Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients: An observational study based on the French national hospital discharge database (PMSI).

INTRODUCTION: Since 2014, Balloon Pulmonary Angioplasty (BPA) has become an emerging and complementary strategy for chronic thromboembolic hypertension (CTEPH) patients who are not suitable for pulmonary endarterectomy (PEA) or who have recurrent symptoms after the PEA procedure.
OBJECTIVE: To assess the hospital cost of BPA sessions and management in CTEPH patients.
METHODS: An observational retrospective cohort study of CTEPH-adults hospitalized for a BPA between January 1st, 2014 and June 30th, 2016 was conducted in the 2 centres performing BPA in France (Paris Sud and Grenoble) using the French national hospital discharge database (PMSI-MCO). Patients were followed until 6 months or death, whichever occurred first. Follow-up stays were classified as stays with BPA sessions, for BPA management or for CTEPH management based on a pre-defined algorithm and a medical review using type of diagnosis (ICD-10), delay from last BPA procedure stay and length of stay. Hospital costs (including medical transports) were estimated from National Health Insurance perspective using published official French tariffs from 2014 to 2016 and expressed in 2017 Euros.
RESULTS: A total of 191 patients were analysed; mainly male (53%), with a mean age of 64,3 years. The first BPA session was performed 1.1 years in median (IQR 0.3-2.92) after the first PH hospitalisation. A mean of 3 stays with BPA sessions per patient were reported with a mean length of stay of 8 days for the first stay and 6 days for successive stays. The total hospital cost attributable to BPA was € 4,057,825 corresponding to €8,764±3,435 per stay and €21,245±12,843 per patient. Results were sensitive to age classes, density of commune of residence and some comorbidities.
CONCLUSIONS: The study generated robust real-world data to assess the hospital cost of BPA sessions and management in CTEPH patients within its first years of implementation in France.

Introduction

Pulmonary hypertension (PH) is a disease defined by the increase of mean pulmonary arterial pressure ≥20 mm Hg [1] Although this definition is the same across PH, subtypes of different prognosis and therapeutic implications exist due to differences in underlying mechanisms [2]. Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare subtype of PH (Group 4), characterized by the presence of organized fibrous tissue (chronic thromboembolic material) occluding varying degrees of the pulmonary arterial tree which may completely block the lumen [3]. In France, the prevalence has been recently estimated at 47 cases per million [4]. The patient’s survival at 1 year, 2 years, and 3 years are approximately 93%, 91%, and 89%, respectively [5].

Management of CTEPH in France is organized around a national reference centre, and affiliated regional centres in university hospitals (known as competence centres). Patients should be evaluated by a multidisciplinary team for suitability for pulmonary endarterectomy (PEA) which may be curative. However, about 40–50% are ineligible to receive this surgical intervention due to distal lesion, advanced age or comorbidities, and some patients may still experience symptoms after the procedure. For these patients, medical treatment of CTEPH and/or Balloon Pulmonary Angioplasty (BPA) are recommended [2, 6]. Furthermore, Riociguat, an oral guanylate cyclase stimulator, and treprostinil, a subcutaneous prostacyclin analogue, are approved (in 2014 and 2020 respectively) for patients with inoperable CTEPH or persistent/recurrent PH after PEA; other PH medications are also off-label used [7]. BPA has been considered recently as an emerging and complementary strategy for CTEPH patients who are not suitable for PEA or CTEPH patients who have recurrent symptoms after the PEA procedure [8, 9]. BPA is an interventional procedure consisting of repeat sessions of catheterizations and dilatations using a balloon catheter to progressively enlarge pulmonary stenosis and recover optimal hemodynamic and pulmonary perfusion [8]. This intervention is less invasive than PEA [10]. The technique of BPA has been reported in 2001 and was improved over the years with the technical advances and the accumulating experience in the management of pulmonary artery stenosis [8]. Given those results, the European Society of Cardiology/European Respiratory Society 2015 recommended BPA “for patients who are technically inoperable or who carry an unfavourable risk/benefit ratio for PEA (class IIb recommendation, level of evidence C)” [2, 3]. Recommendations specified that BPA should only be performed in experienced and high volume CTEPH centres [2]. In France, the BPA procedure has been initiated since 2014 in two centres, Paris Sud University (Bicetre Hospital and Marie Lannelongue Hospital) and Grenoble University Hospital.

Despite the efficacy of BPA and evidence of improvement on short-term symptoms, exercise capacity and hemodynamics [11], there is no data to describe the costs attributable to BPA. Procedure and management are in a learning curve, but it is not clear what their costs are due to recurrence of sessions and risk of complications. Thus, understanding BPA-related costs seems of key importance. To do so, the present study aimed to generate real-world data to assess the hospital cost of BPA sessions and management in patients with CTEPH within its first years of implementation. This study was conducted from the French national health insurance perspective.

Materials and methods

Study design

This was an observational retrospective cohort study of -adult patients with CTEPH hospitalized for a BPA procedure between January 1st, 2014 and June 30th, 2016 (inclusion period, i.e. first years of implementation). As BPA was introduced in France in 2014, all included patients were incident, i.e. included at time of their first BPA session occurring in the 2 French centres performing BPA during the inclusion period (index date). BPA protocol is the same in both centers. Patient spent around 6 days at the hospital with an overnight admission for two BPA sessions repeated within 48 hours.

Patients were followed up during a period of 6 months that we considered relevant to assess cost attributable to BPA session and management—or death, whichever occurred first.

Data sources

The French PMSI-MCO (Medicine, Surgery, Obstetrics) database covers all overnight or day hospitalisations in the public and private sectors involving short-term stays in medical, surgical or obstetric facilities. Each patient in the database is attributed a unique anonymous patient identifier. This identifier can be used to track individual patients across multiple hospitalisations.

At the time of final discharge, a standardised discharge summary (SDS) is issued which lists all hospital procedures undergone by the patient during the stay, identified through standardised procedure codes. The reason for hospitalisation is identified by a diagnosis-related group (DRG) code, based on the International Classification of Diseases, 10th revision (ICD-10) [12], which is used by the hospital administration for costing purposes. Three different types of DRG code may be attributed to an individual stay. The principal diagnosis (PD) corresponds to the condition for which the patient was hospitalised (for example, myocardial infarction); the related diagnosis (RD) corresponds to any underlying condition which may have been related to the PD (for example, coronary artery disease); the significantly-associated diagnosis (SAD) corresponds to comorbidities or complications which may affect the course or cost of hospitalisation (for example, chronic kidney failure). All medical procedures are listed, including surgery, diagnostic tests and other examinations, and the departments in which the patient was hospitalised during the stay are documented. Most medications and non-pharmacological treatments cannot be specifically identified since they are integrated into the DRG cost. However, delivery of certain expensive drugs and recorded in a linked database (FICHCOMP) and can thus be identified individually. Socio-demographic information is limited to gender, age and postcode of residence. No information is available on the outcome of any procedure or the results of any test.

Study population

We included all adult patients (≥18 years) with at least one hospitalisation for PH (ICD-10 codes I270 and I272) as principal, related or significantly associated diagnosis and with an associated BPA procedure (CCAM codes DFAF001, DFAF002, DFAF003, DFAF004) between January 1st, 2014 and June 30th, 2016 in the 2 centres performing BPA in France (Paris Sud and Grenoble). In the absence of specific ICD-10 codes for CTEPH, we assumed that our combination of selection criteria included only patients with CTEPH, due to the exclusive indication of BPA in this PH subtype. Patients with a PEA and a BPA procedure during the same hospital stay were however excluded, considering in this context BPA as a rescue procedure directly linked to the PEA instead of the CTEPH management. We excluded also patients having BPA stays with DRG codes for lung transplant or level 4 cardiothoracic surgical intervention, as costs of these stays are mainly driven by other costs than BPA (outliers stays). Comorbidities were identified based on a medical review of ICD-10 codes reported in hospital stays occurring within the year prior to inclusion (ICD-10 codes are reported in S1 File).

Healthcare resource utilization and costs

Stays were classified into three categories: for BPA sessions, for management of BPA complications or for CTEPH management. Stays with BPA sessions (inclusion and additional stays) were identified as stays with both a diagnosis code (as PD or RD or SAD) for PH and a BPA procedure performed in Paris Sud and/or Grenoble, as per inclusion criteria. Other stays were categorized based on expert’s medical review using the combination of the following criteria: type of diagnosis (ICD-10 codes), delay from last BPA session and length of stay. In case of difficulty to differentiate stays for BPA management or for CTEPH management based on ICD-10 codes and length of stay, a 30-days delay from the last BPA session was considered: hospital stays occurring within 30 days after BPA sessions were categorized as stays related to BPA management; hospital stays occurring more than 30 days after BPA sessions were categorized as stays related to CTEPH management and not directly related to BPA management.

Costing was restricted to direct costs and determined from the perspective of the French social security system (National Health Insurance; NHI). All costs were expressed in Euros. Costs were attributed from official French national tariffs for medical acts applicable in France from 2014 to 2016. These costs were updated to 2017 values to take inflation into account. A standard national tariff was applied to each hospitalization based on the DRG code attributed in the PMSI database. These standard tariffs include medical and related procedures, nursing care, treatments (except specific expensive drugs), food and accommodation, and investment costs for hospitalised patients. Additional costs per day of hospitalisation in an intensive care unit were added to the DRG tariffs when appropriate [13]. For private hospitals, where physicians are reimbursed on a fee-for-service basis, physician fees were identified from the ENCC (Echelle Nationale des Coûts à Méthodologie Commune, the French observatory of real-world spending on healthcare) and added to the DRG tariffs. Expensive drugs were costed using the public retail price. Out of hospital drugs were not included in the present analysis as they are not recorded in the database. The cost of medical transports was also estimated using transports fees for each mode of transport (ambulance, light medical vehicle, taxi, public transport, and personal vehicle) in each department and considering the distance between commune of residence and hospital. As mode of transport is not available in PMSI, the transport cost was then weighted according to the repartition of transport mode published by NHI in 2016 for patients ≥ 60 years with long term diseases (Open DAMIR). The full methodology is detailed in S2 File.

Statistical analyses

Descriptive analyses were performed. Continuous data were presented as mean values with standard deviation (SD) or median values with range (quartile 1 and quartile 3) and categorical data as frequency counts and percentages. Comparative statistical analyses were performed to compare characteristics of patients according to year of inclusion (based on index date of each patient). The Chi-2 test (significant level, 5%) was used for qualitative variables; the Student’s t-test or the Wilcoxon test depending on the nature of the data distribution was used for quantitative variables (significant level, 5%). Random-effect regression models were performed to explore predictive factors associated with costs, considering a factor with random-effect (hospital centre). Statistical Analysis System software, version 9.2 for Windows (SAS Institute Inc., Cary, NC, USA) was used for all analyses.

Ethics

The study was conducted in accordance with International Society for Pharmacoepidemiology (ISPE) Guidelines for good pharmacoepidemiology practices (GPP) and applicable regulatory requirements. Because this was a retrospective study using an anonymized database and had no influence on patient care, ethics committee approval was not required. Use of the PMSI-MCO database for this type of study has been approved by the French national data protection agency (CNIL; annual authorisation #1419102 v8–2015-111111-56-18 / order M14L056).

