Impact of the COVID-19 pandemic on chronic disease management and patient reported outcomes in patients with pulmonary hypertension: The Pulmonary Hypertension Association Registry

To better understand the impact of the COVID-19 pandemic on the care of patients with pulmonary hypertension, we conducted a retrospective cohort study evaluating health insurance status, healthcare access, disease severity, and patient reported outcomes in this population. Using the Pulmonary Hypertension Association Registry (PHAR), we defined and extracted a longitudinal cohort of pulmonary arterial hypertension (PAH) patients from the PHAR\u27s inception in 2015 until March 2022. We used generalized estimating equations to model the impact of the COVID-19 pandemic on patient outcomes, adjusting for demographic confounders. We assessed whether insurance status modified these effects via covariate interactions. PAH patients were more likely to be on publicly-sponsored insurance during the COVID-19 pandemic compared with prior, and did not experience statistically significant delays in access to medications, increased emergency room visits or nights in the hospital, or worsening of mental health metrics. Patients on publicly-sponsored insurance had higher healthcare utilization and worse objective measures of disease severity compared with privately insured individuals irrespective of the COVID-19 pandemic. The relatively small impact of the COVID-19 pandemic on pulmonary hypertension-related outcomes was unexpected but may be due to pre-established access to high quality care at pulmonary hypertension comprehensive care centers. Irrespective of the COVID-19 pandemic, patients who were on publicly-sponsored insurance seemed to do worse, consistent with prior studies highlighting outcomes in this population. We speculate that previously established care relationships may lessen the impact of an acute event, such as a pandemic, on patients with chronic illness

Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p \u3c 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p \u3c 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p \u3c 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization

Long-term results of the DelIVery for Pulmonary Arterial Hypertension trial

BACKGROUND: The DelIVery for Pulmonary Arterial Hypertension clinical trial was a multi-center, prospective, single arm, Investigational Device Exemption study utilizing a fully implantable, programmable intravascular delivery system consisting of a pump and a catheter for intravenous treprostinil. The study met its primary endpoint and demonstrated that the intravascular delivery system significantly reduced catheter related complications at 22,000 subject-days of follow-up compared with a predefined objective performance criterion. Here we summarize the results obtained during a 6.4-year follow-up period. METHODS: Throughout study follow-up, participants had clinic visits and medication refills at least every 12 weeks (dependent on the subjects\u27 dose). All adverse events and intravascular delivery system complications were evaluated and recorded. RESULTS: Sixty pulmonary arterial hypertension subjects were followed post device implantation for approximately 282 patient-years (range 87 days to 6.4 years). Of the 60 subjects, 14 died (1 related to intravascular delivery system pump failure), 2 withdrew after lung transplants, and 2 withdrew due to pump pocket infection. No catheter-related bloodstream infections, catheter thrombosis or occlusions, or catheter kinks occurred through 282 patient-years. Two participants had adverse events of abdominal pain, rash, due to subcutaneous treprostinil leaks after one catheter puncture and one catheter laceration during pump refill and replacement, respectively. Eight pump failure events occurred: seven pump motor stalls and one early replacement (faulty battery). CONCLUSION: Delivery of treprostinil with an intravascular delivery system is a safe alternative to an external delivery system, while providing enhanced life experiences. To preserve the risk-benefit ratio, treatment at specialized pulmonary arterial hypertension centers is recommended until training is disseminated at other sites

Recommendations for the clinical management of patients receiving macitentan for pulmonary arterial hypertension (PAH): A Delphi consensus document

In patients treated with macitentan (Opsumit®, Actelion Pharmaceuticals Ltd., Basel, Switzerland) for pulmonary arterial hypertension (PAH), prevention and/or effective management of treatment-related adverse events may improve adherence. However, management of these adverse events can be challenging and the base of evidence and clinical experience for macitentan is limited. In the absence of evidence, consensus recommendations from physicians experienced in using macitentan to treat PAH may benefit patients and physicians who are using macitentan. Consensus recommendations were developed by a panel of physicians experienced with macitentan and PAH using a modified Delphi process. Over three iterations, panelists developed and refined a series of statements on the use of macitentan in PAH and rated their agreement with each statement on a Likert scale. The panel of 18 physicians participated and developed a total of 118 statements on special populations, add-on therapy, drug-drug interactions, warnings and precautions, hospitalization and functional class, and adverse event management. The resulting consensus recommendations are intended to provide practical guidance on real-world issues in using macitentan to treat patients with PAH

Genotype-phenotype correlations in children with HHT

Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes

Riociguat: Clinical research and evolving role in therapy

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud\u27s phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension

Endothelial FGF signaling is protective in hypoxia-induced pulmonary hypertension

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-β signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-β pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-β signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH

Disease characteristics, treatments, and outcomes of patients with pulmonary arterial hypertension treated with selexipag in real-world settings from the SPHERE registry (SelexiPag: tHe usErs dRug rEgistry)

BACKGROUND: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients. METHODS: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or \u3e60 days, respectively, before enrollment. RESULTS: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), of whom 55.6% were World Health Organization functional class (FC) 3/4; 57.3% were intermediate or high risk per Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0. In patients with pulmonary arterial hypertension, 18-month discontinuation rates for adverse events were 22.0%, 32.0%, and 11.9%, and 18-month survival rates were 89.4%, 84.2%, and 94.5% in the overall, newly, and previously initiated patient populations, respectively. From baseline to month 18, most patients had stable or improved FC and stable or improved REVEAL 2.0 risk category status. Discontinuation for adverse events, hospitalization, and survival were similar regardless of patients\u27 individually tolerated selexipag maintenance dose. No new safety signals were identified. CONCLUSIONS: In this real-world analysis of patients initiating selexipag, most patients had stable or improved FC and REVEAL 2.0 risk category. Similar to the GRIPHON trial, outcomes with selexipag in this real-world study were comparable across maintenance dose strata, with no new safety signals

Mortality in pulmonary arterial hypertension in the modern era: Early insights from the Pulmonary Hypertension Association Registry

Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan-Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment-naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44-68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow-up time of 489 days (281-812 days). The 1-, 2-, and 3-year mortality was 8% (95% CI, 6%-10%), 16% (95% CI, 13%-19%), and 21% (95% CI, 17%-25%), respectively. When stratified into low-, intermediate-, and high-risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment-naïve patients, initial combination therapy was associated with better 1-year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19-0.95]

Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension

Background: Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. Methods: AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to oncedaily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. Results: This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42 (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. Conclusions: Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe