Advances in the treatment of pulmonary arterial hypertension
Introduction
Pulmonary arterial hypertension (PAH) is a form of high blood pressure that affects arteries in the lungs. In patients with PAH, the small arteries in the lungs become thickened and narrowed, restricting blood flow.1 This vascular remodeling leads to increased resistance to blood flow, which causes the heart to work harder to pump blood and increases the blood pressure in the lungs.1 Over time, the heart’s ability to pump blood decreases in patients with PAH.1 Progression of PAH may lead to patients no longer being able to continue their normal daily activities or becoming completely bedridden.2 If left untreated, right ventricular (RV) failure and death can occur.3
PAH is associated with substantial burdens on patients, society and healthcare systems. In January 2025, authors representing the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 reported that worldwide, the burden of PAH was 642,000 disability-adjusted life years (53.3% in women and 46.7% in men) in 2021.4 They also found that the most important burden related to PAH was years of life lost (YLLs), with PAH leading to 624,000 YLLs (53.3% in women and 46.6% in men) in 2021.4 The disease also has a high mortality rate. The 3-year mortality rate of patients with PAH is 21% (95% confidence interval [CI], 17%-25%).5
In addition to its health impact on patients, PAH leads to high payer-paid medical and pharmacy costs, as well as high out-of-pocket costs.6 According to a study of commercial insurance and Medicare Advantage/Supplemental Part D insurance data collected between October 2015 and November 2020, all-cause costs were $14,201 per patient per month (PPPM).7
To overcome the various burdens and challenges associated with PAH treatment, numerous treatments are available, with several new therapies currently being evaluated in clinical trials.8,9 This article explores advances in PAH treatment and prevention as well as managed healthcare considerations.
Disease overview
According to the most recent epidemiological data, there were 192,000 cases (95% uncertainty interval [UI], 155,000-236,000) of PAH worldwide in 2021, corresponding to an incidence of 2.8 per 100,000 people (95% UI, 1.85-2.80). Death occurred in 22,000 patients with PAH (95% UI, 18,200-25,400).4 In the US, 500 to 1,000 new cases of PAH are diagnosed each year, most commonly in women aged 30 to 60 years.1
PAH is a progressive disease that impacts the pulmonary vasculature10 and is caused by interactions between various lung cell types, including vascular, immune and circulating cells. These interactions lead to endothelial dysfunction that reduces the levels of vasodilators (e.g., nitric oxide and prostacyclin) and increases the levels of vasoconstrictors (e.g., endothelin-1), resulting in smooth-muscle cell proliferation and extracellular matrix remodeling.3 Abnormal signaling in the TGF-β and BMPR2 pathways plays a key role in PAH11; mutations in BMPR2, seen in most heritable cases, contribute to excessive endothelial and smooth-muscle cell growth, and increased TGF-β activity worsens vascular dysfunction.3
If the oxygen demand in the body cannot be met, people with PAH will experience severe shortness of breath after exertion, excessive fatigue, weakness, chest pain, dizzy spells and fainting.2 PAH is among several different forms of pulmonary hypertension (PH), and achieving an accurate diagnosis is important for making treatment decisions. Most patients with PH present with abnormalities on chest radiography; however, a normal X-ray does not rule out PH, including PAH.12 Echocardiography can be used when PAH is suspected, including in individuals experiencing symptoms such as unexplained breathlessness, and can help confirm a diagnosis of PAH.12,13
Furthermore, electrocardiogram (ECG) findings, including an increased heart rate and RV dysfunction, strongly support a PAH diagnosis.14 Right axis deviation and RV hypertrophy are also frequently observed on ECG.15 Vasoreactivity testing in patients suspected of having PAH can detect the pulmonary artery response to a vasodilator, such as nitric oxide. A positive response is defined as a reduction in the pulmonary arterial pressure by at least 10 mm Hg, with a mean pressure of no more than 40 mm Hg.15
Economic burden
PAH is associated with high healthcare costs, including hospitalization and pharmacy costs. The annual national burden of PAH in the US related to payer-paid medical and pharmacy costs was $3.1 billion from 2018 to 2020.6 This value was determined by Watzker and colleagues, who examined costs associated with PAH in patients diagnosed with PAH and receiving treatment between January 1, 2019, and November 30, 2020. A total of 11,670 patients were included in the study.6
PPPM payer costs were $6,500 to $14,742, with PAH medications contributing 61% to this number.6 Out-of-pocket costs totaled $341 to $907 PPPM. The inpatient utilization rate for PAH-related admissions was also high at 15 to 58 per 1,000 patients.6
A retrospective study of claims data from the HealthCore Integrated Research Database was performed to evaluate members with either commercial insurance or Medicare Advantage/Supplemental Part D insurance who made at least one claim between October 1, 2015, and November 30, 2020.7 The study included 843 patients with PAH; mean (SD) age of patients was 62.3 (14.1) years, and 64.2% of patients were women. Regarding insurance types, 59.0% had commercial insurance, whereas 41.0% had Medicare Advantage/Supplemental Part D. The results showed that all-cause medical costs decreased from $14,208 to $6,349 PPPM between the six-month baseline and postindex periods. The postindex period was defined as the time after which the first PAH medication was received until health plan disenrollment or December 31, 2020, the study end date.7
Different treatments can lead to widely varying costs, as demonstrated in a retrospective analysis of longitudinal claims data from July 1, 2015 to March 31, 2020.16 Although medication costs did not differ significantly among the 411 patients evaluated in this study, PAH-related costs showed some differences. Among patients taking oral selexipag, intensive-care-unit costs were $5,066 (95% CI, $2,529-$10,144) per-person-per-year, whereas these costs were $2,043 (95% CI, $957-$4,362) in those taking inhaled treprostinil and $12,761 (95% CI, $4,608-$35,373) in patients taking oral treprostinil. PAH-related medical costs were also significantly higher in the inhaled treprostinil group ($40,339) than in the oral selexipag group ($24,351) (p-value=0.006).16
Risk factors and screening
PAH can be heritable or idiopathic and is associated with conditions such as connective tissue disease, HIV infection, portal hypertension, congenital heart disease and schistosomiasis.12 Jones and colleagues showed that autoimmunity is associated with idiopathic PAH. The immune profiles of the patients evaluated included changes in B-cell frequencies and regulatory T-cell profiles as well as increased autoantibody concentrations and high levels of specific immunoglobulins.17 Furthermore, various genetic factors have been shown to be associated with PAH, including the SOX17 and HLA-DPA1/DBP1 loci.18
PH is typically diagnosed more than two years after symptoms first appear, at which time patients present with advanced disease. Therefore, shortening the time to diagnosis is critical for ensuring earlier and effective treatment.12 When PH is suspected, such as from clinical symptoms or abnormal ECG results, detection of low pulmonary function, reduced lung diffusion capacity for carbon monoxide or reduced partial pressure of arterial oxygen can be used for screening to confirm a diagnosis of PAH.12 Detection of these abnormalities should be focused on patients in high-risk groups but who may still be asymptomatic; these include those carrying certain mutations including in BMPR2, people who have HIV and patients with portal hypertension.12
Advancements in early diagnosis
Emerging diagnostic tools such as biomarkers, imaging techniques and noninvasive assessments are under development for diagnosing and guiding treatments for PAH.19,20 A study of patients with PAH showed that computed tomography (CT) data can reveal distinct features of the disease, such as a lower distal pulmonary vascular volume, higher proximal arterial volume and higher arterial tortuosity to distinguish patients with PAH from those with other forms of PH and healthy individuals.19 These results were determined using vascular reconstruction and quantification with artificial intelligence.19 Photon-counting CT may be useful as a noninvasive approach for detecting lung parenchymal structures at ultra-high resolution.20
Magnetic resonance imaging (MRI) involving contrast agents can also be used to examine the pulmonary vasculature. This method can distinguish different types of PH based on vessel properties such as chronic organized thrombotic material, vessel wall thickening and poststenotic dilation.20 Inclusion of certain isotopes into MRI evaluation can also help distinguish PAH from other types of PH. However, use of isotopes for disease-specific diagnosis and monitoring have not been extensively evaluated and require further analysis.20 Other noninvasive techniques under investigation include positron emission tomography, intravascular ultrasound and optical coherence tomography or combinations of these and other techniques, including artificial intelligence/machine learning and computational fluid dynamics.20
