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 >60 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' 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.

Pulmonary arterial hypertension nanotherapeutics: New pharmacological targets and drug delivery strategies.

Pulmonary arterial hypertension (PAH) is a rare, serious, and incurable disease characterized by high lung pressure. PAH-approved drugs based on conventional pathways are still not exhibiting favorable therapeutic outcomes. Drawbacks like short half-lives, toxicity, and teratogenicity hamper effectiveness, clinical conventionality, and long-term safety. Hence, approaches like repurposing drugs targeting various and new pharmacological cascades and/or loaded in non-toxic/efficient nanocarrier systems are being investigated lately. This review summarizes the status of conventional, repurposed, either in vitro, in vivo, and/or in clinical trials of PAH treatment. In-depth description, discussion, and classification of the new pharmacological targets and nanomedicine strategies with a description of all the nanocarriers that showed promising efficiency in delivering drugs are discussed. Ultimately, an illustration of the different nucleic acids tailored and nanoencapsulated within different types of nanocarriers to restore the pathways affected by this disease is presented.

Treprostinil Effectiveness in Higher-Risk Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension.

BACKGROUND: Little is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy. METHODS: Children with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort. Those who received only oral medications were included as the reference cohort. All patients in the study cohort received PAH-related genotyping. Survival was defined as no death. Event-free survival was defined as no death, Potts shunt, or atrial septostomy. RESULTS: Forty-nine children (median age 7.7 years [interquartile range (IQR) 4.2-11.5 years], 65% female) were included in the study cohort and 48 children were included in the reference cohort; 84% of the study cohort had genetic disorders after genetic testing with a dominance of BMPR2 and ACVRL1 mutations. After a median therapy duration of 5.56 months (IQR 2.66-11.12 months), all patients were alive with significant improvements in clinical characteristics. One-, 2-, and 3-year survival rates were 91%, 84%, and 69%, respectively with a median follow-up duration of 19.17 months (IQR 9.7-29.79 months), which was significantly superior to the reference cohort (P = 0.038). Multivariate Cox regression analysis identified World Health Organisation functional class after therapy as a predictor for survival. There was no significant difference in survival among patients with different genotypes. CONCLUSIONS: Treprostinil can significantly improve the prognosis in children with IPAH/HPAH who are at higher risk, despite genetic backgrounds.

Adult-onset idiopathic peripheral pulmonary artery stenosis.

BACKGROUND: Peripheral pulmonary artery stenosis (PPS) refers to stenosis of the pulmonary artery from the trunk to the peripheral arteries. Although paediatric PPS is well described, the clinical characteristics of adult-onset idiopathic PPS have not been established. Our objectives in this study were to characterise the disease profile of adult-onset PPS. METHODS: We collected data in Japanese centres. This cohort included patients who underwent pulmonary angiography (PAG) and excluded patients with chronic thromboembolic pulmonary hypertension or Takayasu arteritis. Patient backgrounds, right heart catheterisation (RHC) findings, imaging findings and treatment profiles were collected. RESULTS: 44 patients (median (interquartile range) age 39 (29-57) years; 29 females (65.9%)) with PPS were enrolled from 20 centres. In PAG, stenosis of segmental and peripheral pulmonary arteries was observed in 41 (93.2%) and 36 patients (81.8%), respectively. 35 patients (79.5%) received medications approved for pulmonary arterial hypertension (PAH) and 22 patients (50.0%) received combination therapy. 25 patients (56.8%) underwent transcatheter pulmonary angioplasty. RHC data showed improvements in both mean pulmonary arterial pressure (44 versus 40 mmHg; p<0.001) and pulmonary vascular resistance (760 versus 514 dyn·s·cm-5; p<0.001) from baseline to final follow-up. The 3-, 5- and 10-year survival rates of patients with PPS were 97.5% (95% CI 83.5-99.6%), 89.0% (95% CI 68.9-96.4%) and 67.0% (95% CI 41.4-83.3%), respectively. CONCLUSIONS: In this study, patients with adult-onset idiopathic PPS presented with segmental and peripheral pulmonary artery stenosis. Although patients had severe pulmonary hypertension at baseline, they showed a favourable treatment response to PAH drugs combined with transcatheter pulmonary angioplasty.

Tyvaso DPI: Drug-device characteristics and patient clinical considerations.

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.

