Inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease with less severe haemodynamics: a post hoc analysis of the INCREASE study.

BACKGROUND: Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. METHODS: Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and <5 WU versus ≥5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. RESULTS: Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs -10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. CONCLUSION: Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Long-term inhaled treprostinil for pulmonary hypertension due to interstitial lung disease: INCREASE open-label extension study.

INTRODUCTION: The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD. METHODS: Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded. RESULTS: At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL-1 at RCT baseline to 359 pg·mL-1 at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49-0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients. CONCLUSIONS: These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.

A Phase-2 Exploratory Randomized Controlled Trial of INOpulse in Patients with Fibrotic Interstitial Lung Disease Requiring Oxygen.

Rationale: Patients with fibrotic interstitial lung disease often progress to the point of requiring supplemental oxygen. This is invariably accompanied by an impaired quality of life and limitations on activities of daily living. Objectives: This study aimed to assess the improvement in physical activity in patients with interstitial lung disease requiring supplemental oxygen treated with pulsed inhaled nitric oxide via INOpulse (Bellerophon Therapeutics). In addition, it sought to explore the safety and clinical benefits of INOpulse on multiple patient-reported outcomes. Methods: Ambulatory patients with fibrotic lung disease on supplemental oxygen were randomized in a 2:1 ratio to inhaled nitric oxide at 45 µg/kg ideal body weight/h (iNO45) or placebo for 4 months (3 months after baseline) of blinded treatment. The study assessed multiple exploratory efficacy endpoints, including moderate to vigorous physical activity as measured by actigraphy and patient-reported outcomes using the University of California San Diego shortness of breath questionnaire and the St. George's Respiratory Questionnaire (SGRQ). Results: A total of 44 patients (30 iNO45 and 14 placebo) were enrolled. A placebo-corrected clinical benefit of 12.3 min/d increase in MVPA was observed in the iNO45 group. Clinically meaningful beneficial trends were observed for the University of California San Diego shortness of breath questionnaire (6.05 points) and the SGRQ total (3.75) scores, as well as the SGRQ activity (5.84), and SGRQ impact (6.30) domains. Conclusions: INOpulse was well tolerated and associated with maintenance of physical activity and improved symptomatology in patients with interstitial lung disease who require supplemental oxygen. Further validation of this beneficial effect warrants further study in a phase-3 trial that is currently underway.

Prevalence and Mortality of Pulmonary Hypertension in ESRD: A Systematic Review and Meta-analysis.

INTRODUCTION: Pulmonary hypertension (PH) in the setting of end-stage renal disease (ESRD) has important prognostic and therapeutic consequences. We estimated the prevalence of PH among patients with ESRD and compared mortality between ESRD patients with and without PH. METHODS: Two independent reviewers searched three databases using a search strategy built around the medical subject headings of "hypertension, pulmonary" and "kidney failure, chronic." Keywords and synonyms were also used. Study selection criteria included (1) Enrollment of patients with ESRD undergoing hemodialysis or peritoneal dialysis, (2) Assessment for the presence of PH using transthoracic echocardiography, and (3) Determination of PH prevalence or associated mortality. The primary outcomes were prevalence of PH or associated mortality. The Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence. RESULTS: The initial search identified 1046 publications, from which 41 studies were selected. The median prevalence of PH identified by echocardiographic criteria among patients with ESRD was 38% (range 8% to 70%), and was significantly increased in patients undergoing hemodialysis (HD) (median 40%, range 16-70%) as compared with peritoneal dialysis (PD) (median 19%, range 8-37%). Meta-analysis demonstrated that overall mortality was higher among ESRD patients with echocardiographic evidence of PH than ESRD patients without echocardiographic evidence of PH (RR 2.02; 95% CI 1.70-2.40). CONCLUSIONS: Echocardiographic evidence of PH is common among ESRD patients undergoing dialysis and associated with increased mortality. Identification of those patients with evidence of pulmonary hypertension on transthoracic echocardiography may warrant further evaluation and treatment.

Therapeutic Challenges And Advances In The Management Of Systemic Sclerosis-Related Pulmonary Arterial Hypertension (SSc-PAH).

Systemic sclerosis (SSc) is a rare autoimmune disorder with multi-organ involvement. SSc-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of morbidity and mortality in the SSc population. With advances in our understanding of pulmonary arterial hypertension (PAH) diagnosis and treatment, outcomes for all PAH patients have significantly improved. While SSc-PAH patients have also benefited from these advances, significant challenges remain. Diagnosis of PAH is a challenging endeavor in SSc patients who often have many co-existing pulmonary and cardiac comorbidities. Given the significantly elevated prevalence and lifetime risk of PAH in the SSc population, screening for SSc-PAH is a critically useful strategy. Treatment with pulmonary arterial (PA) vasodilators has resulted in a dramatic improvement in the survival and quality of life of PAH patients. While therapy with PA vasodilators is beneficial in SSc-PAH patients, therapy effects appear to be attenuated when compared to responses in patients with idiopathic PAH (IPAH). This review attempts to chronicle and summarize the advances in our understanding of the optimal screening strategies to identify PAH in patients with SSc. The article also reviews the advances in the therapeutic and risk stratification strategies for SSc-PAH patients.

