The Clinical and Economic Burden of Pulmonary Arterial Hypertension in Israel, 2014–2022: A Retrospective Analysis of Healthcare Costs and Utilization

ABSTRACT

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with high morbidity and mortality. Real‐world data from Israel are scarce. This study aimed to estimate the incidence, describe treatment patterns, and quantify healthcare utilization and costs associated with PAH in Israel. We conducted a retrospective cohort study using electronic medical records from Maccabi Healthcare Services. Patients diagnosed with PAH between 2014 and 2022 were identified using a multi‐criteria case definition combining administrative, clinical, and free‐text data. Patients with PAH were compared to two control groups: a matched non‐PAH cohort and a cohort with heart failure with reduced ejection fraction (HFrEF). Healthcare resource utilization (HCRU) and costs were annualized and compared using adjusted regression models accounting for age, sex, comorbidities, and socioeconomic status. A total of 106 patients met the diagnostic criteria for PAH, corresponding to an incidence of 0.83 cases per 100,000 person‐years (95% CI: 0.66 to 1.00). The cohort was predominantly female (74%) with a mean age of 65 years. One‐year mortality among patients with PAH was approximately 20 times higher than in non‐PAH controls and 5 times higher than in patients with HFrEF. Mean annual healthcare costs were 12.2 times higher than in non‐PAH controls and 6.5 times higher than in patients with HFrEF, with medications accounting for 79% of total expenditures. PAH imposes a substantial clinical and economic burden in Israel, driven by medication costs with widespread use of monotherapy despite full coverage of combination therapy, supporting the case for concentrated care in expert centers.

1. Background

Pulmonary arterial hypertension (PAH) is a rare, life‐threatening condition characterized by remodeling of the distal pulmonary arteries, resulting in increased pulmonary vascular resistance and pulmonary arterial pressure, ultimately leading to right ventricular failure and death [1, 2]. Right heart catheterization (RHC) is the gold standard for confirming PAH, providing the hemodynamic measurements required for diagnosis [1].

Epidemiological data indicate that PAH is rare, with prevalence estimates varying significantly across regions. European registries report prevalence rates ranging from 5 to 52 cases per million adults; however, prevalence in North America and other developed countries remains less clearly defined. Similarly, reported incidence rates vary considerably, ranging from 0.008 to 1.4 cases per 100,000 person‐years, suggesting substantial geographic variability and/or gaps in global epidemiological knowledge [3, 4, 5, 6]. Over the past two decades, PAH has been increasingly diagnosed in older individuals, many of whom have pre‐existing comorbidities, making their management even more challenging [7]. Despite progress in treatment options, patients with PAH continue to experience disease progression and events associated with right ventricular failure, including hospitalizations, lung transplant or death. Hospitalizations are predictors of disease progression and mortality in patients with RV failure [2].

In Israel, data on PAH are limited, with the last significant publication dating back more than two decades [8]. Currently, there is no available information on treatment patterns, healthcare resource utilization or direct healthcare costs associated with patients with PAH in this country, which has been shown to be significant in other regions [9, 10, 11, 12].

We aimed to describe the clinical and sociodemographic characteristics of patients with PAH in Israel, detail their treatment lines, analyze their healthcare utilization patterns, and estimate their healthcare costs. The PAH cohort was compared to two control groups: a matched non‐PAH cohort, approximating a counterfactual to quantify the incremental burden attributable specifically to PAH; and a cohort of patients with heart failure with reduced ejection fraction (HFrEF), serving as a benchmark to contextualize the burden of PAH relative to a peer cardiopulmonary disease of comparable severity and specialist management.

2. Methods

2.1. Data Source

Maccabi Healthcare Services (MHS) provides coverage to 27% of the population of Israel (over 2.8 million individuals nationwide), with a disengagement rate of less than 1%. Membership in one of the four health funds in Israel is legally mandatory and guaranteed for all residents. MHS maintains a centralized electronic medical records (EMR) database, containing demographic and clinical data from both outpatient and hospital care.

2.2. Study Design and Participants

This retrospective cohort study included individuals aged 18 years or older who were newly diagnosed with PAH between January 1, 2014, and December 31, 2022.

