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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.
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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.
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Antihipertensivos , Epoprostenol , Hipertensión Arterial Pulmonar , Humanos , Epoprostenol/análogos & derivados , Epoprostenol/administración & dosificación , Epoprostenol/efectos adversos , Epoprostenol/uso terapéutico , Persona de Mediana Edad , Femenino , Masculino , Administración Oral , Estudios Prospectivos , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología , Anciano , Consenso , Hipertensión Pulmonar/tratamiento farmacológico , Adulto , Resultado del Tratamiento , Cefalea/inducido químicamente , Sistema de Registros , Náusea/inducido químicamenteRESUMEN
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.
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Hipertensión Arterial Pulmonar , Humanos , Masculino , Método Doble Ciego , Femenino , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , Anciano , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia Vascular/efectos de los fármacos , Administración por Inhalación , Hipertensión Pulmonar/tratamiento farmacológicoRESUMEN
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.
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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.
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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.
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Hipertensión Arterial Pulmonar , Sistema de Registros , Humanos , Masculino , Femenino , Medición de Riesgo/métodos , Persona de Mediana Edad , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/epidemiología , Estudios Prospectivos , Adulto , Curva ROC , Trasplante de Pulmón , Hipertensión Pulmonar/diagnósticoAsunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Nivel de Atención , Hipertensión Pulmonar Primaria Familiar , Hipertensión Pulmonar/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Quimioterapia CombinadaRESUMEN
This JAMA Insights discusses the symptoms, diagnosis, and treatment of chronic thromboembolic pulmonary hypertension.
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Hipertensión Pulmonar , Embolia Pulmonar , Tromboembolia , Humanos , Enfermedad Crónica , Endarterectomía , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/cirugía , Hipertensión Pulmonar/terapia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiología , Embolia Pulmonar/cirugía , Embolia Pulmonar/terapia , Tromboembolia/complicaciones , Tromboembolia/diagnóstico , Tromboembolia/cirugía , Tromboembolia/terapiaRESUMEN
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.
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Pulmonary hypertension secondary to left-sided valvular disease (VHD-PH) is associated with high morbidity and mortality. Angiotensin-receptor neprilysin inhibitor (ARNI) is a novel pharmacotherapy, which reduces afterload with natriuresis and peripheral vasodilation. Our cases demonstrate that ARNI may also have a role in the treatment of combined pre- and postcapillary pulmonary hypertension that is independent of its effect on pulmonary capillary wedge pressure and cardiac output. Future prospective trials are needed to evaluate role of ARNIs in treatment of VHD-PH.
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Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It is approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI utilizes single-use prefilled cartridges to ensure proper dosing. Unlike nebulizer devices, administration of Tyvaso DPI is passive and does not require coordination with the device. The low-flow rate design results in targeted delivery to the peripheral lungs due to minimal drug loss from impaction in the oropharynx. The inert fumaryl diketopiperazine (FDKP) excipient forms microparticles that carry treprostinil into the airways, with a high fraction of the particles in the respirable range. In a clinical study in patients with pulmonary arterial hypertension, Tyvaso DPI had similar exposure and pharmacokinetics, low incidence of adverse events, and high patient satisfaction compared with nebulized treprostinil solution. Tyvaso DPI may be considered as a first prostacyclin agent or for those that do not tolerate other prostacyclin formulations, patients with pulmonary comorbidities, patients with mixed Group 1 and Group 3 pulmonary hypertension, or those that prefer an active lifestyle and need a portable, non-invasive treatment. Tyvaso DPI is a patient-preferred, maintenance-free, safe delivery option that may improve patient compliance and adherence.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Inhaladores de Polvo Seco , Hipertensión Pulmonar/tratamiento farmacológico , Preparaciones Farmacéuticas , Epoprostenol/efectos adversos , Administración por Inhalación , Hipertensión Pulmonar Primaria Familiar/tratamiento farmacológicoRESUMEN