Differences in Right Ventricular Functional Changes during Treatment between Systemic Sclerosis-associated Pulmonary Arterial Hypertension and Idiopathic Pulmonary Arterial Hypertension.

RATIONALE: Patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) continue to have an unacceptably high mortality rate despite the progress achieved with pulmonary arterial vasodilator therapies. OBJECTIVES: We sought to determine whether SSc-PAH is a clinically distinct pulmonary vascular disease phenotype when compared with idiopathic pulmonary arterial hypertension (IPAH) on the basis of progression of echocardiographic right ventricular (RV) dysfunction. METHODS: Retrospective analysis of echocardiographic data in 13 patients with SSc-PAH and 11 patients with IPAH was used to delineate the progression of RV dysfunction during single or combination pulmonary arterial vasodilator therapy. All patients had right heart catheterization-confirmed pulmonary arterial hypertension as well as complete baseline (at the time of diagnosis) and follow-up (most recent) echocardiograms. We excluded patients with significant scleroderma-associated interstitial lung disease. Adjusting for time of follow-up and disease duration, we performed mixed model regression analyses comparing the changes between the two groups for different echocardiographic variables: tricuspid annular plane systolic excursion, tricuspid regurgitation jet velocity, right atrial area, and RV diameter. RESULTS: The mean ages for the SSc-PAH and IPAH groups were 60.8 and 48.2 years, respectively. The mean follow-up periods for the two groups were 3.8 and 1.95 years, respectively. Tricuspid annular plane systolic excursion did not improve in patients with SSc-PAH, whereas it increased in the patients with IPAH (-0.38 mm, P = 0.87; vs. +5.6 mm, P = 0.02). The other echocardiographic variables showed a trend toward worsening in the SSc-PAH group and improvement in the IPAH group. CONCLUSIONS: Our results indicate that, in patients with SSc-PAH, echocardiographic RV function does not improve over time compared with that of patients with IPAH, despite institution of pulmonary artery vasodilator therapies.

A Novel Quantitative Computed Tomographic Analysis Suggests How Sirolimus Stabilizes Progressive Air Trapping in Lymphangioleiomyomatosis.

RATIONALE: The Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) trial demonstrated that sirolimus stabilized lung function and improved measures of functional performance and quality of life in patients with lymphangioleiomyomatosis. The physiologic mechanisms of these beneficial actions of sirolimus are incompletely understood. OBJECTIVES: To prospectively determine the longitudinal computed tomographic lung imaging correlates of lung function change in MILES patients treated with placebo or sirolimus. METHODS: We determined the baseline to 12-month change in computed tomographic image-derived lung volumes and the volume of the lung occupied by cysts in the 31 MILES participants (17 in sirolimus group, 14 in placebo group) with baseline and 12-month scans. MEASUREMENTS AND MAIN RESULTS: There was a trend toward an increase in median expiratory cyst volume percentage in the placebo group and a reduction in the sirolimus group (+2.68% vs. +0.97%, respectively; P = 0.10). The computed tomographic image-derived residual volume and the ratio of residual volume to total lung capacity increased more in the placebo group than in the sirolimus group (+214.4 ml vs. +2.9 ml [P = 0.054] and +0.05 ml vs. -0.01 ml [P = 0.0498], respectively). A Markov transition chain analysis of respiratory cycle cyst volume changes revealed greater dynamic variation in the sirolimus group than in the placebo group at the 12-month time point. CONCLUSIONS: Collectively, these data suggest that sirolimus attenuates progressive gas trapping in lymphangioleiomyomatosis, consistent with a beneficial effect of the drug on airflow obstruction. We speculate that a reduction in lymphangioleiomyomatosis cell burden around small airways and cyst walls alleviates progressive airflow limitation and facilitates cyst emptying.

Role of a 12-lead electrocardiogram in the diagnosis of cardiac tamponade as diagnosed by transthoracic echocardiography in patients with malignant pericardial effusion.