Results

Between January 1st, 2014 and June 30th, 2016, 198 CTEPH adult patients with BPA sessions were identified in the PMSI MCO-database (Fig 1). We excluded 4 patients having a BPA and a PEA procedure performed during the same stay and 3 patients with outliers stays, as per protocol. Finally, 191 CTEPH patients were included (n = 129 in Paris Sud and n = 62 in Grenoble). The inclusion increased over years: 45 patients were included in 2014, 92 in 2015 and 54 in mid-2016 (up to 30/06/2016).

Fig 1

Flow chart of the study population.

Patients’ characteristics

At baseline, the mean age was 64.3 years (SD = 14.7) and 53.4% were male (Table 1). A history of PEA procedure was found for 3.1% of patients. The time interval between the first hospitalization for PH (since 2006) and the first stay for a BPA procedure was a mean of 2.1 years (SD = 2.5) and a median of 1.1 years (IQR 0.3–2.9). Among comorbidities, chronic respiratory disease was reported for 31.4% (n = 60) of patients, heart failure for 28.3% (n = 54), a hospitalization with obesity diagnosis for 14.7% (n = 28), a diabetes mellitus for 9.9% (n = 19), a chronic ischemic heart disease for 9.4% (n = 18) and a chronic renal disease for 6.3% (n = 12). Characteristics of patients were not significantly different according to year of inclusion. The proportion of patients according to quartiles of social deprivation index was respectively, from the most deprived to the most privileged, 16.7%, 23.6%, 25.3% and 34.4%. Half of patients (50.5%) lived in urban environment, 23.4% in semi urban environment, 18.6% in semi-rural environment and 7.5% in rural environment.

Table 1

Demographic and medical characteristics of patients at baseline.

	Total = 191
Age, years, mean (SD)	64.3 (14.7)
Male, n (%)	102 (53.4%)
Social Deprivation index, n (%)
Most deprived	31 (16.7%)
Deprived	44 (23.6%)
Privileged	47 (25.3%)
Most privileged	64 (34.4%)
Missing	5
Population density index, n (%)
Rural	14 (7.5%)
Semi rural	35 (18.6%)
Semi urban	44 (23.4%)
Urban	95 (50.5%)
Missing	3
History of PEA*, n (%)	6 (3.1%)
PH duration*, years, mean (SD)	2.1 (2.5)
Median (IQR)	1.1 (0.3–2.9)
At least one comorbidity among*,**, n (%)
Ascites	3 (1.6%)
Chronic ischaemic heart disease	18 (9.4%)
Chronic renal disease	12 (6.3%)
Chronic respiratory disease	60 (31.4%)
Coagulation disorder	7 (3.7%)
Connective tissue disease	6 (3.1%)
Diabetes mellitus	19 (9.9%)
Heart failure	54 (28.3%)
Hypothyroidism	9 (4.7%)
Liver disease	5 (2.6%)
Obesity	28 (14.7%)
Pacemaker	4 (2.1%)
Sickle cell disease	3 (1.6%)

*Information available since 2006

** ICD-10 codes used to track comorbidities are reported in S1 File.

Healthcare resource utilization

Over the 6 month-follow-up period, patients had several additional stays either for BPA sessions, BPA management or CTEPH management. A total of 146 patients (76.4%) had at least one additional stay with BPA sessions (270 stays, i.e. 1.8 stays per patient), 2 patients (1.0%) had one additional stay for BPA management (2 stays, 1 stay per patient) and 81 patients had at least one additional stay for CTEPH management (103 stays, i.e 1,3 stays per patient) (Table 2). Thus, patients had an average of 2.8 stays with BPA sessions over the study period (including inclusion BPA session). All stays with BPA sessions were overnight hospitalizations and 88.5% of them had an Intensive care unit (ICU) transit. CTEPH management stays were also mainly (84.5%) overnight hospitalizations.

Table 2

Healthcare resource use and cost of hospital stays.

	BPA-related			CTEPH management related
	Sessions at inclusion	Sessions during follow-up	Complications
Number of patients, n	191 (100%)	146 (76.4%)	2 (1,0)	81
Number of stays per patient, n	1.0	1.8	1.0
Day hospitalizations, n (%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	16 (15.5%)
Overnight hospitalizations, n (%)	191 (100.0%)	270 (100.0%)	2 (100.0%)	87 (84.5%)
Length of overnight hospitalization, in days, mean (SD)	7.8 (4.5)	6.0 (2.3)	2.0 (1.4)	3.7 (3.7)
Number of stays with ICU, n (%)	169 (88.5%)	162 (60.0%)	1 (50.0%)	7 (6.8%)
Total cost*		€ 4,057,825		€ 286,061
	€ 1,781,596	€ 2,271,707	€ 4,522
Part of ICU among total cost (%)	€ 335,442 (18.8%)	€ 255,428 (11.2%)	€ 322 (7.1%)	€ 15,016 (5.2%)
Cost/stay, mean (SD)*		€ 8,764 (€ 3,435)		€ 2,777 (€ 2,437)
	€ 9,328 (€ 3,989)	€ 8,414 (€ 2,890)	€ 2,261 (€ 1,702)
ICU cost/stay, mean (SD)	€ 1,756 (€ 1,521)	€ 946 (€ 968)	€ 161 (€ 228)	€ 146 (€ 860)
Cost /patient, mean (SD)*		€ 21,245 (€ 12,843)		€ 3,532 (€ 3,891)
	€ 9,328 (€ 3,989)	€ 15,560 (€10,108)	€ 2,261 (€ 1,702)
ICU cost /patient, mean (SD)	€ 1,756 (€ 1,521)	€ 1,750 (€ 1,679)	€ 161 (€ 228)	€ 185 (€ 967)

*For total cost, cost per stay and cost per patient, the first row provides a pooled costs of stays at inclusion, during follow-up and for management of complications; the second row provides a costs per type of stays, respectively.

