Symptomatic Pulmonary Arterial Hypertension Research Articles

Longitudinal follow-up of mixed connective tissue disease and overlapping autoimmune diseases of childhood onset in the Afro-descendant population of the French West Indies

IntroductionOverlap autoimmune syndromes (OAS) and mixed connective tissue disease (MCTD) are rare in children. We performed a retrospective, longitudinal and descriptive study of Afro-Caribbean patients from the French West Indies followed for MCTD and OAS to describe their characteristics and outcomes during childhood.MethodsRetrospective study from January 2000 to 2023. Listings of patients were obtained from multiple sources: computerized hospital archives and national hospital-based surveillance system, registry of pediatricians and adult specialists in internal medicine and the national registry for rare diseases. MCTD was defined according to Kasukawa’s criteria. OAS was defined as overlapping features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and dermatomyositis/autoimmune myositis (DM/AM).ResultsSixteen patients were included over a 23-year period (10 MCTD and 6 OAS). The incidence was 0.23 per 100,000 children-years. The mean age at diagnosis was 11.9 years old (2.4–17) with median follow up of 7.9 years (2.1–19.6). SLE phenotype was present in the highest, followed by SSc and DM/AM. Patients had an average of three flares during childhood (1–7). A quarter (25%) had symptomatic pulmonary arterial hypertension (PAH). Ninety-four percent received steroids during follow-up and 88% required a corticosteroid-sparing therapy. Three patients (19%) developed SLE after more than 10y of follow-up. There were no death and no chronic organ failure.ConclusionThis is the largest pediatric cohort of MCTD and OAS in Afro-descendant patients treated in a country with a high standard of care. The clinical evolution did not differ between MCTD and OAS. The main complication was PAH, more frequent in our cohort.

Abstract 17599: Sotatercept for the Treatment of Pulmonary Arterial Hypertension: A Systematic Review and Single-Arm Meta-Analysis

Introduction: Pulmonary arterial hypertension (PAH) is associated with progressive clinical worsening and a 50% 5-year survival rate with current PAH therapies. Sotatercept is a first-in-class fusion protein with promising results in preclinical trials, but clinical evidence on its role in treating PAH remains limited. Hypothesis: Sotatercept may provide clinical benefits for patients with symptomatic PAH. Aims: To assess the efficacy of sotatercept in addition to background PAH therapy in this population. Methods: We searched PubMed, Embase, Cochrane and Clinicaltrials.gov in April 2023 for clinical trials assessing efficacy outcomes of sotatercept in patients with PAH. Using a random-effects model, we performed a single-arm meta-analysis of proportions for binary outcomes and applied generic inverse variance weighting formulas to pool arithmetic means and least squares means for continuous outcomes. Statistical analyses were performed using Review Manager 5.4.1 and R software 4.2.2. Results: We included three clinical trials comprising 254 patients with WHO functional class II or III PAH. At 24 weeks, only 2% of patients on sotatercept experienced symptoms of clinical worsening (95% CI 1 to 5; Fig. 1A). Sotatercept was also associated with a reduction in pulmonary vascular resistance (mean change from baseline -199.92 dyn·sec·cm -5 ; 95% CI -256.83 to -143.0; Fig. 1B), while improving 6-minute walk distance (mean change from baseline 45.86 m; 95% CI 28.54 to 63.18; Fig. 1C). Conclusions: These findings suggest that sotatercept may improve exercise capacity while decelerating clinical worsening and attenuating pulmonary vascular resistance in patients with mild to moderate PAH.

