Abstract
Endobronchial valve (EBV) therapy has shown improvement in symptoms and lung function despite limited understanding of ideal patient selection. The impact of lobe selection on EBV therapy is unclear. We performed a retrospective analysis to determine the role of lobe selection and identify preprocedure predictors of response to EBV therapy. A total of 492 patients from the USA and Europe were randomized to EBV or control therapy. Spirometry and functional measurements were taken at baseline and 12 months later. At 365 days patients undergoing EBV therapy showed improvement in FEV1 change compared to control regardless of treatment to upper or lower. There was no difference in FEV1 change between the upper and lower lobe treatment groups (Citation5.99, 7.04, p = 0.75). In addition lobe selection was not identified as a significant modifier of FEV1 change in multiple linear regression analysis. Complete lobe fissure was the only significant predictor of FEV1 change (OR 4.14 (2.29, 7.47)). Our results suggest that lobe selection does not play a major role in EBV therapy response. Complete fissure status preprocedure has the greatest influence on FEV1 improvement. These results have implications on patient selection for current treatment and in future EBV studies.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality throughout the world (Citation1). In appropriately selected patients, lung volume reduction surgery (LVRS) improves symptoms and survival, particularly in a subgroup of patients with heterogeneous upper lobe predominant disease (Citation2). However, procedural related morbidity and mortality are significant (Citation3). As a result less invasive bronchoscopic techniques including endobronchial valve (EBV) therapy have been developed to achieve the benefits of LVRS without the same significant morbidity and mortality (Citation4–6).
The Endobronchial Valve for Emphysema Palliation Trial (VENT study), was a prospective trial which showed that unilateral valve treatment resulted in modest improvement in lung function, symptoms, and exercise tolerance (Citation7). The European cohort of this study reported similar improvements in spirometry, quality of life questionnaire, and cycle ergometry (Citation8). However both studies found that more detailed patient selection may yield better results. The U.S. study showed that fissure completeness and a greater degree of emphysematous destruction in the targeted lobe compared to the ipsilateral non-treated lobe were associated with improved treatment effect. The European cohort echoed the positive effect of fissure completeness and also reported the importance of lobar occlusion. However heterogeneity was not associated with improved results in that study.
EBV treatment with upper lobe targeting may also be more beneficial than lower lobe targeting. This is true of LVRS where upper lobe treated individuals have better outcomes (Citation6). LVRS in those with non-upper-lobe predominant disease showed minor benefits in health related quality of life measures but little changes in exercise tolerance or mortality (Citation9,10). Most endoscopic trials have focused on heterogeneous upper lobe predominant disease with promising results. Valipour et al. provide a physiological reason for greater improvement in upper lobe treated disease (Citation11). Through computer tomography (CT) simulations they surmise that apical alveoli have higher residual volume/Total lung capacity (RV/TLC) ratios compared to lower lobes. Thus treatment of upper lobe would cause larger reduction in overall the RV/TLC ratio that should produce greater improvements in patient symptom.
Both the VENT and European cohort of VENT had a significant number of subjects with upper as well as lower lobe treatments. We retrospectively reviewed the prospectively collected data of both trials. We hypothesized that patients receiving EBV treatment to either upper lobe would demonstrate a greater improvement in FEV1 than those treated in either lower lobe.
Methods
Study design
We performed retrospective analysis of the combined patient dataset from the USA and European VENT studies. Details of the trial design have been reported previously (Citation7,8). In brief major criteria for inclusion were heterogeneous emphysema, FEV1 measurements between 15 and 45%, total lung capacity greater than 100% predicted and residual volumes greater than 150%. Both VENT trials used identical inclusion and exclusion parameters. Patients were distributed in a 2:1 ratio between EBV treatment and medical management groups and protocols for treatment between the cohorts were also identical.
Our retrospective analysis used FEV1 as the primary endpoint evaluated at six and twelve months. As a result only patients with initial FEV1 measurements were included. Clinical endpoints including 6-minute walk test and BODE score were also analyzed. Patients were included even if FEV1 data from 6 months or 12 months was not available. Differences between baseline and the endpoint were expressed as a percentage change. In addition patients were excluded if they did not have values for any of the selection variables below.
Selection variable definitions
The following variables and their impact on FEV1 were analyzed: lobe selection, lung heterogeneity, fissure integrity and total lobe volume change. All variables were selected due to their importance in EBV treatment based on previous literature. Lobe selection was our initial variable and for the purposes of our study patients were grouped into two categories: upper lobe or lower lobe treated. All patients receiving EBV therapy to either their left or right upper lobes were placed in the upper lobe group. Patients that underwent EBV treatment of their left lower lobe or right lower lobe were placed in the lower lobe group. No patients in the group received EBV therapy to the right middle lobe.
Lobe selection in the VENT trial was determined using a semi-automated quantitative analysis of HRCT scans to determine the lobe with the highest percentage of emphysema and heterogeneity. Emphysema percentage was calculated as the number of pixels below -910 Hounsfield units within each lobe. This percentage was then grouped into quartiles and converted to a Likert scale. The degree of heterogeneity was determined by comparing the difference in Likert scores between targeted lobe and its ipsilateral adjacent non-targeted lobe.
Fissure Integrity was calculated using measurements from thin slice HRCT scan. A complete fissure was defined as 90% or greater fissure integrity on at least one axis (sagittal, axial or coronal) of the HRCT. Two independent radiologists confirmed fissure integrity. Finally target Lobe Volume (TLV) was calculated using Volumetric CT Scan at 6 months as a means to assess lobe volume reduction from baseline.
Statistical analysis
Statistical analysis was performed for single variable comparison using a two-sample Student's t-test. Multiple linear regression analysis was used to determine the significance of multiple dependent variables in relation to change in FEV1. A p value of 0.05 was used to confirm statistical significance. Variables were also assessed using odd's ratio calculations with FEV1 as the dependent variable. Predetermined cutoffs for significance in the VENT trial were used to group patients for regression analysis and odds ratio calculations. These cutoffs included a 15% improvement in FEV1, a 15% difference in heterogeneity between lobes and 90% degree of fissure integrity.
Results
Baseline demographics
The EuroVENT and VENT trial comprised 492 patients. OF those 22 did not have their fissure status quantified and were excluded. As a results a total of 470 patients were analyzed in this study of whom 319 were placed in the treatment group and 151 served as controls. Of these, 238 had upper lobe treatments and 82 had lower lobe treatments (). Right upper lobe treated patients comprised the greatest percentage of patients. Control and treatment groups were compared as well as upper and lower lobe treatment groups (). At baseline there were two significant differences between the groups. The first was a difference between BODE scores of the control and treated upper lobe groups. The second was between ages of the upper and lower lobe treatment groups. There were no significant differences between pneumonia, pneumothorax or significant hemoptysis rates between upper and lower lobe treated patients.
Table 1. Baseline characteristics of the patients.
Figure 1. Study flow chart. All 470 patients had initial FEV1 measurements. The patients were divided into two groups, upper and lower lobe, based on treatment lobe. Total patients at baseline and at 365 days by group are represented. EBV: Endobronchial Valve.
Treatment outcomes
Spirometry outcomes:
At 365 days changes in spirometry values and 6 MWT were measured and compared to baseline (). There was a statistically significant improvement in FEV1 between control and treatment in the upper lobe groups (-2.15, 7.04, p = 0.001). There was a trend but no statistically significant difference between control and the lower lobe treatment groups (-0.57, 5.99, p = 0.10). However there was no difference when the treatment arms of the upper lobe and lower lobe were compared (5.99, 7.04, p = 0.75). The population with complete fissure occlusion showed the greatest improvement in FEV1 change compared to control regardless of treatment lobe.
Table 2. Mean percent change of primary outcomes at 365 days.
6 MWT and dyspnea outcomes:
There was no difference in 6MWT results in either group. A significant reduction in mMRC scores was found in the treatment arms of the upper lobe groups (15.3, -8.89, p = 0.03)(not shown). When comparing the treatment groups arms of both the upper lobe and lower lobe groups there was no statistically significant difference in any measured parameter.
Assessment of secondary variables on effect of lobe treatment
Lobe selection was compared to other variables that had been previously identified to have an effect on FEV1 modulation. The first variable assessed was target lobe volume reduction assessed by volumetric CT. Data points of treated lobes at 180 days from the VENT and EuroVent trials were analyzed and grouped by lobes (). The patients with left lobe treatment, regardless of upper or lower lobe, had greater lobe volume reduction than their right lobe counterparts. This suggested that the changes in FEV1 based on upper versus lower lobe selection were independent of the degree of target lobe volume reduction.
Figure 2. The mean percent decrease in target lobe volume between treatment group and control group is shown. Data is separated by target lobe. Results were quantified by volumetric CT scan at 180 days. Standard deviation is represented in the error bars.
Multiple linear regression analysis was then performed to assess the effect on FEV1 by the following dependent variables: Lobe selection, heterogeneity and fissure status (). Fissure integrity was an independent predictor of FEV1 improvement. Patients with complete fissure integrity showed improvement in FEV1 over their incomplete fissure counterparts. However increased lobe heterogeneity, defined as heterogeneity of greater than or equal to 15%, was not a significant predictor of FEV1 improvement. In addition the treatment of patients with upper lobe disease did not show greater improvement in FEV1in relation to lower lobe treated patients.
Table 3. Baseline Predictors of Change in FEV1.
Odds ratio analysis was also performed to again determine significance between the same variables and improvement in FEV1 (). Patients with complete fissure integrity had a significant correlation with improvement in FEV1 (OR 4.14 (2.29, 7.47)). No significant correlation was seen between FEV1 improvement and heterogeneity or lobe selection.
Figure 3. Odds Ratio calculations at 365 days are expressed. The following cut-offs were used to evaluate significance: FEV1 > 15%, Fissure integrity > 90% and Heterogeneity > 15%. A positive correlation between the presence of complete fissure (>90% on CT) and improvement in FEV1 was seen.
Discussion
Our study argues that in contrast to LVRS, patients with either upper or lower lobe emphysema may benefit from bronchoscopic lung volume reduction through EBV therapy. We show that there is no significant difference in FEV1 improvement between upper or lower lobe EBV treatment groups nor is lobe selection a significant pre-procedure modifier of FEV1 improvement. Our study also further supports the findings of Valipour et al. (Citation12) and others that improvement in FEV1 with endobronchial valve placement is associated with complete fissure status pre-procedure. Complete fissure status drives targeted lobe volume reduction and leads to FEV1 improvement. Additionally, our analysis shows that the degree heterogeneity of emphysematous destruction between the EBV treated and its ipsilateral adjacent lobe is not associated with improvements in FEV1.
Currently surgical lung volume reduction is a procedure that is underutilized and limited to patients with emphysema of upper lobe predominant disease and lower exercise tolerance (Citation13). Our findings are intriguing because improvement in FEV1 was not associated with targeted lobe. These results seem to contrast with the findings from the NETT trial that patients with upper lobe predominant disease benefitted from LVRS while non-upper-lobe patients did not. First it is important to point out the definition of non-upper-lobe outlined in the NETT trial. This group included patients with disease on CT predominately affecting either the lower lobes as a whole, primarily the superior segments of the lower lobes or diffuse disease. Additionally LVRS therapy was bilateral while BLVR therapy in this retrospective study was unilateral. As such a direct comparison between the NETT results and this retrospective analysis are difficult.
Multiple explanations for the preferential benefit of LVRS in upper lobe predominant disease have been postulated. One of the most common is the difficulty in the surgery itself due to many factors including limited approach options (Citation3), scarring/destruction of the abutting diaphragm or less distinct target areas. Indeed multivariate regression analysis of operative mortality in NETT trial patients found non-upper-lobe predominant disease to be the only predictor of operative mortality (Citation14). Finally fissure status of treated lobes was unknown in the NETT trial. Significant variability between fissure integrity of the upper and non-upper groups may have been a confounding factor in the study.
