Cost-utility analysis of Cryoballoon ablation versus Radiofrequency ablation in the treatment of paroxysmal atrial fibrillation in Iran.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia (Calkins H, et al. 2012). There are various methods to treat AF of which Ablation is one of the most effective. We aimed to assess the cost-utility of Cryoballoon ablation (CBA) compared to Radiofrequency ablation (RFA) to treat patients with paroxysmal AF in Iran. A cost-utility analysis was done using a decision-analytic model based on a lifetime Markov structure which was drawn considering the nature of interventions and the natural progress of the disease. Costs data were extracted from medical records of 47 patients of Shahid Rajaie Cardiovascular Medical Center in Tehran in 2019. Parameters and variables such as transition probabilities, risks related to side effects, mortality rates, and utility values were extracted from the available evidence. Deterministic and probabilistic sensitivity analysis was also done. TreeAge pro-2020 software was used in all stages of analysis. In the base case analysis, the CBA strategy was associated with higher cost and effectiveness than RFA, and the incremental cost-effectiveness ratio was $11,223 per Quality-adjusted life year (QALY), which compared to Iran's GDP per capita as Willingness to pay threshold, CBA was not cost-effective. On the other hand, considering twice the GDP per capita as a threshold, CBA was cost-effective. Probabilistic sensitivity analysis confirmed the findings of base case analysis, showed that RFA was cost-effective and the probability of cost-effectiveness was 59%. One-way sensitivity analysis showed that the results of the study have the highest sensitivity to changes in the RFA cost variable. Results of sensitivity analysis showed that the cost-effectiveness results were not robust and are sensitive to changes in variables changes. Primary results showed that CBA compared to RFA is not cost-effective in the treatment of AF considering one GDP per capita. But the sensitivity analysis results showed considerable sensitivity to changes of the ablation costs variable.

Introduction

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in which electrical stimulation does not follow a definite pathway. It occurs when an electrical wave has no distinct direct in atria and is described as supraventricular tachyarrhythmia which is accompanied by uncoordinated atrial activity and subsequently atrial mechanical failure [1].

Stages of AF are based on the duration of arrhythmia which is classified into three paroxysmal, persistent and permanent stages. At a paroxysmal stage, the arrhythmia period is more than 30 seconds and shorter than one week, and if arrhythmia lasts for more than 7 days and lesser than one year, the disease will develop in a persistent stage, and finally, if arrhythmia lasts for more than one year, the disease entered into permanent stage [2].

AF affected 21 million men and 13 million women based on 2010 data which prevalence rate is much more in developed countries [3, 4]. According to present evidence, about one-third of cardiac arrhythmia hospitalizations are due to AF and its rate has increased up to 66% over the last 20 years. This increase can be due to the process of aging of the population, an increase in the prevalence of cardiac chronic diseases, and an increase in diagnosis cases due to advances in diagnostic technologies [5].

There are various methods to treat AF, and catheter ablation is one of the most important methods. Ablation is a non-surgical method that removes the region which consists of abnormal pathways with specific waves. Nowadays this method is widely used to treat types of atrial tachycardia (rapid pulse rate), such as AF, atrial flutter, and some types of ventricular tachycardia. In this method, an electrophysiologist inserts into heart cavities one or more catheters with electrodes at the end and uses a type of energy to ablate the abnormal texture of the heart, which causes extra electrical messages. The area of heart tissue that is ablated is too small and does not affect the total function of the heart. A small and safe repaired tissue in this area is formed and the normal rhythm of the heart will return [6, 7].

Ablation has various types. One type is point-by-point ablation around vessels using Radiofrequency ablation (RFA). In this method, a wire is entered through the groin, and the focal point of arrhythmia is burnt by entering these waves [7]. Another type is Cryoballoon ablation (CBA). In this method, the physician enters a wire into the heart through the groin and places it at the focal point of arrhythmia. But this balloon is cooled through nitrogen flow, and the focal point of arrhythmia is ablated through freezing. In uncoordinated arrhythmia of AF which has numerous focal points of the arrhythmia, one type of balloon could be used which spontaneously the focal points are frozen by nitrogen flow [7].

According to recent findings, ablation technologies are the most effective therapeutic methods to improve the status of patients with AF and have the highest effect on preserving cardiac sinus rhythm as well as improving quality of life [8, 9], but besides, also have a different financial burden and risk load rather than other therapeutic methods.

There are some evidence regarding differences between two ablation technologies which some of these studies showed that these two methods have identical clinical efficacy and safety, have almost low side effects and showed no considerable preference in none of the methods [10, 11]. But economically, studies around the world showed sometimes contradictory results regarding the cost-effectiveness of each method. For example, the results of the study by Ming et al. (2019) in china and Murray et al. study (2019) in Germany showed that CBA is a cost-effective strategy compared to RFA. In contrast, in the study by Sun et al. (2019), the results showed the cost-effectiveness of RFA.

In Iran, because CBA is a relatively new technology in Iran, studies on comparing the costs and effectiveness related to this technology with other existing treatment methods are scarce, and based on our information, no full economic evaluation study has been conducted to compare these two technologies, and the present study is the first study in Iran in this regard.

To provide appropriate evidence to decide on application and coverage of the most appropriate technology, the current study was designed to assess the cost-utility of CBA compared to RFA to treat patients with paroxysmal AF in Iran.

Materials and methods

The present study is a full economic evaluation based on a decision-analytic model which compared two strategies of CBA and RFA in Iran. Accordingly, the cost-utility analysis method was used. Various stages of economic evaluation were performed based on reference guideline of the national institute for health and care excellence (NICE) to perform economic evaluation of health technologies [12]. Also, we matched the study reports and findings with the CHEERS checklist [13].

Modeling

The economic model was designed based on a literature review, the natural history of the disease, the process of performing ablation methods in patients with paroxysmal AF, clinical outcomes, probabilities of occurrence of outcomes, and incidence of expenses.