Role of Sildenafil in Severe COVID-19 Pneumonia in Infancy - A Case Series

SARS-CoV-2 virus primarily affects the respiratory system, although other organ systems are also involved. Though pulmonary arterial hypertension (PAH) has been described in as a sequela of COVID pneumonia in adults, only a coincidental association between pre-existing PAH and SARS-CoV-2 infection in children has been reported. To our knowledge, severe COVID pneumoniacausing PAH in children, especially in infancy has not been reported yet. With the meteoric spread of the pandemic and rapid development of newer mutated variants, the timely discovery of new drugs is near impossible. The idea of repurposing existing drugs to treat COVID-19 is an attractive strategy, especially if they are already approved (for other indications) and have wellestablished safety profiles. Sildenafil specifically targets pulmonary vasodilation, endothelial function, and vascular remodelling. It hence has emerged as an effective first - line oral therapeutic agent for patients with symptomatic PAH in all age groups. We present a case series of four cases where Sildenafil has been repurposed for the treatment of PAH associated with severe COVID-19 pneumonia in infancy.

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

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. 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. 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. 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. Bayer AG, Merck Sharp & Dohme.

Anesthetic management for percutaneous reverse Potts shunt creation in children with refractory idiopathic pulmonary arterial hypertension: A case series.

Percutaneous reverse Potts shunt improves right ventricular function in patients with suprasystemic idiopathic pulmonary arterial hypertension. There are no data regarding the anesthesia in this high-risk procedure. We report our experience of the anesthetic management for the creation of percutaneous reverse Potts shunt in children with suprasystemic idiopathic pulmonary arterial hypertension. This study included 10 patients presenting with symptomatic idiopathic pulmonary arterial hypertension despite undergoing medical treatment. All patients underwent gradual induction of anesthesia to maintain hemodynamic stability (etomidate, n=8; ketamine, n=4). Four patients needed extracorporeal life support: 2 were rescued after cardiac arrest and 2 had elective extracorporeal life support due to preprocedural dysfunctional right ventricle and/or small left ventricle volumes with reduced cardiac output. All patients were admitted to the pediatric cardiac intensive care unit (4 [2-5] days). All patients with extracorporeal life support died. None of the six survivors needed pulmonary transplantation. Both ketamine and etomidate support hemodynamics. High-dose opioid technique has the advantage of blunting noxious stimuli and subsequent increase in pulmonary vascular resistance. We recommend using multimodal monitoring with transesophageal echocardiography. The 100% mortality of extracorporeal life support patients, probably too sick to undergo such procedure, may question its usefulness. Further studies should identify suitable candidates for percutaneous reverse Potts shunt creation.

Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: 5 years of experience in Italy

Balloon pulmonary angioplasty (BPA) represents a therapeutic option for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) in patients who are not eligible for surgical pulmonary endarterectomy (PEA) or with persistent/recurrent symptomatic pulmonary arterial hypertension after PEA. This study evaluated the safety of BPA during 5 years of experience of the only Italian center systematically performing this procedure. The BPA program was activated at the S. Orsola Polyclinic in Bologna in June 2015. Life-threatening periprocedural complications were defined as: death <30 days, need for cardiopulmonary support, hemoptysis with the need for endotracheal intubation. Serious complications were vascular complications requiring surgical or percutaneous intervention. Other endpoints of interest were: hemoptysis, pulmonary vascular damage with or without hemoptysis, and pulmonary reperfusion injury with high-resolution computed tomography lung scan at 24 h. From June 2015 to September 2020, 50 patients (45% male, median age 68 years), 42 inoperable and 8 with persistent/recurrent pulmonary hypertension after PEA, underwent 156 BPA procedures at our institution. There was one life-threatening complication (2% of patients, 0.06% of the procedures), i.e. severe hemoptysis requiring endotracheal intubation, and four serious complications (8% of the patients, 2.6% of the procedures), i.e. one pulmonary artery perforation requiring percutaneous treatment and three access-site vascular complications requiring surgery. There were no deaths <30 days. Pulmonary reperfusion injury occurred in 37 patients (74%) for a total of 96 sessions (62%). However, reperfusion injury was limited and with subclinical course in most cases. This study confirmed the relative safety of BPA in patients with CTEPH who are not candidates for heart surgery or with persistent pulmonary hypertension after PEA in the first large Italian experience.

