Pulmonary Arterial Hypertension Drugs Research Articles

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions.

Therapeutic Use of an Inhaled Drug Delivery in Pulmonary Hypertension: A Review.

Pulmonary arterial hypertension (PAH) is a seriouscondition in which there is increased blood pressure in arteries of the lungs (pulmonary arteries). The therapies or drugs for PAH have expanded with the revelation of three key pathological processes - encompassing prostacyclin, nitric oxide (NO), and endothelin pathways. An outlook for patients suffering from PAH is still mediocre amidst recent advancements. The evolution of pre-clinical and clinical research on PAH has facilitated the identification of several new targeted therapies for the disease. In this article, we examine recent data on new pulmonary hypertension physiological pathways, primarily concentrating on administering drugs through the inhalation route and their effects. Although they have been given clinical use approval, medications based on these routes are presently being studied in clinical or pre-clinical settings. To confirm these innovative medicines' therapeutic efficacy and safety, extensive clinical trials are needed.

Quinazoline-based human phosphodiesterase 5 inhibitors exhibited a selective vasorelaxant effect on rat isolated pulmonary arteries involving NO-sGC-cGMP pathway and calcium inhibitory effects

Phosphodiesterase 5 (PDE5) inhibitors are an attractive option among the currently available therapies in the management of pulmonary arterial hypertension (PAH). Good selectivity for PDE5 is associated with reduced side effects and greater vasorelaxant effect on pulmonary arteries (PA). This study investigated the vasorelaxant effects of a series of quinazoline-based PDE5 inhibitors and their precise mechanisms action using rat isolated PA and aorta, as compared to sildenafil. Their effects on rat hepatocytes (viability and CYP activities) were also evaluated. Compounds 5 and 11 displayed lower human PDE5 IC50 of the analogs studied here and induced a greater relaxant effect on PA (EC50 0.94 ± 0.30 and 1.03 ± 0.23 μM, respectively). As compared to sildenafil (EC50 = 0.05 ± 0.02 μM on PA), the relaxant effect of 5 and 11 on PA was lower but their selectivity for PA compared to aorta was higher. The effects of 5 and 11 were reduced by NG-nitro-L-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, but not by indomethacin or potassium channels blockers. They also enhanced the relaxant effect of sodium nitroprusside, and inhibited extracellular Ca2+ influx and intracellular Ca2+release. Compounds 5 and 11 did not reduce hepatocyte viability except at concentration > 10 μM, inhibited CYP3A at 10 μM, like sildenafil, but did not induce CYP1A. In conclusion, this study identified 2 quinazoline analogues with good PDE5 inhibitory activity and good selectivity for the pulmonary vasculature. Their relaxant effect involves both the potentiation of nitric oxide-sGC-cGMP pathway and calcium inhibition. These compounds are potential leads for developing new drugs for PAH.

The role of exercise right heart catheterization to guide pulmonary hypertension therapy in older adults.

The spectrum of patients referred for suspected pulmonary arterial hypertension (PAH) includes a population with clinical features suggestive of pulmonary hypertension due to left heart disease (PH‐LHD). Even after right heart catheterization (RHC) performed at rest, it can be a challenge to identify patients who will clearly benefit from PAH drug therapy. Therefore, the objective of this study was to evaluate the role of exercise RHC to influence decisions regarding prescription of PAH drug therapy in this population. A retrospective cohort study was conducted of older adults with risk factors for PH‐LHD and suspected PH referred for exercise RHC. One year follow‐up was conducted to record clinical outcomes, all changes in PAH drug therapy, and changes in patient‐reported quality of life. The final cohort included 61 patients, mean age of 69 ± 10; 44% and 34% had a history of coronary artery disease and atrial fibrillation respectively. Exercise changed the proportional breakdown of hemodynamic diagnoses from 36% No PH, 44% PAH, and 20% PH‐LHD at rest to 15% No PH, 36% PAH, and 49% PH‐LHD. Although a significant proportion of patients were reclassified as PH‐LHD, there was an overall increase in the proportion of patients receiving PAH drug therapy, particularly for those with PAH confirmed by exercise RHC. A total of 11 PAH drug prescriptions were employed before exercise RHC increasing to 24 after (p = 0.002). Patients receiving PAH therapy demonstrated significant improvement in self‐reported quality of life. Exercise RHC appeared to influence selection of PAH drug therapy.