The first stays with BPA sessions (inclusion stays) had a mean length of 7.8 days (SD = 4.5) including a mean length of stay in ICU of 4.8 days (SD = 3.6) whereas follow-up stays with BPA sessions had a mean length of 6.0 days (SD = 2.3). Moreover, length of BPA stays decreased over the years with a mean of 8.5 days (SD = 4.6) in 2014, 7.9 (SD = 3.8) in 2015 and 6.9 (SD = 5.4) in 2016. Follow-up stays for BPA management and CTEPH management were shorter with a mean length of 2.0 days (SD = 1.4) and 3.7 days (SD = 3.7), respectively.

Cost

Over the study period, the total cost of hospital care for CTEPH adult patients experienced BPA was € 4,343,886. This cost included mainly (€4,057,825, 93%) hospital care related to BPA sessions or management: €1,781,596 for inclusion stays (€ 335,442 in ICU; 18,8%), €2,271,707 for follow-up stays (€255,428 in ICU, 11,2%) and €4,522 for BPA management (€ 322 in ICU;7.1%) (Table 2). CTEPH management accounted for 7% of the total cost, €286,061.

The mean BPA related cost per stay was €8,764 (SD = 3,435): BPA sessions had a mean cost per stay of €9,328 (SD = €3,989) at inclusion (including €1,756 (SD = € 1,521) for ICU), €8,414 (SD = €2,890) during follow-up (including €946 (SD = € 968) for ICU) and BPA management had a mean cost per stay of €2,261 (SD = €1,702) (including € 161 (SD = € 228) for ICU). CTEPH management had a mean cost per stay of €2,777 (SD = €2,437). These costs tended to decrease over the years (Fig 2).

Fig 2

Evolution of mean hospital cost per stay over year of inclusion.

The mean BPA related cost per patient was €21,245 (SD = €12,843) including €2,101 (SD = €1,948) of transportation cost: BPA sessions had a mean cost per patient of €9,328 (SD = €3,989) at inclusion, €15,560 (SD = 10,108) during follow-up and BPA management has a mean cost per patient of €2,261 (SD = 1,702). CTEPH management had a mean cost per patient of €3,532 (SD = €3,891).

Results were also sensitive to age classes, density of commune of residence and some comorbidities. Age intervals of 46–55 years and 56–65 years were significantly associated with a high cost of BPA compared to an age of 18–25 years, after adjusting for sex, density of commune, liver disease and chronic respiratory disease, with respectively an adjusted RR of 1.3 [95% CI:1.0–1.8] and 1.7 [95% CI:1.3–2.3] (Fig 3). No significance was reached for other age classes. Low, high and very high density of commune of residence was associated with a low cost of BPA, compared to very low density of commune of residence with respectively adjusted RR of 0.7 [95% CI:0.5–0.9], 0.8 [95% CI:0.6–1.1] and 0.6 [95% CI:0.5–0.9]. Finally, liver diseases were significantly associated with a high cost of BPA with an adjusted RR 1.8 [95% CI:1.1–2.9]. Chronic respiratory diseases tended to be associated with a low cost of BPA but without significance (RR = 0.8 (95% CI:0.7–1.0].

Fig 3

Factors associated with hospital cost of BPA.

Discussion

To our knowledge, this is the first study assessing in real-life the hospital cost of BPA in patients with CTEPH.

Over a 6-month follow-up period, our study assessed a mean hospital cost for BPA of € 8,764 per stay and €21,245 per patient including both sessions and management. Costs were mainly driven by stays for BPA sessions. Complications did not represent a sizeable proportion of the cost. Costs tended to slightly decrease over the years with the reduction of length of stay, highlighting the learning curve of operators. Higher costs were observed for fragile patients (with an older age, with liver comorbidities) which may be explained by a natural heavier hospital management. Even if we excluded outlier patients, we cannot exclude some extra costs, not associated with BPA, that may still be present in our results. Higher costs were also reported for patients leaving in low-density area, even after exclusion of transportation costs. These higher costs may be explained by a potential delay in the diagnosis due to a later access to specialists for patients leaving far from cities and reference centres. These patients were then probably in more severe conditions at first BPA.

Some of these results could be discussed according to the existing literature. In a previous study, Brenot et al reported a series from the Paris Sud Centre, in which the medical records of 184 patients hospitalized for BPA at Paris Sud from February 2014 to July 2017 were analysed [8]. Our study included some patients who were reported in their series, as well as those from the Grenoble center. Despite expected similarities between the series by Brenot et al and the present study, some differences were observed. First, a history of PEA was identified for 3% of patients versus 8% in Brenot et al., suggesting that PEA may be underestimated in our study. The first BPA session was performed 1.1 years in median (IQR 0.3–2.92) after the first PH hospitalisation. The delay of 68 +/-51 months between PEA and BPA was observed which may be explained. One possible explanation is that we captured only the most recent PEA, occurring after 2006. In addition, an average of 2.8 BPA stays per patient were reported an average of 5.5 BPA sessions by patient in Brenot et al. According to experts’ practice, 2 BPA sessions are usually performed by stay. Therefore around 5.6 BPA sessions by patient could be assumed in the present study. This result was in accordance with Brenot et al. publication. Finally, the proportion of complications were quite low compared to Brenot et al. publication which may be explained by a management during BPA stays with session. Indeed, it seems we could not make a comparison between "stay for BPA complications" in our study and the actual incidence, because the majority of complications related to BPA were managed within the hospitalization during which the BPA is performed. This greatly relativizes both the number of stays for BPA management which are quite infrequent in our study and the value of the cost per patient for BPA management (which is ultimately very low).