Detection of biomarkers is another important emerging therapy for diagnosing PAH. According to a meta-analysis published in 2025, N-terminal prohormone of brain natriuretic protein (NT-proBNP) shows high sensitivity for detecting PAH but exhibited low specificity.21 Other biomarkers that showed unclear application potential include red blood cell distribution width, low-density lipoprotein cholesterol levels, d-dimer levels, interleukin-6 levels and uric acid levels.21
Accurate and early diagnosis of PAH is important for reducing costs and hospitalizations. DuBrock and colleagues retrospectively evaluated administrative health claims information for members of a commercial Medicare Advantage health plan from the Clinformatics Data Mart database from October 2015 to September 2021.22 The study included 538 patients who were divided into categories based on the diagnostic delay of PAH: up to 12 months (n=327; 60.8%), 12 to 24 months (n=126; 23.4%) and more than 24 months (n=85; 15.8%). Healthcare resource utilization rates were lower for patients in the group having a delay of up to 12 months compared to the other two groups. The latter two groups had more hospitalizations, intensive care unit stays and outpatient visits (all p-value<0.05). The group having a delay of more than 24 months also had more emergency department (ED) visits and readmissions within 30 days compared with the group having a delay of up to 12 months.22 As expected, these factors contributed to the greater all-cause healthcare costs PPPM in groups who experienced diagnostic delay. These costs were $12,907, $15,829 and $16,312 in the groups having a delay of up to 12, 12 to 24, or more than 24 months, respectively.22
Current standard of care
Treatment approaches differ for low- versus high-risk patients with PAH (Figure 1).23 According to guidelines developed by the World Symposium on Pulmonary Hypertension, low-risk patients should be treated with an endothelin-1 receptor antagonist (ERA) plus a phosphodiesterase-5 inhibitor (PDE5i). For intermediate-risk patients, an activin-signaling inhibitor or an oral or inhaled prostacyclin pathway agent (PPA) can be added, or patients can be switched to treatment with a PDE5i or soluble guanylyl cyclase stimulator (sGCS). Finally, it is recommended to treat high-risk patients with a triple therapy of PPA, ERA and PDE5i, with transplant referral considered for those with high-risk disease at diagnosis.23
Various supportive therapies can be considered in patients with PAH. Physical activity is encouraged as symptoms allow, as exercise can positively impact exercise capacity and quality of life.12,23 Exercise should only be performed in patients with stable disease and should be supervised.12,23 Long-term oxygen therapy can be added to improve exercise tolerance but is not thought to result in disease improvement.12,23 Use of anticoagulants can also be considered in patients with PAH but should be based on individual factors given their unclear effect on survival and associated risks such as increased bleeding.12,23
To reduce fluid retention in patients with PAH who experience signs of right-side heart failure and edema, it is recommended that patients reduce their fluid intake and use diuretics. The body weight and kidney function of these patients should be monitored regularly.12,23
FDA-approved therapies
Various treatments are available for PAH (Table 1).24-26
ERAs
The ERAs ambrisentan, bosentan and macitentan have been approved by the FDA for treating PAH. These antagonists alleviate the vasoconstriction caused by endothelin-1, thereby reducing intracellular calcium levels.24,25
PDE5is
Through its effects on soluble guanylate cyclase (sGC) in pulmonary vascular smooth muscle, nitric oxide (NO) increases the levels of cyclic guanosine monophosphate to result in vasodilation. Sildenafil and tadalafil stimulate this pathway and vasodilation by inhibiting PDE5. Another agent, riociguat, stimulates sGC through a pathway that does not rely on NO but results in similar effects.24
Prostacyclin Analogs
Epoprostenol, iloprost, treprostinil, beraprost and selexipag are prostacyclin analogs given to restore dysregulated prostacyclin pathways in patients with PAH. These drugs increase the levels of prostaglandin I2, prostacyclin urinary metabolites and vasodilation.24
Transforming Growth Factor-β Targeting
Sotatercept targets the transforming growth factor-β (TGF-β) pathway to exert antiproliferative effects on endothelial and smooth muscle cells, which helps to prevent the vascular remodeling associated with PAH.26
Investigational and pipeline therapies
Numerous trials intended to improve the treatment of PAH are underway or were recently completed (Table 2).27-34
Phase 3 trials
SOTERIA Trial
The phase 3 SOTERIA trial (NCT04796337) is currently underway as a long-term follow-up study to the PULSAR trial to determine the long-term safety and tolerability of sotatercept in patients with PAH who are taking background therapy. The estimated study completion date is February 2031.27
ZENITH Trial
Sotatercept is also being evaluated in the phase 3 ZENITH trial (NCT04896008) in adults with PAH who have a high risk of mortality and are in World Health Organization functional classes III or IV.28 The primary end point is the time to first morbidity or mortality event. Interim results were recently released; they showed that the study met the primary end point with a significant decrease in the risk of morbidity or mortality compared with placebo in addition to background PAH therapy. An independent data monitoring committee has recommended that the trial be stopped early so that all patients can be given sotatercept as part of the SOTERIA open-label extension study.35
IMPAHCT Trial
Because side effects are seen in clinical trials evaluating various formulations of imatinib, additional studies are needed to determine whether this agent can benefit patients with PAH.29 The IMPAHCT trial (NCT05036135) was a phase 2/3b, randomized, double-blind, placebo-controlled, dose-ranging and confirmatory study designed to determine the optimal dosage of oral imatinib for a 24-week treatment period and the safety and efficacy of imatinib in patients on background therapy for PAH. The study organizers included 400 to 500 patients across 140 sites in at least 28 countries. However, the rate of side effects was high in patients taking oral imatinib, and the study was halted because of safety concerns. 29
Gene Therapy
Given the importance of acid ceramidase (AC) in regulating cell proliferation and apoptosis/senescence in pulmonary smooth muscle cells, a preclinical study was conducted to evaluate the safety, feasibility and PH-modulating ability of AC gene transfer in rats.36 The results showed that AC gene therapy partially reversed pulmonary vascular remodeling, with large increases in the medial thickness and number of remodeled vessels in PH model rats compared to those in rats treated with AC gene therapy. Rats that did and did not receive AC gene therapy showed significant differences in the mean (SD) percentage of occluded vessels (39.5% [5.26%] vs 21.6% [4.81%]; p-value < 0.001) and mean (SD) medial wall thickness (26.2% [4.31%] vs 14.21% [1.49%]; p-value < 0.001). This therapy also protected the alveolar-capillary endothelial layer from injury in the rats; their endothelial cells had a mostly normal nucleus shape and decreased numbers of inflammatory cells.36
RNA-Based Approaches
Therapies involving microRNAs have been mentioned as having the potential to treat PAH, but data are limited, and studies are only in the beginning stages. Noncoding RNAs are important regulators of gene expression; they influence pulmonary vascular development and several other PAH-related pathways in cells. Factors under consideration before RNA-based therapies can be realized include the delivery route, delivery mode and potential for off-target effects.37
Combination Treatments and Personalized Medicine
The AMBITION trial (NCT01178073), a multicenter, randomized, double-blind, phase 3/4 study evaluating combination treatment with tadalafil or ambrisentan, revealed a longer time to the first clinical failure event as well as improved levels of NT-proBNP and the number of patients who achieved a clinical response by 24 weeks compared to the effects of monotherapy with each agent. There were also no major safety concerns with the use of combination treatment.30,38 Another trial (SERAPHIN; NCT00660179) showed reductions in the first PAH-related event in patients treated with a combination of macitentan and a non-ERA background therapy (mostly PDE5i).31 Similar results were observed in the GRIPHON trial (NCT01106014) of selexipag combined with background therapy (PDE5i, ERA or both).32,38
Prostacyclin Receptor Agonist
Ralinepag has been demonstrated to be an effective and strong prostacyclin receptor agonist that exerts antiproliferative and vasodilating effectsin vitro. In a clinical trial of the drug (NCT02279160; Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension), oral ralinepag significantly reduced the median pulmonary vascular resistance compared with the effects of placebo (-163.9 vs -0.7 dyn·s·cm-1; p-value=0.02).39 Given its 24-hour half-life, this drug may require only daily administration, compared with twice-daily administration of selexipag.39 Ralinepag is currently being evaluated in phase 3 trials (NCT03626688; NCT03683186).33,34,38
Managed healthcare considerations
Barriers to access, equity, cost-effectiveness and policy play a role in the treatment of PAH in a managed healthcare setting.
