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Background: The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction., Methods: Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event., Results: Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35-1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients., Conclusions: Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH., Objective: To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial., Methods: This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response)., Results: In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups., Conclusions: This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy., Trial Registration Number: NCT01178073, post results., Competing Interests: Competing interests: JGC: grants and personal fees from Actelion and GlaxoSmithKline; personal fees from Bayer, Endotronix, Pfizer and United Therapeutics. NG: grants and personal fees from Actelion, Bayer, GlaxoSmithKline and Pfizer. JAB: personal fees from Actelion, Almirall, Bayer, GlaxoSmithKline and Pfizer; grants from Actelion, Bayer, GlaxoSmithKline and Pfizer. AEF: funds for the conduct of the study from Baylor College of Medicine; honoraria and travel/lodging expense for participating on the study's Steering Committee; grants from Actelion, Bayer, Gilead and United Therapeutics; personal fees from Actelion, Bayer, Gilead, Ikaria and United Therapeutics; non-financial support from Bayer and Novartis. H-AG: grants from Actelion, Bayer, Novartis and Pfizer; board membership and consultancy for Actelion, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer and Takeda; consultancy for Lilly; payment for lectures from Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer. MMH: personal fees from Actelion, Bayer, Gilead, GlaxoSmithKline, Merck and Pfizer. MK: grants and personal fees from Actelion, Bayer and Pfizer; personal fees from GlaxoSmithKline. VVM: grants and personal fees from Actelion, Bayer, Gilead, Ikaria and United Therapeutics; grants from Novartis; personal fees from Steadymed and Akros. AJP: grants and personal fees from Actelion, Bayer, Gilead and GlaxoSmithKline; personal fees from United Therapeutics. GS: grants and personal fees from Actelion, Bayer, Gilead and GlaxoSmithKline. J-LV: grants from Actelion and GlaxoSmithKline; speaker fees from Actelion, Bayer, GlaxoSmithKline and Pfizer; advisory board honoraria from Actelion and Merck. CB: employee of Gilead; stock options in Gilead. HG: former employee of Gilead; patent pending in relation to the use of selective ERA's and PDE5 inhibitors. KLM: employee of Gilead; stock options in Gilead. JHNH: employee of GlaxoSmithKline; stock options in GlaxoSmithKline. JL: employee of GlaxoSmithKline. LJR: personal fees from Gilead., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN)., Methods: In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians., Results: The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%)., Conclusions: Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival., Methods: We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with ambrisentan and tadalafil, ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy., Findings: The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42-1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06-0·73)., Interpretation: These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies., Funding: Gilead, GlaxoSmithKline., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: Imatinib mesylate, as add-on therapy in patients with pulmonary arterial hypertension (PAH) who remain inadequately treated despite receiving at least two PAH-specific drugs, improves exercise capacity and haemodynamics. We evaluated whether 24 weeks of add-on therapy with imatinib compared with placebo also improves right ventricular (RV) function assessed by echocardiography., Methods and Results: Echocardiograms were obtained at baseline, 12 weeks, and 24 weeks in 74 patients randomized to imatinib or placebo in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial. Right ventricular function was assessed by tissue Doppler tricuspid annular peak systolic velocity (TA S'), tricuspid annular plane systolic excursion (TAPSE), RV Tei index, and RV fractional area change. Between-treatment-group differences in the changes from baseline to week-24 were assessed using an ANCOVA with the last observation carried forward. At week-24 patients randomized to imatinib demonstrated greater improvements in TA S' (1.6 ± 2.3 imatinib vs. 0.5 ± 2.4 cm/s placebo, P = 0.007) and RV Tei index (-0.11 ± 0.18 imatinib vs. 0.05 ± 0.18 placebo, P = 0.005) compared with placebo, but not in TAPSE (0.07 ± 0.44 imatinib vs. 0.03 ± 0.32 cm placebo, P = 0.08). Imatinib therapy was also associated with significant reduction in peak tricuspid regurgitation velocity, increase in LV size, and improvement in LV early diastolic relaxation velocity., Conclusions: Among patients with advanced PAH who remain symptomatic on at least two PAH-specific drugs, treatment with imatinib compared with placebo is associated with significant improvements in echocardiographic measures of RV function, in addition to LV size and LV early diastolic relaxation., Clinical Trial Registration: NCT00902174 (Clinicaltrials.gov)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

There has been substantial progress in the treatment of pulmonary arterial hypertension using specific disease-targeted therapies. As the number of agents available grows, and as new treatment strategies emerge, it is essential that the endpoints we use to assess efficacy are sufficiently meaningful and sensitive enough to detect changes that are often subtle. Although the six-minute walk has been the traditional primary endpoint in clinical trials, there is now a move towards more patient-centred composite endpoints such as time to clinical worsening. These endpoints need to be more clearly defined and universally applied so as to make direct comparison between new drugs and new combinations possible., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH., Methods and Results: In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46±15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease-targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively)., Conclusions: On-treatment changes in cardiac MRI-derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH.

2011 to 2012 has seen an explosion in published research in the field of pulmonary vascular disease, especially pulmonary hypertension. In conjunction with this research has been an explosion in clinical interest in treating pulmonary hypertension. This is possible because we now have three different generic classes of drug therapy: endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclins. Clearly, however, we need to be careful that we are treating the correct disease with the correct drug and measuring the correct response. Herein, I will review the papers published over the last year that offer the most insight into the pathobiology, but also those that give us the clinical information we need in epidemiology, treatment and end-points so that we can treat this devastating group of disease.

Hypoxia-induced endothelial dysfunction plays a crucial role in the pathogenesis of hypoxic pulmonary hypertension. p38 MAPK expression is increased in the pulmonary artery following hypoxic exposure. Recent evidence suggests that increased p38 MAPK activity is associated with endothelial dysfunction. However, the role of p38 MAPK activation in pulmonary artery endothelial dysfunction is not known. Sprague-Dawley rats were exposed to 2 wk hypobaric hypoxia, which resulted in the development of pulmonary hypertension and vascular remodeling. Endothelium-dependent relaxation of intrapulmonary vessels from hypoxic animals was impaired due to a reduced nitric oxide (NO) generation. This was despite increased endothelial NO synthase immunostaining and protein expression. Hypoxia exposure increased superoxide generation and p38 MAPK expression. The inhibition of p38 MAPK restored endothelium-dependent relaxation, increased bioavailable NO, and reduced superoxide production. In conclusion, the pharmacological inhibition of p38 MAPK was effective in increasing NO generation, reducing superoxide burden, and restoring hypoxia-induced endothelial dysfunction in rats with hypoxia-induced pulmonary hypertension. p38 MAPK may be a novel target for the treatment of pulmonary hypertension.

Rationale: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies., Objectives: To investigate the prognosis of CTEPH in a national setting during recent years., Methods: All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records., Measurements and Main Results: A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%., Conclusions: The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition.