Pulmonary Arterial Hypertension Medications Research Articles

A case report on Sjögren Syndrome: it‘s more than just autoimmune epithelitis

Background. Primary Sjögren’s syndrome (pSS) is an autoimmune epithelitis associated with various pulmonary manifestations, including PAH (pulmonary arterial hypertension), a severe complication often found in collagen tissue disorders. Case presentation. A 26-year-old female having chest pain and exertional dyspnea diagnosed with severe PAH associated with pSS is presented in this case study. Clinical, laboratory, and imaging findings supported the diagnosis, and treatment involved immunosuppressive therapy and standard PAH medications. Discussion and conclusion. The report highlights the complexities of diagnosing and treating PAH associated with pSS, emphasizing the importance of early intervention for improved long-term outcomes. The prognosis for PAH in connective tissue diseases, encompassing pSS, remains challenging, underscoring the need for accurate diagnosis and timely management with immunosuppressants and PAH-specific therapies.

Racial disparities in treatment patterns, healthcare resource use, and outcomes in patients with pulmonary arterial hypertension in the United States

Objective This retrospective study using claims data compared demographics, clinical characteristics, treatment patterns, healthcare resource utilization, and clinical outcomes in Black and White patients with pulmonary arterial hypertension (PAH) in the United States. Methods Patients (aged ≥18 years) had ≥1 pharmacy claim for PAH medication, ≥6 months’ continuous healthcare plan enrollment, ≥1 inpatient/outpatient medical claim with a pulmonary hypertension diagnosis ≤6 months before first PAH medication, and race recorded. Results This analysis included 836 Black and 2896 White patients. Black patients were younger, with lower levels of education and annual household income, and higher comorbidity scores versus White patients. Only ∼14% of Black and White patients received index combination therapy. Lower adherence to index treatment was observed in Black patients. Although adjusted regression analysis in the overall population showed no differences in outcomes between groups, Black patients <65 years were 36% less likely to receive index combination therapy (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.41–0.99), and 46% less likely to adhere to index treatment (OR 0.54; 95% CI 0.33–0.90). Other disparities included 24% higher all-cause health care resource utilization, 75% higher all-cause costs, and higher risk of clinical composite outcome. Social determinants of health (education, income, health insurance plan) partially mediated these race effects. Conclusions Differences in demographics, clinical characteristics, and treatment patterns between Black and White patients with PAH were observed. Disparities between Black and White patients <65 years were only partially mediated through social determinants of health variables, suggesting other factors may be involved.

Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study

BackgroundIn the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.MethodsPatients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.ResultsOf 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001).ConclusionIn SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.

Factors associated with discontinuation of treatment for pulmonary arterial hypertension in the United States.

Information on factors leading to pulmonary arterial hypertension (PAH) treatment discontinuation is limited. This study analyzed 12,902 new PAH medication users to identify predictors of treatment discontinuation. Treatment by accredited pulmonary hypertension centers and combination therapy with PAH agents from different classes were less likely to result in discontinuation.

Sotatercept for Pulmonary Arterial Hypertension in the Inpatient Setting.

Patients with pulmonary arterial hypertension (PAH) who are admitted to the hospital pose a challenge to the multidisciplinary healthcare team due to the complexity of the pathophysiology of their disease state and PAH-specific medication considerations. Pulmonary arterial hypertension is a progressive disease that may lead to death as a result of right ventricular (RV) failure. During acute on chronic RV failure it is critical to decrease the pulmonary vascular resistance with the goal of improving RV function and prognosis; therefore, aggressive PAH-treatment based on disease risk stratification is essential. Pulmonary arterial hypertension treatment for acute on chronic RV failure can be impacted by end-organ damage, hemodynamic instability, drug interactions, and PAH medications dosage and delivery. Sotatercept, a first in class activin signaling inhibitor that works on the bone morphogenetic protein/activin pathway is on track for Food and Drug Administration approval for the treatment of PAH based on results of recent trials in where the medication led to clinical and hemodynamic improvements, even when added to traditional PAH-specific therapies. The purpose of this review is to highlight important considerations when starting or continuing sotatercept in patients admitted to the hospital with PAH.