BACKGROUND: Few studies have looked at the utility of the 12-lead electrocardiogram (ECG) in diagnosing cardiac tamponade in malignant pericardial effusion (PE). The aim of this study was to determine the sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) of 12-lead ECG in diagnosing cardiac tamponade in PE. HYPOTHESIS: Abnormalities on a 12 lead ECG can be used to diagnose or exclude cardiac tamponade in patients with malignant PE. METHODS: Using echocardiography as the gold standard for diagnosis of cardiac tamponade, we determined the Se, Sp, PPV, and NPV for individual and combinations of the 3 ECG abnormalities (low-voltage complexes, electrical alternans, and sinus tachycardia). RESULTS: For PEs of all sizes, the Se, Sp, PPV, and NPV for detecting cardiac tamponade were: low-voltage complexes (56%, 74%, 81%, 46%), electrical alternans (23%, 98%, 95%, 39%), and sinus tachycardia (76%, 60%, 79%, 56%), respectively. Presence of all 3 and any of the 3 ECG abnormalities had a Se, Sp, PPV, and NPV of 8%, 100%, 100%, 36% and 89%, 47%, 77%, 69%, respectively, for cardiac tamponade. The odds ratios for cardiac tamponade in PE were 3.7 (95% confidence interval [CI]: 1.65-8.30) for low-voltage complexes, 12.3 (95% CI: 1.58-95.17) for electrical alternans, and 4.9 (95% CI: 2.22-10.80) for sinus tachycardia. Presence of any of 3 ECG abnormalities had an odds ratio of 7.3 (95% CI: 2.9-18.1) for cardiac tamponade. CONCLUSIONS: In malignant PE, combination of ECG abnormalities can supplement clinical examination in the diagnosis of echocardiographic cardiac tamponade. Due to its low NPV, 12-lead ECG cannot be used as a screening tool to exclude cardiac tamponade with malignant PE.

Multiorgan system dysfunction in the chylomicronemia syndrome.

OBJECTIVE: To describe an extreme presentation of the chylomicronemia syndrome resulting in multiorgan system dysfunction. PATIENT: A 40-year-old African American male with no past medical history presented with multiorgan system dysfunction manifested by acute respiratory failure and acute kidney injury. He was noted to have very-high triglyceride levels (>5000 mg/dL) at admission. INTERVENTIONS: An echocardiogram showed normal cardiac function. Amylase and lipase were normal. We confirmed the chylomicronemia syndrome with a triglyceride assay. The associated hyperviscosity was treated with plasmapheresis to reduce the plasma triglyceride level. RESULTS: After 3 sessions of plasmapheresis, his triglyceride levels were significantly reduced, his oxygenation improved, and his acute kidney injury resolved. He was successfully extubated on day 7 of the intensive care unit stay. His diabetes and hypertriglyceridemia were newly diagnosed and drug therapy was instituted with home discharge on day 14. CONCLUSIONS: Severe chylomicronemia can cause multiorgan system dysfunction related to hyperviscosity. Early institution of plasmapheresis to reduce the triglyceride-rich lipoproteins can improve tissue perfusion and prevent further organ damage.

Baseline regional perfusion impacts exercise response to endobronchial valve therapy in advanced pulmonary emphysema.

BACKGROUND: Advanced heterogeneous emphysema with hyperinflation impacts exercise tolerance in COPD. Bronchoscopic lung volume reduction using Zephyr endobronchial valves (EBVs) has been shown to improve lung function in patients with heterogeneous emphysema. It is unclear whether the target lobe perfusion of patients receiving EBV therapy impacts exercise tolerance as measured by the 6-min walk test distance (6MWTD). METHODS: We performed a retrospective analysis on the treatment group of the Endobronchial Valve for Emphysema Palliation Trial (VENT) to evaluate the impact of perfusion, measured by 99mTc-MAA-perfusion scintigraphy, on the 6-month improvement in 6MWTD. A mixed-model analysis was performed for the treatment outcome, adjusting for other variables such as age, target lobe position, fissure integrity, BMI, sex, destruction score, and lobar exclusion. RESULTS: Dichotomized at the median, of the 169 patients who received EBV therapy, 88 had a low target lobe regional perfusion and 81 had high target lobe regional perfusion at baseline. Patients with a low target lobe regional perfusion had a significant improvement in 6MWTD when compared with those with a high baseline target lobe regional perfusion (30.24 m vs 3.72 m, P = .03). Shifts in perfusion after EBV therapy occurred only in patients with high baseline perfusion and did not correlate with improved 6MWTD. CONCLUSIONS: Patients having heterogeneous emphysema with a low baseline target lobe regional perfusion benefit from EBV therapy, independent of the degree of target lobe destruction. This effect is attenuated if the EBV therapy is not occlusive. Characterization of baseline perfusion may enhance clinical results of patients with emphysema undergoing EBV therapy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00000606; URL: www.clincialtrials.gov.