Economic and Social Burden of Pulmonary Arterial Hypertension in Italy: A Cost-of-Illness Study

Abstract

Introduction

Pulmonary arterial hypertension (PAH) is a rare, chronic and progressive disease with a significant clinical, social, and economic impact. Despite available therapies, none address the underlying cause but rather focus on symptom management.

Objectives

This study aims to estimate the economic and social burden of PAH in Italy, including direct healthcare costs, direct nonhealthcare costs, and indirect costs related to productivity loss.

Methods

A bottom-up prevalence-based cost-of-illness model was developed using epidemiological data and healthcare resource consumption from national and international literature, validated by a panel of expert clinicians with extensive experience in the management of the condition across different regions of Italy. The analysis was conducted from a societal perspective over a 1-year horizon.

The economic burden included direct healthcare costs (hospitalization, pharmaceuticals, and specialist care), direct nonhealthcare costs, and indirect costs related to productivity loss.

Results

In Italy, the prevalent population of patients with PAH is estimated between 2100 and 3500 individuals, with 2–5% in functional class (FC) I, 28–31% in FC II, 53–57% in FC III, and 7–11% in FC IV. The total annual expenditure for treatment and management is estimated between 263 million and 438 million euros, with 74% attributable to direct healthcare costs, 9% to direct nonhealthcare costs, and 17% to indirect costs. The mean annual cost per patient is approximately 125,000 € and increases with disease severity, ranging from 46,303 € for FC I to 252,176 € for FC IV.

Conclusions

PAH has a substantial economic burden, increasing with disease severity. Early diagnosis and targeted interventions could improve patient outcomes, reduce complications, and optimize resource allocation for the National Health Service and society.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40801-025-00520-y.

Key Points for Decision Makers

Pulmonary arterial hypertension (PAH) imposes a substantial economic burden on the Italian healthcare system, with the majority of costs attributable to direct healthcare expenses related to hospitalizations and advanced therapies.

The economic impact of PAH increases with disease severity, with per-patient costs rising from 46,303 € in functional class (FC) I to 252,176 € in FC IV. In general, the primary driver of direct costs is related to drug expenses. Early diagnosis and timely therapeutic interventions are crucial for improving patients’ quality of life and reducing disease progression with an expected positive impact on patients, the NHS, and society.

Introduction

Pulmonary arterial hypertension (PAH) is a rare and progressive disease, characterized by an increase in blood pressure in the arteries owing to vascular lesions. Severe PAH can lead to significant pulmonary hypertension and subsequent right ventricular failure, which, in extreme cases, can result in the patient’s death [1]. PAH does not present specific symptoms, making early-stage diagnosis challenging [1]; however, once detected, the presence of chest pain, arrhythmias, syncope, hemoptysis, and right heart failure can serve as significant indicators for accurate diagnosis [2]. PAH can occur independently, known as idiopathic pulmonary arterial hypertension, associated with drugs or heritable or in association with other conditions such as connective tissue disease, congenital heart diseases, or human immunodeficiency virus (HIV) infection [1, 3]. The World Health Organization (WHO) classifies pulmonary hypertension (PH) into four functional classes (FC), each representing the severity and progression of the disease: (1) class I—PH does not affect physical activity, (2) class II—PH slightly affects physical activity, (3) class III—PH significantly affects physical activity, and (4) class IV—PH causes incapacity in the patient [4].

Studies conducted in Europe and the USA suggest that PAH more frequently affects patients older than 65 years, particularly those with cardiovascular or pulmonary comorbidities [5]; the traditional epidemiology has been reported in old registry where PAH was a disease of predominantly young females [5].

Over the past 20 years, particularly within the last decade, novel therapeutic strategies for the disease have been developed. These strategies are designed to mitigate symptoms, enhance patients’ quality of life, decelerate disease progression, and extend overall survival [6].

The epidemiology of PAH exhibits significant heterogeneity across European countries, with prevalence rates ranging from 15 cases per million in France among patients aged 18 years and older [7] to 26 cases per million in Scotland among adults aged 16–65 years [8]. A study conducted across developed countries, utilizing national systemic registry data [9], reported a prevalence range of PAH between 22.4 and 54.7 cases per million. However, estimates of prevalence are contingent upon study classification and the demographic structure of respective countries.

Currently, limited research has been conducted in Europe to assess the economic burden of PAH. A retrospective study in France [10] reported annual hospitalization costs amounting to 3,640,382 €, with an average hospital-stay cost of 2860 € (ranging from 1280 to 7285 €). In the UK [11], the average annual economic burden associated with PAH between 2013 and 2017 was estimated at £8.6 million, of which £6.7 million were attributable to hospitalizations. In Spain, the annual cost of PAH was estimated to range from 67,891,405 € to 106,131,626 € [12], while in Sweden [13], costs associated with PAH were estimated at 176,600 € 5 years after diagnosis, encompassing hospitalizations, outpatient care, medications, and productivity loss. Lastly, a systematic review [14] quantifying and synthesizing the direct costs linked with PAH on a worldwide scope reported a monthly cost range of US $2476 to US $11,875 per patient.

Currently, there are no studies in Italy assessing the direct and indirect costs related to PAH and its management. Therefore, the aim of this investigation is to evaluate the social and economic impact of PAH in Italy, utilizing real-world data derived from documents published by Italian national institutions [15] and analyzing both national and international literature. Specifically, we analyzed the economic and social impact of the disease according to FC.

Methods

A bottom-up prevalence approach was used to estimate the economic burden of PAH in Italy on the basis of epidemiological data and resource consumption from national and international literature. These data were reviewed and, where necessary, adapted to the Italian clinical context through structured interviews with a panel of expert clinicians with extensive experience in the management of the condition across different regions of Italy, all of whom are authors of this manuscript. The analysis was conducted from the perspective of the National Health Service (NHS) and society, with a 1-year time horizon. The economic impact was estimated by considering direct healthcare costs (treatment, outpatient and laboratory care, emergency room visits, hospitalizations, and transplants), direct nonhealthcare costs (supportive therapies, medical devices, and formal and informal care), and indirect costs, primarily related to the loss of productivity of patients during the 1-year follow-up period. All cost data were used as reported in their original sources and were not adjusted for inflation. This choice was made because most of the unit cost estimates obtained from literature referred to relatively recent data (Zozaya et al. [2022] whose costs refer to the year 2020) or to tariffs currently applied in the Italian healthcare system [16, 17], and were thus considered sufficiently representative for the purposes of the analysis.

The analyses were stratified by the functional class of the patients, as defined by the expert clinicians.

Direct Healthcare and Nonhealthcare Costs

Regarding the costs of treatments, for each drug class considered in the model, the annual therapy cost was calculated considering ex-factory prices net of mandatory discounts. Further details on the treatments included, the dosing regimens considered, unit costs, and the assumptions made for the calculation of annual therapy costs are provided in the Supplementary Material. However, the costs associated with drug administration were not included in the analysis. For the purpose of estimating the total cost associated with treatments, for each functional class, the percentage of use of each treatment obtained from expert opinion was considered (Table 1). This expert opinion was collected through a structured consultation with a panel of expert clinicians. Although based on clinical judgment, this approach aimed to capture the heterogeneity of clinical practice at the national level.

Table 1.

Acquisition costs and distribution of patients by therapy

Treatment	FC I	FC II	FC III	FC IV	Cost per year
ERA	5%	5%	–	–	15,923 €
PDE5i	5%	5%	–	–	4754 €
ERA + PDE5i	60%	50%	45%	–	20,677 €
ERA + sGCs	5%	5%	10%	–	48,788 €
ERA + sGCs + PCA	5%	5%	20%	5%	102,050 €
ERA + sGCs + PCY	-	-	5%	5%	221,543 €
ERA + PDE5i + PCA	15%	25%	10%	5%	73,939 €
ERA + PDE5i + PCY	5%	5%	10%	80%	193,432 €
ERA/PDE5i + PCY	–	–	–	5%	183,093 €

ERA endothelin receptor antagonist, PDE5i phosphodiesterase type-5 inhibitor, PCA prostacyclin analogue, PCY prostacyclin, sGCs soluble guanylate cyclase stimulators

Other direct healthcare costs were calculated by multiplying resource consumption by their respective unit costs. The frequencies of healthcare resource use considered in the analysis and hospitalization rate were obtained from Zozaya et al. [12]. To ensure alignment with the Italian healthcare context, these data were refined with input from a panel of expert clinicians, whose clinical expertise and knowledge of regional healthcare delivery informed adjustments to more accurately reflect the heterogeneity of resource utilization across Italy in relation to disease severity. Since national data were available for Italy, the number of transplants was obtained from the Hospital Discharge Records (HDR) report by the Ministry of Health [15], with reference to the volume of hospitalizations for Diagnosis Related Group (DRG) 103 (heart transplant) and 495 (lung transplant). The values obtained were then associated with each functional class maintaining the distribution assumed in Zozaya et al. [12]. Unit costs were derived from national tariffs, available literature, and clinical expert opinion and are presented in Table 2.

Table 2.

Nonpharmaceutical healthcare-resource consumption per patient and unit costs

	Resource consumption per year				Reference for resource consumption	Unit cost	Reference for unit cost
HCR	FC I	FC II	FC III	FC IV
General practitioner	2.6	2.6	3.8	5.39	Adapted from [12]	22.00 €	[16]
Nurse	2.8	2.8	5.5	8.8		30.09 €	[17]
Specialized care	2.8	2.8	4.2	7.1		97.50 €	[16]
Emergency care visits	1	3.5	3.6	7.2		241.00 €	[17]
Electrocardiogram	2.5	2.5	3.5	4		11.60 €	[16]
Cardiopulmonary exercise test	1	1	1	1		83.65 €	[16]
6-minute walk test	2.5	2.5	3.5	4		56.50 €	[16]
Echocardiogram	1	1	1	2		66.00 €	[16]
Biochemistry	2.5	2.5	3.5	4		28.60 €	[16]
Extended biochemistry	0	0	0	0		282.22 €	[16]
V/Q scan	0.5	0.5	0.5	0.5		285.00 €	[16]
Right heart catheterization	1	1	2	2		2500.00 €	KOL assumption
CT angiogram	0.5	1	1	1		90.85 €	[16]
Oxygen saturation	2.5	2.5	3.5	6		9.50 €	[16]
Chest X-ray	1	1	1	2		15.45 €	[16]
Hospitalizations (days)	0.94	8.46	10.8	22.8		834.41 €	[18]
Transplants	–	–	3.75	4.25	[12, 15]	70,079.50 €	[15, 19]

HCR healthcare resource, V/Q ventilation–perfusion, CT computed tomography, KOL key opinion leader

Direct nonhealthcare costs included supportive therapies (such as physiotherapy, nutritional support, psychotherapy, and social work sessions), medical devices (including wheelchairs, walkers, and adjustable beds), as well as personal care costs. The latter encompassed both formal and informal care, referring to assistance with daily activities provided either by professional caregivers or by family members and other nonprofessionals. Altogether, these components reflect the multidimensional and nonmedical support needs of patients with PAH beyond standard healthcare interventions. Annual costs for each functional class were inferred from literature [12] and were about 6558 € for FC II, 13,742 € for FC III, and 16,314 € for FC IV. For FC I the cost is assumed to be zero in line with expert opinion.

Indirect Costs

A human capital approach was considered to evaluate indirect costs related to productivity loss, including working days or hours lost owing to the disease, temporary and permanent leaves, and early retirement. For temporary leave, 75% of the annual working hours were considered, while for early retirement and permanent disability, leave losses of 100% of working hours were considered. The input data associated with the loss of productivity were obtained from literature [12] and validated by clinical experts. No loss of productivity was assumed for patients in FC I. To calculate the costs associated with productivity lost, the average estimates of hourly and daily wages were considered. The data used for calculating indirect costs are presented in Table 3.

Table 3.

Annual labor productivity losses and cost input for the estimation of indirect costs

Loss of patient productivity	FC I	FC II	FC III	FC IV	References
Workdays lost owing to disability	–	20	–	–	[12] and KOL
Temporary leave	–	20%	–	–
Permanent leave	–	53%	86%	100%
Early retirement	–	7%	14%	–
Cost input					References
Daily salary	124,13 €				Calculation (annual salary [20] divided by 254 working days in a year)
Hourly wage	18,61 €				Calculation (annual salary [20] divided by 1694 h worked in 1 year [21])

Results

In Italy, the prevalent population of patients with PAH is estimated to be between approximately 2100 [18] and 3500 individuals [19], among whom 2–5% are categorized in functional class (FC) I, 28–31% in FC II, 53–57% in FC III, and 7–11% in FC IV. On the basis of the average distribution per FC, the aggregate annual expenditure for the treatment and management of patients with PAH is estimated approximately between 263 million and 438 million euros. This expenditure is composed of 74% direct healthcare costs, 9% direct nonhealthcare costs, and 17% indirect costs (Fig. 1).

Fig. 1.

Distribution of costs by category

The mean annual cost per patient, approximately 125,000 €, shows a direct correlation with the severity of the condition. In fact, costs increase progressively with disease progression, rising from 46,303 € for FC I to 252,176 € for FC IV (Fig. 2). In general, the primary driver of direct costs is related to drug expenses (Table 4).

Fig. 2.

Average cost per patient by costs category and functional class

Table 4.

Average direct healthcare costs per patient by functional class

Functional class	Percentage patients	Drugs	Outpatients	Hospitalizations and transplant	Total
I	2–5%	41,745 €	3774 €	784 €	46,303 €
II	28–31%	47,071 €	4422 €	7059 €	58,552 €
III	53–57%	72,408 €	7296 €	9143 €	88,847 €
IV	7–11%	183,777 €	8735 €	19,798 €	212,310 €
Total	–	76,391 €	6515 €	9460 €	92,366 €

Sensitivity Analysis

To verify the uncertainty of the model, a deterministic sensitivity analysis (DSA) was performed, considering a 20% variability of all inputs [20].

The sensitivity analysis highlights that the variable with the greatest impact on the average cost per patient is the annual treatment cost of triple therapy endothelin receptor antagonist (ERA) + phosphodiesterase type-5 inhibitor (PDE5i) + prostacyclin (PCY), as shown in the tornado graph in Fig. 3.

Fig. 3.

Tornado diagram: variation in average cost per patient vs. base case. FC Functional Class, ERA Endothelin Receptor Antagonist, PDE5i Phosphodiesterase type-5 inhibitor, PCA Prostacyclin analogue, PCY Prostacycli

Discussion

To our knowledge, this is the first study to estimate the annual societal burden of PAH in Italy, integrating real-world data with published evidence and expert opinion. While the economic impact of PAH has been investigated in a limited number of studies, few have adopted a comprehensive societal perspective, and none have been conducted within the Italian healthcare context. As a result, our analysis often relied on comparisons with older research to fill existing gaps. The limited availability of up-to-date national data and the rapid evolution of therapeutic strategies underscore the importance of periodically reassessing the burden of rare diseases such as PAH.

Our analysis estimates that the annual economic burden associated with the treatment and management of PAH in Italy is approximately between 263 million and 438 million euros. The mean annual cost per patient is approximately 125,000 €, with a clear gradient across functional classes, rising from 46,303 € for FC I to 252,176 € for FC IV. These findings confirm that disease severity is a key cost driver, consistent with previous literature. The expense associated exclusively with direct healthcare costs per patient is 92,366 €, which is broadly in line with the estimate reported by Zozaya et al. [12] (98,839 €) but notably higher than that observed in a Greek cohort (49,130 €) [21].

There are limited data regarding the indirect costs and productivity loss associated with PAH. Our study found that indirect costs account for 17% of the total expenditure. These costs were particularly substantial in intermediate stages of disease, representing 22% and 19% of total costs in FC II and III, respectively, before declining to 9% in FC IV. This pattern aligns with previous research, which has highlighted the reduced employment rate among more severely affected patients [22].

Notably, patients in FC IV—representing only 11% of the PAH population—are responsible for 22% of total costs, highlighting the disproportionate burden of advanced disease.

In their study, Runheim et al. [13] highlighted the significant social costs associated with PAH, demonstrating that increased healthcare resource utilization and productivity loss begin several years before diagnosis and continue to rise thereafter. Their findings emphasize the substantial economic and clinical burden of PAH, underscoring the importance of early diagnosis and more effective treatment strategies to potentially reduce these impacts. Our results support these conclusions, reinforcing the need for early intervention, not only to improve patient outcomes but also to contain the economic burden associated with disease progression. Establishing therapeutic goals aimed at preventing disease advancement is essential. In addition, adopting a multidisciplinary approach whenever possible allows for closer patient monitoring and maintenance at less severe functional class levels.

Despite its strengths, this study is subject to several limitations. First, the estimation of the number of patients with PAH in Italy is based on dated prevalence data, due to the lack of more recent national epidemiological studies. Nevertheless, this estimate was critically reviewed and validated by the panel of national experts involved in the study to ensure its plausibility in the current epidemiological context.

Second, indirect costs were estimated without accounting for productivity losses associated with premature mortality. Furthermore, the analysis did not incorporate quality-of-life decrements, which contribute substantially to the overall societal burden. In addition, other consequences of PAH, such as increased rates of depression and other comorbidities, were not captured, which may further underestimate the true economic impact of the disease.

Third, several inputs—particularly those related to direct nonhealthcare costs—were derived from studies conducted outside Italy. In the absence of national data, these parameters were adapted and subsequently validated by a multidisciplinary panel of Italian experts to ensure contextual relevance. Moreover, the influence of these assumptions was explored through sensitivity analyses, confirming the robustness of the model.

Finally, costs related to drug administration were not included in the annual treatment expenditure, potentially leading to an underestimation of direct healthcare costs.

These limitations underscore the importance of future research to improve the accuracy of cost estimates, broaden data collection to encompass all-cause healthcare resource use, and assess the long-term economic impact of novel and evolving treatment options. Strengthening the evidence base in these areas will be crucial to inform health policy decisions and promote efficient resource allocation in the management of PAH.

Conclusions

Despite inherent limitations in the available data sources, our study highlights the substantial disease burden associated with PAH, although it is a rare disease and the need for further investigations into the direct and indirect costs experienced by this patient population. Strategies that promote early diagnosis and timely intervention, enhancing adherence to treatment guidelines, may improve patients’ quality of life and reduce disease progression with an expected positive impact for patients, the NHS, and society.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

None.

Declarations

Conflicts of Interest

The authors have no relevant financial or nonfinancial interests to disclose.

Availability of Data and Material

Not applicable.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

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Code Availability:

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Author Contributions

All authors contributed to the study conception. PS and MP developed the study design and the economic and statistical analysis. The first draft of the manuscript was written by PS and MP, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.