To design the model, specialized panels were formed with the presence of a team of clinical specialists and economic team. After trial and error of various models, the final model was extracted by consensus and considering the most important clinical and economical outcomes based on natural history. The designed economic evaluation model is demonstrated in Fig 1. The structure is the same for both arm.

Fig 1

Markov model for CUA of CBA vs RFA.

The model structure is designed so that each strategy is based on a lifetime Markov structure with a one-year cycle length. In each Markov structure, five health states including AF pre-intervention, normal sinus rhythm (NSR), AF post-intervention, AF post-re-intervention, post-stroke, and death were considered. Individuals in both comparable groups were at the AF before ablation health state in zero cycle. It was assumed that individuals in each health state remained at the end of each cycle or went through other health states or died. Also, patients can place in are-ablation state once, and due to lack of sufficient evidence, third ablations and higher were not considered in the model, and considering AF post-re-intervention health state was for this purpose.

To extract evidence regarding mortality rate and other evidence, the mean age of 50 years (due to the mean age of patients undergoing ablation based on accessible hospital information from Shahid Rajaie Cardiovascular Medical and Research Center in Tehran) for patients at initiation of Markov models were considered.

Extracting parameters and analyzes

This study was performed from the perspective of Iran’s health system and as mentioned, the time horizon was considered as lifetime, and costs and outcomes were estimated accordingly.

Since the current study was a full economic evaluation, the quality-adjusted life years (QALYs) index was considered as outcome measure and its value at each health state is computed by estimating patients’ utility at each state. Also, in this section, the amount of disutility caused by the side effects of ablation in health states was considered.

The Status of cost-effectiveness of each strategy was finally assessed based on cost per unit of QALY. Evidence related to patients’ utility at each health state was extracted from international studies. Regarding costs, due to the study perspective, direct medical costs were only considered.

The cost of each strategy was estimated by the cost of various health states based on cost units used in interventions. Cost of performing the procedure of CBA and RFA including the cost of CBA and RFA, costs related to management and supervision of receiving services in hospital, costs of hospitalization, supportive, therapeutic, and pharmaceutical cares, and costs related to side effects were considered. Data collection for costing was from medical records of 47 patients of Shahid Rajaie Cardiovascular Medical and Research Center in Tehran in 2019–20. Since all the medical records related to 2019–20 were accessible, sampling was not done for this purpose, and hospital bills of all patients undergoing both ablation methods were assessed. Accordingly, 27 and 20 medical records related to CBA and RFA were assessed, respectively. The cost of other medical attempts required at health states independent from the cost of the procedure was determined based on therapeutic protocols. Accordingly, the type of anti-coagulant and anti-arrhythmic medications, and their doses until a definite time, cost of hiring a Holter monitor device, and cost of electrical cardioversion were determined. All the mentioned cases were different in various patients and therefore, by consultation with clinical specialists, a moderate amount of costs was considered. The cost of side effects was estimated based on evidence of previous studies and re-costing based on tariffs and domestic currency (Table 1).

Table 1

Model inputs and parameters.

Statistic variable	Base case	SD/(CI)	Distribution	Source
Annual discount rate (Costs and QALYs)	0.05	(0–0.1)	Beta
Time Horizon(year)	Life Time
Transition Probabilities (CBA group)
AF recurrence after ablation, first year	0.269	±0.0538	Beta	[14]
AF recurrence after ablation, >first year	0.0938	±0.0235	Beta	[15]
Re-intervention with RFA	0.5516	±0.11032	Beta	[15]
Re-intervention with CBA	0..0951	±0.01902	Beta	[15]
Probability of Complications (CBA group)
pericardial effusion or cardiac tamponade	0.0084			[14]
permanent phrenic nerve palsy	0.032			[14]
vascular complications	0.0156			[14]
Stroke rate per year	0.05			[16]
Transition Probabilities (RFA group)
AF recurrence after ablation, first year	0.3326	±0.0665		[14]
AF recurrence after ablation, >first year	0.1055	±0.0264		[15]
Re-intervention with RFA	0.5685	±0.1137		[15]
Re-intervention with CBA	0.0587	±0.01174		[15]
Probability of Complications (RFA group)
pericardial effusion or cardiac tamponade	0.0231			[14]
permanent phrenic nerve palsy	0.0005			[14]
vascular complications	0.023			[14]
Stroke per year	0.05			[16, 17]
Probability of death
Annually probability of death of 50 yrs Normal Population (First year)*	0.0037			Iran Life Table [18]
Probability of operative death	0.000487			[19]
Stroke-specific mortality	0.3536			[20]
Costs($)
AF average annual costs	372.81	±55.92	Gamma	Our Study
NSR average annual costs	273.32	±40.99	Gamma	Our Study
CBA	7751.88	±516.72	Gamma	Our Study
RFA	5027.10	±1530.66	Gamma	Our Study
Stroke costs, first year	1804.49	±180.44	Gamma	Our Study
Post-stroke costs, >first year	541.34	±54.13	Gamma	Our Study
pericardial effusion or cardiac tamponade	1060.19	±106.01	Gamma	[9], adjustment
permanent phrenic nerve palsy	11.09	±106.01		[9], adjustment
vascular complications	60.23			[9], adjustment
Utilities
NSR	0.8	±0.00577	Beta	[21]
AF	0.6	±0.0721	Beta	[21]
Post-stroke	0.46	±0.0577	Beta	[22]
Disutility due to complications	-0.0314		Beta	[23]
Disutility due to stroke, first year	-0.296		Beta	[24]

* A complete table of Probability of death at different ages is given as S1 Table.

All the stages of costing were calculated by holding a specialized panel with a clinical team and based on governmental tariffs of Iran’s Ministry of Health. All costs were calculated based on 2019–20 prices.

Other parameters and variables related to transition probabilities among health states of two strategies, the risk of mortality at each health state, mortality risk caused by ablation methods, the efficacy of interventions, and other parameters including the risk of side effects of each ablation method were extracted from international evidence. In this regard, based on each parameter, a distinct literature review was performed in scientific databases, and studies with appropriate evidence were classified and finally, the best evidence was extracted. In terms of side effects, we included “pericardial effusion”, “cardiac tamponade”, “permanent phrenic nerve palsy”, “vascular complications” and “Stroke” as side effects of the technologies in the model, which we considered both their related cost and the disutility values. The choice of side effects in the present study was based on the evidence from previous studies and also in consultation with the clinical specialists. Values of parameters and variables of the model and their references are given in Table 1.

We used a 5% the discount rate for both costs and QALYs in the model based on the recommendation of the Health Technology Assessment Office of Iran’s Ministry of Health for this study.

Cost-effectiveness analysis

To perform analysis and determine the most cost-effective strategy, due to the costs and effectiveness of each strategy, the incremental cost-effectiveness ratio (ICER) was calculated.

The equation for this index was as below:

In, C1, 2 represents the cost of CBA and RFA, and E1, 2 represents their effectiveness.

In this study, the cost-effectiveness threshold was considered to be one time of GDP per capita equal to $7142. This choice was made on the recommendation of the World Health Organization to select 1 to 3 times the per capita GDP in developing countries [25].

To perform all stages of modeling and analysis of results, TreeAge 2020 software was used.

Sensitivity analysis

Given the uncertainty regarding some parameters used in the model, Deterministic and Probabilistic Sensitivity Analysis of the results of the model was performed.

To perform Deterministic Sensitivity Analysis (DSA), one-way sensitivity analysis, and Tornado diagram, and two-way sensitivity analysis were used.

PSA was performed considering the probability distribution of uncertain variables using Monte Carlo simulation. The range used for uncertainty in point estimation of each variable and statistical distributions used in PSA is presented in Table 1. For example, for the cost variables gamma distribution and other variables such as the transition probabilities, the beta distribution was considered. In cases in which no evidence regarding the variance of the variable was found, 10% or 20% of the mean values of variable were considered as standard deviation, and appropriate distribution was selected due to the type of variable.

Ethics approval and consent to participate

The Present study did not make use of human or animal subjects and/or tissue.

This research was approved by the ethical committee of Tehran University of Medical Sciences (TUMS) by the code of IR.TUMS.VCR.REC.1399.453.

Results

Base case analysis

Table 2 represents the results of the cost-utility analysis. Accordingly, the results showed that average lifetime costs per patient associated with CBA and RFA were $14,198 and $12,005, respectively. Average QALYs per patient were estimated at 8.469 and 8.273 for both strategies, respectively. Accordingly, ICER was estimated at $11,223.85 per QALY unit, which compare to Iran’s WTP threshold represents a lack of cost-effectiveness of CBA technology compare to RFA.

Table 2

Results of base case cost-effectiveness analysis.

Strategy	RFA	CBA
Cost($)	12,005.20	14,198.36
QALYs	8.273	8.469
Incremental Cost($)	-	2,193.16
Incremental QALYs	-	0.195
ICER($/QALY)	-	11,223.85

Fig 2 also showed the cost-effectiveness plane of analysis. As observed, the CBA strategy is associated with higher costs and higher effectiveness than the RFA, and this amount of QALYs obtained in exchange for the increased cost due to CBA is not cost-effective based on the considered threshold.

Fig 2

Cost-effectiveness analysis of CBA vs RFA.

Deterministic Sensitivity Analysis (DSA)

One-way DSA of all uncertain variables is presented in Fig 3 using the Tornado diagram. Variables include the cost of CBA, cost of RFA, probability of recurrence after CBA, and RFA and probability of re-ablation using CBA in the RFA group were considered for DSA. As observed in Fig 3, changes in values of RFA cost had the highest effect, and the probability of recurrence after CBA had the lowest effect on the results of the study. Besides, based on the diagram, all uncertain variables except for recurrence after RFA consist threshold and in distinct values change results of final analysis according to the considered confidence interval. It should be noted that to assess the uncertainty of parameters more precisely, the confidence interval of variables was considered widely.

Fig 3

One way sensitivity analysis using Tornado diagram.

Fig 4 shows the results of one-way sensitivity analysis of RFA cost. As observed, this variable consists of the threshold at the value of $5738 (about $714 higher than the base case), and at this value, the results of the cost-utility analysis were changed and showed approximately high sensitivity to changes in this variable. To assess more precisely, two-way sensitivity analysis was done based on the changes in the cost of CBA and RFA variables. As observed in Fig 5, the results of the cost-utility analysis show sensitivity to changes in these two variables.

Fig 4

One way sensitivity analysis (RFA cost).

Fig 5

Two way sensitivity analysis (RFA cost and CBA cost).

In general, the results of DSA showed that the results of analysis have considerable sensitivity to changes in uncertain variables.

Probabilistic Sensitivity Analysis (PSA)

By considering the function of the probability distribution of uncertain variables, PSA was done using Monte Carlo simulation by considering a number of the 10,000 times of repeating simulation and sampling.

Fig 6 shows that Incremental Cost-Effectiveness scatter plot of CBA versus RFA in 10000 times of repeating sampling and simulation. In addition, Table 3 presented a report on the probability of placement of the CBA strategy at each cost-effectiveness plot region compared to the RFA strategy. As it is observed, the probability of placement of CBA at regions of I, III, and IV and below the WTP threshold (cost-effectiveness regions) was 41%, and the probability of cost-effectiveness of RFA was 59% which these results, confirmed base case analysis results.

Fig 6

Incremental cost-effectiveness scatter plot for PSA.

Table 3

Report of the cost-effectiveness probability in each cost-effectiveness plane quadrants.