Diagnoses were based on the International Classification of Diseases, Ninth Revision (ICD‐9), as used in the MHS database. Although an ICD‐9 code for Primary Pulmonary Hypertension exists, it refers to an obsolete term no longer in use, and also in practice is not used with sufficient specificity in EMRs to reliably distinguish PAH from other forms of PH. To address this limitation, we developed a diagnostic algorithm to more accurately identify patients with PAH. To qualify as a PAH case, individuals had to have at least one ICD‐9 diagnosis code for 416.0 (primary pulmonary hypertension), 416.8 (other chronic pulmonary heart diseases), or 416.9 (chronic pulmonary heart disease, unspecified), or equivalent codes used in the MHS system, along with initiation of a specific PAH‐approved medication—endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, prostacyclin analogues (prostanoids) or guanylate cyclase stimulators—within 3 months of the first recorded PAH diagnosis. Additionally, patients were required to undergo RHC within 6 months before the initiation of PAH medication. RHC is considered the standard criterion; however, any heart catheterization was accepted if the side of the heart was unspecified in the data. Patients who underwent exclusively left heart catheterization were excluded. Patients prescribed phosphodiesterase type 5 (PDE‐5) inhibitor monotherapy solely for erectile dysfunction or prostatism were also excluded.

Given the potential non‐specificity of these ICD‐9 codes, which may capture pulmonary hypertension groups 2 or 3, two additional measures were implemented to enhance diagnostic stringency: (1) all patients had to appear in the MHS drug approval system with a documented PAH indication, and (2) explicit mentions of PAH disease had to be present within physician notes (as free‐text mentions) in the EMR. This textual evidence was identified using a PAH‐specific ontology designed to capture permutations, common misspellings, synonyms, and negations (see Supplementary Table S1).

Two control groups were employed for comparison. The first comprised MHS members without PAH (non‐PAH), matched 1:10 to patients with PAH based on sex, age, socioeconomic status (SES), and three comorbidities: diabetes mellitus, hypertension, and cardiovascular diseases. The second control group consisted of patients with heart failure with reduced ejection fraction (HFrEF), included as a comparator representing a well‐studied disease with a defined course and costs. HFrEF was chosen due to its management by similar specialists and the acknowledgment that PAH can progress to heart failure. For patients with PAH, the index date was defined as the date of their first PAH medication purchase. For HFrEF patients, it was the date of their initial HFrEF diagnosis, and for non‐PAH controls, the index date was aligned with the corresponding PAH patient's index date. Follow‐up continued until death, termination of MHS membership, or December 31, 2022, whichever occurred first. All participants were required to have at least 2 years of continuous enrollment in MHS prior to their index date.

2.3. Study Variables

Individual‐level demographic data included sex and age at the index date. SES was determined at the area level using coded Geographical Statistical Areas (GSAs), the smallest administrative units defined by the Israeli census, assigned by Israel's Central Bureau of Statistics on a scale from 1 (lowest) to 10 based on socioeconomic parameters including household income, educational qualifications, household crowding, and car ownership. For analysis, the 1–10 index was collapsed into three categories: low (clusters [1–4]), middle (clusters [5–7]), and high (clusters [8–10]). Members whose residential GSA had no assigned index value were classified as unknown (“Other”). Data on chronic conditions were extracted from MHS automated registries and included cardiovascular diseases (CVD), hypertension (HTN), diabetes mellitus (DM), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). CVD is a composite category encompassing all cardiovascular conditions; IHD, stroke, and congestive heart failure are reported separately as constituent subcategories of CVD. The Charlson Comorbidity Index (CCI) was calculated using diagnoses recorded in the EMR. Each registry is defined by a structured algorithm with fixed eligibility rules combining diagnostic codes, laboratory results, and medication purchases. These algorithms run nightly, registering eligible cases with their entry date, providing more standardized disease definitions than a direct query of raw ICD‐9 codes from the EHR. Additional health indicators, such as body mass index (BMI) and smoking status, were included, with smoking categorized as current or past smoker, never smoker, or unknown. All the characteristics were assessed at baseline.

2.4. Statistical Methods

The study compared baseline characteristics and outcomes between groups using descriptive statistics and hypothesis testing. Continuous variables were reported as means with standard deviations (SD) and categorical variables as frequencies and percentages. Standardized mean differences (SMDs) were used to assess balance between groups, with an SMD < 0.1 considered indicative of adequate balance.

Incidence of PAH is presented as the number of newly diagnosed cases per 100,000 person years from the summed person‐years of average population at risk during the research period. The 95% confidence interval (CI) was calculated using the Wald method. For each of the three groups, 1‐year survival probabilities with 95% confidence intervals were estimated using Kaplan‐Meier curves adjusted via a Cox proportional hazards model, standardized to the mean age, sex, and CCI of the PAH cohort.