Our results suggest that EBV therapy may be beneficial to a wider range of patients than those with upper lobe predominant disease. However our findings also support the need for pre-procedural planning to identify the patient that is most likely to benefit from EBV therapy. This type of planning has been used in the LIBERATE and in the recently published BeLieVer-HIFi trial (Citation15). Results from the BeLieVer-HiFi trial showed improved outcomes in lung function and exercise capacity amongst patients with intact interlobar fissures on CT.
When compared to control, patients with upper lobe treated disease had statistically significant improvement while lower lobe patients had a trend toward significance. The most likely reason that lower lobe patients did not achieve statistical significance was the relatively smaller number of patients in that group. Upper lobe patients (286) outnumbered lower lobe patients (98) by almost 3:1. Despite these differences there was no significant difference in treatment arms. Our subsequent linear regression analysis further supports the assertion that treatment based on upper lobe or lower lobe disease is not significant.
Fissure status is important because it may predict target lobe atelectasis which likely drives improvement in FEV1, exercise tolerance, breathlessness and survival (Citation16,17). The reason for more successful EBV placement in those with complete fissure status may be lack of collateral ventilation (Citation18). A complete fissure corresponds to lack of interlobar collateral ventilation (Citation19). Significant research shows the presence of collateral ventilation blunts the clinical response to EBV therapy (Citation20).
Fissure status and collateral ventilation provides two possible explanations for our findings that average TLVR was greater in patients undergoing treatment of their left lung. First, the left lung appears to have less collateral ventilation than the right lung (Citation21). Second, the right lung has two major fissures compared to the left lung's one. This allows for two separate areas for interlobar communication.
Another method available to evaluate collateral ventilation is the Chartis Pulmonary Assessment System (Pulmonx Inc, Redwood City, CA, USA) (Citation22). This system allows temporary airway occlusion and measurement of flow and pressure distal to the point of balloon inflation. Both Chartis and use of CT scan fissure status can aid the precision of picking lung lobes most likely to develop complete atelectasis following EBV therapy. In a study comparing the Chartis system and fissure completeness on CT scan, both had similar accuracy for predicting targeted volume atelectasis (Citation23). Additionally, patients who experienced targeted lobe reductions > 350 ml showed statistically significant improvements in lung function, exercise performance and quality of life questionnaires. These data support our findings that completeness of fissure status instead of an upper or lower lobe location of the treatment lobe are most important to meaningful outcomes with EBV therapy.
Degree of heterogeneity is another debated topic in EBV therapy. Heterogeneity has been shown in LVRS to be important with upper lobe predominant disease phenotype to benefit from surgery. However select patients with homogenous emphysema have also shown significant and persistent benefit with quality of life with LVRS (Citation24). We found that heterogeneity was not a predictor of improvement in lung function. This result highlights one of the major differences between the VENT Trial and the EuroVENT trial. The EuroVENT trial did not support the previous VENT Trial finding that degree of emphysema heterogeneity was a significant modifier of FEV1. The differences between the two studies are unclear, although one hypothesis presented in the EuroVENT trial is that patients in the VENT trial were not individually identified. As a result significant overlap between heterogeneous and complete fissure patients could not be excluded.
Our study has multiple limitations. First, this is a retrospective analysis of prospectively collected data and as such is limited by selection biases that may have contributed to the initial statistical significance found when comparing upper and lower lobe. We attempted to limit this bias by subsequently performing multiple linear analysis of the data. Second, the data was combined from two separate trials. However the two trials were performed by collaborating groups and as such the protocol, inclusion parameters and exclusion criteria were the same. In addition cutoffs for heterogeneity and fissure status were identical.
Another limitation to our study is the inclusion of patients with heterogeneous emphysema. As a result it would be unfair to extrapolate our results on patients with homogenous emphysema despite our assertion that heterogeneity is not an essential predictor of success. Finally two independent radiologists using thin slice HRCT evaluated fissure status in this study. Studies by Koenigkam-Santos et al. showed improvement in fissure status analysis with a semiquantitative evaluation using volumetric thin-section CT images, especially in patients with small fissure gaps (Citation25,26). As fissure status appears to be crucial to success the most precise assessment of this parameter is needed. In addition assessment of collateral ventilation through the Chartis System would also likely improve the identification of likely responders (Citation27).
Conclusion
Pre-procedure patient selection is crucial in achieving functional and mortality benefit after EBV therapy. Our retrospective analysis suggests that lobe selection is not an important predictor of EBV therapy success. Complete fissure status is the most important inclusion criteria to predict a reduction in targeted lung volume with EBV therapy as it drives FEV1 improvement. With the discovery of more effective tools to assess fissure integrity newer EBV studies may show improved outcomes. Other selection criteria such as emphysema heterogeneity may not be an important modifier of FEV1 improvement with EBV therapy.
Declaration of interest statement
The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References
- Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J 2006; 28(3):523–532.
- Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348(21):2059–2073.
- DeCamp MM, McKenna RJ, Deschamps CC, Krasna MJ. Lung volume reduction surgery: technique, operative mortality, and morbidity. Proc Am Thorac Soc 2008; 5(4):442–446. doi: 10.1513/pats.200803-023ET.
- Sterman DH, Mehta AC, Wood DE, Mathur PN, McKenna RJ Jr, Ost DE, et al. A multicenter pilot study of a bronchial valve for the treatment of severe emphysema. Respiration 2010; 79(3):222–233. doi: 10.1159/000259318.
- Criner GJ, Pinto-Plata V, Strange C, Dransfield M, Gotfried M, Leeds W, et al. Biologic lung volume reduction in advanced upper lobe emphysema: Phase 2 results. Am J Respir Crit Care Med 2009; 179(9):791–798. doi:10.1164/rccm.200810-1639OC.
- Herth FJ, Gompelmann D, Stanzel F, Bonnet R, Behr J, Schmidt B, et al. Treatment of advanced emphysema with emphysematous lung sealant (AeriSeal®). Respiration 2011;82(1):36–45. doi:10.1159/000322649.
- Sciurba FC, Ernst A, Herth FJ, Strange C, Criner GJ, Marquette CH, et al. A randomized study of endobronchial valves for advanced emphysema. N Engl J Med 2010; 363(13):1233–1244. doi: 10.1056/NEJMoa0900928.
- Herth FJF, Noppen M, Valipour A, Leroy S, Vergnon JM, Ficker JH, et al. Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort. Eur Respir J 2012; 39(6):1334–1342. doi: 10.1183/09031936.00161611
- Naunheim KS, Wood DE, Mohsenifar Z, Sternberg AL, Criner GJ, DeCamp MM, et al. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg 2006; 82(2):431–443.e19.
- Naunheim KS, Wood DE, Krasna MJ, DeCamp MM Jr, Ginsburg ME, McKenna RJ Jr, et al. Predictors of operative mortality and cardiopulmonary morbidity in the National Emphysema Treatment Trial. J Thorac Cardiovasc Surg 2006; 131(1):43–53.
- Valipour A, Kramer MR, Stanzel F, Kempa A, Asadi S, Fruchter O, et al. Physiological modeling of responses to upper versus lower lobe lung volume reduction in homogeneous emphysema. Front Physiol 2012; 3:387. doi: 10.3389/fphys.2012.00387
- Valipour A, Herth FJF, Burghuber OC, Criner GJ, Vergnon JM, Goldin J, et al. Target lobe volume reduction and COPD outcome measures after endobronchial valve therapy. Eur Respir J 2013; 43(2):387–396. doi:10.1183/09031936.00133012
- Criner GJ, Cordova F, Sternberg AL, Martinez FJ. The National Emphysema Treatment Trial (NETT): Part II: Lessons learned about lung volume reduction surgery. Am J Respir Crit Care Med 2011; 184(8):881–893. doi: 10.1164/rccm.201103-0455CI
- Naunheim KS, Wood DE, Krasna MJ, DeCamp MM Jr, Ginsburg ME, McKenna RJ Jr, et al. Predictors of operative mortality and cardiopulmonary morbidity in the National Emphysema Treatment Trial. J Thorac Cardiovasc Surg 2006; 131:43–53.