Effects of inhaled seralutinib on right ventricular-pulmonary arterial (RV-PA) coupling and right heart function in pulmonary arterial hypertension (PAH)

Abstract Background Impaired RV-PA coupling portends a poor prognosis in PAH, and right ventricular free wall strain/systolic pulmonary artery pressure (RVFWS/sPAP) has been reported as a measure of RV-PA coupling. Furthermore, increased RVFWS and right atrial area (RAA), as well as decreased pulmonary artery compliance (PAC) are associated with increased mortality risk in PAH. Seralutinib is a novel, small molecule kinase inhibitor that targets PDGFR, CSF1R, and c-KIT administered via dry powder inhaler. TORREY, a phase 2, double-blind, randomised, placebo-controlled study of inhaled seralutinib in patients with PAH (NCT04456998) met its primary endpoint, demonstrating a significant reduction in pulmonary vascular resistance (PVR) from baseline (BL) to Week 24 compared to placebo. In addition, seralutinib significantly decreased NT-proBNP. Purpose To test the hypothesis that seralutinib would improve RVFWS/sPAP and other measures of right heart function after 24 weeks of treatment compared to placebo in the TORREY study. Methods Eighty-six patients with WHO Group 1 PH (Functional Class II, III), ages ≥18 years, pulmonary vascular resistance ≥400 dyne*s/cm5, and on stable PAH standard of care therapy (the majority of whom were on double and triple therapy with approved PAH medications) were enrolled. Right heart catheterisation (RHC) and full echocardiography were performed at BL and Week 24 and at BL, Week 12, and Week 24, respectively; both were analysed in a blinded central laboratory. To calculate RVFWS/sPAP, the pulmonary artery systolic pressure from RHC was used. PAC was calculated from RHC data with the formula (SV/(PAS-PAD)). Statistical analysis was performed using ANCOVA. Results At Week 24, the change in RVFWS/sPAP was lower in the seralutinib group compared to placebo (Table). The changes in RVFWS and RAA were lower in the seralutinib group vs placebo at Week 12 and Week 24 (Table). Change in NT-proBNP correlated with change in RAA (r = 0.43). At Week 24, change in PAC was greater in the seralutinib group (-0.02 ± 0.085 placebo, 0.19 ± 0.089 seralutinib; LSMD 0.22 (0.104) p = 0.04). There was no effect of seralutinib on left ventricular ejection fraction. Conclusion Treatment with seralutinib was associated with a significant reduction of RVFWS/sPAP. In addition, significant differences in RVFWS itself, RAA, and PAC were observed. These treatment effects support improved RV-PA coupling and right heart function. In conjunction with concordant reductions in PVR and NT-proBNP, these data suggest potential favourable effects of seralutinib in PAH. Seralutinib is in clinical development as a potential new treatment option for patients with PAH.

Abstract 12978: Real-World Treatment Patterns in Hispanic and White Patients With Pulmonary Arterial Hypertension (PAH) in the United States

Introduction: ESC/ERS guidelines recommend initial double oral combination therapy (endothelin-receptor antagonist plus phosphodiesterase 5 inhibitor) in low or intermediate risk PAH patients without cardiopulmonary comorbidities. Upfront use of prostacyclin pathway analogue (PPA) is recommended for patients with high risk of 1-year mortality. Few studies have evaluated treatment patterns/adherence in PAH patients across ethnic groups. Aims: To describe demographic/clinical characteristics and treatment patterns in US Hispanic and White PAH patients. Methods: A retrospective, observational, analysis using Optum’s de-identified Clinformatics ® Data Mart database identified patients aged ≥18 years with pulmonary hypertension (PH) diagnosis (excluding chronic thromboembolic PH) and were new users of PAH medications. Index date was the 31 st day after first PAH-specific medication use (1 Jan 2016-30 Jun 2022); the 30-day window between first PAH medication use and index date was used to identify the initial PAH regimen. Patient characteristics and PAH treatment patterns were analyzed descriptively, with standardized mean differences (SMD) between cohorts assessed (SMD &gt;0.1 indicated significant difference). Results: Hispanic patients were younger, with lower income, lower education level, and higher comorbidity burden than White patients (Table). Few patients received initial combination PAH treatment with similar use of combination therapy in the two cohorts (~14% in each). Hispanic patients were less likely to receive a PPA-containing index treatment regimen and had lower index treatment adherence (Table). Conclusions: In Hispanic and White patients, index combination PAH therapy use was low. Hispanic patients were less likely to receive a PPA-containing index treatment and had lower index treatment adherence. Further research and awareness of the influence of ethnicity on treatment management is needed to improve PAH care.