An evaluation of selexipag for the treatment of pulmonary hypertension

ABSTRACT Introduction Selexipag is a first-in-class, oral, long-acting, selective, non-prostanoid agonist of the prostacyclin receptor (IP receptor), indicated for the treatment of symptomatic adult pulmonary arterial hypertension (PAH). It was designed with the objective to surpass the inconveniences associated with standard prostanoid therapy, presenting fewer adverse effects and comparable hemodynamic benefits. Areas covered This review describes the pharmacologic properties of selexipag and presents the clinical trials that have been completed or are currently ongoing regarding its clinical efficacy, safety, and tolerability. The pivotal GRIPHON study is extensively presented. Expert opinion Selexipag is the first IP receptor to reduce the morbidity/mortality composite endpoint of the GRIPHON study, a large, randomized, placebo-controlled study. The TRITON study failed to demonstrate a clear benefit of initial triple oral therapy including selexipag compared to initial double oral therapy. Current guidelines do not provide definitive recommendations regarding the place of selexipag in the treatment algorithm of PAH. Finally, the possibility of transition between the several drugs acting in the prostacyclin pathway, and the potential role of selexipag in chronic thromboembolic pulmonary hypertension and pediatric PAH is currently being examined, possibly expanding its future use.

First in human: the effects of biventricular pacing on cardiac output in severe pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) carries high morbidity and mortality despite available treatment options. In severe PAH, right ventricular (RV) diastolic pressure overload leads to interventricular septal bowing, hindering of left ventricular diastolic filling and reduced cardiac output (CO). Some animal studies suggest that pacing may mitigate this effect. We hypothesized that eliminating late diastole via ventricular pacing could improve CO in human subjects with severe PAH. Using minimal to no sedation, we performed transvenous acute biventricular (BiV) pacing and right heart catheterization in six patients with symptomatic PAH. Hemodynamic measurements were taken at baseline and during BiV pacing at various 20-ms intervals of V-V timing. We compared baseline CO to (1) CO while pacing the RV first by 80ms (mimicking RV-only pacing), and then to (2) CO during pacing at the V-V timing that resulted in the highest CO. All participants were female, PASP 74 ± 14mmHg, QRS duration 104 ± 20ms. Compared with baseline, the CO decreased when the RV was paced first by 80ms (7.2 ± 1.0 vs. 6.2 ± 1.1 L/min, p = 0.028). Pacing with optimal V-V timing produced CO similar to baseline (7.2 ± 1.0 vs. 7.4 ± 1.4, p = 0.92). Two patients (33%) met the predefined endpoint of a 15% increase in CO during pacing at the optimal V-V timing. In symptomatic PAH, V-V optimized acute BiV pacing does not consistently improve CO. However, acute BiV pacing did improve CO in a subset of this cohort. Further research is needed to identify predictors of response to cardiac resynchronization therapy in this population.

Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality

BackgroundRegistry data suggest that disease progression in pulmonary arterial hypertension (PAH) is indicative of poor prognosis. However, the prognostic relevance of PAH-related morbidity has not been formally evaluated in randomized controlled trials. ObjectivesThe purpose of these analyses was to assess the impact of morbidity events on the risk of subsequent mortality using the landmark method and data from the SERAPHIN and GRIPHON studies. MethodsFor each study, the risk of all-cause death up to the end of the study was assessed from the landmark time point (months 3, 6, and 12) according to whether a patient had experienced a primary endpoint morbidity event before the landmark. Each analysis was conducted using data from all patients who were available for survival follow-up at the landmark. ResultsIn the SERAPHIN study, on the basis of the 3-month landmark time point, patients who experienced a morbidity event before month 3 had an increased risk of death compared with patients who did not (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.94 to 5.92). In the GRIPHON study, on the basis of the 3-month landmark time point, there was also an increased risk with a HR of 4.48; (95% CI: 2.98 to 6.73). Analyses based on 6-month and 12-month landmarks also showed increased risk in patients who experienced morbidity events, albeit with a reduced HR. ConclusionsThese results demonstrate the prognostic relevance of PAH-related morbidity as defined in the SERAPHIN and GRIPHON studies, highlighting the importance of preventing disease progression in patients with PAH and supporting the clinical relevance of SERAPHIN and GRIPHON morbidity events. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension [SERAPHIN]; NCT00660179; Selexipag [ACT-293987] in Pulmonary Arterial Hypertension [GRIPHON]; NCT01106014)

