Arschang Valipour

Efficacy predictors of lung volume reduction with zephyr valves in a european cohort

The Endobronchial Valve for Emphysema Palliation Trial (VENT) was a multi-centre, prospective, randomised, controlled trial conducted to evaluate the safety and effectiveness of unilateral endobronchial valve (EBV) treatment. The purpose of this analysis was to assess outcomes in the previously unreported European VENT study cohort. Patients with advanced emphysema were randomly assigned (2:1) to receive Zephyr® (Pulmonx Inc., Redwood City, CA, USA) EBV treatment (n=111) or medical management (n=60). At 6 months, EBV patients demonstrated a significant improvement compared with the controls for mean±sd change in forced expiratory volume in 1 s (7±20% versus 0.5±19%; p=0.067), cycle ergometry (2±14 W versus -3±10 W; p=0.04) and St George’s Respiratory Questionnaire (-5±14 points versus 0.3±13 points; p=0.047). At 12 months, the magnitude of the difference between groups for change from baseline was of similar magnitude to the differences seen at 6 months. Rates for complications did not differ significantly. EBV patients with computed tomography (CT) scans suggestive of complete fissure and lobar occlusion had a mean±sd lobar volume reduction of -80±30% and >50% met minimal clinical difference thresholds. The degree of emphysema heterogeneity did not preclude excellent outcomes. Unilateral lobar volume reduction using EBV treatment is safe and superior clinical results correlated with CT suggestive of complete fissures and successful lobar occlusion. Emphysema heterogeneity was not critical for determining positive outcomes.

Bronchoscopic thermal vapour ablation therapy in the management of heterogeneous emphysema

The need for a less invasive procedure than surgical lung volume reduction that can produce consistent improvements with reduced morbidity remains a medical goal in patients with emphysema. We sought to determine the effect of bronchoscopic thermal vapour ablation (BTVA) on lung volumes and outcomes in patients with emphysema. 44 patients with upper lobe-predominant emphysema were treated unilaterally with BTVA. Entry criteria included: age 40–75 yrs, forced expiratory volume in 1 s (FEV1) 15–45% predicted, previous pulmonary rehabilitation and a heterogeneity index (tissue/air ratio of lower lobe/upper lobe) from high-resolution computed tomography (HRCT) ≥1.2. Changes in FEV1, St Georges Respiratory Questionnaire (SGRQ), 6-min walk distance (6MWD), modified Medical Research Council (mMRC) dyspnoea score, and hyperinflation were measured at baseline, and 3 and 6 months post-BTVA. At 6 months, mean±se FEV1 improved by 141±26 mL (p<0.001) and residual volume was reduced by 406±113 mL (p<0.0001). SGRQ total score improved by 14.0±2.4 points (p<0.001), with 73% improving by ≥4 points. Improvements were observed in 6MWD (46.5±10.6 m) and mMRC dyspnoea score (0.9±0.2) (p<0.001 for both). Lower respiratory events (n=11) were the most common adverse event and occurred most often during the initial 30 days. BTVA therapy results in clinically relevant improvements in lung function, quality of life and exercise tolerance in upper lobe predominant emphysema.

Efficacy of Bronchoscopic Thermal Vapor Ablation and Lobar Fissure Completeness in Patients with Heterogeneous Emphysema

Background: Bronchoscopic thermal vapor ablation (BTVA) ablates emphysematous tissue through a localized inflammatory response followed by contractive fibrosis and tissue shrinkage leading to lung volume reduction that should not be influenced by collateral ventilation. Objectives: To determine the correlation of clinical data from a trial of BTVA with fissure integrity visually assessed by computed tomography (CT). Methods: We conducted a single-arm study of patients with upper lobe-predominant emphysema (n = 44). Patients received BTVA either to the right upper lobe or left upper lobe, excluding the lingula. Primary efficacy outcomes were forced expiratory volume in 1 s (FEV1) and St. George’s Respiratory Questionnaire (SGRQ) at 6 months. Lobar volume reduction from CT was another efficacy outcome measurement. The fissure of the treated lobe was analyzed visually on preinterventional CT. Incompleteness of the small fissure, the upper half of the right large fissure and the whole left large fissure were estimated visually in 5% increments, and the relative amount of fissure incompleteness was calculated. Pearson correlation coefficients were calculated for the association between fissure incompleteness and change in efficacy outcomes (baseline to 6 months) of BTVA. Results: A total of 38 out of 44 patients (86%) had incompleteness in the relevant fissure. Calculated relevant fissure incompleteness was a mean of 13% of fissure integrity (range 0–63). Correlation coefficients for the association of incompleteness with outcomes were as follows: FEV1 = 0.17; lung volume reduction = –0.27; SGRQ score = –0.10; 6-min walk distance = 0.0; residual volume (RV) = –0.18, and RV/total lung capacity = –0.14. Conclusions: Lobar fissure integrity has no or minimal influence on BTVA-induced lung volume reduction and improvements in clinical outcomes.

Segmental volume reduction using thermal vapour ablation in patients with severe emphysema: 6-month results of the multicentre, parallel-group, open-label, randomised controlled STEP-UP trial.

BACKGROUNDnLung volume reduction of emphysematous lobes results in clinical improvement for patients with severe emphysema. However, some segments within a lobe are often substantially more diseased than others, thereby warranting a more targeted approach of the emphysematous parts of a lobe. We therefore did a study to assess whether or not selective sequential treatment of the more diseased upper lobe segments with bronchoscopic vapour ablation led to clinical improvement.nnnMETHODSnFor the multicentre, parallel-group, randomised, controlled, open-label Sequential Staged Treatment of Emphysema with Upper Lobe Predominance (STEP-UP) trial, adult patients aged 45-75 years with severe, upper lobe-predominant emphysema with a forced expiratory volume in 1 s (FEV1) between 20% and 45%, substantial hyperinflation, and post-rehabilitation 6-min walk test (6MWT) greater than 140 m were enrolled from 13 hospital sites in Europe (ten sites) and Australia (three sites). A computer-generated blocked randomisation scheme (block size three per site based on a random table from an independent biostatistician) stratified by site was used to randomly assign enrolled patients 2:1 to segmental vapour ablation (treatment group) or standard medical management (control group). Patients and investigators were not masked to group assignment. The primary efficacy endpoints were statistically significant changes in FEV1 and St Georges Respiratory Questionnaire (SGRQ-C) scores between trial groups at 6 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01719263.nnnFINDINGSnBetween June 30, 2013, and Oct 1, 2014, 134 patients were screened and 70 were enrolled and randomly assigned: 46 to the treatment group and 24 to the control group. One patient in the treatment group did not receive treatment because of physician decision post-randomisation; this patient is excluded from all analyses. The mean relative improvement in FEV1 between the treatment group versus the control group was 14·7% (95% CI 7·8-21·5%; p<0·0001) and in SGRQ-C was -9·7 points (95% CI -15·7 to -3·7; p=0·0021). COPD exacerbation was the most common serious adverse event, occurring in 11 (24%) of 45 patients in the treatment group and one (4%) of 24 in the control group. One exacerbation resulted in a patient death 84 days after treatment; this was judged by the data and safety monitoring board to be possibly related to treatment. No pneumothorax occurred within 30 days of treatment.nnnINTERPRETATIONnCompared with standard medical management, targeted thermal vapour ablation of more diseased segments and preservation of less diseased segments resulted in clinically meaningful and statistically significant improvements in lung function and quality of life at 6 months, with an acceptable safety profile.nnnFUNDINGnUptake Medical.

Pneumothorax following endobronchial valve therapy and its impact on clinical outcomes in severe emphysema.

Background: Patients who achieve significant target lobe volume reduction (TLVR) following endobronchial valve (EBV) treatment may experience substantial improvements in clinical outcome measures. However, in cases of rapid TLVR, the risk of pneumothorax increases due to parenchymal rupture of the adjacent untreated lobe. Target lobe collapse may be more likely in EBV-treated patients who have low collateral ventilation. Objectives: The aim of this study was to evaluate the impact of pneumothorax on outcome following EBV treatment. Methods: Data from three prospective clinical trials (the US and European cohorts of VENT and the Multicenter Chartis study) were retrieved for the analysis. All patients had undergone chest X-ray within 24 h of EBV implantation to explore the presence of pneumothorax. TLVR was assessed at either 30 (Chartis study) or 180 days (VENT), and clinical outcome measures (forced expiratory volume in 1 s (FEV1), St. Georges Respiratory Questionnaire (SGRQ) and 6-min-walk distance (6-MWD)) were assessed 180 days after implantation. Results: The overall rate of pneumothorax following valve therapy was 5.9% (25/421). Among these patients, 68% had a prolonged air leak for >7 days. However, patients who experienced a pneumothorax benefitted from EBV therapy, with a mean TLVR of 65% (n = 20). The mean percent change in FEV1 was 15 ± 15%, and the mean change in SGRQ was -7 ± 12 points. Conclusions: Although pneumothorax is a complication of EBV placement, it does not appear to have a negative impact on clinical outcome in terms of FEV1 and health-related quality of life.

Effect of fissure integrity on lung volume reduction using a polymer sealant* in advanced emphysema

Rationale Interlobar fissure integrity has previously correlated with responsiveness to endobronchial lung volume reduction therapy in patients with advanced emphysema. Objective This report summarises the effect of interlobar fissure integrity on responses to treatment with a novel endoscopic tissue sealant (AeriSeal emphysematous lung sealant (ELS)) that collapses hyperinflated lung. Methods Fissure status, lung volumes, tissue density and disease heterogeneity were assessed radiographically in 28 patients (age 63.4±6.1u2005years, 20 men) with advanced upper lobe predominant emphysema (density=888.0±18.2 HU; upper lobe tissue density <−950=2.62±1.74). Post-treatment changes in lobar volume, pulmonary function, exercise capacity, symptoms and quality of life were compared in patients with complete fissures (CFs) and incomplete fissures (ICFs). Results ELS therapy reduced lung volumes independent of interlobar fissure integrity. In patients with upper lobe emphysema and CFs, lobar volume reduction was 214±127u2005ml/treatment compared with 256±175u2005ml/treatment in those with ICFs (p=0.453). Reductions in gas trapping and improvements in spirometry, functional capacity and quality of life were similar in patients with CFs and ICFs. Stepwise multiple regression modelling confirmed that fissure integrity did not contribute to post-treatment changes in forced expiratory volume in 1 s, residual volume/total lung capacity ratio or lobar volume measured by CT analysis. Conclusions Interlobar fissure integrity, an important determinant of responsiveness to endobronchial lung volume reduction therapy in prior studies, had minimal impact on physiological and functional responses to ELS therapy in patients with severe upper lobe predominant emphysema. Clinical trial registration number Registration numbers for trials contributing to datasets in this report: NCT00884962, NCT01051258 and NCT01181466.

Characterization of outcomes 1 year after endoscopic thermal vapor ablation for patients with heterogeneous emphysema

Introduction Endoscopic lung volume reduction has been developed as a therapeutic option for advanced emphysema. Six-month results following treatment with endoscopic thermal vapor ablation (InterVapor™; Uptake Medical, Tustin, CA) were described previously, and here we report observations from the 12-month assessment. Methods Two multicenter, international, single-arm trials of InterVapor (unilateral upper lobe treatment) in patients with upper lobe predominant emphysema were conducted. Inclusion criteria: forced expiratory volume in 1 second (FEV1) 15%–45% predicted, residual volume > 150%, total lung capacity > 100%, 6-minute walk distance (6MWD) >140 m, and diffusing capacity for carbon monoxide > 20% predicted. Efficacy endpoints: spirometry, body plethysmography, lung volumes by high-resolution computed tomography, St George’s Respiratory Questionnaire, modified Medical Research Council dyspnea scale, and 6MWD. All adverse events were collected and independently adjudicated. Results Forty four patients were treated at a mean (standard deviation) age of 63 (5.6) years, FEV1 0.86 mL (0.25 mL) (n = 22 men and 22 women). Mean (standard deviation) changes from baseline at 12 months were: FEV1 86.2 mL (173.8 mL), St George’s Respiratory Questionnaire −11.0 (14.0) units, treated lobar volume from high-resolution computed tomography −751.8 mL (653.9 mL), residual volume −302.8 mL (775.6 mL), 6MWD 18.5 m (63.7 m), and modified Medical Research Council dyspnea scale score −0.83 (0.97) (P < 0.05 for all except 6MWD). Improvements were numerically larger at 6 versus 12 months. GOLD stage III and IV patients had similar outcomes at 6 months; however, improvements relative to baseline were numerically higher in GOLD stage IV patients. Larger improvements were observed in patients with higher heterogeneity. In total, 39 serious adverse events were reported in 23 patients with 10 events in 8 patients between 6 and 12 months. Conclusion Unilateral lobar InterVapor treatment of heterogeneous emphysema improved lung function and health outcomes 1 year following treatment. The magnitude of improvement was larger at 6 months compared to 12 months. Improvements relative to baseline continue to be exhibited at 12 months despite the expected disease related decline over time. Clinical trials NCT 01041586 and NCT 01102712

Target lobe volume reduction and COPD outcome measures after endobronchial valve therapy.