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

RATIONALE: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint. OBJECTIVES: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension. METHODS: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16. RESULTS: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction. CONCLUSION: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Safety and efficacy of transitioning from selexipag to oral treprostinil in pulmonary arterial hypertension: Findings from the ADAPT registry.

PURPOSE: Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil. METHODS: ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions. RESULTS: Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging. CONCLUSION: Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Transitioning intravenous epoprostenol to oral selexipag in idiopathic pulmonary arterial hypertension: a case report.

Intravenous (i.v.) prostacyclin is the cornerstone treatment in high-risk pulmonary arterial hypertension (PAH) patients. Selexipag is an orally available prostacyclin receptor agonist. Limited data are available regarding the feasibility of transitioning from i.v. epoprostenol to selexipag. A 50-year-old woman with idiopathic PAH was diagnosed in a World Health Organization (WHO) Functional Class (FC) IV. She improved with upfront triple combination therapy, including i.v. epoprostenol. Over 2 years of follow-up, the patient remained at low risk and expressed strong preference towards oral therapies. After careful risk-benefit clinical consideration, she was transitioned from i.v. epoprostenol to selexipag. Selexipag was started at dosage of 200 µg twice daily (b.i.d.) and titrated up to 1600 µg b.i.d. over 8 weeks (up-titration of 200 µg b.i.d. every week). Simultaneously, i.v. epoprostenol was down-titrated 3.0 ng/kg/min every week from a dosage of 27.5 ng/kg/min. The transition occurred under strict medical surveillance and was well tolerated. One year after discontinuation of epoprostenol, the patient remains in WHO FC I and has no signs of clinical deterioration. Although not generalizable to most PAH patients, this case highlights that a carefully planned transition from epoprostenol to selexipag is feasible in selected low-risk patients within a shared medical decision-making framework.

Severe Pulmonary Arterial Hypertension in Healthy Young Infants: Single Center Experience.

OBJECTIVE: We studied the clinical presentation and management of acute pulmonary arterial hypertension (PAH) in healthy young infants, and the effect of thiamine therapy. METHODS: Review of hospital records was conducted for 56 healthy infants (aged below 6 month) who developed sudden onset of pulmonary arterial hypertension as diagnosed on 2D echocardiography, and were admitted at our institution. RESULTS: All patients received supportive care and pulmonary vasodilator therapy, whereas those admitted after Sep-tember, 2019 (n=28) received thiamine in addition, as per the institute's protocol. Overall, complete recovery was seen in 80% (n=45). Infants who died had significantly lower mean pH (7.05 vs 7.27; P=0.001) and serum bicarbonate (9.1 vs 14.9; P=0.007), higher arterial lactate (72.7 vs 61.5; P=0.92), ventricular dysfunction (16 vs 10; P=0.01) and shock (7 vs 9; P=0.008) when compared to those who survived. Baseline characteristics, severity of acidosis and pulmonary hypertension, time taken to recover from PAH, presence of ventricular dysfunction were comparable among those who received thiamine and those who did not receive it. Similarly, recovery (89% vs 71%; P=0.17) and mortality (11% vs 29%) were also comparable between the two groups. CONCLUSIONS: A significant proportion of infants with PAH improve with supportive treatment and pulmonary vasodilator therapy. Thiamine supplementation may not give any additional benefit in these patients.

Heterogeneity of treatment effects by risk in pulmonary arterial hypertension.

BACKGROUND: It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH. METHODS: We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening. RESULTS: Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86-19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms. CONCLUSIONS: We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.

Loss of response to calcium channel blockers after long-term follow-up treatment in patients with idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (PAH) patients with a positive response to acute vasodilator challenge and a clinical response to calcium channel blockers (CCBs) for at least one year are traditionally designated true responders. Nevertheless, little is known about a sustained response to CCBs over longer periods of time. We evaluated the loss of response to CCBs after long-term treatment in a cohort of idiopathic PAH patients previously classified as being true responders. Our data suggest that idiopathic PAH patients can lose clinical response to CCBs even after one year of clinical stability, reinforcing the need for constant multidimensional reevaluation to assess the need for targeted PAH therapies and to classify these patients correctly.

Refined risk stratification, current treatment, and new therapeutic approaches in pulmonary arterial hypertension.

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for pulmonary hypertension have introduced a refined risk stratification to guide both initial and subsequent treatment of pulmonary arterial hypertension (PAH). The risk stratification at PAH diagnosis still comprises three risk categories (low, intermediate, high) and lists some new parameters. As the estimated 1­year mortality is more than 20% in high-risk patients after diagnosis, an initial triple-combination therapy including parenteral prostacyclin analogues is recommended for this group. All other patients should receive a dual-combination therapy with an endothelin receptor antagonist and a phosphodiesterase­5 inhibitor. However, this approach of initial combination therapy is only recommended for classic PAH, while monotherapy followed by regular follow-up and individualized therapy should be used for patients with cardiopulmonary comorbidities. For PAH patients without cardiopulmonary comorbidities, it is recommended to assess their risk at follow-up with a new 4­strata classification, where the intermediate-risk group is split on the basis of three noninvasive parameters. Importantly, changes from intermediate-high to intermediate-low risk have been shown to be associated with a better prognosis. In addition, the recommendations on treatment escalation became more precise with the addition of a prostacyclin receptor agonist or switching a phosphodiesterase­5 inhibitor to a soluble guanylate cyclase stimulator for intermediate-low risk and proceeding to triple-combination therapy with parenteral prostacyclin analogues already for intermediate-high risk. With sotatercept, the first non-vasodilator PAH treatment will become available in the near future to further enrich our treatment options for this chronic and still severe disease.

Pulmonary hypertension inhaled therapies: An updated review.

Treatments of pulmonary hypertension (PH) continue to evolve with approval of new therapies. The currently FDA approved inhaled PH therapies include inhaled iloprost for group 1 pulmonary arterial hypertension (PAH), inhaled treprostinil solution and treprostinil dry powder inhaler for both group 1 PAH and group 3 PH associated with interstitial lung disease (PH-ILD). Inhaled treprostinil was recently approved for group 3 PH-ILD based on the results of INCREASE trial and the newer formulation of treprostinil dry powder that comes with a new inhaler was recently approved for both group 1 PAH and group 3 PH-ILD based on BREEZE study. The pipeline for inhaled PH therapies includes several promising molecules that can enrich the current PH therapeutic era and mitigate several systemic side effects by directly delivering the drug to the target organ. In this review article we summarize the evidence for the currently approved inhaled PAH/PH therapies, discuss the available inhalation devices, present a roadmap for successful treatment strategy, and present several inhaled PAH/PH therapies in the pipeline.

The role of riociguat in combination therapies for pulmonary arterial hypertension.

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.

Ambrisentan for in pediatric pulmonary arterial hypertension: A cost-utility analysis.

INTRODUCTION: Despite the growing evidence of efficacy, little is known regarding the efficiency of ambrisentan to decrease cost and improve the functional classes of pediatric patients with pulmonary arterial hypertension. This study aims to determine the cost-utility of ambrisentan regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. METHODS: A decision tree model was used to estimate the cost and quality-adjusted life-years (QALYs) of ambrisentan, or sildenafil in pediatric patients with pulmonary arterial hypertension. Multiple sensitivity analyses were conducted to evaluate the robustness of the model. Cost-effectiveness was evaluated at a willingness-to-pay (WTP) value of US$5180. RESULTS: The base-case analysis showed that compared with sildenafil, ambrisentan was associated with higher costs and higher QALYs. The expected annual cost per patient with ambrisentan was US$16,105 and with sildenafil was US$1431. The QALYs per person estimated with ambrisentan was 0.40 and for sildenafil was 0.39. The estimated improvement in quality of life and reduced costs results in an estimate of economic dominance for sildenafil over ambrisentan. CONCLUSION: Our economic evaluation shows that ambrisentan is not cost-effective regarding sildenafil to treat pediatric patients with pulmonary arterial hypertension in Colombia. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines.

Combined pre- and post-capillary pulmonary hypertension in left heart disease.

Patients with heart failure (HF) often have pulmonary hypertension (PH), which is mainly post-capillary; however, some of them also develop a pre-capillary component. The exact mechanisms leading to combined pre- and post-capillary PH are not yet clear, but the phenomenon seems to start from a passive transmission of increased pressure from the left heart to the lungs, and then continues with the remodeling of both the alveolar and vascular components through different pathways. More importantly, it is not yet clear which patients are predisposed to develop the disease. These patients have some characteristics similar to those with idiopathic pulmonary arterial hypertension (e.g., young age and frequent incidence in female gender), but they share cardiovascular risk factors with patients with HF (e.g., obesity and diabetes), with both reduced and preserved ejection fraction. Thanks to echocardiography parameters and newly introduced scores, more tools are available to distinguish between idiopathic pulmonary arterial hypertension and combined PH and to guide patients' management. It may be hypothesized to treat patients in whom the pre-capillary component is predominant with specific therapies such as those for idiopathic pulmonary arterial hypertension; however, no adequately powered trials of PH-specific treatment are available in combined PH. Early evidence of clinical benefit has been proven in some trials on phosphodiesterase type 5 inhibitors, while data on prostacyclin analogues, endothelin-1 receptor antagonists, and soluble guanylate cyclase stimulators are still controversial.

Clinical efficacy and safety of selexipag in children and young adults with idiopathic and heritable pulmonary arterial hypertension.

OBJECTIVE: This study aimed to investigate the safety, tolerability, and efficacy of selexipag in children and young adults with idiopathic and heritable pulmonary arterial hypertension. METHODS: This retrospective cohort study included clinical data from five children and six young adults with pulmonary arterial hypertension receiving selexipag as add-on therapy or as a transition from beraprost sodium or epoprostenol infusion therapy. Clinical efficacy was evaluated by measuring improvement in clinical variables from baseline, including hemodynamic parameters. RESULTS: Of the 11 patients, 6 were switched from beraprost sodium to selexipag and one paediatric patient transitioned from epoprostenol to selexipag. The median maintenance dose of selexipag in children was 80 µg/kg/day. In nine patients undergoing repeat catheterisation, statistically significant improvements were observed after the initiation of selexipag in terms of mean pulmonary arterial pressure (p < 0.01), pulmonary vascular resistance index (p < 0.05), and cardiac index (p < 0.01). None of the patients had clinical worsening after selexipag during follow-up, but one young adult patient discontinued treatment due to severe headache. The most common side effect profiles were headache, nausea, abdominal pain, jaw pain, myalgia, and diarrhoea. CONCLUSIONS: Selexipag may have a favourable safety profile and potential efficacy in children and young adults with pulmonary arterial hypertension.

Efficacy and safety of non-prostanoid prostacyclin receptor agonist for pulmonary hypertension: A meta-analysis.

BACKGROUND: Oral non-prostanoid prostacyclin receptor agonists therapies have been recommended for pulmonary arterial hypertension in many countries. OBJECTIVE: We aimed to evaluate the specific impact of non-prostanoid prostacyclin receptor agonists on pulmonary hypertension and to explore the influence of study characteristics on results. METHODS: PubMed, Embase, and ClinicalTrials.gov were systematically searched from inception to July 12, 2022. Randomized controlled trials comparing non-prostanoid prostacyclin receptor agonists administration with placebo for treating pulmonary hypertension were included. Two researchers independently selected eligible studies, assessed the bias risk and extracted related data. RevMan5.1 was used for performing the statistical analysis and the assessment of bias risk of the enrolled studies. PROSPERO registered number CRD42022304172. RESULTS: Seven trials involving 1727 patients were included. Pooled analyses indicated non-prostanoid prostacyclin receptor agonists significantly reduced clinical worsening events (risk ratio [RR], 0.63; 95% confidence interval [CI], 0.54 to 0.74), increased 6-min walk distance (mean difference [MD], 10 m; 95% CI, 3-17 m), decreased pulmonary vascular resistance (MD, -121 dyn s/cm5; 95% CI, -172 to -69 dyn s/cm5) and increased cardiac index (MD, 0.38 L/min/m2; 95% CI, 0.26-0.50 L/min/m2) compared with the control. No significant differences in all-cause mortality (RR, 0.86; 95% CI, 0.26 to 2.78), NYHA/WHO functional class (RR, 1.16; 95% CI, 0.61 to 2.18), mean pulmonary artery pressure (MD, -0.88 mmHg; 95% CI, -2.20 to 0.44 mmHg), right atrial pressure (MD, 0.66 mmHg; 95% CI, -0.59 to 1.90 mmHg) and total adverse events (RR, 1.05; 95% CI, 0.99 to 1.10) were found between non-prostanoid prostacyclin receptor agonists group and control group. CONCLUSION: Non-prostanoid prostacyclin receptor agonists treatment exerted benefits on clinical worsening, pulmonary vascular resistance, and cardiac index in pulmonary hypertension patients, without increasing the incidence of total adverse events.