Contemporary Treatment of Pulmonary Arterial Hypertension: A US Perspective.

Pulmonary arterial hypertension (PAH) is a complex fatal condition which requires aggressive treatment with close monitoring. Significant progress has been made over the last three decades in the treatment of PAH but despite this progress, survival has remained unacceptably low. In the quest to improve survival, therapeutic interventions play a central role. In the last few years, there have been remarkable attempts to identify novel treatments. Finally, we have had a breakthrough with the discovery of the fourth treatment pathway in PAH. Activin signaling inhibition distinguishes itself as a potential antiproliferative intervention as opposed to the traditional therapies which mediate their effect primarily by vasodilatation. With this novel treatment pathway, we stand at an important milestone with an exciting future ahead and the natural question of when to utilize Activin signaling inhibitor (ASI) for the treatment of PAH. In this state-of-the-art review, we focus on the placement of this novel agent in the PAH treatment paradigm based on the available evidence, with special focus on the US patient population. This review also provides an expert opinion of the current treatment algorithm on important subgroups of patients with comorbidities from the US perspective.

Practical management of oral treprostinil in patients with pulmonary arterial hypertension: Lessons from ADAPT, EXPEDITE, and expert consensus.

BACKGROUND: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies. STUDY DESIGN AND METHODS: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use. RESULTS: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76 % female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62 % (78/126) of patients reported headache and diarrhea, and 40 % (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61 % headache, 44 % diarrhea, 70 % nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron, were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6. CONCLUSION: Patient selection for, and initiation and titration of, oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help patients reach higher and more efficacious doses of oral treprostinil.

Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.

Recovery from kidney failure associated with chronic thromboembolic pulmonary hypertension following pulmonary thomboendarterectomy.

The occurrence of renal failure in pulmonary hypertension (PH) is an ominous sign and implies excessive adverse hemodynamic factors. Pharmacologic agents to treat the PH are the mainstay of management, whereas diuretics assist in management of fluid overload. However, when such measures fail, dialysis and ultrafiltration (UF) become necessary to manage progressive azotemia and hypervolemia. Reversal of PH is essential to interrupt this vicious cycle of multisystem failure; otherwise, the need for renal replacement therapy would be permanent.

Comparison of Contemporary Risk Scores in All Groups of Pulmonary Hypertension: A Pulmonary Vascular Research Institute GoDeep Meta-Registry Analysis.

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. RESEARCH QUESTION: Are risk scores originally developed for PAH predictive in PH groups 1 through 4? STUDY DESIGN AND METHODS: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including Registry to Evaluate Early and Long-Term PAH Disease Mangement (REVEAL) Lite 2, REVEAL 2.0, ESC/ERS 2022, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 3-strata, and COMPERA 4-strata. RESULTS: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (interquartile range, 33-52 mm Hg) and pulmonary vascular resistance of 7 Wood units (WU) (interquartile range, 4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH). INTERPRETATION: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT05329714; URL: www. CLINICALTRIALS: gov.

Comparison Between REVEAL Lite 2 and COMPERA 2.0 for Risk Stratification in Pulmonary Arterial Hypertension.

BACKGROUND: Risk stratification is the cornerstone of the management of pulmonary arterial hypertension (PAH). Current European Society of Cardiology/European Respiratory Society guidelines recommend using the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) three-strata risk model at baseline and the COMPERA 2.0 four-strata model at follow-up. However, the guidelines did not take into consideration other available risk scores such as the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2. RESEARCH QUESTION: Is REVEAL Lite 2 better at discriminating risk than the COMPERA risk assessment models at baseline or follow-up evaluations? STUDY DESIGN AND METHODS: This study analyzed data from patients with PAH consecutively enrolled between June 2011 and February 2022 in the PAH registry at our expert Pulmonary Hypertension Center. Patients were stratified according to REVEAL Lite 2 and COMPERA three- and four-strata risk scores at baseline and follow-up to predict the composite outcome for lung transplantation or death. Receiver-operating characteristic curves in predicting the binary outcome at 3, 5, and 7 years were plotted. Areas under the curve of the scores were compared by using the χ2 test. The performance of the scores was determined according to the Harrel C statistic. RESULTS: A total of 296 patients were included for baseline and 196 for follow-up evaluation. The overall transplant-free survival in the patient population at 1, 3, 5, and 7 years was 93.6%, 81.3%, 75.1%, and 68.8%, respectively. At baseline, the C statistic of REVEAL Lite 2 was 0.74 (95% CI, 0.69-0.80), compared with 0.68 (95% CI, 0.63-0.74) for the COMPERA four-strata model and 0.63 (95% CI, 0.58-0.69) for the COMPERA three-strata model. All C statistic differences between REVEAL Lite 2 and the other models were statistically significant at baseline. INTERPRETATION: Our analysis showed that REVEAL Lite 2 was better at baseline at discriminating risk in this patient population. Future guidelines should consider including REVEAL Lite 2 in the management algorithm to help clinicians make informed decisions. Further analysis in larger cohorts could help validate these findings.