Other results were in line with this publication: 121 patients were included between January 2014 and July 2016 (30 months) with the PMSI database in Paris Sud i.e around 4 patients/month versus 5 patients/month in Brenot et al study which included a more recent inclusion period. The mean age of patients was 64.3 years+/-14.7 versus 63 years+/-14 years in Brenot et al. and 53.1% were male versus 51% in Brenot et al. Furthermore, the mean length of stay for BPA of 6.7 days (incl. at inclusion and during follow-up), was consistent with what reported in a recent Japanese single center study of 125 patients who underwent BPA between November 2012 and September 2017 (6.6 days) [14]. We also found the same trend of shortening of hospital stay over years.

Our study presents however some limitations, mainly inherent to claims data sources. Some of them have no specific impact. As mentioned in the method section, CTEPH patients could not be identified directly because of the lack of specific ICD-10 codes for this rare disease. However, as BPA is a new therapeutic approach introduced in France in 2014 in only 2 centres of reference, a specific algorithm with the combination of ICD-10 codes for PH, specific procedure codes for BPA and hospital location of BPA session allowed to identify patients with a good accuracy. Moreover, the number of BPA sessions performed by BPA stays is not reported in PMSI. However, the cost of stay is valued based on DRG, therefore the number of procedures within a stay have no impact on stay valorisation. The study is focusing on the cost of BPA within its first years of implementation in France. However hospital practice and tariffs didn’t change since this period. We also found in the study that complications stays were rare and should be even rarer over years. Therefore current hospital cost should not be different as those estimated in our study. The main limitation remained the lack of clinical data, as discussed above, potentially leading to lack of information regarding severity of the disease and underestimation of comorbidities. Since no information on clinical severity is available in the PMSI database, New York Hospital Association (NHYA) functional class cannot notably be assigned in our study as well as hemodynamic parameters and biomarkers. Comorbidities were estimated using ICD-10 codes reported in hospital stays occurring during the year prior to inclusion. Therefore, only recent and severe diseases (leading to hospitalization) were reported. Underreporting is therefore anticipated for these variables. In addition, costs could only be determined for in-hospital resource consumption, whereas community costs, such as primary care consultations, monitoring in community clinics and ambulatory prescription of PH-specific medication were not available.

Conclusions

To conclude, our data suggested BPA had a mean hospital cost of € 8,764 per stay and €21,245 per patient within its first years of implementation in France. These results are especially interesting at a time when the position of BPA in the therapeutic algorithm is regularly discussed.

ICD-10 codes of comorbidities.

(DOCX)

Click here for additional data file.

Medical transports method.

(DOCX)

Click here for additional data file.

14 Jun 2021

PONE-D-21-11711

Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients: an observational study based on the French National hospital discharge database (PMSI)

PLOS ONE

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If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

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Within your Competing Interests Statement, please confirm that these commercial affiliations does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and  there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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

Reviewer #2: No

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. 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

Reviewer #2: No

**********

4. 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

Reviewer #2: Yes

**********

5. Review Comments to the Author

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: The authors performed a important study looking at the cost of BPA for CTEPH in France.

The analysis is well conducted with limitations that are adequately addressed in the discussion.

The manuscript is well written.

Minor suggestions:

1. In the discussion, line 217-218, the authors mentioned "additional with BPA session"; how was this determined in comparison to planned additional BPA sessions?

2. It would be helpful to have a description of the BPA planning in the methods section, ie how many sessions were planned with the number of session per admission, admission the night before the first BPA, etc. Also it would be very informative to know whether there was nay differences between the two centers performing BPA in France.

Reviewer #2: 1. Why are three MSD employees co-authors of this study? I would rather have a CTEPH surgeon included, and some other members of the local CTEPH teams. BPA is a team decision and that should be reflected in authorships. MSD employees have a conflict of interest that cannot be overcome.

2. In the introduction the market approval of subcutaneous Treprostinil for the treatment of not operated CTEPH, and persistent recurrent PH after pulmonary endarterectomy should be mentioned. The guideline recommendation is of 2015 and today outdated.

3. The period for which the cost analysis was performed includes the French BPA learning curve and may not be representative of today‘s cost. Authors should calculate cost for a cohort that is more contemporary, for example 2018-2019.

4. What if diagnostic procedures were done in the same hospital stay as the first BPA SESSION? Were these stays counted as BPAs? Particularly in patients from distance diagnosis and treatments are oftentimes performed within the same stay.

5. …follow-up stays had a mean length of 6.0 days…Authors need to provide a precise definition of follow-up stays. Is this corresponding to stays after the first BPA session? Why 6 days, and later 2?

6. Were cost for Drugs included, or paid by healthcare plans outside the hospital?

7. Was riociguat given?

8. How often could riociguat or prostacyclins be stopped because of successful BPA?

9. Authors should calculate annual cost of vasodilatior therapy given to patients prior to and after BPA. This should serve as a comparator because these treatments would be the placeholder for BPA if that were not paid for.

10. Transportation cost should be covered by the patients.

11. A mean hospital cost for BPA of € 8,764 per stay and two BPA procedures is very expensive in my eyes. For BPA one needs 200mL contrast, a guiding sheath, a guiding catheter, a wire and a few balloons at a cost of € 30 each. Was peripheral or coronary material used? Were any CTOs done?