Exercise-Induced Electrocardiography Changes in Pulmonary Arterial Hypertension

Cardiopulmonary exercise testing (CPET) is an important tool in assessing the functional status of patients with pulmonary arterial hypertension (PAH). During CPET, continuous electrocardiography (ECG) is used as a marker of exercise-induced ischemia or arrhythmia. We hypothesize that ECG changes with exercise may be an early indicator of clinical worsening in PAH and could predict adverse outcomes. Clinical, hemodynamic, and CPET data of 155 children and young adult patients with PAH who underwent CPET between 2012 and 2019 in our pulmonary hypertension (PH) center were included in this retrospective analysis. ECGs were analyzed for ST depressions and T-wave inversions, along with coincident hemodynamic data. These data were correlated with adverse outcomes divided into 2 categories: severe worsening (death or receiving lung transplant) and mild to moderate worsening (PAH medication escalation, hospitalization, shunt creation, or listing for lung transplant). The median age was 19years (range 7 to 40years), 69% were female, and the average follow-up time was 5years (range 1 to 8years). A total of 63 patients (41%) had at least 1 adverse outcome. A total of 39 patients (25%) demonstrated significant ST-T-wave changes with exercise. Patients with ST-T-wave changes were 20% more likely to die or need lung transplant than those without. The multiple linear regression found that ST-T-wave changes were a predictor of elevated mean pulmonary arterial pressure (mPAP) found on catheterization (R=0.489, p=0.003), although not of pulmonary vascular resistance index (R=-0.112, p=0.484). An mPAP of 55mm Hg was the most sensitive and specific point in identifying when ST-T-wave changes with exercise begin to appear. In conclusion, ST-T-wave changes on exercise ECG are significantly associated with adverse outcomes in PH in a medium-term follow-up study, and the presence of ST-T-wave changes correlates with higher mPAP. These ECG changes with exercise may be used as early indicators of clinical worsening in PH and predictors of adverse outcomes.

Impact of selexipag use within 12 months of pulmonary arterial hypertension diagnosis on hospitalizations and medical costs: A retrospective cohort study.

Oral selexipag, a prostacyclin pathway agent (PPA), is effective in patients with pulmonary arterial hypertension (PAH). The objective of this study is to assess the impact of initiating oral selexipag within 12 months of diagnosis on health outcomes. This retrospective cohort study used data from Optum's de-identified Clinformatics® Data Mart Database. PAH patients between 1 October 2015 and 30 September 2019 were included. Patients were also required to have received PAH medication within 12 months of their initial diagnosis. Study groups included patients who initiated selexipag within 12 months of PAH diagnosis (SEL ≤ 12) and those who did not initiate any PPA within 12 months of PAH diagnosis (No PPA ≤ 12). Inverse probability of treatment weighting was used to remove potential confounding between groups. Cox and Poisson regression models were used to compare hospitalization and disease progression. Generalized linear model with gamma distribution and log link was used to compare costs. SEL ≤ 12 had lower rate of all-cause hospitalizations (rate ratio: 0.76, 95% confidence interval [CI]: 0.60, 0.96) versus no PPA ≤ 12, but no differences in PAH-related hospitalization rate (rate ratio: 1.03, 95% CI: 0.79, 1.33) or risk of disease progression (hazard ratio: 1.01, 95% CI: 0.71, 1.44). SEL ≤ 12 incurred lower all-cause (mean difference: -$23 623; 95% CI: -35 537, -8512) and PAH-related total medical costs (mean difference: -$12 927; 95% CI: -19 559, -5679) versus no PPA ≤ 12. Selexipag initiation within 12 months of PAH diagnosis demonstrated reductions in all-cause hospitalization rate and medical costs.

A Bioinformatic Algorithm based on Pulmonary Endoarterial Biopsy for Targeted Pulmonary Arterial Hypertension Therapy.

Optimal pharmacological therapy for pulmonary arterial hypertension (PAH) remains unclear, as pathophysiological heterogeneity may affect therapeutic outcomes. A ranking methodology based on pulmonary vascular genetic expression analysis could assist in medication selection and potentially lead to improved prognosis. To describe a bioinformatics approach for ranking currently approved pulmonary arterial antihypertensive agents based on gene expression data derived from percutaneous endoarterial biopsies in an animal model of pulmonary hypertension. We created a chronic PAH model in Micro Yucatan female swine by surgical anastomosis of the left pulmonary artery to the descending aorta. A baseline catheterization, angiography and pulmonary endoarterial biopsy were performed. We obtained pulmonary vascular biopsy samples by passing a biopsy catheter through a long 8 French sheath, introduced via the carotid artery, into 2- to 3-mm peripheral pulmonary arteries. Serial procedures were performed on days 7, 21, 60, and 180 after surgical anastomosis. RNA microarray studies were performed on the biopsy samples. Utilizing the medical literature, we developed a list of PAH therapeutic agents, along with a tabulation of genes affected by these agents. The effect on gene expression from pharmacogenomic interactions was used to rank PAH medications at each time point. The ranking process allowed the identification of a theoretical optimum three-medication regimen. We describe a new potential paradigm in the therapy for PAH, which would include endoarterial biopsy, molecular analysis and tailored pharmacological therapy for patients with PAH.

Pulmonary sarcoidosis: A comprehensive review: Past to present

Sarcoidosis is a sterile non-necrotizing granulomatous disease without known causes that can involve multiple organs with a predilection for the lung and thoracic lymph nodes. Worldwide it is estimated to affect 2–160/100,000 people and has a mortality rate over 5 years of approximately 7%. For sarcoidosis patients, the cause of death is due to sarcoid in 60% of the cases, of which up to 80% are from advanced cardiopulmonary failure (pulmonary hypertension and respiratory microbial infections) in all races except in Japan were greater than 70% of the sarcoidosis deaths are due to cardiac sarcoidosis.Scadding stages for pulmonary sarcoidosis associates with clinical outcomes. Stages I and II have radiographic remission in approximately 30%–80% of cases. Stage III only has a 10%–40% chance of resolution, while stage IV has no change of resolution. Up to 40% of pulmonary sarcoidosis patients progress to stage IV disease with lung parenchyma fibroplasia, bronchiectasis with hilar retraction and fibrocystic disease. These patients are at highest risk for the development of precapillary pulmonary hypertension, which may occur in up to 70% of these patients. Sarcoid patients with pre-capillary pulmonary hypertension can respond to targeted pulmonary arterial hypertension medications. Stage IV fibrocytic sarcoidosis with significant pulmonary physiologic impairment, >20% fibrosis on HRCT or pre-capillary pulmonary hypertension have the highest risk of mortality, which can be >40% at 5-years.First line treatment for patients who are symptomatic (cough and dyspnea) with parenchymal infiltrates and abnormal pulmonary function testing (PFT) is oral glucocorticoids, such as prednisone with a typical starting dose of 20–40 mg daily for 2 weeks to 2 months. Prednisone can be tapered over 6–18 months if symptoms, spirometry, PFTs, and radiographs improve. Prolonged prednisone may be required to stabilize disease. Patients requiring prolonged prednisone ≥10 mg/day or those with adverse effects due to glucocorticoids may be prescribed second and third line treatements. Second and third line treatments include immunosuppressive agents (e.g., methotrexate and azathioprine) and anti-tumor necrosis factor (TNF) medication; respectively. Effective treatments for advanced fibrocystic pulmonary disease are being explored. Despite different treatments, relapse rates range from 13% to 75% depending on the stage of sarcoid, number of organs involved, socioeconomic status, and geography. ConclusionThe mortality rate for sarcoidosis over a 5 year follow up is approximately 7%. Unfortunately, 10%–40% of patients with sarcoidosis develop progressive pulmonary disease, and >60% of deaths resulting from sarcoidosis are due to advance cardiopulmonary disease. Oral glucocorticoids are the first line treatment, while methotrexate and azathioprine are considered second and anti-TNF agents are third line treatments that are used solely or as glucocorticoid sparing agents for symptomatic extrapulmonary or pulmonary sarcoidosis with infiltrates on chest radiographs and abnormal PFT. Relapse rates have ranged from 13% to 75% depending on the population studied.

Provision of ambrisentan from a health-system specialty pharmacy affiliated with a pulmonary hypertension Center of Comprehensive Care.

This descriptive report describes the process used to obtain access to providing ambrisentan from a health-system specialty pharmacy (HSSP) affiliated with a pulmonary hypertension Center of Comprehensive Care, develop a pulmonary arterial hypertension (PAH) care team at the HSSP, and characterize medication adherence and access metrics. PAH is a rare disease treated with several specialty medications requiring intensive monitoring. Historically, specialty medications used to treat PAH have been provided by only select specialty pharmacies due to restricted drug distribution channels. It is recommended that patients with PAH receive their care at centers with expertise in the diagnosis and management of this disorder, but the HSSPs at these expert centers are unable to provide specialty PAH medications. The current care model for PAH leads to patients receiving their medical and pharmaceutical care from separate entities. This descriptive report describes a multidisciplinary team's approach to gaining access to providing ambrisentan and developing a disease state care team within an established HSSP. After implementing this service, specialty pharmacy metrics were assessed, including proportion of days covered (PDC), time to first fill, patient contact rate, Risk Evaluation and Mitigation Strategy (REMS) program compliance, time to prior authorization (PA) approval, rate of optimal adherence (PDC of >80%), and PA renewal rate, to demonstrate a proof-of-concept HSSP model for PAH. In this model, the HSSP was able to demonstrate high-quality specialty pharmacy metrics with regard to medication adherence, medication access, and REMS program compliance. The development of a PAH care team to provide ambrisentan at an existing HSSP was associated with high adherence rates, efficient and reliable medication access, and REMS program compliance.

Safety and effectiveness of ambrisentan in real clinical practice in pulmonary arterial hypertension: Results from the Korean post-marketing surveillance.

This regulatory post-marketing surveillance (PMS) was organized to identify the safety and effectiveness of ambrisentan in the Korean population. This was an open-label, multi-center PMS conducted from 31 institutions in Korea for 6 years from August 2015 to 2021, to evaluate the use of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). Inclusion criteria are Korean subjects with the World Health Organization functional classification (WHO Fc) II or III PAH who are new users or repeated users with ambrisentan (Volibris®) Tablet 5 or 10 mg per day (age >18 years old). A total of 293 cases were analyzed. The overall incidence of adverse events (AE) was 52.22% and adverse drug reactions (ADR) was 10.92%. Severe AEs occurred in 20.82% of patients. However, only 2 subjects (0.68%) reported serious ADR. The difference in AE incidence was statistically significant for concomitant medications other than PAH medications in the safety analysis and the new users (p = 0.0041 and p = 0.0299, respectively) and elderly population in the repeated users (p = 0.0319). Among the long-term 223 subjects, the WHO Fc II and III were 41.26% and 58.74% before ambrisentan, and changed after treatment to 3.09%, 66.05%, and 30.86% for Fc I/II/III, respectively. 217 of 249 subjects (87.15%) considered their symptoms to have 'improved' after the last administration. In real-world practice, ambrisentan demonstrated tolerable safety and favorable effectiveness in PAH patients in Korea. Age and concomitant drug use can affect the occurrence of AE.

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives.

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials.

Many retrospective studies suggest that risk improvement may be a suitable efficacy surrogate endpoint for pulmonary arterial hypertension (PAH) medication trials. This prospective multicenter study assessed the efficacy of domestic ambrisentan in Chinese PAH patients and observed risk improvement and time to clinical improvement (TTCI) under ambrisentan treatment. Eligible patients with PAH were enrolled for a 24-week treatment with ambrisentan. The primary efficacy endpoint was 6-min walk distance (Δ6MWD). The exploratory endpoints were risk improvement and TTCI, defined as the time from initiation of treatment to the first occurrence of risk improvement. A total of 83 subjects were enrolled. After ambrisentan treatment, Δ6MWD was significantly increased at week 12 (42.2 m, P < 0.0001) and week 24 (53.4 m, P < 0.0001). Within 24 weeks, risk improvement was observed in 53 (64.6%) subjects (P < 0.0001), which is higher than WHO-FC (30.5%) and TAPSE/PASP (32.9%). Kaplan-Meier analysis of TTCI showed a median improvement time of 131 days and a cumulative improvement rate of 75.1%. Also, TTCI is consistent across different baseline risk status populations (log-rank P = 0.51). The naive group had more risk improvement (P = 0.043) and shorter TTCI (log-rank P = 0.008) than the add-on group, while Δ6MWD did not show significant differences between the two groups. Domestic ambrisentan significantly improved the exercise capacity and risk status of Chinese PAH patients. TTCI has a relatively high positive event rate within 24-week treatment duration. Compared to Δ6MWD, TTCI is not affected by baseline risk status. Additionally, TTCI could identify better improvements in patients, which Δ6MWD does not detect. TTCI is an appropriate composite surrogate endpoint for PAH medication trials. NCT No. [ClinicalTrials.gov], identifier [NCT05437224].

Novel Drugs for the Treatment of Pulmonary Arterial Hypertension: Where Are We Going?

Pulmonary arterial hypertension (PAH) is a progressive disease that despite advances in therapy is associated with a 7-year survival of approximately 50%. Several risk factors are associated with developing PAH, include methamphetamine use, scleroderma, human immunodeficiency virus, portal hypertension, and genetic predisposition. PAH can also be idiopathic. There are traditional pathways underlying the pathophysiology of PAH involving nitric oxide, prostacyclin, thromboxane A2, and endothelin-1, resulting in impaired vasodilation, enhanced vasoconstriction and proliferation in the pulmonary vasculature. Established PAH medications targets these pathways; however, this paper aims to discuss novel drugs for treating PAH by targeting new and alternative pathways.

Left Heart Disease Phenotype in Elderly Patients with Pulmonary Arterial Hypertension: Insights from the Italian PATRIARCA Registry.

Pulmonary arterial hypertension (PAH) in the elderly is often associated with left heart disease (LHD), prompting concerns about the use of pulmonary vasodilators. The PATRIARCA registry enrolled ≥70 year-old PAH or chronic thromboembolic pulmonary hypertension (CTEPH) patients at 11 Italian centers from 1 December 2019 through 15 September 2022. After excluding those with CTEPH, post-capillary PH at the diagnostic right heart catheterization (RHC), and/or incomplete data, 23 (33%) of a total of 69 subjects met the criteria proposed in the AMBITION trial to suspect LHD. Diabetes [9 (39%) vs. 6 (13%), p = 0.01] and chronic kidney disease [14 (61%) vs. 12 (26%), p = 0.003] were more common, and the last RHC pulmonary artery wedge pressure [14 ± 5 vs. 10 ± 3 mmHg, p < 0.001] was higher and pulmonary vascular resistance [5.56 ± 3.31 vs. 8.30 ± 4.80, p = 0.02] was lower in LHD than non-LHD patients. However, PAH therapy was similar, with 13 (57%) and 23 (50%) subjects, respectively, taking two oral drugs. PAH medication patterns remained comparable between LHD and non-LHD patients also when the former [37, 54%] were identified by atrial fibrillation and echocardiographic features of LHD, in addition to the AMBITION criteria. In this real-world snapshot, elderly PAH patients were treated with pulmonary vasodilators, including combinations, despite a remarkable prevalence of a LHD phenotype.

Association Between Copayment and Adherence to Medications for Pulmonary Arterial Hypertension.

Background Pharmacologic treatment for pulmonary arterial hypertension (PAH) improves exercise capacity, functional class, and hemodynamic indexes. However, monthly prescription costs often exceed $4000. We examined associations between (1) medication copayment and (2) annual household income with adherence to pulmonary vasodilator therapy among individuals with PAH. Methods and Results We used administrative claims data from an insured population in the United States to identify individuals diagnosed with PAH between 2015 and 2020. All individuals had ≥1 medication claim for endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, prostanoids or prostacyclin receptor agonists, or the soluble guanylate cyclase stimulator riociguat. We defined copayments as low, medium, or high, as determined by their distributions for each medication class. Annual household income was categorized as <$40 000, $40 000 to $74 999, and ≥$75 000. The primary outcome was medication adherence, defined by proportion of days covered ≥80%. We studied 4025 adults (aged 65.9±13.3 years; 71.2% women). Compared with those with annual household income ≥$75 000, individuals in the <$40 000 and $40 000 to $74 999 categories had no significant differences in medication adherence. Compared with those with low copayments, individuals with high copayments had decreased adherence to prostanoids (odds ratio [OR], 0.36 [95% CI, 0.20-0.65]; P<0.001) and combination therapy with endothelin receptor antagonist and phosphodiesterase type-5 inhibitor (OR, 0.61 [95% CI, 0.38-0.97]; P=0.03). Conclusions We identified associations between copayment and adherence to prostanoids and combination therapy among individuals with PAH. Copayment may be a structural barrier to medication adherence and merits inclusion in studies examining access to pharmacotherapy among individuals with PAH.

Abstract 10899: Excessive Right Ventricular Afterload in Pulmonary Arterial Hypertension: Effects on Diastolic Function and the Left Ventricle

Introduction: Right ventricular (RV) diastolic dysfunction in pulmonary arterial hypertension (PAH) remains poorly understood. In this study, we used RV pressure-volume (PV) loops to assess RV diastology as a function of afterload in PAH. Methods: RV PV loops were prospectively measured in control (n=9) and PAH (n=39) patients at rest and during supine bike exercise. PAH patients were stratified by effective arterial elastance (Ea), a lumped measure of total afterload, into two groups: high afterload (HA, n=20) and severe afterload (SA, n=19). Results: PAH groups were matched with respect to age, sex, and PAH medication usage. Ea at rest and exercise was higher in SA PAH (1.8 vs. 0.6 mmHg/ml, P &lt;0.0001 at rest; 2.3 vs 0.8 mmHg/ml, P &lt; 0.0001 with exercise). In the SA group, RV end-diastolic pressure (RVEDP) was higher at rest (13.3 vs 7.6 mmHg, P = 0.0017) and rose markedly with exertion (23.4 vs 13.1 mmHg, P=0.0001). Because RV volumes changed similarly in both groups, SA patients exhibited stiffer RVs (dP/dV 0.30 vs 0.11 mmHg/mL, P=.024). To understand pericardial-interventricular interactions, we calculated the RVEDP-to-pulmonary capillary wedge pressure (PCWP) ratio and the left ventricular (LV) transmural filling pressure (LVTMFP). RVEDP/PCWP was substantially higher in SA (2.1 vs 1.0, P=.005). Therefore, even though PCWP rose considerably in SA (mean 16 mmHg), exercise LVTMFP was significantly reduced in SA vs HA PAH (-7.5 vs 2.55 mmHg, P=0.002). Along with reduced LV size seen by concomitant echo, we thus revealed blunted LV filling specifically in SA PAH. Accordingly, exercise cardiac index, stroke volume index, and LV stroke work index were all markedly reduced in SA PAH. Conclusions: Severe afterload in PAH results in high RV diastolic pressures and RV stiffening, which in turn blunt LV filling and LV output with exertion. Due to ventricular interactions, exercise PCWP may rise considerably in PAH, thus reducing its ability to differentiate from left heart disease.

Long-term outcomes of transcatheter Potts shunt in children with suprasystemic pulmonary arterial hypertension.

Transcatheter Potts shunt (TPS) is a palliation alternative for children with severe pulmonary arterial hypertension (PAH). Debates on the long-term outcomes remain unsolved. To evaluate long-term clinical and procedural outcomes of TPS intervention. Single-center retrospective data review of children with severe PAH who had TPS between 2009 and 2018. Patients who died per-operatively and early post-procedure were excluded. Long-term outcomes of survivors were evaluated. Out of 13 identified patients (53.8% males), 7 had endovascular stenting of probe/patent arterial ducts, while 6 individuals had aorta-to-pulmonary radiofrequency perforation and covered stent placement. Compared to baseline, the overall clinical condition significantly improved at discharge (p < 0.001) and stayed better at the last visit (p < 0.05) despite frequent clinical worsening events across follow-up. Improvement in functional class across follow-up was significant (p < 0.001). There was, however, no significant improvement in other disease markers (TPASE, 6MWD z-scores, and NT-proBNP levels) or reduction in PAH medications. The median follow-up was 77.4 months (IQR, 70.7-113.4). Survival was 100% at 1 year and 92.3% at 6 years. Freedom from reinterventions was 77% at 1 year and 21% at 6 years. Nine (69.2%) patients had stent reinterventions at a median of 25 months (IQR, 9.5-56) postoperative. Balloon dilatation and restenting were performed in 53.8% and 46.2% of patients, respectively. High-pressure post-dilatation of implanted stents was performed in 53.8% of patients during TPS intervention for incomplete stent expansion and/or residual pressure gradient and was associated with higher rates of reinterventions (p = 0.021). Stent malfunctioning was present in 46.2% of patients at last follow-up. Two patients are listed for heart-lung transplantation. Survivors of TPS procedures experience significant improvement in functional class that can be durable. Clinical worsening and stent malfunctioning are frequent morbid events indicating recurrent transcatheter reinterventions throughout follow-up. Six-year survival is, however, satisfactory.