Introducing novel hybridization technique for solubility enhancement of Bosentan formulation

Bosentan is choice of drug for pulmonary arterial hypertension. It belongs to BCS class-II category. Due to poor solubility in aqueous media, treatment leads to frequent dosing & increasing cost of therapy subsequently. One cannot unseen the shortcomings of commonly existing solubility enhancement techniques such as physical and chemical modifications of the drug, salt formation, solid dispersion, complexation because of the need for sophisticated equipment, decreased yield, incomplete removal of organic solvents, etc. The novel hybridization technique is a fusion of complexation and liquisolid technique. In this research work, Bosentan was complexed with captisol in the first step. In the second step, the complex was dispersed in non-volatile solvent & mixed with the carrier using mortar-pestle followed by the addition of coating material to form a free-flowing powder. It was then compressed into tablets by mixing with other excipients. The formulation was characterized by phase solubility study, DSC, FTIR, and XRD to confirm drug-excipients compatibility, crystallinity etc. The phase solubility study showed ∼28.85 fold increase in solubility. From screening, Avicel PH101 & Parteck SLC 500 as carrier and coating material respectively & PEG-600 as non-volatile solvent were selected. Explotab as super-disintegrant and Pearlitol 100SD as direct compressible excipient were used. Optimization by 32 factorial design gave Bosentan tablet with disintegrate in time of 7–8 min and showed 87.264±0.823% drug release in 30 min higher than marketed tablet i.e. 61.750±1.226%. From the stability study, the Novel hybridization technique was proved as a choice for solubility enhancement.

FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.

The proliferation, migration and apoptotic resistance of pulmonary artery smooth muscle cells (PASMCs) are central to the progression of pulmonary arterial hypertension (PAH). Our previous study identified that fibroblast growth factor 21 (FGF21) regulates signalling pathway molecules, such as peroxisome proliferator‐activated receptor gamma (PPARγ), to play an important role in PAH treatment. However, the biological roles of miRNAs in these effects are not yet clear. In this study, using miRNA sequencing and real‐time PCR, we found that FGF21 treatment inhibited miR‐130 elevation in hypoxia‐induced PAH in vitro and in vivo. Dual luciferase reporter gene assays showed that miR‐130 directly negatively regulates PPARγ expression. Inhibition of miR‐130 expression suppressed abnormal proliferation, migration and apoptotic resistance in hypoxic PASMCs, and this effect was corrected upon PPARγ knockdown. Both the ameliorative effect of FGF21 on pulmonary vascular remodelling and the inhibitory effect on proliferation, migration and apoptotic resistance in PASMCs were observed following exogenous administration of miR‐130 agomir. In conclusion, this study revealed the protective effect and mechanism of FGF21 on PAH through regulation of the miR‐130/PPARγ axis, providing new ideas for the development of potential drugs for PAH based on FGF21.

A Review of Pulmonary Arterial Hypertension Treatment in Extracorporeal Membrane Oxygenation: A Case Series of Adult Patients.

