Showing papers by "Lewis J. Rubin published in 2012"

ARIES-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension.

Abstract: SUMMARY Introduction: Ambrisentan is an oral, once daily, endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension (PAH). Previous studies of ambrisentan were limited to patients with Group 1 PAH and often excluded patients receiving other pulmonary hypertension (PH) therapies. Aims: ARIES-3 was an open-label study evalu- ating efficacy and safety of ambrisentan in patients with various PH etiologies and back- ground PH medications. Patients received 5 mg ambrisentan once daily for 24 weeks. The primary endpoint was change from baseline in 6-minute walk distance (6MWD) at week 24. Results: A total of 224 patients with PH due to idiopathic and familial PAH (31%), con- nective tissue disease (18%), chronic hypoxemia (22%), chronic thromboembolic disease (13%), or other etiologies (16%) were enrolled and 53% of patients received stable back- ground PAH therapies. After 24 weeks of therapy, an increase in 6MWD (+21 m; 95% CI: 12-29) and a decrease in B-type natriuretic peptide (-26%; 95% CI: -34 to -16%) was ob- served in the overall population compared to baseline; however, increases in 6MWD were not observed in several non-Group 1 PH subpopulations. Peripheral edema, headache, and dyspnea were the most common adverse events. Conclusion: This study reconfirms the results of previous placebo-controlled studies, which demonstrate that ambrisentan is well tolerated and provides benefit in patients with PAH. Definitive conclusions regarding the safety and efficacy of ambrisentan in specific non-Group 1 PH etiologies cannot be deter- mined and larger, controlled studies will be necessary to determine the efficacy and safety of ambrisentan in these populations.

Pulmonary arterial hypertension therapy may be safe and effective in patients with systemic sclerosis and borderline pulmonary artery pressure.

Abstract: Objective Borderline pulmonary arterial hypertension (PAH), characterized by a marked exercise-induced increase in pulmonary artery pressure (PAP) with normal resting values, may precede overt PAH in systemic sclerosis (SSc). We undertook the present study to investigate whether PAH treatment is safe in these patients and might attenuate hemodynamic progression. Methods SSc patients with borderline PAH underwent right heart catheterization at baseline, after a 12-month observation period, and subsequently after 6 months of bosentan therapy. Changes in mean PAP at 50W during the observation period versus during therapy were compared. Results Ten patients completed the study. Mean PAP at rest, at 50W, and during maximal exercise increased significantly during the observation period (mean ± SD increases of 2.5 ± 3.0 mm Hg [P = 0.03], 4.0 ± 2.9 mm Hg [P = 0.002], and 6.8 ± 4.1 mm Hg [P = 0.0005], respectively) and tended to decrease during the treatment period (decreases of 2.5 ± 3.9 mm Hg [P = 0.07], 1.5 ± 4.5 mm Hg [P = 0.32], and 1.8 ± 7.0 mm Hg [P = 0.43], respectively). The changes during the observation period versus the therapy period were significantly different (P = 0.03 at rest, P = 0.01 at 50W [primary end point], and P = 0.02 during maximal exercise). The changes in resting pulmonary vascular resistance were also significantly different during the observation period (increase of 8 ± 25 dynes · seconds · cm−5) versus during the therapy period (decrease of 45 ± 22 dynes · seconds · cm−5) (P < 0.0005). Changes in resting pulmonary arterial wedge pressure were not significantly different between the observation period and the treatment period, despite the significant increase during the observation period (2.6 ± 2.5 mm Hg [P = 0.01]). No relevant adverse effects were reported. Conclusion In SSc patients with borderline abnormal pulmonary hemodynamics, resting and exercise PAP may increase significantly within 1 year of observation. Bosentan might be safe and effective to attenuate these changes. Randomized controlled trials are warranted to confirm the exploratory findings of this hypothesis-generating pilot study.

The pulmonary arterial hypertension quality enhancement research initiative: comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH

Abstract: Objective The objective of this report is to compare baseline, management and survival characteristics in idiopathic pulmonary arterial hypertension (IPAH) with systemic sclerosis-associated pulmonary arterial hypertension (SSc-APAH) using data from the prospectively enrolled PAH Quality Enhancement Research Initiative. Methods Between August 2005 and July 2007, patients with IPAH and SSc-APAH were enrolled across 60 US sites and followed up for 3 years. Data on diagnostic tests, clinical variables, pulmonary arterial hypertension (PAH) medication and outcomes were recorded. Results With some exceptions, baseline clinical and laboratory characteristics were similar between the 279 patients with IPAH and the 228 with SSc-APAH. Patients with SSc-APAH were older at the time of PAH diagnosis, were more likely to be female and were antinuclear antibody positive. Patients with SSc-APAH had poorer spirometric results. During the 3-year follow-up, both groups were managed with prostacyclin and prostacyclin analogue treatment, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors (PDE5i) singly or in combination. At 3 years, patients with SSc-APAH were more likely to be treated with PDE5i alone or with an endothelin receptor antagonist. Patients with SSc-APAH had a significantly lower survival rate compared to patients with IPAH (60% vs 77%, p Conclusions The cohort with SSc-APAH was older, was more severely ill, was more likely to be female, was managed with PDE5i and had reduced 3-year survival compared with the cohort with IPAH.

Inhaled treprostinil: a therapeutic review.