12. What was procedural cost? Was it different between Paris and Grenoble?

13. What was included in the SOPs for lung injury? Were chest CT scans mandatory?

**********

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Reviewer #1: No

Reviewer #2: No

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18 Aug 2021

Editor comments

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We verified that the manuscript meets PLOS ONES’s style requirements

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Answer to response 2 :

Due to the sensitive nature of the data that support the findings, access to them is restricted and can only be granted by the Ethics and scientific committee for health research, studies, and evaluations (CESREES, Comité Ethique et Scientifique pour les Recherches, les Etudes et les Evaluations dans le domaine de la Santé) and/or the French data protection authority (Comité National de l’Informatique et des Libertés, CNIL), and so are not readily available. The data are part of the National health data system (SNDS, Système national des Données de Santé) a database maintained by the HDH (Health Data Hub). The HDH can be contacted at https://www.health-data-hub.fr/contact.

3. Thank you for stating the following in the Financial Disclosure section:

'This study was financed by MSD. LB, AH and LLB are employees of MSD and participated to the study design, review of the protocol, publication planning and preparation of the manuscript. AV is one of the co-founders of the CRO HEVA; FR and GC are employees of HEVA, a company who received funding from the study sponsor for the conduct of this study. VC, JD, HB and PB are independent experts who received fees for participating in the scientific committee of the study.'

We note that one or more of the authors have an affiliation to the commercial funders of this research study:

MSD France and HEVA France.

a. Please provide an amended Funding Statement declaring these commercial affiliations, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement. “The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

Answer to response 3.a.

The funder allowed to perform the study. The funder provided support in the form of salaries for authors [LB,AH and LLB], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

b. Please also provide an updated Competing Interests Statement declaring these commercial affiliations along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.

Within your Competing Interests Statement, please confirm that these commercial affiliations does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors

http://journals.plos.org/plosone/s/competing-interests). If this adherence statement is not accurate and there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Answer to response 3.b.

We updated Competing Interests Statement declaring that these commercial affiliations does not alter our adherence to all PLOS ONE policies on sharing data and materials (detail below).

c. Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests:

http://journals.plos.org/plosone/s/competing-interests.

Answer to response 3.c.

We provided an updated Funding Statement and Competing Interests Statement in the cover letter (and detail below).

Competing interests

I have read the journal's policy and the authors of this manuscript have the following competing interests:

Experts:

VC, JD, HB and PB are independent experts who received fees for participating in the scientific committee of the study. Outside the submitted work, VC reports personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Bayer / MSD, personal fees from Novartis, personal fees and non-financial support from Roche / Promedior, personal fees from Sanofi, personal fees from Celgene / BMS, personal fees from Galapagos, personal fees from Galecto, personal fees from Shionogi, personal fees from Astra Zeneca, personal fees from Fibrogen, personal fees from RedX, personal fees from PureTech. Outside the submitted work, HB has received personal fees and/or non-financial support from MSD, Actelion, GSK. Outside the submitted work, PB and JD have no competing interest in relation with this topic to declare.

MSD employees:

LB, AH and LLB are employees of MSD, the company which financed the study.

HEVA employees:

AV is one of the co-founders of the CRO HEVA; FR and GC are employees of HEVA, a company who received funding from the study sponsor for the conduct of this study and for the analysis of the data.

These commercial affiliations does not alter adherence to all PLOS ONE policies on sharing data and materials.

Financial statement

This study was financed by MSD. The funder provided support in the form of salaries for authors [LB,AH and LLB], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. LB, AH and LLB are employees of MSD and participated to the study design, study analysis, decision to publish and preparation of the manuscript. AV is one of the co-founders of the CRO HEVA; FR and GC are employees of HEVA, a company who received funding from the study sponsor for the conduct of this study. VC, JD, HB and PB are independent experts who received fees for participating in the scientific committee of the study.

Reviewers' comment

Reviewer #1: The authors performed a important study looking at the cost of BPA for CTEPH in France.

The analysis is well conducted with limitations that are adequately addressed in the discussion.

The manuscript is well written.

Minor suggestions:

1. In the discussion, line 217-218, the authors mentioned "additional with BPA session"; how was this determined in comparison to planned additional BPA sessions?

Answer to response 1 :

Thank you for the positive assessment of the study and manuscript. CTEPH patients were included at time of first BPA session (index date). However BPA sessions are iterative and there is possibility of revision at distance of first intervention. Stays with a BPA session occurring after the index date (defined as the first stay with a BPA session) and during the 6 month - follow up period, were defined as additional BPA session in the manuscript. We used the same algorithm to identify first BPA session and additional BPA session in the data set.

The line 217-218 was not modified but we clarified the term “additional” before in the text in Material and methods section (line 144-146):

“Stays with BPA sessions (inclusion and additional stays) were identified as stays with both a diagnosis code (as PD or RD or SAD) for PH and a BPA procedure performed in Paris Sud and/or Grenoble, as per inclusion criteria.“

2. It would be helpful to have a description of the BPA planning in the methods section, ie how many sessions were planned with the number of session per admission, admission the night before the first BPA, etc. Also it would be very informative to know whether there was any differences between the two centers performing BPA in France.

Answer to response 2 :

In France, the patient is admitted the night before the intervention. Two sessions of BPA are planned separated from 48 hours. Patient stays around 6 days at hospital. This protocol of BPA is the same in all French centers, and notably in Paris Sud University and Grenoble University hospital.

We described the protocol in Material and methods section (line 102-104):

“ BPA protocol is the same in both centers. Patient spent around 6 days at the hospital with an overnight admission for two BPA sessions repeated within 48 hours.“

Reviewer #2:

1. Why are three MSD employees co-authors of this study? I would rather have a CTEPH surgeon included, and some other members of the local CTEPH teams. BPA is a team decision and that should be reflected in authorships. MSD employees have a conflict of interest that cannot be overcome.