Little data is published describing the use of medications prescribed for pulmonary arterial hypertension (PAH) in patients receiving extracorporeal membrane oxygenation (ECMO). Even though many patients with PAH may require ECMO as a bridge to transplant or recovery, little is reported regarding the use of PAH medications in this setting. This retrospective case series summarizes the clinical experience of 8 patients with PAH receiving ECMO and reviews medication management in the setting of ECMO. Eight PAH patients, 5 of whom were female, ranging in age from 21 to 61 years old, were initiated on ECMO. Veno-arterial (VA) ECMO was used in 4 patients, veno-venous (VV) ECMO and hybrid ECMO configurations in 2 patients respectively. Common indications for ECMO included cardiogenic shock, bridge to transplant, and cardiac arrest. All patients were on intravenous (IV) prostacyclin therapy at baseline. Refractory hypotension was noted in 7 patients of whom 5 patients required downtitration or discontinuation of baseline PAH therapies. Three patients had continuous inhaled epoprostenol added during their time on ECMO. In patients who were decannulated from ECMO, PAH therapies were typically resumed or titrated back to baseline dosages. One patient required no adjustment in PAH therapy while on ECMO. Two patients were not able to be decannulated from ECMO. The treatment of critically ill PAH patients is challenging given a variety of factors that could affect PAH drug concentrations. In particular, PAH patients on prostacyclin analogues placed on VA ECMO appear to have pronounced systemic vasodilation requiring vasopressors which is alleviated by temporarily reducing the intravenous prostacyclin dose. Patients should be closely monitored for potential need for rapid titrations in prostacyclin therapy to maintain hemodynamic stability.

654 Fragility of functional/symptomatic endpoints to assess the efficacy of drugs for pulmonary arterial hypertension

Abstract Aims Drugs for pulmonary arterial hypertension (PAH) have historically been evaluated for their efficacy in improving functional capacity and decreasing symptoms. However, these measures of treatment effect are approximate and subject to substantial variability, and therapeutic choices based on them may be aleatory. Methods and results We reviewed the articles reporting the results of phase 3 PAH randomized controlled trials (RCTs) and calculated the fragility index (FI) for the outcomes exploring functional capacity and symptoms. The FI corresponds to the number of events that need to be added to the arm with the smallest number of events to make a significant result non-significant: the lower the FI, the fragile the trial with respect to the endpoint examined. For RCTs with non-significant results, we calculated the FI as the number of events that need to be removed from the investigational drug (ID) group to reach a P-value <0.05. When possible, we also computed the FI for PAH hospitalization. Data about the rate of functional/symptomatic improvement were available for 22 (63%) of 35 RCTs (Table). The ID was superior to placebo or comparator with P < 0.05 in 10 (45%) of these 22 studies. The median FI was 2 [interquartile range (IQR): 6.5], with 4 RCTs having a FI = 1 and only 2 > 10 (Table). For the 12 RCTs in which the effect of the ID was neutral (P > 0.05), the median FI was 6 (IQR 4.25) (Table). The hospitalization FI was determined for 17 (77%) of the 22 RCTs and was overall higher than the one for the functional/symptomatic outcome (median 6, IQR 8). Conclusions Accessible information about the effects of PAH drugs on functional capacity and/or symptoms is published for 6 in 10 RCTs, in which very few events in one arm could have flipped the results from non-significant to significant or, more remarkably, from significant to non-significant. The evidence supporting the reduction of PAH hospitalizations as a treatment goal appears to be more robust.

380 Left heart disease phenotype and use of pulmonary vasodilators in elderly patients with pulmonary arterial hypertension: the Patriarca registry

Abstract Aims The prevalence of occult left heart disease (LHD) and the feasibility of vasodilator therapy in the progressively growing population of elderly subjects with pulmonary arterial hypertension (PAH) are under scrutiny. We evaluated the presence of a LHD phenotype and the patterns of vasodilator treatment in such patients. Methods and results The PATRIARCA registry collected cross-sectional data from 180 subjects with PAH or chronic thromboembolic pulmonary hypertension and ≥70 years of age in 11 Italian centres between 1 December 2019 and 15 September 2020. After excluding patients with CTEPH or incomplete follow-up haemodynamic parameters, 77 individuals with PAH diagnosed at ≥ 65 years of age according to current guidelines were included in the analysis. A LHD phenotype was defined as follows, expanding the criteria adopted in the AMBITION trial: (i) ≥3 among body mass index ≥30 kg/m2, systemic hypertension, diabetes, and significant coronary artery disease; (ii) 2 of the risk factors for LHD above and ≥1 among permanent atrial fibrillation, left ventricular (LV) hypertrophy, LV ejection fraction <50%, at least moderate mitral or aortic valve disease, and left atrial dilation; (iii) pulmonary vascular resistance (PVR) between 3 and 3.75 WU or PVR between 3.75 and 6.25 WU in the presence of a pulmonary artery wedge pressure (PAWP) of 13–15 mmHg. Forty-one (53%) patients had a LHD phenotype according to the most recent clinical and haemodynamic evaluation, which was performed 16 (4–35) months after diagnosis (Figure). As per definition, they had higher rates of comorbidities and more often echocardiographic signs of LHD (not shown). The frequency of NYHA classes I–II was comparable between the two groups, while the 6 min-walking distance tended to be lower in subjects with a LHD phenotype than in those without (Figure, left panel). Furthermore, these latter had lower PVR and higher PAWP. No differences were seen in treatment with pulmonary vasodilators, with around 50% of patients receiving double oral combination therapy in both groups (Figure, right panel). During the study period, 7 (17%) and 4 (11%) patients died in the LHD and no-LHD groups, respectively (P = 0.40). Conclusions In this real-world cohort of elderly patients, a LHD phenotype was common despite an initial haemodynamic diagnosis of PAH. However, it did not appear to cause simplification or discontinuation of pulmonary vasodilator therapy. Longitudinal studies are needed to determine whether and how a LHD phenotype affects the use and effects of PAH drugs in the elderly.

Abstract 13113: Fragility of Functional/Symptomatic Endpoints to Assess the Efficacy of Drugs for Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) drugs have historically been evaluated for the effects on functional capacity and symptoms. However, these assessments are approximate and the ensuing therapeutic choices may be aleatory. Methods: We reviewed the articles describing phase 3 PAH randomized controlled trials (RCTs) and calculated the fragility index (FI) for the outcomes exploring functional capacity and symptoms. For RCTs with a significantly different outcome rate between the investigational drug (ID) and placebo/comparator arms, the FI corresponded to the number of events that needed to be added to the arm with the smallest number of events to made the RCT result non-significant. For RCTs with non-significant results (neutral), the FI was the number of events that needed to be removed from the ID group to reach a p value <0.05. In general, the lower the FI, the fragile the RCT with respect to the endpoint examined. When possible, we also computed the FI for PAH hospitalization. Results: Data about the rate of functional/symptomatic improvement were available for 22 RCTs (Table). The ID was superior to placebo/comparator with p <0.05 in 10 (45%) of these studies. The median FI was 2 (IQR 6.5), with 4 RCTs having a FI = 1 and only 2 a FI >10. For the 12 RCTs in which the effect of the ID was neutral, the median FI was 6 (IQR 4.25). No correlation was found between FI and sample size or year of publication for either significant (R = 0.57, p = 0.08 and R = 0.23, p = 0.52, respectively) or neutral (R = 0.51, p = 0.09 and R = -0.18, p = 0.58) RCTs. The hospitalization FI was determined for 17 (77%) of the 22 RCTs and was overall higher than the one for functional/symptomatic outcomes (median 6, IQR 8) (Table). Conclusions: Very few events in one arm could have flipped the results of PAH RCTs from non-significant to significant or, more remarkably, from significant to non-significant. The evidence supporting the reduction of PAH hospitalizations as a treatment goal appears to be more robust.

Pulmonary hypertension associated with busulfan.