Abstract: Pulmonary arterial hypertension (PAH) is a life-threatening disease which, if untreated, leads to right ventricular failure and often death. Several effective therapies are now available for PAH, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. The prostacyclin analog treprostinil has proven efficacious when delivered by subcutaneous or intravenous infusion, and most recently by inhalation. Inhaled treprostinil has been shown to be 64%–72% bioavailable in healthy volunteers. Pilot clinical studies have elucidated the acute hemodynamic effects and relative pulmonary selectivity of this agent, as well as established target dosing in PAH and nonoperable chronic thromboembolic PAH. Likewise, chronically administered inhaled treprostinil resulted in clinical and hemodynamic improvement. Both pilot studies confirmed a satisfactory safety profile in patients with PAH. The pivotal Phase III trial, TRIUMPH-I, demonstrated the efficacy and safety of inhaled treprostinil (target dose of 54 μg four times daily) in PAH patients added to background therapies of bosentan or sildenafil, as assessed by improvements in the primary endpoint, peak six-minute walk distance (median placebo-corrected treatment effect of 20 m), as well as select secondary endpoints. Inhaled treprostinil is approved by the US Food and Drug Administration for patients with World Health Organization Group I PAH to improve exercise ability. Studies establishing effectiveness included predominately patients with New York Heart Association functional class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

Safety and Efficacy of Transition from Systemic Prostanoids to Inhaled Treprostinil in Pulmonary Arterial Hypertension

Abstract: Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.

The 6-minute walk test in pulmonary arterial hypertension: how far is enough?

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Safety and efficacy evaluation of ambrisentan in pulmonary hypertension.

Abstract: Introduction: Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, which can lead to right heart failure and death. Endothelin-1 binding ETA and ETB receptors seem to play a critical role in the pathogenesis and progression of the disease, and oral endothelin receptor antagonists (ERAs) have been shown to be an effective treatment. Bosentan and ETA-selective ambrisentan are the ERAs currently available for PAH treatment. Areas covered: On the basis of the analysis of the literature, this paper addresses the efficacy and safety of ambrisentan in the treatment for PAH. Expert opinion: Ambrisentan has shown an efficacy comparable with other ERAs. Compared with bosentan, ambrisentan seems to have a better safety profile with regards to hepatic safety and drug–drug interactions. On the other hand, ambrisentan shows a higher rate of other adverse events, such as nasal congestion and peripheral edema. Ambrisentan is a viable option for PAH treatment. However, th...

Pulmonary arterial hypertension: bridging the present to the future.

Abstract: The past decade has witnessed extensive progress in basic and clinical research in the field of pulmonary hypertension (PH), a group of chronic conditions characterised by high pressure in the pulmonary circulation. National and international PH registries have achieved much to advance our understanding of the epidemiology, demographics, aetiology, clinical course, haemodynamics, disease management and treatment outcomes of PH [1–7]. Therapies available to target the pathology of pulmonary arterial hypertension (PAH) have expanded considerably and more options are expected in the near future [8, 9]. Although this progress has steadily improved the outlook for PAH patients, there remains a need for further developments to ensure that advances continue to be made. The articles and case reports in this issue of the European Respiratory Review discuss key and current issues in the management of patients with PH. The authors, all experts in the field of PH, delivered the presentations upon which the articles are based at the 11th International Pulmonary Hypertension Forum in Dublin, Ireland on May 12–13, 2012. This annual platform for the exchange of knowledge and experience among clinicians and researchers was attended by over 1,000 healthcare professionals from all over the world, highlighting the continuing interest in this devastating group of diseases. The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines provide a clear classification of the major clinical subcategories of PH [10, 11], based on shared pathophysiological mechanisms, similar clinical presentations and therapeutic approaches [12]. It is Group 1 PH, namely PAH, that has been subject to the most rapid advancement in terms of knowledge and treatment options in the past decade. Because this group of patients is treatable, accurate and prompt diagnosis are particularly critical; PAH patients receiving treatment in World …

Exercise training for pulmonary hypertension: another prescription to write?

Abstract: For over 30 years I have been advising my patients with pulmonary hypertension (PH) to be physically active to a level of exertion that does not produce severe dyspnoea persisting post-exercise, dizziness, syncope or chest pain, based on the assumption that inactivity was bad both physically and mentally. This empirical advice meant little in the years before effective medical and surgical methods of treating PH were developed, but gained importance both as a conditioning practice for patients considered for transplantation or pulmonary endarterectomy, and as an adjunct to long-term medical therapy [1]. Only recently, however, has evidence supporting a meaningful benefit of physical activity been generated, dispelling the notion that there may be more harm than good resulting from attempting to increase blood flow through a restricted and presumed noncompliant pulmonary vascular bed [2]. In this issue of the European Respiratory Journal , Grunig et al . [3] bring …

Developing a heart score: next steps.

Abstract: The meeting of the Advisory Board of Experts in Pulmonary Hypertension (ABEPH) in 2011 discussed the potential development of a prognostic score for pulmonary arterial hypertension (PAH) based on parameters associated with right ventricular function. During the discussion, a shortlist of parameters derived from hemodynamic, echocardiography, magnetic resonance imaging, and biomarker analysis was developed. This shortlist is the starting point for developing a score that reflects heart function; such a score could have potential in the future clinical management of patients with PAH.

Current and Future Management of Chronic Thromboembolic Pulmonary Hypertension

Abstract: Although pulmonary endarterectomy (PEA) has been proven a very effective treatment for chronic thromboembolic pulmonary hypertension, it cannot be performed in a substantial proportion of patients. Here, we outline a proposed treatment algorithm, outlining therapeutic alternatives: (1) PEA should be considered as the first treatment option, where possible; (2) medical intervention is a possible option in inoperable patients and those with significant arteriopathy, although only chronic anticoagulation has been widely used to date (advanced medical treatment options could include prostanoids, endothelin receptor antagonists, or phosphodiesterase-5 inhibitors, but randomized clinical trials are required); (3) pulmonary hypertension is likely to persist after PEA in patients with significant small-vessel arteriopathy, resulting in poor clinical outcome and increased perioperative mortality (medical therapy could also be applied here); (4) anticoagulation therapy and, possibly, advanced medical treatment with...