Management and Outcomes of Kidney Transplant Candidates With Severe Pulmonary Hypertension: A Single-center Strategy and Experience.

Background: Severe pulmonary hypertension (PH) is associated with high mortality posttransplant and thus is considered a contraindication to kidney transplantation. In this study, we describe the pretransplant management and posttransplant outcomes in patients with severe PH using a multidisciplinary approach. Methods: Between 11 of 2013 and 8 of 2022, we identified all patients with severe PH on initial pretransplant workup who underwent ultrafiltration (UF) or medical therapy for PH before transplant. Posttransplant we evaluated the perioperative course, renal function, graft, and patient survival. We compared survival to those who remained waitlisted or were delisted. Results: Three-two patients (mean age = 55.03 ± 10.22 y) diagnosed with severe PH on pretransplant screening echocardiogram. Thirty patients (94%) were subjected to a median of 4 (range, 3-8) UF sessions with an average weight loss of 4.33 ± 2.6 kg. Repeat assessment of PH revealed a decline in mean pulmonary artery systolic pressure from 67 ± 12 mm Hg to 43 ± 13 mm Hg (P < 0.0001). Seventeen patients (53%) received a kidney transplant. The mean estimated Glomerular Filtration Rate at 3, 6, 9, and 12 mo was 72 ± 27, 72 ± 28, 75 ± 29, and 75 ± 29 mL/min/1.73 m2. Among, those who underwent transplantation both graft and patient survival was 100% at 1-y posttransplant. Overall, since the UF intervention, at a median follow-up of 88 ± 12 mo those transplanted had a patient survival of 88% while those who remained on dialysis had a survival of 53% (P = 0.0003). Conclusion: In this single-center study, we report postcapillary PH can be a significant contributor to elevations in pulmonary artery systolic pressure. Using a multidisciplinary approach, PH can improve with volume removal and phosphodiesterase 5 inhibitors therapy leading to a successful posttransplant outcome.

Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by high mean pulmonary arterial pressure (≥ 20 mmHg) and remodeling of the vascular arteries. Approved therapies improve symptoms and delay clinical worsening in the long term, but they do not relieve acute exertional symptoms. RT234, a drug/device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers the phosphodiesterase 5 inhibitor vardenafil to the lungs via inhalation, has been shown to reduce pulmonary vascular resistance in patients with PAH. This study aims to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH. METHODS: This prospective, multi-center, open-label, two-cohort, dose-escalation, phase IIb trial in patients with PAH will evaluate the safety and efficacy of RT234 in improving exercise parameters. The trial began in September 2020 and is expected to be completed by early 2024. Patients eligible for enrollment will have a right heart catheterization-confirmed diagnosis of PAH, a 6-minute walking distance of ≥ 150 m, a minute ventilation/carbon dioxide production slope of ≥ 36, and will be on up to three stable oral and/or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, who will be divided into two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and cohort 2 will receive 1.0 mg RT234. Each cohort will contain two subgroups based on the number of PAH background medications (up to two vs three). The trial will assess patients' changes from baseline in peak oxygen consumption (VO2) during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg RT234, the change in the 6-minute walking distance, and the pharmacokinetics and safety profile of single doses of RT234. CONCLUSION: This is the first trial involving an as-needed medication for PAH. The trial will provide insights into the safety and efficacy of as-needed RT234 in treating the acute symptoms of PAH during exercise and will inform the design of further trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04266197.

Anticoagulation in pulmonary arterial hypertension - association with mortality, healthcare utilization, and quality of life: The Pulmonary Hypertension Association Registry (PHAR).

BACKGROUND: Routine long-term anticoagulation in pulmonary arterial hypertension (PAH) is controversial. To date, anticoagulation has been found to be beneficial or neutral in idiopathic disease (IPAH) and neutral-to-harmful in connective tissue disease (CTD-PAH). We sought to examine the association between anticoagulation and mortality, healthcare utilization, and quality of life (QoL) in PAH. METHODS: The PHAR is a prospective registry of PAH patients referred to 58 pulmonary hypertension care centers in the United States. We compared patients who received anticoagulation during enrollment (questionnaire documented) to those who did not. Cox proportional hazard models were used for mortality, Poisson multivariate regression models for healthcare utilization, and generalized estimating equations for QOL RESULTS: Of 1175 patients included, 316 patients were treated with anticoagulation. IPAH/hereditary PAH (HPAH) comprised 46% of the cohort and CTD-PAH comprised 33%. After adjustment for demographics, clinical characteristics, site and disease severity, anticoagulation was not associated with mortality in the overall population (HR, 1.00; 95% CI, 0.72-1.36), IPAH/HPAH (HR, 1.19; 95% CI, 0.74-1.94), or CTD-PAH (HR 0.87; 95% CI, 0.53-1.42). Anticoagulation was associated with an increased rate of emergency department visits (IRR: 1.41), hospitalizations (IRR: 1.30), and hospital days (IRR 1.33). QOL measured by emPHasis-10 score was worse in patients receiving anticoagulation (mean difference 1.74; 95% CI 0.40-3.09). CONCLUSIONS: Anticoagulation is not associated with higher mortality, but is associated with increased healthcare utilization in the PHAR. PAH-specific QoL may be worse in patients receiving anticoagulation. The risks and benefits surrounding routine prescription of anticoagulation for PAH should be carefully considered.

Utility of plasma volume status in ambulatory patients with pulmonary hypertension.

Plasma volume status (PVS) is a noninvasive estimate of intravascular volume status. We studied the utility of PVS to predict short-term outcomes in patients with pulmonary hypertension. Patients with lower PVS had decreased risk of hospitalization and death within 90 days of clinic visit, compared to those with higher PVS.

Hispanic Ethnicity and Social Determinants of Health in Pulmonary Arterial Hypertension: The Pulmonary Hypertension Association Registry.

Rationale: There is a noticeable underrepresentation of minorities in clinical trials and registries in pulmonary arterial hypertension (PAH). Prior studies evaluating the association between Hispanic ethnicity and clinical outcomes in patients with PAH have not assessed the socioeconomic profile of Hispanic individuals or the significance of social determinants of health in clinical outcomes. Objectives: To determine the association between Hispanic ethnicity, social determinants of health, and clinical outcomes in PAH. Methods: This was a prospective cohort study of adult participants with PAH enrolled in the Pulmonary Hypertension Association Registry, a multicenter U.S.-based registry of patients treated at pulmonary hypertension care centers. Participants were classified as Hispanics and non-Hispanic White individuals, based on self-reported ethnicity. A comparison of baseline clinical and sociodemographic characteristics between groups was performed as well using absolute standardized differences (ASD). The primary outcome of the study was to assess transplant-free survival between Hispanics and non-Hispanic White individuals. A Cox proportional hazards model was used for the multivariable analysis after adjusting for age, sex, PAH etiology, annual income, education level, and health insurance. Results: A total of 683 individuals were included, 98 (14.3%) of Hispanic ethnicity. Hispanic patients had impaired access to health care (31.6% vs. 12.9% Medicaid/uninsured; ASD, 0.35), lower education level (72.6% vs. 94.0% high school graduates or higher; ASD, 0.60), and lower annual income (32.0% vs. 17.4% with income <20,000 U.S. dollars; ASD, 0.47), compared with non-Hispanic White individuals. Hispanic patients had a higher frequency of emergency room visits and a higher number of hospitalizations, despite having similar disease severity (incidence rate ratio, 1.452; 95% confidence interval [CI], 1.326-1.590; and 1.428; 95% CI, 1.292-1.577, respectively). Although the unadjusted analysis showed a lower transplant/death hazard ratio for Hispanics (hazard ratio, 0.47; 95% CI, 0.24-0.94; P = 0.032), there was no association between Hispanic ethnicity and outcome in the multivariable model after adjusting for social determinants of health and other covariates (HR, 0.76; 95% CI, 0.35-1.62; P = 0.474). Conclusions: Hispanic ethnicity was not associated with differences in survival after adjusting for social determinants of health and other factors. Social determinants of health are important to consider when assessing the association between ethnicity and outcomes in PAH.

Health-related quality of life and hospitalizations in chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension: an analysis from the Pulmonary Hypertension Association Registry (PHAR).

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health-related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis-10 (E10) and SF-12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty-one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow-up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six-minute walk distance (IRR 1.66, 95%CI 1.04-2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six-minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.

Residence at moderately high altitude and its relationship with WHO Group 1 pulmonary arterial hypertension symptom severity and clinical characteristics: the Pulmonary Hypertension Association Registry.

BACKGROUND: WHO Group 1 pulmonary arterial hypertension is a progressive and potentially fatal disease. Individuals living at higher altitude are exposed to lower barometric pressure and hypobaric hypoxemia. This may result in pulmonary vasoconstriction and contribute to disease progression. We sought to examine the relationship between living at moderately high altitude and pulmonary arterial hypertension characteristics. METHODS: Forty-two US centers participating in the Pulmonary Hypertension Association Registry enrolled patients who met the definition of WHO Group 1 pulmonary arterial hypertension. We utilized baseline data and patient questionnaire responses. Patients were divided into two groups: moderately high altitude residence (home ≥4000 ft) and low altitude residence (home <4000 ft) based on zip-code. Clinical characteristics, hemodynamic data, patient demographics, and patient reported quality of life metrics were compared. RESULTS: Controlling for potential confounders (age, sex at birth, body mass index, supplemental oxygen use, race, 100-day cigarette use, alcohol use, and pulmonary arterial hypertension medication use), subjects residing at moderately high altitude had a 6-min walk distance 32 m greater than those at low altitude, despite having a pulmonary vascular resistance that was 2.2 Wood units higher. Additionally, those residing at moderately high altitude had 3.7 times greater odds of using supplemental oxygen. CONCLUSION: Patients with pulmonary arterial hypertension who live at moderately high altitude have a higher pulmonary vascular resistance and are more likely to need supplemental oxygen. Despite these findings, moderately high altitude Pulmonary Hypertension Association Registry patients have better functional tolerance as measured by 6-min walk distance. It is possible that a "high-altitude phenotype" of pulmonary arterial hypertension may exist. These findings warrant further study.

A Survey-based Estimate of COVID-19 Incidence and Outcomes among Patients with Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension and Impact on the Process of Care.

Rationale: Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) typically undergo frequent clinical evaluation. The incidence and outcomes of coronavirus disease (COVID-19) and its impact on routine management for patients with pulmonary vascular disease is currently unknown.Objectives: To assess the cumulative incidence and outcomes of recognized COVID-19 for patients with PAH/CTEPH followed at accredited pulmonary hypertension centers, and to evaluate the pandemic's impact on clinic operations at these centers.Methods: A survey was e-mailed to program directors of centers accredited by the Pulmonary Hypertension Association. Descriptive analyses and linear regression were used to analyze results.Results: Seventy-seven center directors were successfully e-mailed a survey, and 58 responded (75%). The cumulative incidence of COVID-19 recognized in individuals with PAH/CTEPH was 2.9 cases per 1,000 patients, similar to the general U.S. population. In patients with PAH/CTEPH for whom COVID-19 was recognized, 30% were hospitalized and 12% died. These outcomes appear worse than the general population. A large impact on clinic operations was observed including fewer clinic visits and substantially increased use of telehealth. A majority of centers curtailed diagnostic testing and a minority limited new starts of medical therapy. Most centers did not use experimental therapies in patients with PAH/CTEPH diagnosed with COVID-19.Conclusions: The cumulative incidence of COVID-19 recognized in patients with PAH/CTEPH appears similar to the broader population, although outcomes may be worse. Although the total number of patients with PAH/CTEPH recognized to have COVID-19 was small, the impact of COVID-19 on broader clinic operations, testing, and treatment was substantial.

Drug repositioning in pulmonary arterial hypertension: challenges and opportunities.

Despite many advances in medical therapy for pulmonary arterial hypertension (PAH) over the past 20 years, long-term survival is still poor. Novel therapies which target the underlying pathology of PAH and which could be added to current vasodilatory therapies to halt disease progression and potentially reverse pulmonary vascular remodeling are highly sought after. Given the high attrition rates, substantial costs, and slow pace of new drug development, repositioning of "old" drugs is increasingly becoming an attractive path to identify novel treatment options, especially for a rare disease such as PAH. We here summarize the limitations of current PAH therapy, the general concept of repurposing and repositioning, success stories of approved repositioned drugs in PAH as well as novel repositioned drugs that show promise in preclinical models of pulmonary hypertension (PH) and are currently tested in clinical trials. We furthermore discuss various data-driven as well as experimental approaches currently used to identify repurposed drug candidates and review challenges for the "repositioning community" with regards to funding and patent and regulatory considerations, and to illustrate opportunities for collaborative solutions for drug repositioning relevant to PAH.

Intravenous Vitamin C Administered as Adjunctive Therapy for Recurrent Acute Respiratory Distress Syndrome.

This case report summarizes the first use of intravenous vitamin C employed as an adjunctive interventional agent in the therapy of recurrent acute respiratory distress syndrome (ARDS). The two episodes of ARDS occurred in a young female patient with Cronkhite-Canada syndrome, a rare, sporadically occurring, noninherited disorder that is characterized by extensive gastrointestinal polyposis and malabsorption. Prior to the episodes of sepsis, the patient was receiving nutrition via chronic hyperalimentation administered through a long-standing central venous catheter. The patient became recurrently septic with Gram positive cocci which led to two instances of ARDS. This report describes the broad-based general critical care of a septic patient with acute respiratory failure that includes fluid resuscitation, broad-spectrum antibiotics, and vasopressor support. Intravenous vitamin C infused at 50 mg per kilogram body weight every 6 hours for 96 hours was incorporated as an adjunctive agent in the care of this patient. Vitamin C when used as a parenteral agent in high doses acts "pleiotropically" to attenuate proinflammatory mediator expression, to improve alveolar fluid clearance, and to act as an antioxidant.

The Role of Hyperglycemia and Insulin Resistance in the Development and Progression of Pulmonary Arterial Hypertension.

Pulmonary hypertension is a progressive disorder which often leads to right ventricular failure and death. While the existing classification system for pulmonary hypertension does not account for the impact of diabetes mellitus, evidence is emerging that suggests that diabetes is associated with pulmonary hypertension and that diabetes modifies the course of pulmonary hypertension. There is also growing radiographic, hemodynamic, biochemical, and pathologic data supporting an association between diabetes and pulmonary hypertension. More robust epidemiologic studies are needed to confirm an association between diabetes and pulmonary hypertension and to show that diabetes is a disease modifier in pulmonary hypertension. In addition, evaluating the effects of glucose control in animals with pulmonary hypertension and diabetes (as well as in humans) is warranted.

Management of pulmonary vasodilator therapy in patients with pulmonary arterial hypertension during critical illness.

Pulmonary arterial hypertension (PAH) is commonly treated with pulmonary arteriolar vasodilator therapy. When a patient on PAH medication is admitted to intensive care, determining how to manage their medication during the critical illness is often complicated. There may be considerations related to the inability to take medication by mouth, related to acute renal failure or acute liver injury, related to altered mental status or delirium, or related to hypotension and bacteremia. Decisions of how to manage these medications can have a major impact on the patient's clinical course. Presently, provider experience is the major tool in navigating the decisions regarding these medications. In this review, we offer our recommendations of how to manage PAH patients with critical illness who are on PAH medications. These recommendations include how to deliver medications via feeding tubes, how to dose medications in the setting of acute renal failure or acute liver failure, and how to manage medications during hypotension or when a tunneled catheter needs to be removed.

The end-of-life experience for a cohort of patients with pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive and ultimately fatal disease of the pulmonary circulation. There has never been an investigation of the end-of-life symptoms in patients with PAH. In this investigation, we surveyed surrogates of recent decedents with PAH. We evaluate their responses to better understand the end-of-life experience of patients with PAH. METHODS: The survey instrument includes demographic information and the Edmonton Symptoms Assessment Scale. Accredo Therapeutics mailed the survey to surrogates of recent decedents with PAH, and responses were anonymously returned to investigators at Virginia Commonwealth University and used in our descriptive analysis. RESULTS: Of 100 surveys distributed over 24 months (February 2009 to February 2011), we obtained 36 responses (response rate 36%). We found that most patient deaths (90%) were related to PAH, that the majority of patients died in the hospital (67%), with the majority of in-hospital deaths (83%) occurring in intensive care. Palliative care was infrequently involved in patients' care, and many surrogates were unaware of palliative care and hospice services available to the decedents. Patients died with a high symptom burden, especially dyspnea. CONCLUSION: In this cohort, patients with PAH usually died from their disease, often in the hospital setting with a high symptom burden. Further study will be needed to confirm the findings from this study and to better understand the forces leading to the trends uncovered in this investigation.

Epoprostenol use for pulmonary arterial hypertension in the palliative care setting.

Prostacyclin analogues such as epoprostenol (Flolan®) are commonly used in the treatment of pulmonary arterial hypertension (PAH). However, their complex administration and significant cost may limit the access that patients with PAH have to palliative and hospice care. We herein report our experience using epoprostenol in a dedicated palliative care unit and present our inpatient protocol for the drug's administration.