Outcomes of pulmonary arterial hypertension therapy in Australia: is monotherapy adequate?

In Australia, government-subsidised treatment of pulmonary arterial hypertension (PAH) is limited to monotherapy. Recent international guidelines advocate that initial combination therapy be considered for all symptomatic PAH patients. To characterise 'real-life' outcomes in PAH patients initiated on monotherapy. We performed a retrospective analysis of 100 consecutive PAH patients at a single centre who were commenced on monotherapy for PAH between 2004 and 2015. The composite clinical end-point of 'treatment failure' was prospectively defined as (i) >15% fall in 6-min walk distance (6MWD) on follow up, (ii) physician judgement of inadequate treatment response, (iii) adverse drug effect requiring cessation and (iv) death or transplantation. At initiation of therapy, mean age was 54 ± 18 years, and underlying diagnoses included idiopathic (36%), connective tissue disease-associated (37%) and congenital heart disease-associated-PAH (25%). Baseline 6MWD was 360 ± 140 m, and 75% were in either the New York Heart Association functional classes III or IV. Over a median follow up of 38 months (interquartile range 20-67), 62% of the subjects met the criteria for a clinical failure event. Median time to monotherapy failure was 24 months (95% confidence interval 14-34), with death or transplantation being the most common clinical failure event. Estimated 1-, 3- and 5-year survival rates from time of treatment initiation were 92, 75 and 66%. The majority of patients failed initial monotherapy therapy within 2 years of treatment initiation. Broader access to approved PAH agents is needed to enable combination therapy in line with evidence-based international guidelines.

Riociguat: a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension.

Despite advances in treatments and improved survival, patients with pulmonary hypertension still experience poor exercise and functional capacity, which has a significant detrimental impact on their quality of life. The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine 3′,5′-monophosphate (cGMP) pathway has been shown to play an important role in cardiovascular physiology, especially in vasodilation and pulmonary vascular tone. The oral sGC stimulator riociguat has a dual mode of action on the NO–sGC–cGMP pathway: direct stimulation of sGC independent of NO and indirect simulation via sensitization of sGC to endogenous NO. Riociguat is now licensed in >50 countries worldwide, including in Europe, the USA, Canada, and Japan. Approval for the treatment of pulmonary arterial hypertension (PAH) was based on Phase III data from the PATENT studies, in which riociguat significantly improved exercise capacity, pulmonary vascular resistance, a range of secondary end points, and hemodynamic parameters in patients with symptomatic PAH. In the Phase III CHEST studies, riociguat consistently improved exercise capacity in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy and is now the only drug to be approved for this indication. Riociguat was well tolerated in long-term studies of PAH and CTEPH. This review describes the role of the NO–sGC–cGMP pathway in the pathophysiology of pulmonary hypertension, and reviews the clinical efficacy and safety of riociguat in patients with PAH and inoperable or persistent/recurrent CTEPH. Based on its demonstrated efficacy and established safety profile, riociguat is a promising treatment option for patients with PAH and CTEPH.

