Safety and efficacy of direct oral anticoagulants in patients with chronic thromboembolic pulmonary hypertension.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) remains an underdiagnosed disease. Anticoagulation is essential in its therapy to prevent recurrent venous thromboembolism (VTE). According to some international guidelines, vitamin K antagonists (VKA) remain the gold standard. Nevertheless, direct oral anticoagulants (DOAC) are widely used, partly because of numerous advantages. The objective of this study was to determine if DOAC is an effective and safe alternative to VKA in CTEPH patients. MATERIALS AND METHODS: A retrospective observational study was conducted between 2001 and 2021 in a CTEPH Clinic of a tertiary care hospital. We recorded demographic characteristics, anticoagulant therapies and pulmonary hypertension treatments received. Safety outcomes were bleeding events and deaths while efficacy outcomes were recurrent VTE events. RESULTS: Among the study population (N = 205), the distribution of anticoagulant used transitioned from majority on VKA to majority on DOAC. In 2020, 23 (19 %) were on VKA and 97 (78 %) on DOAC. Among 11 VTE events occurring during follow-up, 7 were in the VKA group (1.10 %/person-year) and 1 in the DOAC group (0.32 %/person-year). Rates of VTE recurrence were not significantly different in those treated with DOAC compared to VKA (P = 0.21). Total bleeding rate on VKA (2.52 %/person-year) and DOAC (2.52 %/person-year) were the same (P = 1.00). Among 27 patients who died, no deaths occurred as a consequence of bleeding or VTE events. CONCLUSION: Bleeding and VTE events were not higher in CTEPH patients receiving DOAC compared to VKA which adds confidence to considering DOAC as an effective and safe alternative for long term anticoagulation in CTEPH patients.

Riociguat and the right ventricle in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive diseases that can lead to right heart failure and death. Right ventricular dysfunction, hypertrophy and maladaptive remodelling are consequences of increased right ventricular (RV) afterload in PAH and CTEPH and are indicative of long-term outcomes. Because RV failure is the main cause of morbidity and mortality in PAH and CTEPH, successful treatments should lead to improvements in RV parameters. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of PAH and inoperable or persistent/recurrent CTEPH after pulmonary endarterectomy. This review examines the current evidence showing the effect of riociguat on the right ventricle, with particular focus on remodelling, function and structural parameters in preclinical models and patients with PAH or CTEPH.

The Paradox of Pulmonary Vascular Resistance: Restoration of Pulmonary Capillary Recruitment as a Sine Qua Non for True Therapeutic Success in Pulmonary Arterial Hypertension.

Exercise-induced increases in pulmonary blood flow normally increase pulmonary arterial pressure only minimally, largely due to a reserve of pulmonary capillaries that are available for recruitment to carry the flow. In pulmonary arterial hypertension, due to precapillary arteriolar obstruction, such recruitment is greatly reduced. In exercising pulmonary arterial hypertension patients, pulmonary arterial pressure remains high and may even increase further. Current pulmonary arterial hypertension therapies, acting principally as vasodilators, decrease calculated pulmonary vascular resistance by increasing pulmonary blood flow but have a minimal effect in lowering pulmonary arterial pressure and do not restore significant capillary recruitment. Novel pulmonary arterial hypertension therapies that have mainly antiproliferative properties are being developed to try and diminish proliferative cellular obstruction in precapillary arterioles. If effective, those agents should restore capillary recruitment and, during exercise testing, pulmonary arterial pressure should remain low despite increasing pulmonary blood flow. The effectiveness of every novel therapy for pulmonary arterial hypertension should be evaluated not only at rest, but with measurement of exercise pulmonary hemodynamics during clinical trials.

Oral anticoagulants (NOAC and VKA) in chronic thromboembolic pulmonary hypertension.

EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1-4 years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH.