Barriers to Access and Equity in PAH Treatment
PAH is a costly disease. Indeed, the diagnosis process involves expensive tests and evaluations, including ECG, transthoracic cardiogram, pulmonary function testing, six-minute walk test, chest X-ray, ventilation-perfusion imaging, various laboratory tests, cardiac catheterization and consultations with a cardiologist or pulmonologist.40 These factors may be cost-prohibitive for many patients. Following a diagnosis of PAH, patients experience direct costs that are four- to five-fold higher than those for matched controls, and disease progression further increases these costs.40
Furthermore, Dalton and colleagues showed that the outcomes of patients with PAH vary significantly according to demographic and socioeconomic characteristics. Although there were not differences in mortality, ED visits and hospitalization rates were higher for Black patients with PAH than for non-Hispanic White patients.41 Among patients experiencing high levels of social deprivation, ED visits and hospitalization rates were higher than among patients with lower levels of social deprivation.41
Various factors, such as income, occupation, education, socioeconomic status and health insurance status interact to create barriers to effective PAH care. These factors can prevent patients from being evaluated using advanced diagnostic approaches, hinder timely diagnosis, lead to poor healthcare access, delay referrals to specialty centers and influence treatment and clinical outcomes.42
Access to healthcare can be improved through provider education that focuses on the importance of early diagnosis and referral and risk factors for PAH, such as environmental exposure, substance abuse and comorbid conditions. Cross-cultural training can also help improve communication between patients and providers.42 Another strategy for improving care involves ensuring that insurance companies are aware of the benefits of advanced treatment methods, which have high upfront costs but lower long-term costs. Community outreach programs may also help patients be more aware of the disease.42
Cost-Effectiveness and Policy Implications
Various restrictions by health plans can impede patient access to care. According to a 2024 study by Rucker and colleagues, nearly half of health plan policies require step therapy for PAH, including steps through generic alternative treatments.43 Steps also included prescription of oral agents before gaining access to intravenous treatments. The number of health plans imposing at least one restriction increased by nearly two-fold between 2017 and 2022. Health plans also tended to cite older guidelines when making coverage determinations. The authors suggested that these policies can delay access to care, prevent patients from receiving the most effective care and influence patient outcomes.43
Prior authorization (PA) requirements also impose barriers to care. Housten and Brown explained that acquiring PA is time-consuming, nontransparent and affected by frequent rule changes. The necessity of obtaining PA can negatively impact pain management and result in higher rates of ED visits, increased drug discontinuation and higher medical costs.44
Although not specifically aimed at evaluating insurance coverage of PAH, a systematic review conducted by Zhang and colleagues suggested that expanding insurance coverage, improving healthcare quality and reducing health disparities can lead to greater medication use and disease control in US adults.45 The authors evaluated blood pressure control in patients with hypertension. Their results showed that coverage expansion was associated with improved antihypertensive treatment and blood pressure control. Studies of cost-sharing demonstrated that PA and higher copayments were associated with decreased medication adherence. Furthermore, efforts to improve the quality of care were associated with improved treatment and blood pressure control.45
Burgoyne reported that using early, appropriately targeted therapies in the upfront setting can reduce other costs such as hospitalization, a main contributing factor to PAH-related costs.46,47 Managed-care pharmacists can also become more involved in educating patients and providers on dosing, medication counseling and medication safety and helping to obtain insurance approval.46 Improving access to PAH therapies can lead to greater treatment adherence.46,47
Conclusion
PAH is a complex and costly disease with high morbidity and mortality rates. Advances in investigational therapies, including promising agents such as sotatercept and ralinepag, as well as emerging approaches, including gene and RNA-based therapies, may lead to improved outcomes. Combination treatments and personalized medicine strategies can be used to refine PAH management by providing patients with more effective and individualized care. However, despite these advancements, barriers to access, disparities in healthcare access and cost-related challenges remain.
