assessment in Health Care, 2004, 20; 3: 375-380.
Weerasooriya, R, Jais P, Hocini M, Scavée C, Macle L, Hsu LF, et al., Effect of catheter ablation on quality of life of patients with paroxysmal atrial fibrillation, Heart Rhythm, 2005, 2: 619-623.
Burström K, Rhenberg C, Hälsorelaterad livskvalitet i Stockholms län 2002. Resultat per åldergrupp och kön, utbildningsnivå, födelseland samt sysselsättningsgrupp – en befolkningsundersökning med EQ-5D. Centrum för folkhälsa. Enheten för Socialmedicin och Hälsoekonomi. Rapport 2006:1.