The treatment patterns of patients with PAH were studied, focusing on categorization by specific treatment combinations and lines of therapy. Patients were categorized into four groups (not mutually exclusive): (1) monotherapy using one of the following drug classes: endothelin receptor antagonist (ERA), PDE‐5 inhibitor, prostanoid, or soluble guanylate cyclase (sGC) stimulator; (2) two‐drug combination therapy from these same classes; (3) combination therapy involving three or more drugs from these classes; and (4) a distinct category defined by therapy with prostanoids administered orally, by inhalation or parenterally (by continuous subcutaneous [SC] or intravenous [IV] infusion). Within each category, patients were further stratified by lines of therapy (first through fourth or beyond) and subcategorized by sex and age.

Treatment patterns were further analyzed based on specific drug combinations administered during the disease course. Combinations were stratified according to the number of drugs used (monotherapy, dual therapy, or triple therapy) and therapy lines, denoted L1 through L4 (representing first to fourth lines of therapy). Each therapy line was defined as a distinct treatment sequence with a minimum interval of 2 months between the first and last medication purchase. For each drug combination, the total number of patients (N) and their distribution across therapy lines are reported.

We evaluated the economic and healthcare burden associated with PAH by analyzing both healthcare resource utilization (HCRU) and actual costs across three groups: patients with PAH, non‐PAH controls, and HFrEF controls. HCRU reflects the intensity and frequency of healthcare services utilized, including visits to family medicine/general practitioner, specialist consultations (cardiologist and/or pulmonologist), emergency department visits, number of distinct hospital admissions, and number of hospitalization days.

Health care costs provide a direct measure of the financial impact of PAH, and in this study, we included expenditures on medications, hospital stays and inpatient procedures. For these services we used official prices denominated in New Israeli Shekel (NIS) that were set by the Israeli Ministry of Health and were prevalent at the time‐of‐service utilization we used in the study. To convert the costs to United States Dollar (USD), the costs in NIS were divided by an average exchange rate (2014‐2022) of 3.57 NIS to USD. Because of the varied follow‐up time, HCRU and costs of each participant were annualized by dividing the incurred HCRU quantities and costs by the number of contributed follow‐up days and then multiplying by 365. For each group, the mean, standard deviation, median and IQR of annualized total costs and hospitalization costs during the research period are reported. Additionally, for PAH and HFrEF groups, similar statistics for annualized costs were provided for each year of follow‐up, spanning years 1 through 8.

To compare mean annual HCRU between patients with PAH and two matched control groups, we fitted a zero‐inflated negative binomial (ZINB) model. The ZINB combines (i) a logistic component for the probability of no utilization and (ii) a negative binomial count component (log link) for positive counts, accommodating the excess zeros observed [13]. Mean annual direct costs were analyzed with a two‐part model:

$$\mathrm{E}[Y|\mathit{PAH}]=\text{Pr}\left(Y>0\right|\mathit{PAH})\ast E\left[Y\right|Y>0,\mathit{PAH}]$$

where the first part $\text{Pr}\left(Y>0\right|\mathit{PAH})$ was estimated via logistic regression and the second part via a gamma‐family generalized linear model with a log link [14].

All models were adjusted for age (continuous), sex, SES, CCI, CKD stage, and calendar year. For the non‐PAH comparison, adjustment for age as a continuous variable captures residual imbalance within the 3‐year matching caliper; for the HFrEF comparison, where matching was restricted to diagnosis date, adjustment for age and sex was necessary given the substantial imbalance between groups.

3. Results

3.1. Patient Identification

We identified 106 individuals diagnosed with PAH between 2014 and 2022. Based on the research source population of MHS, the incidence of PAH was 0.83 cases per 100,000 person‐years (95% CI: 0.66–1.00).

3.2. Patient Characteristics

Of the 106 patients with PAH, 78 were women (74%), and mean age at diagnosis was 64.7 years (SD 15.6). Two control groups were established, each consisting of 1,060 individuals. The first control group (non‐PAH) comprised individuals without PAH, matched to patients with PAH by sex, age (±3 years), SES, and three baseline comorbidities: DM (39%), HTN (64%), and CVD (55%). The second control group consisted of patients with HFrEF and was selected based on the time of diagnosis, without matching of demographic or clinical characteristics. The HFrEF group consisted of 80% males (p < 0.001 cf. the PAH group) with a mean age at diagnosis of 67.9 years (SD 12.3; p = 0.01). The SES distribution of patients with PAH closely resembled that of the comparator groups (p = 0.94), with approximately one‐third of participants in the middle SES range (Table 1). The mean follow‐up duration was 1,113 days (SD 833) for patients with PAH, 1,551 days (SD 834) for non‐PAH controls, and 1,423 days (SD 834) for HFrEF patients. No participants were lost to follow‐up (specifically none discontinued MHS membership), with censoring occurring only at the end of the study period or death.

Table 1.

Baseline characteristics of patients with PAH and the two comparison groups.

	PAH	Non‐PAH	HFrEF	PAH vs non‐PAH	PAH vs HFrEF
	(N = 106)	(N = 1060)	(N = 1060)	SMD	SMD
Age (Mean (SD))	64.7 (15.6)	64.7 (15.6)	67.9 (12.3)	0.001	0.23
Sex ‐Female (N,%)	78 (73.6%)	780 (73.6%)	216 (20.4%)	< 0.001	1.26
District (N,%)				< 0.001	0.09
Central	62 (58.5%)	620 (58.5%)	665 (62.7%)
North	23 (21.7%)	230 (21.7%)	217 (20.5%)
South	21 (19.8%)	210 (19.8%)	178 (16.8%)
Socio‐economic status (N,%)				< 0.001	0.081
High	31 (29.2%)	310 (29.2%)	320 (30.2%)
Middle	65 (61.3%)	650 (61.3%)	633 (59.7%)
Low	10 (9.4%)	100 (9.4%)	104 (9.8%)
Other	0 (0%)	0 (0%)	3 (0.3%)
CCI cat.				0.1	0.56
0	16 (15.1%)	180 (17.0%)	26 (2.5%)
1	13 (12.3%)	131 (12.4%)	75 (7.1%)
2	23 (21.7%)	257 (24.2%)	299 (28.2%)
3	35 (33.0%)	328 (30.9%)	336 (31.7%)
>=4	19 (17.9%)	164 (15.5%)	324 (30.6%)
Diabetes mellitus (N,%)	41 (38.7%)	410 (38.7%)	461 (43.5%)	< 0.001	0.01
Cardiovascular disease (N,%)(1)	58 (54.7%)	580 (54.7%)	853 (80.5%)	< 0.001	0.57
Ischemic heart disease (N,%)	27 (25.5%)	215 (20.3%)	683 (64.4%)	0.12	0.85
Stroke (N,%)	1 (0.9%)	79 (7.5%)	98 (9.2%)	0.33	0.38
Congestive heart failure (N,%)	21 (19.8%)	35 (3.3%)	255 (24.1%)	0.54	0.10
Hypertension (N,%)	68 (64.2%)	680 (64.2%)	677 (63.9%)	< 0.001	0.006
Chronic kidney disease (eGFR < 30) (N,%)	6 (5.7%)	44 (4.2%)	78 (7.4%)	0.07	0.07
Chronic obstructive pulmonary disease (N,%)	16 (15.1%)	75 (7.1%)	138 (13.0%)	0.26	0.06
Smoking status (N,%)				0.01	0.4
Current/Former	35 (33.0%)	377 (35.6%)	543 (51.2%)
Never	70 (66.0%)	672 (63.4%)	495 (46.7%)
Unknown	1 (0.9%)	11 (1.0%)	22 (2.1%)
BMI (Mean (SD))	29.3 (6.3)	28.7 (5.9)	28.5 (5.1)	0.09	0.13
Missing	2 (1.9%)	19 (1.8%)	33 (3.1%)

Note: Non‐PAH controls were matched to patients with PAH (1:k, k ≤ 10) on age, sex, socioeconomic status, diabetes mellitus, hypertension, and cardiovascular disease. HFrEF patients were matched on diagnosis date only. An SMD below 0.1 indicates adequate balance. Continuous variables are summarized as mean (SD).

Abbreviations: BMI, body mass index; CCI, Charlson Comorbidity Index; eGFR, estimated glomerular filtration rate (mL/min/1.73 m²); HFrEF, heart failure with reduced ejection fraction; PAH, pulmonary arterial hypertension; SD, standard deviation; SMD, standardized mean difference.

Patients with PAH had a markedly worse prognosis than their controls, with an estimated 1 year survival of 80% (95% CI: 71%, 86%) compared to 96% (95% CI: 94%, 97%) for HFrEF patients and 99.0% (98.4%, 99.4%) for non‐PAH individuals (Figure 1).

Figure 1.

Adjusted survival curves for patients with PAH and the two comparison groups. Curves are derived from a Cox proportional hazards model adjusted for age, sex, and CCI. Shaded areas represent 95% confidence intervals. One‐year survival probabilities with 95% CI are shown below the figure. Abbreviations: PAH, pulmonary arterial hypertension; HFrEF, heart failure with reduced ejection fraction; CCI, Charlson Comorbidity Index; CI, confidence interval.

Among patients with PAH, first‐line treatment was monotherapy in 55 (52%), dual therapy in 45 (42%), and triple therapy in 6 (6%). Among those starting on monotherapy, 19 of 55 (35%) escalated to dual therapy after a median of 7.8 months. Among those starting on dual therapy, 11 of 45 (24%) escalated to triple therapy after a median of 5.6 months. Treatment combinations by line are shown in Table S2, with transitions between regimens shown in Figure 2.

Figure 2.

Treatment transitions across successive lines of therapy in patients with PAH. The Sankey diagram shows how patients move between treatment categories from one line to the next. Regimens are classified as monotherapy with a non‐prostacyclin agent, monotherapy with a prostacyclin only, combination therapy without a prostacyclin, and combination therapy including at least one prostacyclin. Bar height represents the number of patients on a given regimen at that line, and flow width the number transitioning between categories. Missing treatment lines are retained for structural consistency and rendered visually neutral. Abbreviation: PAH, pulmonary arterial hypertension.

Parenteral prostacyclins (intravenous or subcutaneous) were used alone or in combination by 20 patients (19%), with the proportion rising across treatment lines from 10% (11/106) at first line to 30% (7/37) at second line and 40% (4/10) at third line. Oral or inhaled prostanoids were prescribed in 34 patients (32%), primarily as first line (n = 14) and second line (n = 18). Compared with oral or inhaled formulations, parenteral prostanoids were more often prescribed to females (91% vs 69%, p < 0.001) and to younger patients (median age 53 years, IQR 43 to 62, vs 69 years, IQR 57 to 78, p < 0.001).

3.3. Healthcare Resource Utilization and Costs

All‐cause HCRU differed substantially across the PAH, HFrEF, and non‐PAH groups, with patients with PAH using more resources in every category. The defining pattern was specialty management. The median annual pulmonologist visit count among patients with PAH was 2.2 (IQR 0.9, 3.5) versus 0.4 (IQR 0, 2) for cardiologists, and 82% and 58% had at least one annual pulmonologist or cardiologist consultation, respectively, indicating that PAH in Israel is managed primarily by pulmonologists. Model‐based differences and ratios for all resource categories are presented in Table 2, with annualized summaries by group in Table S3.

Table 2.

Adjusted differences and ratios in annual healthcare resource utilization between patients with PAH and each comparison group.

	Comp. group	Mean diff. (95% C.I.)	Mean ratio (95% C.I.)
Family Phy. visits
	non‐PAH	12.7 (10.3, 15.7)	2.1 (1.9, 2.5)
	HFrEF	8.4 (6, 10.9)	1.6 (1.4, 1.8)
Cardiologist visits
	non‐PAH	0.7 (0.4, 1)	2.7 (2, 3.6)
	HFrEF	−0.8 (−1.2, −0.4)	0.6 (0.4, 0.8)
Pulmonologist visits
	non‐PAH	2 (1.8, 2.4)	23.3 (18.3, 30.2)
	HFrEF	1.8 (1.5, 2.2)	15.2 (12, 20.5)
ER. visits
	non‐PAH	0.3 (0.1, 0.4)	2.1 (1.5, 2.8)
	HFrEF	0.1 (0, 0.3)	1.3 (0.8, 1.7)
Hosp. days
	non‐PAH	4.8 (3, 7.6)	3.6 (2.5, 5.4)
	HFrEF	2.3 (0.7, 4.7)	1.6 (1.1, 2.2)

Note: Estimates are adjusted for sex, age, CCI, SES, CKD stage, and calendar year, with 95% bootstrap confidence intervals.