Endobronchial valve (EBV) therapy may be associated with improvements in chronic obstructive pulmonary disease-related outcomes and may therefore be linked to improvements in the body mass index, airflow obstruction, dyspnoea, exercise capacity (BODE) index. Data from 416 patients with advanced emphysema and hyperinflation across Europe and USA, who were randomised to EBV (n=284) or conservative therapy (n=132) were analysed. Quantitative image analysis was used to compare the volume of the targeted lobe at baseline and at 6 months to determine target lobe volume reduction (TLVR). 44% of patients receiving EBV therapy (versus 24.7% of controls) had clinically significant improvements in the BODE index (p<0.001). BODE index was significantly reduced by mean±sd 1.4±1.8, 0.2±1.3 and 0.1±1.3 points in patients with TLVR >50%, 20%–50% and <20%, respectively (intergroup differences p<0.001), but increased by 0.3±1.2 points in controls. Changes in BODE were predicted by baseline BODE and correlated significantly with lobar exclusion and lung volumes at 6 months. A greater proportion of patients in the treatment group than in the control group achieved a clinically meaningful improvement in BODE index; however, the likelihood of benefit was less than half in both groups. Patients in whom TLVR was obtained had greater improvements in clinical outcomes. Patients treated with EBV were more likely to have a significantly reduced BODE score (44% treated versus 25% controls) http://ow.ly/qXRUy

Expert Statement: Pneumothorax Associated with Endoscopic Valve Therapy for Emphysema - Potential Mechanisms, Treatment Algorithm, and Case Examples

The use of endoscopically placed unidirectional valves for the treatment of emphysema is increasing. With better patient selection, there is also an increased likelihood of complications associated with the procedure, such as postprocedural pneumothorax. There is, however, little evidence of pneumothorax management in patients with severe COPD and emphysema. This report describes an expert recommendation that has been developed to outline pneumothorax management after valve placement to inform physicians and patients of the risk-benefit profile and to assist them in decision making. Skilled and aggressive pneumothorax management is necessary in this patient population, and by following these recommendations traumatic scenarios, prolonged drainage, extended hospitalizations, and/or surgery might be avoided in many cases.

Targeted lung denervation for moderate to severe COPD: a pilot study

Background Parasympathetic pulmonary nerves release acetylcholine that induces smooth muscle constriction. Disruption of parasympathetic pulmonary nerves improves lung function and COPD symptoms. Aims To evaluate ‘targeted lung denervation’ (TLD), a novel bronchoscopic therapy based on ablation of parasympathetic pulmonary nerves surrounding the main bronchi, as a potential therapy for COPD. Methods This 1-year, prospective, multicentre study evaluated TLD in patients with COPD forced expiratory volume in 1u2005s (FEV1)/forced vital capacity (FVC) (FEV1/FVC <0.70; FEV1 30%–60% predicted). Patients underwent staged TLD at 20 watts (W) or 15u2005W following baseline assessment off bronchodilators. Assessments were repeated on tiotropium before treatment and off bronchodilators at 30, 90, 180, 270 and 365u2005days after TLD. The primary endpoint was freedom from documented and sustained worsening of COPD directly attributable to TLD to 1 year. Secondary endpoints included technical feasibility, change in pulmonary function, exercise capacity, and quality of life. Results Twenty-two patients were included (n=12 at 20u2005W, n=10 at 15u2005W). The procedures were technically feasible 93% of the time. Primary safety endpoint was achieved in 95%. Asymptomatic bronchial wall effects were observed in 3 patients at 20u2005W. The clinical safety profiles were similar between the two energy doses. At 1u2005year, changes from baseline in the 20 W dose compared to the 15 W dose were: FEV1 (+11.6%±32.3 vs +0.02%±15.1, p=0.324), submaximal cycle endurance (+6.8u2005min±12.8 vs 2.6u2005min±8.7, p=0.277), and St Georges Respiratory Questionnaire (−11.1 points ±9.1 vs −0.9 points ±8.6, p=0.044). Conclusions Bronchoscopic TLD, based on the concept of ablating parasympathetic pulmonary nerves, was feasible, safe, and well tolerated. Further investigation of this novel therapy is warranted. Trial registration number NCT01483534.