Busulfan is widely used to treat malignant diseases, particularly for therapeutic intensification prior to an autologous stem cell graft. Numerous side effects consecutive to busulfan are described, but few descriptions of pulmonary hypertension exist, while bronchiolitis obliterans remains a rare complication. We report the clinical observations of four patients from the French Pulmonary Hypertension Registry who experienced subacute pulmonary hypertension after receiving busulfan as preparation regimen before an autologous stem cell graft for malignancies (Hodgkin’s disease, Ewing’s sarcoma and primary large B cell lymphoma of the brain). Patients experienced severe pulmonary arterial hypertension 2 to 4.5 months after busulfan administration. Pulmonary hypertension improved after treatment with approved drugs for pulmonary arterial hypertension and/or corticosteroids. During the follow-up period, two patients developed chronic respiratory insufficiency due to interstitial lung disease, leading to double lung transplantation. The pathological assessment of explanted lungs revealed interstitial lung fibrosis with advanced bronchiolar lesions and severe pulmonary vascular damage. Three of the four patients were still alive after 36 to 80 months and the fourth died unexpectedly and suddenly after 5 months. In conclusion, PAH is a rare but severe complication associated with busulfan chemotherapy in adults. Histological examinations provide evidence for diffuse pulmonary vascular damage combined with interstitial lung injury in most cases.

Treatment of pulmonary arterial hypertension in children.

Pulmonary arterial hypertension (PAH) is a devastating illness causing already significant morbidity in childhood. Currently approved treatment options for children comprise the endothelin receptor antagonist bosentan, as well as the phosphodiesterase-5 inhibitor sildenafil. But PAH treatment has advanced significantly over the past decade, and new classes of targeted drug therapies, such as stimulators of the soluble guanylate cyclase (riociguat) or prostacyclin receptor agonists (selexipag), are currently evaluated regarding their efficacy and safety in children, in order to limit off-label use. Due to the different etiologies in children, such as PAH-CHD, there is no evidence that initial combination therapy in children is superior to a mono-therapy with respect to survival. Special attention should also be paid to the pharmacology of PAH drugs in children, which might be impacted by ontogeny or drug-drug-interactions. Therapeutic drug monitoring may be useful in pediatric patients. There is a clear need for more controlled studies of PAH medications, alone or in combination therapy in the pediatric age group. Data from clinical trials as well as from patient registries should be pooled to optimize drug development and evaluation, trial design, and evidence-based pharmacotherapy in pediatric patients with PAH. In this review, the current treatment options of pediatric PAH are summarized, and an overview of new treatment concepts, which are already evaluated in adults, is presented.

Network module-based drug repositioning for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling leading to increased pulmonary vascular resistance and pulmonary arterial pressure. PAH is a highly morbid cardiopulmonary disease adversely affecting lifespan and quality of life. Despite increased awareness and advances of medical therapies in recent decades, long‐term prognosis and survival remain poor for patients with PAH. Novel therapies that can target the underlying pathobiology of PAH and reverse pulmonary vascular remodeling are clearly needed. In this study, we develop a network module‐based framework to examine potential drug repositioning for PAH. The rationale for this approach is that in order to have therapeutic effects, the targets of potential drugs must be significantly proximate to the disease module of interest in the human protein‐protein interactome. Based on 15 existing drugs for treating PAH, our framework integrates drug‐drug interactions, drug‐drug chemical similarity, drug targets, and PAH disease proteins into the human interactome, and prioritizes candidate drugs for PAH. We identified 53 drugs that could potentially be repurposed for PAH. Many of these candidates have strong literature support. Compared to black‐box‐like machine learning models, network module‐based drug repositioning can provide mechanistic insights into how repositioned drugs can target the underlying pathobiological mechanisms of PAH.

Integrated bioinformatic analysis reveals the underlying molecular mechanism of and potential drugs for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease without a clear mechanism or drugs for treatment. Therefore, it is crucial to reveal the underlying molecular mechanism and identify potential drugs for PAH. In this study, we first integrated three human lung tissue datasets (GSE113439, GSE53408, GSE117261) from GEO. A total of 151 differentially expressed genes (DEGs) were screened, followed by KEGG and GO enrichment analyses and PPI network construction. Five hub genes (CSF3R, NT5E, ANGPT2, FGF7, and CXCL9) were identified by Cytoscape (Cytohubba). GSEA and GSVA were performed for each hub gene to uncover the potential mechanism. Moreover, to repurpose known and therapeutic drugs, the CMap database was retrieved, and nine candidate compounds (lypressin, ruxolitinib, triclabendazole, L-BSO, tiaprofenic acid, AT-9283, QL-X-138, huperzine-a, and L-741742) with a high level of confidence were obtained. Then ruxolitinib was selected to perform molecular docking simulations with ANGPT2, FGF7, NT5E, CSF3R, JAK1, JAK2, JAK3, TYK2. A certain concentration of ruxolitinib could inhibit the proliferation and migration of rat pulmonary artery smooth muscle cells (rPASMCs) in vitro. Together, these analyses principally identified CSF3R, NT5E, ANGPT2, FGF7 and CXCL9 as candidate biomarkers of PAH, and ruxolitinib might exert promising therapeutic action for PAH.

Off-label use of PAH-targeted medications approved for adults and their financial coverage by health insurances are vital for children with pulmonary hypertension.

Pulmonary hypertension (PH), and especially pulmonary arterial hypertension (PAH), are chronic, progressive, and fatal conditions for which - apart from bilateral lung transplantation - there is currently no cure. However, recently developed, so-called "targeted" ("advanced") PAH medications, are now approved for adult PAH, and have improved quality of life and survival of affected children and adults. In 2020, two prospective pediatric observational studies on add-on macitentan and selexipag, respectively, have been published. Due the lack of approved pediatric PAH-medications, the well-founded rationale for combination therapy in childhood, and the absence of serious adverse effects, advanced pharmacotherapy should not be withheld from young PH patients. Such an "off-label use" of PAH-targeted medications in children with PH, and its financial reimbursement by health insurances, are urgently needed. The decision on the specific, vasoactive pharmacotherapy should be made by a PH expert with sufficient experience in the diagnosis and treatment of children with PH - followed by close out-patient monitoring. Combination pharmacotherapy should include the option of combining drugs of all substance classes (phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, drugs targeting prostacyclin pathways, and calcium channel blockers in select cases) - including "off-label, pediatric drug formulations". Neither the lack of approval for modern PAH drugs directed against PAH nor the limited evidence-based study data available for children, should preclude PH expert centers to offer these therapies early and in combination to young patients with progressive PH, in order to improve exercise capacity, quality of life, and survival.

Systematic review and cost-effectiveness of bosentan and sildenafil as therapeutic drugs for pediatric pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease in children, with significant mortality. Because of the limited research on pediatric PAH, first, systematic review of related drugs is conducted, and then economic evaluation of PAH drug treatment programs is conducted, which to provide a reference for the choice of more cost-effective treatment options. The search includes electronic databases such as Pubmed, ScienceDirect, and Embase. Through inclusion and exclusion criteria, screen high-quality randomized controlled trials. We used TreeAge Pro 2011 software to construct the markov model, that to simulate the total medical cost and quality-adjusted life years (QALYs), and to calculate the incremental cost-effectiveness ratio. Sensitivity analysis of transfer probability, utility, and cost was carried out. Incorporate two studies that meet the criteria, one compared the therapeutic effects of bosentan and placebo on pediatric PAH, the other compared therapeutic effects of sildenafil and placebo on pediatric PAH, both articles were of good quality. Compared with the sildenafil group (3.38QALYs and $161,120.14), the QALY of the bosentan treatment group (3.33QALYs and $257,411.29) was reduced by 0.05, and the cost increased by $96,291.15. The estimated improvement to quality of life and reduced costs result in an estimate of economic dominance for sildenafil over bosentan. This dominant result persisted probabilistic analyses. Based on this model, a more cost-effective treatment drug for PAH in children is sildenafil.

Monotherapy in patients with pulmonary arterial hypertension at four German PH centres

BackgroundAlthough combination therapy is the gold standard for patients with pulmonary arterial hypertension (PAH), some of these patients are still being treated with monotherapy.MethodsWe conducted a retrospective analysis at four German PH centres to describe the prevalence and characteristics of patients receiving monotherapy.ResultsWe identified 131 incident PAH patients, with a mean age of 64 ± 13.8 years and a varying prevalence of comorbidities, cardiovascular risk factors and targeted therapy. As in other studies, the extent of prescribed PAH therapy varied with age and coexisting diseases, and younger, so-called “typical” PAH patients were more commonly treated early with combination therapy (48% at 4–8 months). In contrast, patients with multiple comorbidities or cardiovascular risk factors were more often treated with monotherapy (69% at 4–8 months). Survival at 12 months was not significantly associated with the number of PAH drugs used (single, dual, triple therapy) and was not different between “atypical” and “typical” PAH patients (89% vs. 85%).ConclusionAlthough “atypical” PAH patients with comorbidities or a more advanced age are less aggressively treated with respect to combination therapy, the outcome of monotherapy in these patients appears to be comparable to that of dual or triple therapy in “typical” PAH patients.

Outcomes of patients with decreased arterial oxyhaemoglobin saturation on pulmonary arterial hypertension drugs.

Drugs approved for the treatment of pulmonary arterial hypertension (PAH) improve long-term outcomes. These drugs have pulmonary vasodilator properties which may potentially cause a decrease in arterial oxyhaemoglobin saturation (S aO2 ) in some patients. The present retrospective study of the French Pulmonary Hypertension Registry aimed to describe the clinical characteristics and outcomes of patients showing a ≥3% decrease in S aO2 while treated with PAH drugs. We reviewed 719 PAH patients. The exclusion criteria were PAH associated with congenital heart disease and PAH with overt features of venous/capillaries involvement. 173 (24%) patients had a ≥3% decrease in S aO2 . At diagnosis, they were older with a lower diffusing capacity of the lung for carbon monoxide and a shorter 6-min walk distance compared with those who did not display a ≥3% decrease in S aO2 . The percentage of patients meeting the European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria at re-evaluation was significantly lower in those with a ≥3% decrease in S aO2 and more patients started long-term oxygen therapy in this group (16% versus 5%; p<0.001). A ≥3% decrease in S aO2 was associated with a poorer survival (hazard ratio 1.81, 95% CI 1.43-2.34; p<0.0001). In a multivariate Cox analysis, a ≥3% decrease in S aO2 was a prognostic factor independent of age at diagnosis and ESC/ERS risk stratification at follow-up. When treated with PAH drugs, a large subset of patients experience a ≥3% decrease in S aO2 , which is associated with worse long-term outcomes and reduced survival.

Protective effect of baicalin against pulmonary arterial hypertension vascular remodeling through regulation of TNF-α signaling pathway.

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease with high mortality. However, there were no efficient medical drugs for PAH to enormously improve the survival and quality of life measures. The present study aimed to explore the protective effect of baicalin against experimental PAH in vivo and vitro. All the experimental rats received intraperitoneal injection of monocrotaline (MCT) to induce PAH model. Baicalin was given by intragastric administration from 2 days after MCT injection. Forty animals were randomly divided into four groups: Control, MCT, saline‐, and baicalin‐treated groups (n = 10 in each). Post‐operation, hemodynamic data, and index of right ventricular hypertrophy (RVHI) were recorded to evaluate the inhibition of baicalin on MCT‐induced PAH. Furthermore, pulmonary artery smooth muscle cells (PASMCs) model induced by tumor necrosis factor‐α (TNF‐α) was used to observe the inhibition of vascular cells proliferation in vitro. The results demonstrated that baicalin significantly attenuated MCT‐induced right ventricular systolic pressure (RVSP), the index of right ventricular hypertrophy, and vessel wall thickness; inhibit inflammatory and cell proliferation induced by MCT or TNF‐α, respectively. In addition, we found that baicalin might protect against experimental PAH via regulating the TNF‐α/BMPR2 signaling pathway.

Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.

Background:The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.Methods:Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan–Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.Results:Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12–47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.Conclusion:Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings. The reviews of this paper are available via the supplemental material section.