Chronic Thromboembolic Pulmonary Hypertension.

This JAMA Insights discusses the symptoms, diagnosis, and treatment of chronic thromboembolic pulmonary hypertension.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Pulmonary foreign body granulomatosis in a chronic user of powder cocaine / Granulomatose pulmonar de corpo estranho em um usuário crônico de cocaína em pó

ABSTRACT We describe the case of a 33-year-old man, a chronic user of powder cocaine, who presented with dyspnea, fever, night sweats, and significant weight loss. Chest HRCT revealed centrilobular nodules, giving an initial impression of miliary tuberculosis. Therefore, he was started on an empirical, four-drug antituberculosis treatment regimen. Four weeks later, despite the tuberculosis treatment, he continued to have the same symptoms. We then performed transbronchial lung biopsy. Histopathological analysis of the biopsy sample revealed birefringent foreign body granuloma. A corroborative history of cocaine snorting, the presence of centrilobular nodules, and the foreign body-related histopathological findings led to a diagnosis of pulmonary foreign body granulomatosis. This report underscores the fact that pulmonary foreign body granulomatosis should be included in the differential diagnosis of clinical profiles resembling tuberculosis.

RESUMO Descrevemos o caso de um homem de 33 anos de idade, usuário crônico de cocaína em pó, que apresentava dispneia, febre, sudorese noturna e perda de peso significativa. A TCAR de tórax revelou nódulos centrolobulares, dando uma impressão inicial de tuberculose miliar. Por isso, o paciente passou a receber tratamento empírico com quatro tuberculostáticos. Quatro semanas depois, apesar do tratamento antituberculose, o paciente continuou a apresentar os mesmos sintomas. Foi então realizada a biópsia pulmonar transbrônquica. A análise histopatológica da amostra obtida revelou granuloma de corpo estranho birrefringente. A história de uso de cocaína por inalação, a presença de nódulos centrolobulares e os achados histopatológicos de corpos estranhos confirmaram o diagnóstico de granulomatose pulmonar de corpo estranho. Este relato destaca o fato de que a granulomatose pulmonar de corpo estranho deve ser incluída no diagnóstico diferencial de perfis clínicos que se assemelham a tuberculose.

Aspergilloma formation in cavitary sarcoidosis / Formação de uma aspergilloma em sarcoidose com cavitação

Pulmonary cavitation is rather uncommon in patients with sarcoidosis, and aspergilloma is even more uncommon in such cases. Here, we present the case of a 63-year-old female patient with cavitary lung disease who had been under treatment for TB for 9 months. A diagnosis of pulmonary sarcoidosis was established based on the fiberoptic bronchoscopy finding of noncaseating granuloma. Treatment with corticosteroids led to a dramatic improvement in symptoms. While under treatment for sarcoidosis, the patient developed an aspergilloma. She presented immediate skin test reactivity to Aspergillus fumigatus, as well as positivity for A. fumigatus serum precipitins. This is the first reported case of aspergilloma formation in a patient with cavitary sarcoidosis in India.

A cavitação pulmonar é rara em pacientes com sarcoidose, e o aspergiloma é ainda mais raro nestes casos. Apresentamos o caso de uma paciente de 63 anos com doença pulmonar cavitária em tratamento para a TB por 9 meses. Estabeleceu-se o diagnóstico de sarcoidose pulmonar com base nos achados de granuloma não-caseoso na fibrobroncoscopia. Houve grande melhora dos sintomas com o tratamento com corticosteroides. A paciente desenvolveu um aspergiloma durante o tratamento para a sarcoidose. Houve reação imediata ao teste cutâneo para Aspergillus fumigatus, assim como resultado positivo para precipitinas de A. fumigatus no soro. Este é o primeiro caso relatado de formação de aspergiloma em um paciente com sarcoidose com cavitação na Índia.