Ongoing clinical trials are expected to expand treatment options. Treatment innovations may improve the survival and quality of life for PAH patients. Additionally, the integration of artificial intelligence and digital health technologies may lead to earlier diagnosis, improved disease monitoring and treatment optimization.
To achieve these goals, collaboration among providers, policymakers and healthcare systems is necessary. Efforts should focus on improving access to timely diagnosis and advanced therapies, addressing socioeconomic disparities and implementing policies that support equitable and cost-effective PAH management. Prioritizing research, patient-centered care and coverage improvements can bridge treatment gaps and ensure that patients with PAH experience the best possible outcomes.
REFERENCES
1. Learn about pulmonary arterial hypertension. American Lung Association. January 7, 2025. Accessed February 17, 2025. https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-arterial-hypertension/learn-about-pulmonary-arterial-hypertension
2. Pulmonary arterial hypertension. National Organization for Rare Disorders. February 3, 2025. Accessed February 17, 2025. https://rarediseases.org/rare-diseases/pulmonary-arterial-hypertension/
3. Bousseau S, Sobrano Fais R, Gu S, Frump A, Lahm T. Pathophysiology and new advances in pulmonary hypertension. BMJ Med. 2023;2(1):e000137. doi:10.1136/bmjmed-2022-000137
4. GBD 2021 Pulmonary Arterial Hypertension Collaborators. Global, regional, and national burden of pulmonary arterial hypertension, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Respir Med. 2025;13(1):69-79. doi:10.1016/S2213-2600(24)00295-9
5. Chang KY, Duval S, Badesch DB, et al. Mortality in pulmonary arterial hypertension in the modern era: early insights from the Pulmonary Hypertension Association Registry. J Am Heart Assoc. 2022;11(9):e024969. doi:10.1161/JAHA.121.024969
6. Watzker A, Alsumali A, Ferro C, et al. Economic burden associated with pulmonary arterial hypertension in the United States. Pharmacoeconomics. 2025;43(1):83-91. doi:10.1007/s40273-024-01427-2
7. Pizzicato LN, Nadipelli VR, Governor S, et al. Real-world treatment patterns, healthcare resource utilization, and cost among adults with pulmonary arterial hypertension in the United States. Pulm Circ. 2022;12(2):e12090. doi:10.1002/pul2.12090
8. Mayeux JD, Pan IZ, Dechand J, et al. Management of pulmonary arterial hypertension. Curr Cardiovasc Risk Rep. 2021;15(1):2. doi:10.1007/s12170-020-00663-3
9. Weatherald J, Fleming TR, Wilkins MR, et al. Clinical trial design, end-points, and emerging therapies in pulmonary arterial hypertension. Eur Respir J. 2024;64(4):2401205. doi:10.1183/13993003.01205-2024
10. Tang BT, Pickard SS, Chan FP, Tsao PS, Taylor CA, Feinstein JA. Wall shear stress is decreased in the pulmonary arteries of patients with pulmonary arterial hypertension: an image-based, computational fluid dynamics study. Pulm Circ. 2012;2(4):470-476. doi:10.4103/2045-8932.105035
11. Long L, Crosby A, Yang X, et al. Altered bone morphogenetic protein and transforming growth factor-β signaling in rat models of pulmonary hypertension. Circulation. 2009;119(4):566-576. doi:10.1161/CIRCULATIONAHA.108.821504
12. Humbert M, Kovacs G, Hoeper MM, et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. doi:10.1093/eurheartj/ehac237