Rationale: Guidelines recommend using end-expiration pulmonary pressure measurements to determine the hemodynamic subgroups in pulmonary hypertension. Pulmonary artery wedge pressure (PAWP) determinations averaged across the respiratory cycle (PAWPav) instead of PAWP at end-expiration (PAWPee) and cardiac output (CO) measured by Fick (COFick) instead of thermodilution (COTD) may affect the hemodynamic classification of pulmonary hypertension. Objectives: To assess the impact on the pulmonary hypertension hemodynamic classification of the use of PAWPee versus PAWPav as well as COFick versus COTD. Methods: This was a single-center retrospective study of consecutive patients (n = 151) who underwent right heart catheterization with COTD, COFick, PAWPee, and PAWPav. A secondary cohort consisted of consecutive patients (n = 71) who had mean pulmonary artery pressure at end-expiration (mPAPee) and mPAP averaged across the respiratory cycle (mPAPav) measured, as well as PAWPee and PAWPav. Results: The PAWPee and PAWPav were 16.8 ± 6.4 and 15.1 ± 6.8 mm Hg, respectively, with a mean difference of 1.7 ± 2.1 mm Hg. The COTD and COFick determinations were 5.0 ± 2.4 and 5.3 ± 2.5 L/min, respectively, with a mean difference of -0.4 ± 1.3 L/min. The hemodynamic group distribution was significantly different when using PAWPee versus PAWPav, when using either COTD or COFick (P < 0.001 for both comparisons), and these results were consistent in our secondary cohort. The pulmonary hypertension hemodynamic group distribution was not significantly different between COTD and COFick when using either PAWPee or PAWPav. Conclusions: The methodology used to measure PAWP, either at end-expiration or averaged across the respiratory cycle, significantly impacts the hemodynamic classification of pulmonary hypertension.
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Hipertensión Pulmonar , Humanos , Presión Esfenoidal Pulmonar , Hipertensión Pulmonar/diagnóstico , Estudios Retrospectivos , Gasto Cardíaco , Hemodinámica , Cateterismo Cardíaco , Arteria PulmonarRESUMEN
Pulmonary arterial hypertension (PAH) is a progressive, incurable disease that results in significant symptom burden, health care utilization, and eventually premature death. Despite the advancements made in treatment and management strategies, survival has remained poor. End-of-life care is a challenging issue in management of PAH, especially when patients are in younger age group. End-of-life care revolves around symptom palliation and reducing psychosocial disease burden for a dying patient and entails advanced care planning that are often challenging. Thus, support from palliative care specialist becomes extremely important in these patients. Early introduction to palliative care in patients with high symptom burden and psychosocial suffering is suggested. Despite of the benefits of an early intervention, palliative care remains underutilized in patients with PAH, and this significantly raises issues around end-of-life care in PAH. In this review, we will discuss the opportunities offered and the existing barriers in addressing high symptom burden and end-of-life care issues. We will focus on the current evidence, identify areas for future research, and provide a call-to-action for better guidance to PAH specialists in making timely, appropriate interventions that can help mitigate end-of-life care issues.
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Hipertensión Arterial Pulmonar , Cuidado Terminal , Humanos , Cuidados Paliativos/métodos , Cuidados Paliativos/psicología , Hipertensión Arterial Pulmonar/terapia , Calidad de Vida/psicología , Cuidado Terminal/métodos , Cuidado Terminal/psicología , MuerteRESUMEN
Heritable pulmonary artery hypertension (HPAH) is an increasingly recognized type of pulmonary arterial hypertension, in both pediatric and adult population. Intrinsic to hereditary disease, screening for genetic mutations within families is an important component of diagnosis and understanding burden of disease. Recently, consensus guidelines are published for genetic screening in PAH. These guidelines include recommendations for screening at diagnosis, noting individuals with presumed PAH due to familial, or idiopathic etiologies. Cascade genetic testing is specifically recommended as a testing paradigm to screen relatives for detection of mutation carriers, who may be asymptomatic. Without targeted genetic testing, familial mutation carriers may only come to attention when pulmonary vascular disease burden is high enough to cause symptoms, suggesting more advanced disease. Here, we present our collective experience with HPAH in five distinct families, specifically to report on the clinical courses of patients who were diagnosed with genetic mutation at diagnosis versus those who were offered genetic screening. In three families, asymptomatic mutation carriers were identified and monitored for clinical worsening. In two families, screening was not done and affected family members presented with advanced disease.
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Pulmonary arterial hypertension (PAH) is a cardiovascular disease with high mortality rate. Current guidelines propose initiation and escalation of PAH-targeted treatment based on a goal-directed approach targeting hemodynamic, functional, and biochemical variables. This approach has been successfully validated in large Caucasian cohorts. However, given the low number of Hispanic patients enrolled in large PAH trials and registries, it is unknown if the same prognostic tools can be applied to this patient population. We analyzed a single-center outpatient cohort that consisted of 135 Hispanic patients diagnosed with PAH. Baseline characteristics were calculated based on COMPERA, COMPERA 2.0 and REVEAL 2.0 risk scores before the initiation of PAH-targeted therapies. The survival rate at 1 year after diagnosis was 88% for the entire cohort. The three established risk scores to predict PAH outcomes yielded similar results with reasonable discrimination of mortality in the different risk strata (all p < 0.001). Hispanic patients with PAH have a high mortality rate. Our analysis suggests that guideline proposed risk assessment at baseline yields important prognostic information in this patient population.
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Background: Interhospital transfer (IHT) of patients with acute life-threatening pulmonary embolism (PE) is necessary to facilitate specialized care and access to advanced therapies. Our goal was to understand what barriers and facilitators may exist during this transfer process from the perspective of both receiving and referring physicians. Methods: This qualitative descriptive study explored physician experience taking care of patients with life threatening PE. Subject matter expert physicians across several different specialties from academic and community United States hospitals participated in qualitative semi-structured interviews. Interview transcripts were subsequently analyzed using inductive qualitative description approach. Results: Four major themes were identified as barriers that impede IHT among patients with life threatening PE. Inefficient communication which mainly pertained to difficulty when multiple points of contact were required to complete a transfer. Subjectivity in the indication for transfer which highlighted the importance of physicians understanding how to use standardized risk stratification tools and to properly triage these patients. Delays in data acquisition were identified in regards to both obtaining clinical information and imaging in a timely fashion. Operation barriers which included difficulty finding available beds for transfer and poor weather conditions inhibiting transportation. In contrast, two main facilitators to transfer were identified: good communication and reliance on colleagues and dedicated team for transferring and treating PE patients. Conclusion: The most prominent themes identified as barriers to IHT for patients with acute life-threatening PE were: (1) inefficient communication, (2) subjectivity in the indication for transfer, (3) delays in data acquisition (imaging or clinical), and (4) operational barriers. Themes identified as facilitators that enable the transfer of patients were: (1) good communication and (2) a dedicated transfer team. The themes presented in our study are useful in identifying opportunities to optimize the IHT of patients with acute PE and improve patient care. These opportunities include instituting educational programs, streamlining the transfer process, and formulating a consensus statement to serve as a guideline regarding IHT of patients with acute PE.
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Effective clinical decision-making in initial treatment selection and switching or escalations of therapy for pulmonary arterial hypertension (PAH) depends on multiple factors including the patient's risk profile. Data from clinical trials suggest that switching from a phosphodiesterase-5 inhibitor (PDE5i) to the soluble guanylate cyclase stimulator riociguat may provide clinical benefit in patients not reaching treatment goals. In this review, we cover the clinical evidence for riociguat combination regimens for patients with PAH and discuss their evolving role in upfront combination therapy and switching from a PDE5i as an alternative to escalating therapy. Specifically, we review current evidence which suggests or provides a hypothesis for 1) the potential use of riociguat plus endothelin receptor antagonist combinations for upfront combination therapy in patients with PAH at intermediate to high risk of 1-year mortality and 2) the benefits of switching to riociguat from a PDE5i in patients who are not achieving treatment goals with PDE5i-based dual combination therapy and at intermediate risk.