The need to move from 6-minute walk distance to outcome trials in pulmonary arterial hypertension

Assessment of change in exercise capacity using the 6-min walk distance (6MWD) test has been the primary end-point in the majority of pulmonary arterial hypertension (PAH) clinical trials. The 6MWD has some advantages as an end-point in such studies. It is simple and inexpensive to perform, reproducible and validated. In short-term studies with small patient numbers, as is typical in a rare disease like PAH, using change from baseline in 6MWD as the primary outcome measure demonstrated statistically significant differences between placebo and study drugs, leading to their approval. However, there have been increasing calls for clinical trials to employ primary end-points that reflect long-term disease progression and morbidity. While the 6MWD was initially considered to be a potentially reliable surrogate for disease progression in PAH, there is increasing evidence that this is not necessarily the case. Given this, there is a need to re-examine the role of 6MWD in PAH trials, and to evaluate the evidence supporting whether there is a need to move from 6MWD to more robust measures of clinical outcomes, such as morbidity and mortality. However, in the clinic the 6MWD test, alongside symptoms, haemodynamics and biomarkers, remains a useful tool in the assessment and management of PAH patients

Interventional and pharmacological management of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by obstruction of the pulmonary vasculature, leading to increased pulmonary vascular resistance and ultimately right ventricular failure, the leading cause of death in non-operated patients. This article reviews the current management of CTEPH. The standard of care in CTEPH is pulmonary endarterectomy (PEA). However, up to 40% of patients with CTEPH are ineligible for PEA, and up to 51% develop persistent/recurrent PH after PEA. Riociguat is currently the only medical therapy licensed for treatment of inoperable or persistent/recurrent CTEPH after PEA based on the results of the Phase III CHEST-1 study. Studies of balloon pulmonary angioplasty (BPA) have shown benefits in patients with inoperable or persistent/recurrent CTEPH after PEA; however, data are lacking from large, prospective, controlled studies. Studies of macitentan in patients with inoperable CTEPH and treprostinil in patients with inoperable or persistent/recurrent CTEPH showed positive results. Combination therapy is under evaluation in CTEPH, and long-term data are not available. In the future, CTEPH may be managed by PEA, medical therapy or BPA - alone or in combination, according to individual patient needs. Patients should be referred to experienced centers capable of assessing and delivering all options

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 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

Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients.

Abstract BACKGROUND: The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study. METHODS: Exploratory efficacy outcomes included 6-minute walk distance (6 MWD) and WHO FC. Adverse events were recorded. Kaplan-Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival. RESULTS: Median exposure to bosentan (n=173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations>3× upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6 MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death. CONCLUSIONS: The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes

EPITOME-2: An open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension.

Background Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience. Methods The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication. Results Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience. Conclusions Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience

Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

<p>Abstract</p> <p>Background</p> <p>Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation.</p> <p>Methods</p> <p>We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE).</p> <p>Results</p> <p>Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68 and actin revealed adventitial and medial DC- and monocyte-infiltration; in MCT/PE, medial smooth muscle cells were admixed with CD68⁺/vimentin⁺cells.</p> <p>Conclusion</p> <p>Our experimental findings support a new concept of immunologic responses to increased OS in MCT/PE-induced PAH, possibly linking recruitment of dendritic cells and OS-producing mast-cells to characteristic vasculopathy.</p

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

Sex-specific differences in chronic thromboembolic pulmonary hypertension. Results from the European CTEPH registry

BACKGROUND Women are more susceptible than men to several forms of pulmonary hypertension, but have better survival. Sparse data are available on chronic thromboembolic pulmonary hypertension (CTEPH). METHODS We investigated sex-specific differences in the clinical presentation of CTEPH, performance of pulmonary endarterectomy (PEA), and survival. RESULTS Women constituted one-half of the study population of the European CTEPH registry (N = 679) and were characterized by a lower prevalence of some cardiovascular risk factors, including prior acute coronary syndrome, smoking habit, and chronic obstructive pulmonary disease, but more prevalent obesity, cancer, and thyroid diseases. The median age was 62 (interquartile ratio, 50-73) years in women and 63 (interquartile ratio, 53-70) in men. Women underwent PEA less often than men (54% vs 65%), especially at low-volume centers (48% vs 61%), and were exposed to fewer additional cardiac procedures, notably coronary artery bypass graft surgery (0.5% vs 9.5%). The prevalence of specific reasons for not being operated, including patient's refusal and the proportion of proximal vs distal lesions, did not differ between sexes. A total of 57 (17.0%) deaths in women and 70 (20.7%) in men were recorded over long-term follow-up. Female sex was positively associated with long-term survival (adjusted hazard ratio, 0.66; 95% confidence interval, 0.46-0.94). Short-term mortality was identical in the two groups. CONCLUSIONS Women with CTEPH underwent PEA less frequently than men, especially at low-volume centers. Furthermore, they had a lower prevalence of cardiovascular risk factors and were less often exposed to additional cardiac surgery procedures. Women had better long-term survival