Answer to response 1:

Regarding MSD employees co-authors, we included all persons that contributed to this work in accordance with ICJME guidelines. Their role in the study was the following: Laurie Levy-Bachelot wad the project director, Lionel Bensimon was the project leader and Antoinette Hakmé was the medical leader. Your suggestion to involve a surgeon is excellent. Unfortunately, as the study has already been performed, it is no longer possible to add authors who have not yet participated.

2. In the introduction the market approval of subcutaneous Treprostinil for the treatment of not operated CTEPH, and persistent recurrent PH after pulmonary endarterectomy should be mentioned. The guideline recommendation is of 2015 and today outdated.

Answer to response 2:

Thank you for your comment. Please not, that Treprostinil (as mentioned in the ERS statement 2021 ) was not EU approved for CTEPH by the time of the study and is still not reimbursed in France for this indication.

However, since the goal of the study is to assess the "Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients" and not the particular effect of one or other drug we agree with the reviewer describing drug therapies in the introduction of the manuscript may be confusing as it was not included in this work. Therefore in order to avoid any confusion we decided to remove all parts mentioning drug therapies.

3. The period for which the cost analysis was performed includes the French BPA learning curve and may not be representative of today‘s cost. Authors should calculate cost for a cohort that is more contemporary, for example 2018-2019.

Answer to response 3:

You are completely right. As raised in the conclusion, our study is focusing on the cost of BPA within its first years of implementation in France. We agree that it should be interesting to update the study with additional years to see the evolution of costs in recent years. Unfortunately it was not planned at the beginning of the project and then we do not have these data in our dataset and it takes time to perform and interpret the results anyway.

However in France, hospital cost estimation is based on a fixed national tariffication from the Social Security that apply to each hospitalization anywhere in France, and based on the Diagnosis Related Group code attributed in the PMSI database. These standard tariffs include medical and related procedures, nursing care, treatments (except specific expensive drugs), food and accommodation, and investment costs for hospitalised patients. The tariff didn’t change since the initiation of the studied period. Furthermore, BPA hospital practice didn’t change either. Finally the complications were and remained rare over years. Therefore it is unlikely that the current hospital cost differs substantially from those estimated in our study.

But as it’s an important point we added this limitation in the Discussion as follows :

“The study is focusing on the cost of BPA within its first years of implementation in France. However hospital practice and tariffs didn’t change since this period. We also found in the study that complications stays were rare and should be even rarer over years. Therefore current hospital cost should not be different as those estimated in our study. “

4. What if diagnostic procedures were done in the same hospital stay as the first BPA SESSION? Were these stays counted as BPAs? Particularly in patients from distance diagnosis and treatments are oftentimes performed within the same stay.

Answer to response 4:

If diagnostic procedures are performed within the same hospital stay that the first BPA session the cost is including in the cost of the stay.

5. …follow-up stays had a mean length of 6.0 days…Authors need to provide a precise definition of follow-up stays. Is this corresponding to stays after the first BPA session? Why 6 days, and later 2?

Answer to response 5:

Apologies for the lack of clarity. Follow up stays are stays that occurred during the follow up period, after the first BPA session. The mean length of stay for BPA session follow up stays was 6.0 days. However, the mean length of stay for BPA management follow up stays was 2.0 days.

We modified the manuscript in order to precise this point (line 235-239):

“The first stays with BPA sessions (inclusion stays) had a mean length of 7.8 days (SD=4.5) whereas follow-up stays with BPA sessions had a mean length of 6.0 days (SD=2.3). Moreover, length of BPA stays decreased over the years with a mean of 8.5 days (SD= 4.6) in 2014, 7.9 (SD= 3.8) in 2015 and 6.9 (SD= 5.4) in 2016. Follow-up stays for BPA management and CTEPH management were shorter with a mean length of 2.0 days (SD=1.4) and 3.7 days (SD=3.7), respectively.”

6. Were cost for Drugs included, or paid by healthcare plans outside the hospital?

Answer to response 6:

All drugs were paid by the healthcare plan and are included in the fixed national tariffication from the Social Security for a hospital stay. Of note, the study was performed using the French hospital discharge database (PMSI). Therefore only healthcare occurring at hospitals are available in this database. Regarding drugs, most drugs cannot be specifically identified since they are integrated into the Diagnostic Related Group (DRG) cost. However, delivery of certain expensive drugs can be identified individually. In this study we only focused on hospital stay costs. This point was raised in the discussion but we propose to be more specific in order to highlight the drugs mentioned in your next comments.

The sentence will be modified as follows :

« In addition, costs could only be determined for in-hospital resource consumption, whereas community costs, such as primary care consultations, monitoring in community clinics and ambulatory prescription of PH-specific medication were not available ».

7. Was riociguat given?

Answer to response 7:

Riociguat is not available at hospital and was therefore not studied. We propose to modify the sentence in the discussion to precise this point.

The sentence will be modified as follows :

« In addition, costs could only be determined for in-hospital resource consumption, whereas community costs, such as primary care consultations, monitoring in community clinics and ambulatory prescription of PH-specific medication were not available ».

8. How often could riociguat or prostacyclins be stopped because of successful BPA?

Answer to response 8:

These treatment are not available at hospital. We can’t perform the requested analysis that is beyond the aim of the present study.

We have modified the sentence in the discussion as follows.

« In addition, costs could only be determined for in-hospital resource consumption, whereas community costs, such as primary care consultations, monitoring in community clinics and ambulatory prescription of PH-specific medication were not available ».

9. Authors should calculate annual cost of vasodilatior therapy given to patients prior to and after BPA. This should serve as a comparator because these treatments would be the placeholder for BPA if that were not paid for.

Answer to response 9:

Vasodilatator therapy are not available at hospital. We can’t perform the requested analysis. Anyway, the hospital cost is not impacted by treatment cost in the current analysis as a fixed national tariffication from the Social Security is used.

We have modified the sentence in the discussion as follows.

« In addition, costs could only be determined for in-hospital resource consumption, whereas community costs, such as primary care consultations, monitoring in community clinics and ambulatory prescription of PH-specific medication were not available ».

10. Transportation cost should be covered by the patients.

Answer to response 10:

In France, medical transports to hospital are reimbursed by National Health Insurance for patients with severe conditions such as CTEPH. In this study, the costs were estimated from the National Health Insurance perspective, that is the reason why medical transport costs are included. However, we provide in the manuscript the detail of the cost with and without transport. Please kindly refer to the manuscript , Results/page 13.

11. A mean hospital cost for BPA of € 8,764 per stay and two BPA procedures is very expensive in my eyes. For BPA one needs 200mL contrast, a guiding sheath, a guiding catheter, a wire and a few balloons at a cost of € 30 each. Was peripheral or coronary material used? Were any CTOs done?

Answer to response 11:

The hospital cost for BPA includes all costs provided during hospitalization for BPA i.e. medical and related procedures, nursing care, treatments (except specific expensive drugs), food and accommodation, and investment costs for hospitalized patients., not only the material used to perform BPA. In agreement with the reviewer's feeling the costs were driven by hospital stays, not by material use.

12. What was procedural cost? Was it different between Paris and Grenoble?

Answer to response 12:

The procedural cost is defined by the National Health Insurance. It’s the same in all French hospital centers, and notably in Paris Sud University and Grenoble University hospital.

13. What was included in the SOPs for lung injury? Were chest CT scans mandatory?

Answer to response 13:

Chest CT scans are not carried out systematically. Chest radiography can be performed prior to the procedure. However, carrying out these examinations has no significant impact on the hospital cost as to a very larger extent length of stay or hospitalization in an intensive care unit are the major drivers of hospital cost in the present study.

Submitted filename: 2021-08-18_BPA_PMSI_Response to Reviewers.docx

Click here for additional data file.

8 Sep 2021

PONE-D-21-11711R1

Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients: an observational study based on the French National hospital discharge database (PMSI)

PLOS ONE

Dear Dr. Raguideau,

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The reviewers were mostly favorable toward the revised submission. Please address the final few items from reviewer#2 individually.

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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

Reviewer #2: (No Response)

**********

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

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #2: No

**********

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

Reviewer #2: Yes

**********

6. Review Comments to the Author

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: The authors have adequately addressed my concerns.

This paper will be an important contribution to the field.

Reviewer #2: This is a interesting paper that deserves to be published. However,

1. I do not agree with the response to qu 2. One cannot negate that drugs are part of CTEPH management. Therefore, drugs should be mentioned in the introduction, including their availability in France. Authors will need to clarify that drugs costs are not subject of the present analysis as they were paid out-of-hospital.

2. I realized that the important message within authors‘ responses that …intensive care unit are the major drivers of hospital cost in the present study….cannot easily be found in the manuscript. Please, add those cost for intensive care stays to Table 2.

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Reviewer #1: No

Reviewer #2: No

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21 Oct 2021

Reviewer #1: The authors have adequately addressed my concerns.

This paper will be an important contribution to the field.

Reviewer #2:

This is an interesting paper that deserves to be published. However,

1. I do not agree with the response to question 2. One cannot negate that drugs are part of CTEPH management. Therefore, drugs should be mentioned in the introduction, including their availability in France. Authors will need to clarify that drugs costs are not subject of the present analysis as they were paid out-of-hospital.

Response to answer 1 to reviewer 2:

We added the drug authorized for CTEPH management in the introduction part (page 3, lines 64-66) as above :

“Riociguat, an oral guanylate cyclase stimulator, and treprostinil, a subcutaneous prostacyclin analogue, are approved (in 2014 and 2020 respectively) for patients with inoperable CTEPH or persistent/recurrent PH after PEA; other PH medications are also off-label used(6)”

We also precised in the methodology part of the manuscript that out of hospital drugs are not analysed in the present study (page 7, lines 158-159):

“Out of hospital drugs were not included in the present analysis as they are not recorded in the database.”

6. Delcroix M, Torbicki A, Gopalan D, Sitbon O, Klok FA, Lang I, et al. ERS statement on chronic thromboembolic pulmonary hypertension. Eur Respir J. 2021 Jun;57(6):2002828.

2. I realized that the important message within authors‘ responses that …intensive care unit are the major drivers of hospital cost in the present study….cannot easily be found in the manuscript. Please, add those cost for intensive care stays to Table 2.

Response to answer 2 to reviewer 2:

We agree that this information is interesting to add. Therefore, we added the following relevant results regarding ICU in table 2 : number of stays with ICU transit ; mean length of stay in ICU, part of ICU cost among total cost, mean ICU cost/stay and mean ICU cost/patient. We also modified the text in consequence to describe these results.

Submitted filename: 2021-10-21_BPA_PMSI_Response to Reviewers.docx

Click here for additional data file.

11 Nov 2021

Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients: an observational study based on the French National hospital discharge database (PMSI)

PONE-D-21-11711R2

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: no further comments no further comments no further comments no further comments no further comments no further comments

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Reviewer #2: No

16 Nov 2021

PONE-D-21-11711R2

Hospital costs of Balloon Pulmonary Angioplasty (BPA) procedure and management for CTEPH patients: an observational study based on the French National hospital discharge database (PMSI)

Dear Dr. Raguideau:

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.

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