Abbreviations: CCI, Charlson Comorbidity Index; CI, confidence interval; CKD, chronic kidney disease; Comp., comparison; ER, emergency room; HCRU, healthcare resource utilization; Hosp., hospital; PAH, pulmonary arterial hypertension; SES, socioeconomic status; Phy., physician.

Model‐based cost contrasts between patients with PAH and each control group are reported in Table 3. Medical costs were markedly higher in patients with PAH than in either control group. The mean annualized total cost was 100,701 USD (SD 91,840) for patients with PAH, 14,097 USD (SD 24,940) for HFrEF patients, and 6,658 USD (SD 14,208) for non‐PAH individuals. Medication accounted for 79% of total costs in patients with PAH, compared with 27% in HFrEF and 37% in non‐PAH groups (Table S4).

Table 3.

Adjusted differences and ratios in annual healthcare costs between patients with PAH and each comparison group.

		Total cost (95% CI) USD	Drugs cost (95% CI) USD	Hosp. cost (95% CI) USD
Cost difference (PAH ‐ Controls)	Non‐PAH	95,311 (91,835, 100,708)	76,782 (74,202, 79,787)	14,952 (13,709, 17,313)
	HFrEF	82,491 (77,582, 87,624)	73,603 (70,241, 76,716)	9,758 (7,915, 12,175)
Costs ratio (PAH/Controls)	Non‐PAH	12.2 (11.7, 12.9)	24.9 (23.6, 26.5)	4.0 (3.7, 4.6)
	HFrEF	6.5 (6.0, 6.9)	19.1 (18.1, 20.3)	1.9 (1.7, 2.1)

Note: Estimates are adjusted for sex, age, CCI, SES, CKD stage, and calendar year, with 95% bootstrap confidence intervals. All costs are in USD.

Abbreviations: CCI, Charlson Comorbidity Index; CI, confidence interval; CKD, chronic kidney disease; Hosp., hospital; PAH, pulmonary arterial hypertension; SES, socioeconomic status;.

Median annual costs among patients with PAH were highest in the first year (57,893 USD), stabilized at approximately 45,000 USD from year four onward, and rose in years seven and eight, with greater variance likely reflecting the smaller number of surviving patients. In HFrEF patients, median annual costs were substantially lower, decreasing from approximately 6,000 USD in the first year to around 3,900 USD thereafter (Table S5, Figure 3).

Figure 3.

Annualized healthcare costs of patients with PAH and HFrEF by year since diagnosis. Lines show median annual cost. Ribbons span the interquartile range. HFrEF, heart failure with reduced ejection fraction; IQR, interquartile range; PAH, pulmonary arterial hypertension; USD, US dollars.

4. Discussion

We conducted a retrospective cohort study to characterize the clinical and economic burden of PAH in Israel using EMRs from a large nationwide healthcare organization, serving over 2.8 million members. Given the limitations of standard diagnostic codes in accurately identifying patients with PAH in retrospective data, we developed a stringent case definition that incorporates administrative approvals of PAH‐specific medications and natural language processing of free‐text physician notes.

Our estimated PAH incidence of 0.83/100,000 person years aligns with the midrange of values reported in two recent systematic reviews. Leber et al. reported incidence ranging from 0.15 to 3.2/100,000/yr (median 0.55, interquartile range 0.3–0.92/100,000) [4]. Another systematic review published the same year (2021) reported an incidence ranging from 0.008 to 1.4/100,000/yr [5]. Earlier Israeli studies reported an incidence of 0.71/100,000/yr in a study performed 1998–2005 [15] and 0.14/100,000/yr in an earlier study from 1988 to 1997 [8]. Several factors may account for the wide variability in reported PAH incidence. First, methodological differences are substantial—for instance, our analysis relied on EMR data from a large health maintenance organization (HMO), whereas Applebaum et al. employed a nationwide physician survey approach [8]. Second, increasing awareness of PAH, improved access to specialized care, and evolving diagnostic criteria may all enhance detection over time.

Our cohort's sex and age distribution is consistent with ranges reported in a recent systematic review (55%–81% female, mean age 43–67 years) [4].

More than half of our cohort received monotherapy as first‐line treatment. This contrasts with recent clinical guidelines, which generally discourage monotherapy for most patients with PAH [6, 16]. One possible explanation for the wide use of monotherapy is that recommendations against monotherapy were not introduced until quite late in our study period (2014–2022). The 2022 ESC‐ERS guidelines were the first to unequivocally recommend first line dual oral therapy for low and intermediate risk patients with PAH, but still recommended oral monotherapy in patients who have cardiopulmonary comorbidities [6]. The high prevalence of cardiopulmonary comorbidities in our cohort may also partly explain monotherapy use.