Association between CD4+ Lymphocyte Count and Left Ventricular Diastolic Function and Geometry in Newly Diagnosed Highly Active Antiretroviral Therapy (HAART) Naive HIV/AIDS Patients Seen at University of Port Harcourt Teaching Hospital, Port Harcourt, Rivers State, Nigeria

Background: Human Immunodeficiency Virus (HIV) infection is one of the leading causes of acquired heart diseases and specifically of symptomatic heart failure and pulmonary arterial hypertension. In the clinical course of HIV infection, CD4 + count decreases with disease progression and it has been considered to be correlated with LV dysfunction in the disease process. Method: This was a cross-sectional case-control study. One hundred newly diagnosed HAART naive HIV/ AIDS individuals seen in the retroviral clinic were evaluated clinically. One hundred age and sex matched HIV negative controls were recruited. Those with other cardiovascular risk factors were excluded. Blood samples were screened and confirmed for HIV1 and 2 infections using double ELISA. CD4 + count was estimated using the flow cytometry method. Left ventricular diastolic function and geometry were assessed using transthoracic echocardiography. Results: The mean age of cases with HIV/AIDS was 35.7 ± 10.13 years. Females were more than males in a ratio of 2.3:1. Diastolic dysfunction assessed by E/A ratio, deceleration time and isovolumic relaxation time (IVRT) occurred more in the cases compared to the controls (40% versus 6%) and this was statistically significant (x2=38.15, p=0.001). Abnormal geometry assessed using LVMI and RWT was commoner in the cases than in the control group and this was statistically significant (x2=25.49, p=0.01). There was an insignificant negative correlation between CD4 + count and IVRT (R=- 0.0086, P=0.393). Subjects with CD4 + count <200 cells/μL were more likely to have diastolic dysfunction (OR=1.680, P=0.2112). Lastly, there was an insignificant negative correlation between CD4 + count and LVMI (R=- 0.303, P=0.816). Subjects with CD4 + count<200 cells/μL were more likely to have abnormal geometry (OR=1.182, P=0.6312). Conclusion: Left ventricular diastolic dysfunction and abnormal geometry were shown in this study to be more common in people with HIV/AIDS than in the control group and there was association between degree of immunosuppression and diastolic dysfunction as well as abnormal geometry, although these were statistically not significant.

Sildenafil citrate therapy for secondary pulmonary arterial hypertension due to chronic obstructive lung disease

Pulmonary arterial hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure and premature death. Pathobiologic mechanisms of the disease include pulmonary endothelial dysfunction, which leads to impaired production of vasodilators, such as nitric oxide and prostacyclin, and overexpression of vasoconstrictors, such as endothelin-1.Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung. MethodsIn this prospective study 139 patients with symptomatic pulmonary arterial hypertension (2ry to COPD) received placebo or sildenafil (20mg) orally three times daily for 12weeks. The end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. ResultsThe distance walked in six minutes increased from baseline in sildenafil group; the mean placebo-corrected treatment effects were 51m (+13.0 percent), for 20mg of sildenafil, (P<0.001). Sildenafil dose reduced the mean pulmonary-artery pressure (P=0.04), and was associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. ConclusionSildenafil improves exercise capacity, and hemodynamic in patients with symptomatic pulmonary arterial hypertension.

Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: a new patient-reported outcome instrument for PAH.