The Role of Thyroid Disorders, Obesity, Diabetes Mellitus and Estrogen Exposure as Potential Modifiers for Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive disorder characterized by a chronic in-crease in pulmonary arterial pressure, frequently resulting in right-sided heart failure and potentially death. Co-existing medical conditions are important factors in PH, since they not only result in the genesis of the disorder, but may also contribute to its progression. Various studies have assessed the impact of thyroid disorders and other endocrine conditions (namely estrogen exposure, obesity, and diabetes mellitus) on the progression of PH. The complex interactions that hormones may have with the cardiovascular system and pulmonary vascular bed can create several pathogenetic routes that could explain the effects of endocrine disorders on PH development and evolution. The aim of this review is to summarize current knowledge on the role of concomitant thyroid disorders, obesity, diabetes mellitus, and estrogen exposure as potential modifiers for PH, and especially for pulmonary arterial hypertension, and to discuss possible pathogenetic routes linking them with PH. This information could be valuable for practicing clinicians so as to better evaluate and/or treat concomitant endocrine conditions in the PH population.

Pulmonary capillary recruitment and distention in mammalian lungs: species similarities.

Pulmonary arterial pressure rises minimally during exercise. The pulmonary microcirculation accommodates increasing blood flow via recruitment of pulmonary capillaries and, at higher flows, by distention of already perfused capillaries. The flow transition range between recruitment and distention has not been studied or compared across mammalian species, including humans. We hypothesised that the range would be similar. Functional pulmonary capillary surface area (FCSA) can be estimated using validated metabolic techniques. We reviewed data from previous studies in three mammalian species (perfused rabbit lungs and dog lung lobes, and exercising humans) and generated blood flow-FCSA curves over a range of flows. We noted where the curves diverged from the theoretical line of pure recruitment (Recruitment) and determined the flow where the curve slope equalled 50% that of Recruitment, or equalled that of a theoretical curve representing full capillary distention (Distention). The three mammalian species have similar flow ranges for the transition from predominantly recruitment to predominantly distention, with dogs having the highest transition point. Within the physiological range of most daily activity, the species are similar and accommodate increasing blood flow mainly via recruitment, with progressive distention at higher flows. This is highly relevant to pulmonary physiology during exercise.

Effect of riociguat on right ventricular function in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: In the Phase III PATENT-1 (NCT00810693) and CHEST-1 (NCT00855465) studies, riociguat demonstrated efficacy vs placebo in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Clinical effects were maintained at 2 years in the long-term extension studies PATENT-2 (NCT00863681) and CHEST-2 (NCT00910429). METHODS: This post hoc analysis of hemodynamic data from PATENT-1 and CHEST-1 assessed whether riociguat improved right ventricular (RV) function parameters including stroke volume index (SVI), stroke volume, RV work index, and cardiac efficiency. REVEAL Risk Score (RRS) was calculated for patients stratified by SVI and right atrial pressure (RAP) at baseline and follow-up. The association between RV function parameters and SVI and RAP stratification with long-term outcomes was assessed. RESULTS: In PATENT-1 (n = 341) and CHEST-1 (n = 238), riociguat improved RV function parameters vs placebo (p < 0.05). At follow-up, there were significant differences in RRS between patients with favorable and unfavorable SVI and RAP, irrespective of treatment arm (p < 0.0001). Multiple RV function parameters at baseline and follow-up were associated with survival and clinical worsening-free survival (CWFS) in PATENT-2 (n = 396; p < 0.05) and CHEST-2 (n = 237). In PATENT-2, favorable SVI and RAP at follow-up only was associated with survival and CWFS (p < 0.05), while in CHEST-2, favorable SVI and RAP at baseline and follow-up were associated with survival and CWFS (p < 0.05). CONCLUSION: This post hoc analysis of PATENT and CHEST suggests that riociguat improves RV function in patients with PAH and CTEPH.

Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality. METHODS: Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850. FINDINGS: Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period. INTERPRETATION: Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality. FUNDING: Bayer AG, Merck Sharp & Dohme.

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry.

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. RESULTS: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]). CONCLUSION: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry.

OBJECTIVE: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. METHODS: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms. RESULTS: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years. CONCLUSION: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.

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's 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.

Assessment of the REPLACE study composite endpoint in riociguat-treated patients in the PATENT study.