Component	Quadrant	Incre Eff(IE)*	Incre Cost(IC)**	Incre CE***	Frequency	Proportion (%)
C1	IV	IE>0	IC<0	Superior	1,388	0.1388
C2	I	IE>0	IC>0	ICER<3.0E8	2,772	0.2772
C3	III	IE<0	IC<0	ICER>3.0E8	35	0.0035
C4	I	IE>0	IC>0	ICER>3.0E8	3,103	0.3103
C5	III	IE<0	IC<0	ICER<3.0E8	41	0.0041
C6	II	IE<0	IC>0	Inferior	2,661	0.2661
Indiff	origin	IE = 0	IC = 0	0/0	0	0

*Incremental Effectiveness

**Incremental Cost

***Incremental Cost Effectiveness

Discussion

This study aimed to analyze the comparative cost-utility of two technologies of CBA and RFA in the treatment of patients with paroxysmal AF in Iran.

Evidence review of these two novel technologies showed that in most countries they have better safety and efficacy rather than anti-arrhythmia medications in returning NSR [26-28]. Regarding the clinical efficacy of two technologies in the treatment of AF patients, most review studies showed that there is no significant difference between the two methods as well as their side effects, and in this regard, none of them is superior [7, 10, 29, 30]. Of course, some other studies show a little superiority of CBA in this regard [14]. Therefore, it seems that economic assessment of these two technologies through applying them in the health care system is of most importance. Results of the present study showed that in a base case analysis of CBA and RFA comparison, CBA at WTP threshold of $7,142 was not cost-effective, but was cost-effective at a WTP of $14,285 (twice the GDP per capita).

Previous studies comparing these two technologies in various countries also show controversial results. For example, studies by Murray et al. (2018) in Germany and Sun et al. (2019) in china confirmed our findings [9, 31], in contrast, a study by Ming et al. (2019) in China showed that CBA compared to RFA is the dominant strategy in the treatment of patients with AF due to lower cost and QALY values [15].

PSA of results also confirmed findings of base case analysis, and accordingly, results showed that by repeating sampling and simulation based on statistical distributions of uncertain variables, RFA strategy by the probability of about 60% would be cost-effective. DSA showed that results of analysis have a higher sensitivity to changes of some variables, and in some values, variables have a threshold and could change total results. Results of the study had the highest sensitivity to changes in RFA costs. Accordingly, as observed, if the cost of the RFA is $5,738 instead of $5,127, the results will change and CBA will be cost-effective.

By more assessment on variables of RFA and CBA costs and considerable difference in cost of these two technologies, it was clarified that a part of this cost difference might be due to re-use of some procedure requirements and not applying some sidelong tools in the procedure of RFA which decreases costs of this intervention. This issue could increase the risk of side effects and decrease the efficacy of treatment considering comments of specialists, but since no appropriate evidence was found for this issue, it was not considered in the economic evaluation model. In other words, decreasing in costs was considered in the model due to re-use of procedure requirements, but negative outcomes related to that were not considered due to lack of appropriate evidence, which this issue increased the chance of RFA for cost-effectiveness. Accordingly, it seems that the results of the study must be interpreted and used cautiously.

The present study is the first economic evaluation for the comparison of ablation technologies in Iran. As mentioned, just hospital data of a specialized hospital was used, and due to lack of access to hospital data of other centers, a comparison of costs at various centers was not achieved. Besides, since clinical studies regarding the efficacy of technologies and associated side effects in Iran were not found, the best present evidence of international studies was just used. Although in many cases there is no significant difference between different contexts regarding clinical evidence, this is one of the possible limitations of this study that can be effective in the final results. However, to eliminate this possible limitation as much as possible, in the present study we performed a sensitivity analysis of a wide range for uncertain parameters. Another limitation of the study was regarding re-ablations. So that, appropriate evidence-based on substitution of each technology in case of failure of primary ablation was not found in Iran, and thereby, international evidence was also used in this regard.

Conclusions

Findings obtained from our study showed that based on Iran’s Health system perspective, CBA technology compared to RFA is not a cost-effective strategy to treat patients with paroxysmal AF at a threshold of one time of Iran’s GDP per capita. This is while, considering twice the GDP per capita and higher as the threshold, CBA was cost-effective. On the other hand, the results of sensitivity analysis showed that results of the evaluation model have considerable sensitivity to changes in uncertain variables such as ablation costs. In general, it is not possible to conclude with certainty about the cost-effectiveness of CBA against RFA in Iran.

Probability of death at different ages (Iran Life Table).

(DOCX)

Click here for additional data file.

26 Jan 2022

Cost-Utility Analysis of Cryoballoon Ablation versus Radiofrequency Ablation in the Treatment of Paroxysmal Atrial Fibrillation; Case Study: Iran

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Reviewer #1: General comments:

This paper focusses on the cost-effectiveness of two alternative treatment methods (Cryoballoon Ablation versus Radiofrequency Ablation) for paroxysmal Atrial Fibrillation. I would like to thank the authors for their work. I think the study is interesting and it can be brought to a publishable level after some revisions.

I think the authors need to use a checklist to ensure a high-quality standard of reporting, such as CHEERS. More details and justification needed when explaining the model and the parameters. I think the probabilistic sensitivity analyses need to be repeated as I have some concerns over the choice of comparator. There are also some inconsistencies between the Figures and the text. I think some the tables need to be re-organised as well. I explain these below.

The text needs to be updated to improve the flow and it should be grammatically checked. The authors may find using online applications (such as Grammarly) helpful. There is repetition at some places, so please make sure there is not two different sentences with the same meaning. Please also add page numbers to the manuscript.

Specific comments:

Page 9 – Abstract:

Line 51. Please provide a reference here.

Line 52. "should be of which"

Line 53. Please add paroxysmal before AF to be clear. I also suggest removing "analysis" and inserting "the" before cost utility.

Line 60. Please remove the word “rather” as it is not used to make comparisons.

Line 61. I think "one time" unnecessary here since when it is just the GDP we understand that it is one time of the GDP.

Line 62. Please remove “but” to avoid redundancy

Lines 63 and 65. It sounds as if PSA and Monte Carlo simulation are two different analyses while in fact, they refer to the same analysis. I suggest re-writing this sentence. Also, instead of saying "by probability of 60%" it might be clearer to say, "the probability of cost-effectiveness was 60%."

Page 10 – Introduction:

I think in the introduction, there is too much focus on the clinical aspects and too little on the cost-effectiveness. The authors need to explain what we already know about the cost-effectiveness of CBA and RFA then tell us about the limitations of existing economic models and why a new model was needed.

Line 73. It is hard to follow this sentence so, I suggest dividing into two or three sentences.

Page 11

Line 115. Please, here and everywhere in the text, add "paroxysmal" to be clear

Page 12

Line 121. This guideline is not for health projects but for health technologies.

Line 124. I think the authors refer to the design of the economic model - I'd update this sentence as “The economic model was designed based on a literature review ...”

Line 130. The word “observed” is not meaningful here it should be replaced with a word like “demonstrated”.

Line 132. For consistency, please consider updating the first state's name to "before intervention" or the word "intervention" in the other states to "ablation".

Lines 136 and 138. Please re-phrase this sentence to be clear and I'd suggest starting it with "It was assumed that..."

Page 13

Figure 1. I think the model demonstration in Figure 1 doesn't match the description in the text.

I think the authors should draw another tree. For example, one of the health states is Atrial Fibrillation I think this should be pre-intervention. Similarly, it is confusing to see CBA just after Atrial Fibrillation but not RFA.

In the methods section, the authors need to explain and justify why specific complications were chosen and not the others.

Additionally, the price year needs to be stated in the methods section.

Line 139. Evidence is a singular word: we cannot write evidence. Please correct this everywhere

Line 140. This needs to be explained more which hospital? The hospital that you took the cost data. You may also cite the existing studies here. Additionally, please rephrase this sentence.

Lines 152 and 153. I don't understand this sentence: could you please rephrase?

Line 163. This needs to be supported with published evidence.

Page 14

Lines 165 and 166. A list of costs which shows the figures taken from the literature and the figures estimated by the authors should be presented as an Appendix.

Line 168. Is it publicly available? If so, please provide a reference or provide a summary table as an Appendix.

Table 1. The authors state following the NICE recommendations; however, they used a discount rate of 0.05. This should be explained and justified.

Table 1 includes mortality during first year, but it is not clear what probability was used after the first year. The authors need to explain this in the text.

Table 1 reports the probabilities for complications under the title of “transition probabilities” and this is really confusing. I think Table 1 needs to be re-organised such that the transition probabilities and morbidity risks are clear.

The SD or CI should be provided for all the probabilities

What is a life table? Please cite a reference or provide this table as an Appendix.

In Table 1 some parameters were identified through “survey and calibration” this needs to be explained in the text. What do you mean when you say survey and calibration? We need to see the original figures/values and those used in the model after adjustments.

Page 16

Line 189. Citation needed here. I think WHO recommends using three times of GDP as the threshold. Please explain why you have chosen to use the GDP. Please see this paper on the thresholds recommended by WHO https://www.who.int/bulletin/volumes/93/2/14-138206.pdf

Line 200. This needs to be more specific. 10%, 20% or a range of values between 10% and 20%?

Line 201. Please provide a reference here to show how you have chosen the appropriate distributions.

Page 17

Line 204. Please use commas for costs to make sure these are clear. For example, is it $14,198.3?

Table 2. Please re-organise this table and report the incremental figures in a separate raw. Also, please change the column name from Eff** to QALYs to be more specific.

Page 18

Figure 3. This figure is confusing because the impact on the net benefit was demonstrated which was not mentioned anywhere in the text. Please repeat this analysis to show the impact of changing inputs on ICER calculations. Additionally, we cannot tell which lower and upper values were used. So, please provide these on the graph. Please re-label the parameters and try not to use abbreviations. Please

also explain what EV represents. Again, use commas for costs.

Figures 4 and 5. Please repeat these analyses using ICERs not net benefits.

Line 242. Why 1000 times? why not 5000 or 10000? This needs to be justified.

Line 243. This sentence raises concern. It was said that the cost-effectiveness of CBA would be estimated compared to RFA. However, the PSA was conducted to estimate the cost-effectiveness of CBA and RFA compared to something else which was not explained to the reader. Is the probability of CBA being cost-effective compared to RFA 59% as stated in the abstract or is the probability of CBA being cost-effective compared to something else is 59%? The authors need to clarify this and repeat the analysis to compare CBA to RFA.

Page 19

Figure 7. This figure is in line with the text, so maybe use this on and remove Figure 6 and related text. Here, please change effectiveness to QALYs.

Table 3. I don't think this makes sense. We don't need this table, just remove it please.

Page 20

Lines 262 and 265. This part should be moved to introduction.

Line 269. Please don't repeat the results here - it would be enough just to say that it was not cost-effective at a WTP of $7,142 but cost-effective at a WTP of $14,285.

Line 273. It would be good to spell out why your results are different than theirs.

Line 279. Why would the cost of RFA increase? Please rephrase this as "the cost of RFA is $5,738 not $5,127 ..."

Line 282. I don't understand this phrase (re-use of necessities). Please explain what this means.

Page 21

Line 298. We wouldn't say viewpoint to describe the perspective in economic evaluations.

Reviewer #2: • Please remove "Case Study" from the title. English language of the manuscript needs to be improved. - Proof-editing the manuscript because grammar, punctuation and use of acronyms is rather poor. Please check keywords with Mesh terms. The authors should harmonize the cost-utility/ cost utility in the manuscript. Lines 188-189: please add some references. Line 190: TreeAge 2011 software/ line 59: TreeAge pro 2020 software. Please correct.

**********

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Reviewer #1: Yes: Tuba Saygin Avsar

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11 Mar 2022

Reviewer 1 Comments:

Dear reviewer

Thank you for your invaluable comments and guidance to improve our manuscript.

We presented the responses one by one on your comments as follows:

Reviewer #1: General comments:

This paper focusses on the cost-effectiveness of two alternative treatment methods (Cryoballoon Ablation versus Radiofrequency Ablation) for paroxysmal Atrial Fibrillation. I would like to thank the authors for their work. I think the study is interesting and it can be brought to a publishable level after some revisions.

I think the authors need to use a checklist to ensure a high-quality standard of reporting, such as CHEERS. More details and justification needed when explaining the model and the parameters. I think the probabilistic sensitivity analyses need to be repeated as I have some concerns over the choice of comparator. There are also some inconsistencies between the Figures and the text. I think some the tables need to be re-organised as well. I explain these below.

The text needs to be updated to improve the flow and it should be grammatically checked. The authors may find using online applications (such as Grammarly) helpful. There is repetition at some places, so please make sure there is not two different sentences with the same meaning. Please also add page numbers to the manuscript.

Response: Thanks for your invaluable comments. Final manuscript was revised by native English editor. We matched the study reports and findings with the CHEERS checklist. Also, we applied other specific comments as much as possible.

Specific comments:

Page 9 – Abstract:

Line 51. Please provide a reference here.

Response: It was revised based on your comment.

Line 52. "should be of which"

Response: Thanks for your comment. It was revised based on your comment.

Line 53. Please add paroxysmal before AF to be clear. I also suggest removing "analysis" and inserting "the" before cost utility.

Response: Thanks for your comment. It was revised based on your comment.

Line 60. Please remove the word “rather” as it is not used to make comparisons.

Response: It was removed.

Line 61. I think "one time" unnecessary here since when it is just the GDP we understand that it is one time of the GDP.

Response: Thanks for your comment. It was removed based on your comment.

Line 62. Please remove “but” to avoid redundancy

Response: It was revised based on your comment.

Lines 63 and 65. It sounds as if PSA and Monte Carlo simulation are two different analyses while in fact, they refer to the same analysis. I suggest re-writing this sentence. Also, instead of saying "by probability of 60%" it might be clearer to say, "the probability of cost-effectiveness was 60%."

Response: Thanks for your comment. It was revised based on your comment.

Page 10 – Introduction:

I think in the introduction, there is too much focus on the clinical aspects and too little on the cost-effectiveness. The authors need to explain what we already know about the cost-effectiveness of CBA and RFA then tell us about the limitations of existing economic models and why a new model was needed.

Response: Thanks for your comment. It was revised based on your comment. We explain results of some similar studies in “Introduction” section. In Iran, as mentioned in the text, no full economic evaluation study has been conducted to compare these two technologies, and present study is the first study in Iran in this regard. Due to the fact that the results of similar economic evaluation studies are different in different contexts, the present study was conducted for the first time in Iran.

Line 73. It is hard to follow this sentence so, I suggest dividing into two or three sentences.

Response: It was revised based on your comment.

Page 11

Line 115. Please, here and everywhere in the text, add "paroxysmal" to be clear

Response: Thanks for your comment. It was revised based on your comment.

Page 12

Line 121. This guideline is not for health projects but for health technologies.

Response: Thanks for your comment. It was revised.

Line 124. I think the authors refer to the design of the economic model - I'd update this sentence as “The economic model was designed based on a literature review ...”

Response: Thanks. It was revised based on your comment.

Line 130. The word “observed” is not meaningful here it should be replaced with a word like “demonstrated”.

Response: Thanks for your comment. It was revised based on your comment.

Line 132. For consistency, please consider updating the first state's name to "before intervention" or the word "intervention" in the other states to "ablation".

Response: Thanks for your comment. It was revised based on your comment.

Lines 136 and 138. Please re-phrase this sentence to be clear and I'd suggest starting it with "It was assumed that..."

Response: Thanks for your comment. Sentences revised based on your comment.

Page 13

Figure 1. I think the model demonstration in Figure 1 doesn't match the description in the text.

Response: Description Sentences was revised. Figure 1 and related description was matched.

I think the authors should draw another tree. For example, one of the health states is Atrial Fibrillation I think this should be pre-intervention. Similarly, it is confusing to see CBA just after Atrial Fibrillation but not RFA.

Response: Thanks for your comment. Given that the structure of the model is similar in the two comparison arms, in Figure 1 we only included the model structure of one arm. Also, we revised the health state name from “Atrial Fibrillation” to Pre-intervention Atrial fibrillation. Please See revised Fig 1.

In the methods section, the authors need to explain and justify why specific complications were chosen and not the others.

Additionally, the price year needs to be stated in the methods section.

Response: It was revised based on your comment. As mentioned in the text (method section) we included “pericardial effusion” , “cardiac tamponade”, “permanent phrenic nerve palsy”, “vascular complications” and “Stroke” as side effects of the technologies in the model, which we considered both their related cost and the disutility values. The choice of side effect in present study was based on the evidence from previous studies and also in consultation with the clinical specialists.

Line 139. Evidence is a singular word: we cannot write evidence. Please correct this everywhere

Response: It was revised based on your comment.

Line 140. This needs to be explained more which hospital? The hospital that you took the cost data. You may also cite the existing studies here. Additionally, please rephrase this sentence.

Response: Thanks for your comment. It was revised based on your comment and highlighted.

Lines 152 and 153. I don't understand this sentence: could you please rephrase?

Response: It was revised.

Line 163. This needs to be supported with published evidence.

Response: Thanks for your comment. It was revised based on your comment.

Line 168. Is it publicly available? If so, please provide a reference or provide a summary table as an Appendix.

Response: Thanks for your comment. All the parameters, values and evidence used are given in Table 1.

Table 1. The authors state following the NICE recommendations; however, they used a discount rate of 0.05. This should be explained and justified.

Response: We used the NICE reference case to conduct economic evaluations. Only regarding the discount rate, considering the context of Iran, we decided to use a higher discount rate. However, we considered lower and higher values in the sensitivity analysis.

Table 1 includes mortality during first year, but it is not clear what probability was used after the first year. The authors need to explain this in the text.

Response: Thanks for your comment. As you know, the probability of mortality increases with age and this issue is considered in Markov model using table. In Table 1, we only mentioned the probability of death in the first year. We can include the entire probability of death table (Iran Life Table) as S1 in Supporting Information. Please see S1 in Supporting Information.

Table 1 reports the probabilities for complications under the title of “transition probabilities” and this is really confusing. I think Table 1 needs to be re-organised such that the transition probabilities and morbidity risks are clear.

Response: Table 1 revised based on your comment.

The SD or CI should be provided for all the probabilities

Response: Thanks for your comment. We provide SD or CI for variables which were used in sensitivity analysis only. SD or CI for other variables were not used for other variables in the model.

What is a life table? Please cite a reference or provide this table as an Appendix.

Response: Thanks for your comment. As mentioned above, we include the entire probability of death of normal population (Iran Life Table) as S1 in Supporting Information. Please see S1 in Supporting Information. Also, reference was added in table 1.

In Table 1 some parameters were identified through “survey and calibration” this needs to be explained in the text. What do you mean when you say survey and calibration? We need to see the original figures/values and those used in the model after adjustments.

Response: Thanks for your comment. By “survey and calibration” we mean that the values are not used from another reference and are obtained in the present study. But to avoid misunderstandings we replaced it with “our study” in table 1.

Page 16

Line 189. Citation needed here. I think WHO recommends using three times of GDP as the threshold. Please explain why you have chosen to use the GDP. Please see this paper on the thresholds recommended by WHO https://www.who.int/bulletin/volumes/93/2/14-138206.pdf

Response: Thanks. We added reference. WHO recommended 1 to 3 times the per capita GDP for cost effectiveness threshold in developing countries.

Also, the following articles have reviewed the threshold recommended by who, saying that three times the per capita GDP as a cost-effectiveness threshold is high. Please see:

1. Bertram MY, Lauer JA, De Joncheere K, et al. Cost-effectiveness thresholds: pros and cons. Bull World Health Organ. 2016;94(12):925–930.

2. Marseille E, Larson B, Kazi DS, Kahn JG, Rosen S. Thresholds for the cost–effectiveness of interventions: alternative approaches. Bull World Health Organ. 2015;93(2):118–124.

Line 200. This needs to be more specific. 10%, 20% or a range of values between 10% and 20%?

Response: As mentioned in manuscript about PSA, in cases which no evidences regarding variance of the variable were found, 10-20% of mean values of variable was considered as standard deviation. In some cases 10% and in some cases 20%.

Line 201. Please provide a reference here to show how you have chosen the appropriate distributions.

Response: Thanks for your comment. As mentioned in manuscript, the range used for uncertainty, statistical distributions and related reference of each variable used in PSA are presented in table 1. In cases which no evidences regarding variance of the variable were found, 10-20% of mean values of variable was considered as standard deviation. In some cases 10% and in some cases 20%.

Page 17

Line 204. Please use commas for costs to make sure these are clear. For example, is it $14,198.3?

Response: Thanks for your comment. It was revised based on your comment.

Table 2. Please re-organise this table and report the incremental figures in a separate raw. Also, please change the column name from Eff** to QALYs to be more specific.

Response: It was revised based on your comment. Please see revised Table 2.

Page 18

Figure 3. This figure is confusing because the impact on the net benefit was demonstrated which was not mentioned anywhere in the text. Please repeat this analysis to show the impact of changing inputs on ICER calculations. Additionally, we cannot tell which lower and upper values were used. So, please provide these on the graph. Please re-label the parameters and try not to use abbreviations. Please

also explain what EV represents. Again, use commas for costs.

Response: Thanks for your comment. It was revised based on your comment. Also, we mentioned EV (Expected Value) represents ICER. Please see revised figure 3. Also, commas were used in whole text for costs.

Figures 4 and 5. Please repeat these analyses using ICERs not net benefits.

Response: Thanks for your comment. We repeat the sensitivity analysis again based on your comment. Please see revised figure 3.

Line 242. Why 1000 times? why not 5000 or 10000? This needs to be justified.

Response: Thanks for your comment. As you know, there is no specific reference to how many times we do the sampling in monte-carlo simulation, and researchers usually determine this amount based on the study, which is usually considered 100 or 1000 times in most studies. But in order to be more precise in this regard, we repeat the monte-carlo simulation by 10,000 times sampling. Please see.

Line 243. This sentence raises concern. It was said that the cost-effectiveness of CBA would be estimated compared to RFA. However, the PSA was conducted to estimate the cost-effectiveness of CBA and RFA compared to something else which was not explained to the reader. Is the probability of CBA being cost-effective compared to RFA 59% as stated in the abstract or is the probability of CBA being cost-effective compared to something else is 59%? The authors need to clarify this and repeat the analysis to compare CBA to RFA.

Response: We definitely meant that the probability of CBA being cost-effective compared to RFA is 59% based on strategy selection diagram. Of course, we deleted this chart based on reviewers’ comment at this stage. We reported the PSA findings solely on the basis of the Scatter plot and 10,000 iterations.

Page 19

Figure 7. This figure is in line with the text, so maybe use this on and remove Figure 6 and related text. Here, please change effectiveness to QALYs.

Response: It was revised based on your comment.

Table 3. I don't think this makes sense. We don't need this table, just remove it please.

Response: Thanks for your comment. We reported this table to determine the exact percentage placement of interventions in each quadrant of the cost-effectiveness plane. However, if you insist on this comment, we can delete this section in the next step.

Page 20

Lines 262 and 265. This part should be moved to introduction.

Response: Thanks. We would like this section not to be removed from the discussion. In fact, we used this as an introduction to this section to compare the effectiveness and cost-effectiveness of technologies. However, if you insist on this comment, we can delete this section in the next step.

Line 269. Please don't repeat the results here - it would be enough just to say that it was not cost-effective at a WTP of $7,142 but cost-effective at a WTP of $14,285.

Response: Sentences was revised based on your comment.

Line 279. Why would the cost of RFA increase? Please rephrase this as "the cost of RFA is $5,738 not $5,127 ..."

Response: We rephrased it. Please see.

Line 282. I don't understand this phrase (re-use of necessities). Please explain what this means.

Response: We revised this phrase. Please see discussion.

Page 21

Line 298. We wouldn't say viewpoint to describe the perspective in economic evaluations.

Response: Thanks for your comment. It was revised based on your comment.

Reviewer #2:

Thank you for your invaluable comments and guidance to improve our manuscript.

We presented the responses one by one on your comments as follows:

Please remove "Case Study" from the title.

Response: Thanks for your comment. It was revised based on your comment.

English language of the manuscript needs to be improved.

Response: Thanks for your comment. Manuscript was revised by native English editor.

Proof-editing the manuscript because grammar, punctuation and use of acronyms is rather poor.

Response: Thanks for your comment. Manuscript was revised by native English editor.

Please check keywords with Mesh terms.

Response: It was revised based on your comment.

The authors should harmonize the cost-utility/ cost utility in the manuscript.

Response: Thanks for your comment. Manuscript was revised based on your comment.

Lines 188-189: please add some references.

Response: Thanks for your comment. Reference was added.

Line 190: TreeAge 2011 software/ line 59: TreeAge pro 2020 software. Please correct.

Response: Thanks for your comment. It was revised. We used TreeAge pro 2020 software.

Submitted filename: response to reviewers.docx

Click here for additional data file.

16 May 2022

23 May 2022

Response to reviewers: Round 2

Reviewer 1 Comments:

Dear reviewer

Thank you for your invaluable comments and guidance to improve our manuscript.

We presented the responses one by one on your comments as follows:

Reviewer #1: General comments:

I thank the authors for their work, and I think the manuscript has been improved significantly. I have some additional comments.

A final, through proof-reading is needed since there are some grammatical errors (for example tense inconsistencies) and several sentences that could be improved. Add page numbers, please.

Response: Thanks for your comment. Another proof-reading was conducted.

Introduction

Line 74 – Please replace the word “pass” with “follow”.

Response: It was revised based on your comment.

Line 106 – Please replace the word “various” with “some”.

Response: It was revised based on your comment.

Line 116 – Please rephrase this sentence as follows: “Because CBA is a relatively new technology in Iran, …”

Response: Thanks for your comment. It was revised based on your comment.

Figure 1 – Please make a note at the bottom of the Figure to state that the structure is the same for the control arm.

Response: Thanks. It was revised based on your comment.

Line 152 – Please write QALY in full here since it is the first time that it is been used. So, it should be: “quality adjusted life years (QALYs)”

Response: Thanks. It was revised based on your comment.

Please write the discount rate here and explain why you used 5% instead of 3% as suggested by NICE. Is there a guideline in Iran which suggests that 5% should be used?

Response: We did not have a guideline for this purpose in Iran until the study. We used 5% as discount rate for both costs and QALYs in the model based on the recommendation of the Health Technology Assessment Office of the Iran’s Ministry of Health for this study. This descriptions was also added in the Methods section of the manuscript.

The price year must be provided in the methods section. Are these 2021 $?

Response: Thanks for your comment. We mentioned in line 175 of the manuscript that “All costs were calculated based on 2019-20 prices”. Please see.

Please provide the “uncalibrated” figures and the “calibrated” figures. This way the reader can tell if the authors’ calibrations were correct. I’d call them adjustments rather than calibrations.

Response: Thanks for your comment. As mentioned in the previous correspondence, by “survey and calibration” we mean that the values are not used from another reference and are obtained in the present study. But to avoid misunderstandings we replaced it with “our study” in table 1.

Also, in cases where calibration is included with a reference as a variable source, the reader can see the original value of the variable by referring to the reference. Also, we replaced calibration with adjustment.

Line 197 – I think this sentence is abundant given that the next sentence clearly explains which WTP was used.

Response: It was revised based on your comment.

Line 211 – Please replace “10-20%” with “10% or 20%” for clarity.

Response: Thanks. It was revised based on your comment.

Figure 3 – Please refrain from using EV instead of ICER because it might be confused with another type of analysis (expected value of information). Please only use ICER.

Response: It was revised based on your comment.

Discussion

Most of the clinical and the cost data came from a study conducted in China. I think this is an important limitation and should be acknowledged. Please discuss the potential impacts of this. How can decision-makers be sure that these results are applicable to Iran? Please also discuss the potential impact on health inequalities.

Response: Thanks for your comment. As you know, the use of clinical evidence from past studies is very common in economic evaluation studies and is not usually considered as a limitation. In present study we used the best present evidence of international studies for clinical parameters, and for cost items we used internal evidence. As mentioned in the text, although in many cases there is no significant difference between different contexts regarding clinical evidence, but this is one of the possible limitations of this study that can be effective in final results. However, to eliminate this possible limitation as much as possible, in present study we performed sensitivity analysis to a wide range for uncertain parameters.

Submitted filename: response to reviewers r2.docx

Click here for additional data file.

15 Jun 2022

Cost-Utility Analysis of Cryoballoon Ablation versus Radiofrequency Ablation in the Treatment of Paroxysmal Atrial Fibrillation in Iran

PONE-D-21-27154R2

Dear Dr. Daroudi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Elena Pizzo, PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I would like to thank the authors for their valuable work.

I do not have any further comments.

Best wishes

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

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21 Jun 2022

PONE-D-21-27154R2

Cost-Utility Analysis of Cryoballoon Ablation versus Radiofrequency Ablation in the Treatment of Paroxysmal Atrial Fibrillation in Iran

Dear Dr. Daroudi:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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