Another factor that may contribute to the predominance of monotherapy is that both patients and clinicians often hesitate to adopt complex, multi‐drug regimens. In contrast, cost is unlikely to drive this tendency: in Israel, quarterly co‐payments for all chronic medications are capped at roughly USD 300, and double‐ or triple‐combination therapies for PAH are fully covered by the national health‐insurance system. Finally, our cohort excludes individuals prescribed PDE‐5 inhibitors solely for erectile dysfunction, ruling out this indication as a contributor to the observed monotherapy pattern.

In our study, patients with PAH who received parenteral prostanoids were significantly younger and more likely to be women. These drugs, delivered by continuous infusion using specialized pumps, are a highly effective treatment for PAH, but carry high financial cost, significant inconvenience and a high burden of side effects. Patients or their household members must learn to maintain the treatment in the patient's home. Intravenous therapy requires the maintenance of a permanent intravenous catheter using meticulous sterile technique. Subcutaneous treatment requires periodic re‐implantation of the infusion needle. Pumps need to be refilled every 1–3 days. Adverse effects are common, and have a major adverse effect on patients' quality of life. Thus patients and providers might be more likely to use parenteral prostanoids in younger patients with fewer comorbidities, who have a better benefit/risk profile for these drugs.

To contextualize the disease burden of PAH, we compared our PAH cohort with two comparator groups serving distinct analytical purposes. The matched non‐PAH cohort approximates a counterfactual, isolating the incremental burden attributable specifically to PAH, net of the burden explained by age, sex, socioeconomic status, and comorbidities. The HFrEF cohort serves as a benchmark for evaluating what is unique to PAH relative to a peer disease: a condition with many similarities to PAH in terms of specialist management and disease trajectory (many patients with PAH progress to right heart failure), yet clearly distinct in etiology and pathophysiology, with HFrEF primarily a disease of the left ventricle that is usually distinguishable from PAH by echocardiography.

The 20‐fold and fivefold higher 1‐year mortality in PAH compared with non‐PAH and HFrEF cohorts respectively places our findings within the high‐risk range described in recent literature. Recent literature reports approximately 20% 1‐year mortality in patients with PAH classified as high risk [17]. We believe the high mortality observed in our cohort is due to the long time period assessed in our study which included patients treated prior to the new treatment guidelines, emphasizing the importance of treatment combinations [6]. Notably, the 80% 1‐year survival we observed in our PAH cohort is consistent with a systematic review [5] which identified 6 reports of PAH survival in which the diagnosis, as in our study, was based on ICD‐9 codes. The 1‐year survival reported in these studies ranged from 72% to 91% (average 84%).

HCRU and adjusted annual costs were significantly higher in patients with PAH than in either control group. Total costs were 12‐fold higher than in non‐PAH controls and sixfold higher than in patients with HFrEF, with medication costs the principal driver, accounting for 79% of total expenditures in patients with PAH compared with 37% and 27% in non‐PAH and HFrEF respectively.

Differences between studies of health care costs in PAH may stem from several factors. First, there are differences between countries in how healthcare is organized and regulated, which can result in major differences in specific costs. For example, in Israel healthcare is provided by HMOs that are non‐profit organizations by law. Procedure and hospitalization costs are determined by the Ministry of Health. Medication costs are initially negotiated by the pharmaceutical companies with the governmental Health Basket Committee and later are often discounted in further negotiations between the companies and the HMOs. In contrast, in the US most healthcare insurers and providers are for‐profit businesses. Governmental regulation of healthcare costs is minor. Second, changes over time have a major influence on costs. Examples pertinent to PAH include the growing use (recommended by treatment guidelines) of prostanoids, increased use of combination therapy and the development of novel and costly drugs, all of which drive costs up; and the relatively recent availability of generics, which reduce costs.

In our study, 79% of direct healthcare costs of PAH were for medication. This is similar to 50% reported in a recent study performed in Spain [10] and significantly higher than what has been reported in studies in the US (28%–44% in a study performed 2016–2018 [9] and 15% in an earlier study, performed 2002–2007) [18]. Apart from the differences between the organizations of the healthcare systems in the countries studied, there are notable differences in medication use. In our study, first‐line therapy for patients with PAH included PDE5 inhibitors in 68% of cases, ERAs in 58%, and prostanoids in 22%. In contrast, Tsai et al. reported that, in Taiwan, 93.6% of patients received either PDE5 inhibitors or sGC stimulators as first‐line treatment, while only 4.3% received ERAs [19]. A Spanish study which reported on treatment use across all lines of therapy, found corresponding proportions of 38% for PDE5 inhibitors, 47% for ERAs, and 12% for prostanoids [10].

These findings carry implications across clinical practice, healthcare system organization, and policy. Clinically, the widespread use of monotherapy in our cohort, contrasting with current guideline recommendations for upfront combination therapy in most patients, warrants attention through clinician education, structured risk stratification at diagnosis, and adherence monitoring. At the healthcare system level, the combination of high cost and rarity makes a strong case for concentrating PAH care in dedicated expert centers, as international guidelines recommend. Expert centers can improve diagnostic accuracy, ensure guideline‐concordant treatment, and reduce unjustified use of expensive PAH‐specific medications. At the policy level, the dominance of medication costs, accounting for 79% of total expenditure, underscores the need for ongoing negotiation of PAH drug prices within the national health basket framework, and the value of payer‐tracked quality metrics tied to combination therapy initiation and management within designated PAH centers. Together, these measures would address both the clinical undertreatment observed in our cohort and the economic burden imposed on the healthcare system.

This retrospective study has limitations. First, despite rigorous definitions, misclassification between other types of PH and PAH may persist, as we did not have access to the detailed hemodynamics from right heart catheterization. The coexistence of PAH and COPD in 16 patients raises concern about inadvertent inclusion of WHO Group 3 pulmonary hypertension. We sought to minimize misclassification by using drug approvals and targeted text mining of EMR notes. The case definition was not formally validated against an external reference standard. The sensitivity and specificity of the algorithm are therefore unknown. Our stringent multi‐criteria approach likely improves specificity at a cost to sensitivity, potentially underestimating incidence. The effect of the stringency of our inclusion criteria on cost and utilization estimates is harder to predict: if missed cases are systematically less severely ill, the observed estimates may overstate the average burden per patient; if they represent patients who died before completing the diagnostic workup, the estimates may be conservative.

Second, annual costs and HCRU were calculated by extrapolating partial follow‐up periods to a full year, assuming constant expenditure rates. This assumption can inflate or underestimate costs, especially for infrequent or intermittent events, and shorter follow‐up increases bias. However, consistent disparities between patients with PAH and controls suggest these biases do not affect conclusions.

Third, cost variability is smaller in homogeneous populations (PAH, HFrEF) compared to healthier controls. Within PAH, variability arises from diverse treatment regimens (monotherapies to expensive triple therapies), physician practices, evolving standards, and changing medication prices.

Lastly, although absolute costs and incidence estimates from the MHS population may not generalize to the broader Israeli population or to international settings, the observed patterns in healthcare utilization and drug burden are likely to hold relevance both nationally and internationally.

In conclusion, our study demonstrates that healthcare costs associated with PAH are high, even when compared to those of HFrEF. The high economic burden of PAH is driven by medication costs. Given the high mortality associated with PAH, as shown in our analysis, there is an urgent need to prioritize access to appropriate and guideline‐based treatment for this condition.

Author Contributions

C.M., L.L.B., S.G., Y.S., M.H., T.P., and M.J.S. contributed to the design and implementation of the research. Y.S., S.G., C.M., R.N., E.B.‐d., M.H., S.S.M., M.S., M.J.S., I.S., and Y.A. contributed to the analysis of the results and to the writing of the manuscript.

Ethics Statement

This study was approved by the MHS (Maccabi Healthcare Services) Institutional Review Board (IRB, 0120‐23‐MHS). Due to the retrospective design of the study, informed consent was waived by the IRB, and all identifying details of the participants were removed before computational analysis.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File

Saciuk Y, Mamane C, Patalon T, et al., “The Clinical and Economic Burden of Pulmonary Arterial Hypertension in Israel, 2014–2022: A Retrospective Analysis of Healthcare Costs and Utilization,” Pulmonary Circulation 16 (2026): e70366. 10.1002/pul2.70366.

Data Availability Statement

According to the Israeli Ministry of Health regulations, individual‐level data cannot be shared openly. Specific requests for remote access to de‐identified community‐level data should be referred to the Maccabi Healthcare Services Research and Innovation Center. Research data are not shared.