The goal of treatment in patients with pulmonary arterial hypertension is to achieve a low risk status, indicating a favorable long-term outcome. The REPLACE study investigated the efficacy of switching to riociguat in patients with pulmonary arterial hypertension and an insufficient response to phosphodiesterase-5 inhibitors. In this post hoc analysis, we applied the REPLACE composite endpoint of clinical improvement to the placebo-controlled PATENT-1 study of riociguat in pulmonary arterial hypertension and its long-term extension, PATENT-2. Clinical improvement was defined as ≥2 of the following in patients who completed the study without clinical worsening: ≥10% or ≥30 m improvement in 6-minute walking distance; World Health Organization functional class I or II; ≥30% decrease in N-terminal prohormone of brain natriuretic peptide. At PATENT-1 Week 12, patients treated with riociguat were more likely to achieve the composite endpoint vs. placebo (P < 0.0001), with similar results in pretreated (P = 0.0189) and treatment-naïve (P < 0.0001) patients. Achievement of the composite endpoint at Week 12 was associated with a 45% reduction in relative risk of death and a 19% reduction in relative risk of clinical worsening in PATENT-2. Overall, these data suggest that use of the REPLACE composite endpoint in patients with pulmonary arterial hypertension is a valid assessment of response to treatment.

Canadian Cardiovascular Society/Canadian Thoracic Society Position Statement on Pulmonary Hypertension.

The landscape of pulmonary hypertension (PH) has changed significantly since the last Canadian Cardiovascular Society/Canadian Thoracic Society position statement in 2005. Since then, advances in our understanding of the pathophysiology of PH and improvements in diagnostic and therapeutic options have transformed the care of patients with PH. Globally, PH has an estimated prevalence of 1%, increasing to 10% in those aged 65 years and older, most commonly due to left heart or lung disease. Although pulmonary arterial hypertension (PAH) is less common, the morbidity and mortality is significant and early diagnosis and treatment are essential. This document is targeted at clinicians and describes a framework for screening and diagnosis of PH, with recommendations for performance and interpretation of echocardiography, cardiac magnetic resonance imaging, and right heart catheterization. In addition, the current approach to PAH management in Canada including risk stratification and pharmacologic therapy aimed at achieving a low-risk profile is discussed. The rationale to avoid specific PAH therapy in patients with left heart disease and lung disease-related PH is emphasized, along with special considerations for the diagnosis and management of chronic thromboembolic PH. Future advancements in the identification of novel pathways and therapies, personalized approaches to direct therapy, as well as interventional approaches such as balloon pulmonary angioplasty for chronic thromboembolic PH promise to continue the rapid evolution of this field.

Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies).

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg-maximum (N = 131 pretreated patients) and placebo (N = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: -8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.

Knockdown of bone morphogenetic protein type II receptor leads to decreased aquaporin 1 expression and function in human pulmonary microvascular endothelial cells.

Bone morphogenetic proteins (BMPs) were once considered only to have a role in bone formation. It is now known that they have pivotal roles in other organ diseases, including heritable pulmonary arterial hypertension (PAH), where genetic mutations in the type II BMP receptor (BMPR2) are the commonest cause of receptor dysfunction. However, it has also recently been demonstrated that aquaporin 1 (Aqp1) dysfunction may contribute to PAH, highlighting that PAH development may involve more than one pathogenic pathway. Whether reduction in BMPR2 affects Aqp1 is unknown. We therefore studied Aqp1 in BMPR2-silenced human pulmonary microvascular endothelial cells (HPMECs). We demonstrated reduced Aqp1 mRNA, protein, and function in the BMPR2-silenced cells. Additionally, BMPR2-silenced cells exhibited lower expression of BMP-signaling molecules. In conclusion, decreased BMPR2 appears to affect Aqp1 at the mRNA, protein, and functional levels. This observation may identify a contributory mechanism for PAH.

Identifying potential parameters associated with response to switching from a PDE5i to riociguat in RESPITE.

BACKGROUND: RESPITE evaluated patients with pulmonary arterial hypertension and an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i) who switched to riociguat. This post hoc analysis assessed response to this switch in parameters associated with clinical improvement. METHODS: RESPITE was a 24-week, uncontrolled pilot study (n = 61). Differences in functional, hemodynamic, and cardiac function parameters, REVEAL risk score (RRS), and biomarkers were compared between responders (free from clinical worsening, World Health Organization functional class I/II, and ≥30 m improvement in 6-min walking distance at Week 24) and non-responders. RESULTS: Of 51 patients (84%) completing RESPITE, 16 (31%) met the responder endpoint. At baseline, there were significant differences between responders and non-responders in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15), and RRS, whereas there were no differences in hemodynamics or cardiac function. At Week 24, responders had significant improvements in pulmonary arterial compliance, pulmonary vascular resistance, and mean pulmonary arterial pressure, while non-responders showed no significant change. Cardiac efficiency and stroke volume index significantly improved irrespective of responder status. CONCLUSIONS: NT-proBNP, GDF-15, and RRS were identified as potential predictors of response in patients switching from PDE5i to riociguat. Further prospective controlled studies are needed to confirm the association of these parameters with response.

Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension With Oral Prostacyclin Pathway Agents.

BACKGROUND: Treatment of pulmonary arterial hypertension (PAH) has evolved substantially over the past two decades and varies according to etiology, functional class (FC), hemodynamic parameters, and other clinical factors. Current guidelines do not provide definitive recommendations regarding the use of oral prostacyclin pathway agents (PPAs) in PAH. To provide guidance on the use of these agents, an expert panel was convened to develop consensus statements for the initiation of oral PPAs in adults with PAH. METHODS: A systematic literature search was conducted using MEDLINE. The established RAND/University of California Los Angeles appropriateness method, which incorporates the Delphi method and the nominal group technique, was used to create consensus statements. Idiopathic, heritable, repaired congenital heart defect, and drug- or toxin-induced PAH (IPAH+) was considered as one etiologic grouping. The process was focused on the use of oral treprostinil or selexipag in patients with IPAH+ or connective tissue disease-associated PAH and FC II or III symptoms receiving background dual endothelin receptor antagonist/phosphodiesterase type 5 inhibitor therapy. RESULTS: The panel developed 14 consensus statements regarding the appropriate use of oral PPAs in the target population. The panel identified 13 clinical scenarios in which selexipag may be considered as a treatment option. CONCLUSIONS: The paucity of clinical evidence overall, and particularly from randomized trials in this setting, creates a gap in knowledge. These consensus statements are intended to aid physicians in navigating treatment options and using oral PPAs in the most appropriate manner in patients with PAH.

Impact of saline loading at cardiac catheterization on the classification and management of patients evaluated for pulmonary hypertension.

BACKGROUND: The extent to which saline loading (SL) during cardiac catheterization influences clinical practice in pulmonary hypertension (PH) is unknown. We surveyed a national cohort of PH specialists to determine how SL affected diagnosis and management. METHODS: Relevant clinical and hemodynamic data pre-SL for patients with a baseline pulmonary arterial wedge pressure (PAWP) ≤15 mm Hg were presented as surveys to 7 PH specialists. The specialists were asked to classify patients according to the WHO classification scheme, rate their confidence, and state their treatment plans. Hemodynamic data following 500 mL of SL was then presented, and specialists answered the same questions. A positive fluid challenge (PFC) was defined as PAWP >18 mm Hg after SL. RESULTS: Seven specialists evaluated 48 cases, for a total of 336 surveys. SL influenced PH classification with 19.6% of cases reclassified as having a component of Group 2 PH. SL increased confidence in PH classification (mean difference 0.25; 95% CI 0.15-0.35). With a PFC, physicians were more likely to classify patients as PH due to left heart disease (OR 6.1; 95% CI 2.8-13.1), extend time to follow-up (OR 3.2; 95% CI 1.6-6.7), and discharge patients from PH clinic (OR 5.0; 95% CI 1.9-13.1). SL changed the treatment plan in 6.5% of cases, mostly with a PFC causing reconsideration in treatment initiation. CONCLUSION: The addition of SL to hemodynamic assessment of PH can impact physicians' classification and management decisions. However, decisions are not solely based on the SL results, but rather the entirety of the clinical data available.