Riociguat for Sarcoidosis-Associated Pulmonary Hypertension: Results of a 1-Year Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Riociguat is effective in delaying the time to clinical worsening (TCW) in patients with groups 1 and 4 pulmonary hypertension. RESEARCH QUESTION: Is riociguat more effective than placebo in prolonging TCW in sarcoidosis-associated pulmonary hypertension (SAPH)? STUDY DESIGN AND METHODS: This was a double-blind placebo-controlled trial. Patients with SAPH confirmed by right heart catheterization were randomized 1:1 to riociguat or placebo. Patients underwent 6-min walk distance (6MWD) and spirometry testing every 8 weeks. The primary end point was TCW, which was defined by the time to the first of the following: (1) all-cause mortality, (2) need for hospitalization because of worsening cardiopulmonary status attributable to progression of disease, (3) > 50 m decrease in the 6MWD test, or (4) worsening of World Health Organization functional class. RESULTS: A total of 16 patients were randomized to riociguat (n = 8) or placebo (n = 8). No difference was found in pulmonary artery mean, pulmonary vascular resistance, initial 6MWD, or FVC between the two groups. Five of eight patients who received placebo met TCW criteria, whereas none of the patients who received riociguat experienced a qualifying event. By log-rank analysis, patients who received riociguat were in the study for a significantly longer period (χ 2 = 6.259; P = .0124). The 6MWD decreased in the placebo group (median, -55.9 m; range, -176.8 to 60 m), but rose in the riociguat group (median, +42.7 m; range, -7.5 to +91.4 m; P = .0149), with a placebo-corrected difference of 94 m (P < .01). Four of eight patients who received riociguat, but only 1 of 8 patients who received placebo, showed a > 30-m improvement in 6MWD (P > .05). No significant adverse events associated with riociguat occurred. INTERPRETATION: Over the 1 year of the study, riociguat was effective in preventing clinical worsening and improving exercise capacity in patients with SAPH. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02625558; URL: www.clinicaltrials.gov.

The small airways in chronic obstructive pulmonary disease: pathology and effects on disease progression and survival.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is caused by a mixture of small airway disease (obstructive bronchitis) and parenchymal lung tissue destruction (emphysema). The relative contributions of these two pathologic states vary from person to person. Having the ability to phenotype patients into predominately small airways disease or emphysema may affect the clinical management. RECENT FINDINGS: Pathologic studies have shown that the progression of COPD from Global Initiative for Chronic Obstructive Lung Disease stages 0 to 4 is most strongly associated with small airway wall thickening as a result of lung repair or remodeling. The narrowing and loss of small airways occurs prior to emphysematous destruction. There is an increase in the amount of neutrophils and CD8⁺ T lymphocytes (cells that induce apoptosis and necrosis) in the small airways in COPD. Small airways disease can be identified on pulmonary function testing, using multiple nitrogen breath washout testing, indirectly through high-resolution chest computed tomography (CT) imaging or MRI, or directly by using microCT of resected lung tissue. There may be increased mortality in advanced COPD and concomitant small airway disease. There are newer methods to deliver respiratory therapies to reach the small airways. SUMMARY: The current techniques utilized to assess patients for small airway disease need to be improved, so clinicians can more effectively phenotype patients with COPD and small airways disease. This will allow new therapies that target the small airways to be developed and tested, and positively impact on the natural progression of COPD.

Automated telecommunication to obtain longitudinal follow-up in a multicenter cross-sectional COPD study.

BACKGROUND: It can be challenging to maintain longitudinal follow-up of subjects in clinical studies. COPDGene is a multicenter, observational study designed to identify genetic factors associated with COPD and to characterize COPD-related phenotypes. To obtain follow-up data on patient's vital status and outcomes, the COPDGene Longitudinal Follow-up (LFU) Program was developed to supplement its parent study. METHODS/RESULTS: We used a telecommunication system that employed automated telephone contact or web-based questions to obtain longitudinal follow-up data in our subjects. A branching questionnaire asked about exacerbations, new therapies, smoking status, development of co-morbid conditions, and general health status. Study coordinators contacted subjects who did not respond to one of the automated methods. We enrolled 10,383 subjects in the COPDGene study. As of August 29, 2011, 7,959 subjects completed 19,955 surveys. On the first survey, 68.8% of subjects who completed their survey did so by electronic means, while 31.3% required coordinator phone follow-up. On each subsequent survey the number of subjects who completed their survey by electronic means increased, while the number of subjects who required coordinator follow-up decreased. Despite many of the patients in the cohort being chronically ill and elderly, there was broad acceptance of the system with over half the cohort using electronic response methods. CONCLUSIONS: The COPDGene LFU Study demonstrated that telecommunications was an effective way to obtain longitudinal follow-up of subjects in a large multicenter study. Web-based and automated phone contacts are accepted by research subjects and could serve as a model for LFU in future studies.