- Davey C, Zoumot Z, Jordan S, McNulty WH, Carr DH, Hind MD, et al. Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (The BeLieVeR-HIFi trial): a randomized controlled trial. Lancet 2015; 9998:1066–1073.
- Hopkinson NS, Toma TP, Hansell DM, Goldstraw P, Moxham J, Geddes DM, et al. Effect of bronchoscopic lung volume reduction on dynamic hyperinflation and exercise in emphysema. Am J Respir Crit Care Med 2005; 171(5):453–460.
- Hopkinson NS, Kemp SV, Toma TP, Hansell DM, Geddes DM, Shah PL, et al. Atelectasis and survival after bronchoscopic lung volume reduction for COPD. Eur Respir J 2011; 37(6):1346–1351. doi:10.1183/09031936.00100110.
- Terry PB, Traystman RJ, Newball HH, Batra G, Menkes HA. Collateral ventilation in man. N Engl J Med 1978; 298:10–5.
- Reymond E, Jankowski A, Pison C, Bosson JL, Prieur M, Aniwidyaningsih W, et al. Prediction of lobar collateral ventilation in 25 patients with severe emphysema by fissure analysis with CT. Am J Roentgenol 2013; 201(4):W571–575. doi: 10.2214/AJR.12.9843.
- Shah PL, Herth FJ. Current status of bronchoscopic lung volume reduction with endobronchial valves. Thorax 2014 Mar 1;69(3):280–286. doi: 10.1136/thoraxjnl-2013-203743
- Herzog D, Hippenstiel S, Schürmann D, Dӧllinger F, Pӧllinger A, Temmesfeld-Wollbrück B, et al. Prevalence of interlobar collateral ventilation in COPD patients. Eur Respir J 2014; 44(Suppl 58).
- Gompelmann D, Eberhardt R, Michaud G, Ernst A, Herth FJ. Predicting atelectasis by assessment of collateral ventilation prior to endobronchial lung volume reduction: A feasibility study. Respiration 2010; 80(5):419–425. doi: 10.1159/000319441
- Herth FJ, Eberhardt R, Gompelmann D, Ficker JH, Wagner M, Ek L, et al. Radiological and clinical outcomes of using Chartis to plan endobronchial valve treatment. Eur Respir J 2013; 41(2):302–308. doi: 10.1183/09031936.00015312.
- Weder W, Tutic M, Lardinois D, Jungraithmayr W, Hillinger S, Russi EW, et al. Persistent benefit from lung volume reduction surgery in patients with homogeneous emphysema. Ann Thorac Surg 2009; 87(1):229–237. doi: 10.1016/j.athoracsur.2008.10.012.
- Koenigkam-Santos M, de Paula WD, Owsijewitsch M, Wielpütz MO, Gompelmann D, Schlemmer HP, et al. Incomplete pulmonary fissures evaluated by volumetric thin-section CT: Semi-quantitative evaluation for small fissure gaps identification, description of prevalence and severity of fissural defects. Eur J Radiol 2013; 82(12):2365–2370. doi: 10.1016/j.ejrad.2013.08.029.
- Koenigkam-Santos M, Puderbach M, Gompelmann D, Eberhardt R, Herth FJ, Kauczor HU, et al. Incomplete fissures in severe emphysematous patients evaluated with MDCT: Incidence and interobserver agreement among radiologists and pneumologists. Eur J Radiol 2012; 81(12):4161–4166. doi: 10.1016/j.ejrad.2013.08.029.
- Gompelmann D, Eberhardt R, Slebos DJ, Brown MS, Abtin F, Kim HJ, et al. Diagnostic performance comparison of the Chartis System and high-resolution computerized tomography fissure analysis for planning endoscopic lung volume reduction: CV assessment with Chartis and HRCT. Respirology 2014; 19(4):524–530. doi: 10.1111/resp.12253.