BackgroundRegulators and clinical experts increasingly recognize the importance of incorporating patient-reported outcomes (PROs) in clinical studies of therapies for pulmonary arterial hypertension (PAH). No PAH-specific instruments have been developed to date in accordance with the 2009 FDA guidance for the development of PROs as endpoints in clinical trials. A qualitative research study was conducted to develop a new instrument assessing PAH symptoms and their impacts following the FDA PRO guidance.MethodsA cross-sectional study was conducted at 5 centers in the US in symptomatic PAH patients aged 18–80 years. Concept elicitation was based on 5 focus group discussions, after which saturation of emergent concepts was reached. A PRO instrument for PAH symptoms and their impacts was drafted. To assess the appropriateness of items, instructions, response options, and recall periods, 2 rounds of one-on-one cognitive interviews were conducted, with instrument revisions following each round. Additional interviews tested the usability of an electronic version (ePRO). PRO development considered input from an international Steering Committee, and translatability and lexibility assessments.ResultsFocus groups comprised 25 patients (5 per group); 20 additional patients participated in cognitive interviews (10 per round); and 10 participated in usability interviews. Participants had a mean ± SD age of 53.1 ± 15.8 years, were predominantly female (93 %), and were diverse in race/ethnicity, WHO functional class (FC I/II: 56 %, III/IV: 44 %), and PAH etiology (idiopathic: 56 %, familial: 2 %, associated: 42 %). The draft PRO instrument (PAH-SYMPACT®) was found to be clear, comprehensive, and relevant to PAH patients in cognitive interviews. Items were organized in a draft conceptual framework with 16 symptom items in 4 domains (respiratory symptoms, tiredness, cardiovascular symptoms, other symptoms) and 25 impact items in 5 domains (physical activities, daily activities, social impact, cognition, emotional impact). The recall period is the past 24 h for symptoms, and the past 7 days for impacts.ConclusionsThe PAH-SYMPACT® was shown to capture symptoms and their impacts relevant to PAH patients, demonstrating content saturation, concept validity, and ePRO usability. Final content and psychometric validation of the instrument will be based on the results of an ongoing Phase IIIb clinical trial in PAH patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0388-6) contains supplementary material, which is available to authorized users.

Riociguat in Combination With Endothelin Receptor Antagonists (ERAs) for the Treatment of Pulmonary Arterial Hypertension (PAH): A Subgroup Analysis of PATENT

SESSION TITLE: Pulmonary Arterial Hypertension Posters II SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM PURPOSE: The ACCP suggests that riociguat may be added to the treatment regimen of PAH patients who remain symptomatic despite stable regimens of an inhaled prostanoid or an ERA. PATENT-1 (the Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial) allowed patients to enroll while on stable regimens of ERAs. Here, we report findings from analysis of the subgroup of patients from the PATENT trial who were on background ERA therapy (BERA). METHODS: Patients were assigned to placebo (N=126; n=54 on BERA), to individualized dosing of riociguat up to 2.5 mg TID (N=254; n=113 on BERA), or to an exploratory riociguat group capped at 1.5 mg TID (N=63; n=27 on BERA). Primary outcome was change from baseline (BL) in 6-minute walk distance (6MWD) at week 12. Secondary exploratory outcomes included change from BL in pulmonary vascular resistance (PVR), NT-proBNP, WHO functional class (WHO-FC), and clinical worsening. RESULTS: All apply to patients (riociguat and placebo) on BERA. For the placebo-corrected mean change from baseline to last visit, 6MWD in riociguat patients (1.0 to 2.5 mg TID) increased by 26 meters (95% CI: 5-46 meters). Mean change in PVR for riociguat patients was -174±202 dyn·s·cm-5, versus -46±266 dyn·s·cm-5 for placebo. Mean change in NT-proBNP was 90±2212 pg/mL for riociguat patients versus 172±759 pg/mL for placebo. By last visit, 26% of riociguat patients had improved one WHO-FC (71% maintained FC, while 4% worsened 1 FC) compared with 13% of placebo patients (76% maintained FC, and 9% and 2% worsened 1 and 2 FC, respectively). Among riociguat patients, only 1 (0.9%) had at least 1 clinical worsening event, compared with 3 (5.6%) among placebo patients, including 1 death. CONCLUSIONS: These data suggest that adding riociguat to stable regimens of ERAs in symptomatic PAH patients has favorable effects on 6MWD, PVR, WHO-FC, and perhaps clinical worsening. CLINICAL IMPLICATIONS: Adding riociguat to stable regimens of ERAs may be beneficial in symptomatic PAH patients but additional studies are needed to further explore this possibility. DISCLOSURE: Nicholas Hill: Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare Namita Sood: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: Bayer Healthcare No Product/Research Disclosure Information

Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study.

Ranolazine, a late inward sodium current and fatty acid oxidation inhibitor, may improve right ventricular (RV) function in pulmonary arterial hypertension (PAH); however, the safety and efficacy of ranolazine in humans with PAH is unknown. Therefore, we sought to (1) determine whether ranolazine is safe and well tolerated in PAH and (2) explore ranolazine's effect on symptoms, exercise capacity, RV structure and function, and hemodynamic characteristics. We therefore conducted a 3-month, prospective, open-label pilot study involving patients with symptomatic PAH (n = 11) and echocardiographic evidence of RV dysfunction. We evaluated the safety and tolerability of ranolazine and compared symptoms, exercise capacity, exercise bicycle echocardiographic parameters, and invasive hemodynamic parameters between baseline and 3 months of ranolazine therapy using paired t tests. Of the 11 patients enrolled, one discontinued ranolazine therapy due to a drug-drug interaction after 3 days of therapy. All 10 of the remaining patients continued therapy for 3 months, and 8 (80%) of 10 completed all study tests. After 3 months, ranolazine administration was safe and associated with improvement in functional class (P = 0.0013), reduction in RV size (P = 0.015), improved RV function (improvement in RV strain during exercise at 3 months; P = 0.037), and a trend toward improved exercise time and exercise watts on bicycle echocardiography (P = 0.06 and 0.01, respectively). Ranolazine was not associated with improvement in invasive hemodynamic parameters. In conclusion, in a pilot study involving PAH, ranolazine therapy was safe and well tolerated, and it resulted in improvement in symptoms and echocardiographic parameters of RV structure and function but did not alter invasive hemodynamic parameters. ClinicalTrials.gov Identifier: NCT01174173.

Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension.

The safety and efficacy of adding bosentan to sildenafil in pulmonary arterial hypertension (PAH) patients was investigated.In this prospective, double-blind, event-driven trial, symptomatic PAH patients receiving stable sildenafil (≥20 mg three times daily) for ≥3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all-cause death.Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary end-point event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58-1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9-37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile.In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event.

Use of clinically relevant responder threshold criteria to evaluate the response to treatment in the Phase III PATENT-1 study

In PATENT-1, riociguat significantly improved 6-minute walking distance (6MWD) and a range of secondary end-points in patients with pulmonary arterial hypertension (PAH). We investigated whether riociguat increased the proportion of patients achieving clinically relevant responder thresholds compared with placebo during PATENT-1. In PATENT-1, a randomized, double-blind study, treatment-naïve patients or patients on background PAH-targeted therapy with symptomatic PAH received 12 weeks of treatment with placebo, riociguat up to 2.5 mg 3 times daily, or riociguat up to 1.5 mg 3 times daily. Increases in 6MWD ≥40 m, 6MWD ≥380 m, cardiac index ≥2.5 liter/min/m(2), mixed venous oxygen saturation ≥65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg were chosen as threshold criteria of a positive response. Riociguat increased the proportion of treatment-naïve patients and patients on background PAH-targeted therapy with 6MWD ≥380 m at Week 12 (+21% and +15%, respectively), whereas there was a small reduction in 6MWD in placebo-treated patients for both sub-groups. Riociguat also increased the proportion of treatment-naïve patients and patients on background PAH-targeted therapy achieving World Health Organization functional class I/II (+12% and +19%, respectively) and cardiac index ≥2.5 liter/min/m(2) (+30% and +33%, respectively) at Week 12, whereas there was little change in the respective placebo groups. Compared with placebo, riociguat increased the proportion of treatment-naïve patients and patients on background PAH-targeted therapy who fulfilled criteria defining a positive response to therapy.

Effect of Macitentan on Hospitalizations: Results From the SERAPHIN Trial

ObjectivesThis study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH). BackgroundPAH is a progressive, life-threatening disease often requiring hospitalization. MethodsIn the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated. ResultsOf 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p < 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p < 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non–PAH-related hospitalization was similar between treatment arms. ConclusionsMacitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179)

Macitentan for the treatment of pulmonary arterial hypertension.

Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug–drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial.