Sahay, Sandeep

ABSTRACTPortopulmonary hypertension (PoPH), a type of pulmonary arterial hypertension (PAH) in patients with liver disease, is associated with high morbidity and mortality. The relationship between cardiopulmonary hemodynamics, PAH therapy, and survival in PoPH remains unclear. We performed a retrospective cohort study of PoPH patients from the international pulmonary hypertension (PH) meta‐registry, PVRI GoDeep. PAH was defined by a mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance (PVR) > 2 Wood Units. PoPH diagnoses were assigned by each center's PH specialist based on international guidelines at the time of enrollment. 246 incident PoPH patients met eligibility criteria and were included in the analysis, equally split between males (51%) and females (49%), with a median age of 54 years. When compared to both patients with IPAH and those with other subtypes of PAH (not classified as PoPH or IPAH), those with PoPH had significantly lower 5‐year survival rates (46% vs. 68% vs. 65%, log‐rank p < 0.001). Amongst the PoPH patients, however, there was no significant difference in 5‐year survival when dichotomized by disease severity, either by a PVR of 5 Wood Units or a CI of 2.5 L/min/m2. Treatment of the PoPH patients with PAH‐targeted therapies was associated with significantly higher 5‐year survival rates compared to those not receiving such treatments, as shown by Kaplan–Meier analysis. This survival benefit was observed for PDE5i (50% vs. 34%, log‐rank p = 0.029), ERA (58% vs. 34%, log‐rank p < 0.001), and the combination of PDE5i and/or ERA (51% vs. 22%, log‐rank p < 0.001), as well as any PAH‐targeting treatment (50% vs. 26%, log‐rank p = 0.007). Corresponding survival advantage was noted when including only PoPH patients with MELD Score ≥ 13. PoPH is a disease with significantly worse long‐term survival than other PAH subtypes, but targeted PAH therapy is associated with a robust survival benefit. Survival did not differ across high‐risk PVR and cardiac index thresholds, suggesting the factors that influence prognosis and survival in PoPH may be unique as compared to other PAH subtypes, and warrant further investigation.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

Abstract Pulmonary hypertension is a complex and irreversible pulmonary vascular disease with a significant impact on patients’ lives. Pulmonary hypertension is categorized into five groups according to its etiology. Frailty is a multifaceted disorder that leads to physical, social, cognitive, and psychological decline. Several studies have linked a high occurrence of frailty to heart failure and chronic lung diseases, but the prevalence and impact of frailty in pulmonary arterial hypertension (PAH) remain largely unexplored. At the molecular level, inflammation, oxidative stress, cellular senescence, and mitochondrial dysfunction play pivotal roles in the pathophysiology of frailty in pulmonary hypertension. Dysfunction of cardiac, respiratory, and skeletal muscles results in exercise intolerance, which promotes deconditioning and frailty. Exercise training in PAH, heart failure, and chronic lung disease has shown promise in improving quality of life, exertion tolerance, and frailty scores. Properly designed studies are needed to elucidate the predictive value of frailty and to identify assessment and treatment tools in pulmonary hypertension, particularly PAH, to aid clinicians in individualizing care plans and improving patient outcomes. In this narrative review, we describe the pathobiology of frailty in pulmonary hypertension, assessment tools, the impact of frailty on different pulmonary hypertension groups, and suggestions for potential interventions.

Purpose: New 2022 European Society of Cardiology/European Respiratory Society PAH guidelines recommend treatment guided by a multi-parameter risk assessment. 1 Patients with low/intermediate risk without cardiopulmonary comorbidities should start dual PAH combination therapy; those with cardiopulmonary comorbidities should be reassessed early for rapid escalation to dual therapy. Initial triple therapy is recommended for high-risk patients. We examined use of dual and triple PAH therapy in the US (before guideline update). Methods: We used the Pulmonary Hypertension Association Registry (PHAR), a prospective US registry of pulmonary hypertension (PH) patients, enrolled within 6 months of their first outpatient visit at one of 54 participating PH care centers in the US, between Sep 2015-Jun 2022. We included adults (≥18 years at enrollment) with incident PAH (newly diagnosed and treated within 6 months of enrollment) and ≥1 follow-up clinic visit post baseline visit. Chronic thromboembolic PH patients were excluded. Results: We analyzed (descriptive statistics) 794 incident patients (baseline characteristics in Table 1). Treatment patterns at baseline (n=794)/last follow-up visit (n=610) were 289 (36.4%)/102 (16.7%) on monotherapy, 419 (52.8%)/314 (51.5%) on dual combination, 83 (10.5%)/179 (29.3%) on triple combination therapy, respectively. Mean time from enrollment to dual and triple combination therapy was 86.1 (standard deviation [SD]: 209.0) and 346.1 days (SD: 430.8), respectively. Conclusions: Among incident PHAR patients, half received initial dual and 10% triple upfront combination therapy. At last follow-up, most (>80%) patients had escalated to dual/triple combination therapies. Clinical Implications: At PH care centers, most incident PHAR patients are escalated to dual and triple therapy (at last follow-up) per current guidelines. Reference 1. Humbert M, et al. Eur Heart J. 2022;43:3618-731.

Abstract The INSPIRE trial was a Phase 3, open‐label, multicenter trial (LTI‐301) that enrolled patients with pulmonary arterial hypertension (PAH) ≥ 18 years of age who transitioned to Yutrepia from nebulized treprostinil (Transition) or added Yutrepia to prostacyclin naïve patients on ≤2 nonprostacyclin oral therapies. The objectives of the trial were to evaluate the safety and tolerability of Yutrepia (dry‐powder formulation of treprostinil) in patients with PAH. The primary safety measures were the incidence of adverse events (AEs) and serious AEs. Exploratory efficacy measures were also assessed during the trial. Transition patients initiated Yutrepia at a dose comparable to their nebulized treprostinil dose while prostacyclin naïve patients received 26.5‐mcg QID; up‐titration in 26.5‐mcg increments was permitted for both groups. A total of 121 patients were enrolled, of which 29 patients discontinued from the trial, with the most common reason being AEs. Eighty percent of the Transition group and 96% of the prostacyclin naïve group titrated to a dose ≥79.5 mcg QID at Day 360, respectively, with one patient achieving a dose of 212‐mcg QID. The most common AEs were cough, headache, upper respiratory tract infection, dyspnea, dizziness, throat irritation, diarrhea, chest discomfort, fatigue, and nasopharyngitis. Most of these events were considered treatment‐related though mild to moderate in severity and expected for prostacyclin therapy administered by inhalation. In an evaluation of exploratory efficacy measures, patients remained stable or improved over the 1 year of treatment. Yutrepia was found to be a convenient, safe, and well‐tolerated inhaled prostacyclin treatment option for PAH patients.