13. Kiely DG, Lawrie A, Humbert M. Screening strategies for pulmonary arterial hypertension. Eur Heart J Suppl. 2019;21(suppl K):K9-K20. doi:10.1093/eurheartj/suz204
14. Bonderman D, Wexberg P, Martischnig AM, et al. A noninvasive algorithm to exclude pre-capillary pulmonary hypertension. Eur Resp J. 2011;37(5):1096-1103. doi:10.1183/09031936.00089610
15. Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension: a review. JAMA. 2022;327(14):1379-1391. doi:10.1001/jama.2022.4402
16. Papademetriou E, Liu X, Beaudet A, Tsang Y, Potluri R, Panjabi S. Comparative evaluation of costs and healthcare resource utilization of oral selexipag versus inhaled treprostinil or oral treprostinil in patients with pulmonary arterial hypertension. J Med Econ. 2023;26(1):644-655. doi:10.1080/13696998.2023.2204769
17. Jones RJ, De Bie EMDD, Groves E, et al. Autoimmunity is a significant feature of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2022;206(1):81-93. doi:10.1164/rccm.202108-1919OC
18. Rhodes CJ, Batai K, Bleda M, et al. Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis. Lancet Respir Med. 2019;7(3):227-238. doi:10.1016/S2213-2600(18)30409-0
19. Rahaghi FN, Nardelli P, Harder E, et al. Quantification of arterial and venous morphologic markers in pulmonary arterial hypertension using CT imaging. Chest. 2021;160(6):2220-2231. doi:10.1016/j.chest.2021.06.069
20. Rajagopal S, Bogaard HJ, Elbaz MSM, et al. Emerging multimodality imaging techniques for the pulmonary circulation. Eur Respir J. 2024;64(4):2401128. doi:10.1183/13993003.01128-2024
21. Smits AJ, Botros L, Mol MAE, et al. A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension. ERJ Open Res. 2022;8(2):00009-2022. doi:10.1183/23120541.00009-2022
22. DuBrock HM, Germack HD, Gauthier-Loiselle M, et al. Economic burden of delayed diagnosis in patients with pulmonary arterial hypertension (PAH). Pharmacoecon Open. 2024;8(1):133-146. doi:10.1007/s41669-023-00453-8
23. Chin KM, Gaine SP, Gerges C, et al. Treatment algorithm for pulmonary arterial hypertension. Eur Respir J. 2024;64(4):2401325. doi:10.1183/13993003.01325-2024
24. Shah AJ, Beckmann T, Vorla M, Kalra DK. New drugs and therapies in pulmonary arterial hypertension. Int J Mol Sci. 2023;24(6):5850. doi:10.3390/ijms24065850
25. Zolty R. Pulmonary arterial hypertension specific therapy: the old and the new. Pharmacol Ther. 2020;214:107576. doi:10.1016/j.pharmthera.2020.107576
26. Guglielmi G, Dimopoulos K, Wort SJ. New therapies in pulmonary arterial hypertension: recent insights. Int J Cardiol Congenit Heart Dis. 2025;19:100571. doi:10.1016/j.ijcchd.2025.100571
27. A long-term follow-up study of sotatercept for PAH treatment (MK-7962-004/A011-12) (SOTERIA). ClinicalTrials.gov. Updated January 27, 2025. Accessed February 17, 2025. https://clinicaltrials.gov/study/NCT04796337
28. A study of sotatercept in participants with PAH who FC III or FC IV at high risk of mortality (MK-7962-006/ ZENITH) (ZENITH). ClinicalTrials.gov. Updated March 25, 2025. Accessed March 26, 2025. https://clinicaltrials.gov/study/NCT04896008
29. Gillies H, Chakinala MM, Dake BT, et al. IMPAHCT: a randomized phase 2b/3 study of inhaled imatinib for pulmonary arterial hypertension. Pulm Circ. 2024;14(1):e12352. doi:10.1002/pul2.12352
30. Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844. doi:10.1056/NEJMoa1413687
31. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818. doi:10.1056/NEJMoa1213917
32. Sitbon O, Jaïs X, Savale L, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43(6):1691-1697. doi:10.1183/09031936.00116313
33. A study evaluating the efficacy and safety of ralinepag to improve treatment outcomes in PAH patients. ClinicalTrials.gov. Updated March 5, 2025. Accessed March 15, 2025. https://clinicaltrials.gov/study/NCT03626688
34. A study evaluating the long-term efficacy and safety of ralinepag in subjects with PAH via an open-label extension. ClinicalTrials.gov. Updated October 1, 2024. Accessed March 15, 2025. https://clinicaltrials.gov/study/NCT03683186
35. Merck announces pivotal phase 3 ZENITH trial evaluating WINREVAIRTM (sotatercept-csrk) met primary endpoint at interim analysis. Merck. November 25, 2024. Accessed February 17, 2025. https://www.merck.com/news/merck-announces-pivotal-phase-3-zenith-trial-evaluating-winrevair-sotatercept-csrk-met-primary-endpoint-at-interim-analysis/
36. Katz MG, Hadas Y, Vincek A, et al. Acid ceramidase gene therapy ameliorates pulmonary arterial hypertension with right heart dysfunction. Respir Res. 2023;24(1):197. doi:10.1186/s12931-023-02487-2
37. Spiekerkoetter E, Kawut SM, de Jesus Perez VA. New and emerging therapies for pulmonary arterial hypertension. Annu Rev Med. 2019;70:45-59. doi:10.1146/annurev-med-041717-085955
38. Cassady SJ, Soldin D, Ramani GV. Novel and emerging therapies in pulmonary arterial hypertension. Front Drug Discov. 2022;2:1022971. doi:10.3389/fddsv.2022.1022971
39. Torres F, Farber H, Ristic A, et al. Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial. Eur Respir J. 2019;54(4):1901030. doi:10.1183/13993003.01030-2019
40. Cantres-Fonseca O, Kennedy JLW. Where’s the easy button? The many barriers to care for patients with pulmonary arterial hypertension. J Am Heart Assoc. 2022;11(22):e027967. doi:10.1161/JAHA.122.027967
41. Dalton R, Desai AA, Jiao T, Duarte JD. Disparities in clinical outcomes observed within electronic health record data from a statewide cohort of pulmonary arterial hypertension patients. Pulm Circ. 2025;15(1):e70041. doi:10.1002/pul2.70041
42. Talwar A, Garcia JGN, Tsai H, et al. Health disparities in patients with pulmonary arterial hypertension: a blueprint for action. An official American Thoracic Society statement. Am J Respir Crit Care Med. 2017;196(8):e32-e47. doi:10.1164/rccm.201709-1821ST
43. Rucker JA, Beinfeld MT, Enright DE, et al. US commercial health plan coverage dynamics in pulmonary arterial hypertension therapies. J Manag Care Spec Pharm. 2024;30(6):541-548. doi:10.18553/jmcp.2024.30.6.541
44. Housten T. The burden or prior authorization for pulmonary arterial hypertension medications: a practical guide for managing the process. Adv Pulm Hypertens. 2018;17(3):126-131. doi:10.21693/1933-088X-17.3.126
45. Zhang D, Lee JS, Pollack LM, et al. Association of economic policies with hypertension management and control: a systematic review. JAMA Health Forum. 2024;5(2):e235231. doi:10.1001/jamahealthforum.2023.5231
46. Burgoyne DS. Reducing economic burden and improving quality of life in pulmonary arterial hypertension. Am J Manag Care. 2021;27(suppl 3):S53-S58. doi:10.37765/ajmc.2021.88611
47. Burger CD, Ghandour M, Padmanabhan Menon D, Helmi H, Benza RL. Early intervention in the management of pulmonary arterial hypertension: clinical and economic outcomes. Clinicoecon Outcomes Res. 2017;9:731-739. doi:10.2147/CEOR.S119117
