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Department of Pulmonary Diseases, University Medical Centre Groningen, University of Groningen, Groningen, the NetherlandsGroningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Department of Pulmonary Diseases, University Medical Centre Groningen, University of Groningen, Groningen, the NetherlandsGroningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Department of Pulmonary Diseases, University Medical Centre Groningen, University of Groningen, Groningen, the NetherlandsGroningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Department of Pulmonary Diseases, University Medical Centre Groningen, University of Groningen, Groningen, the NetherlandsGroningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Department of Pulmonary Diseases, University Medical Centre Groningen, University of Groningen, Groningen, the NetherlandsGroningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Department of Pulmonary Diseases, University Medical Centre Groningen, University of Groningen, Groningen, the NetherlandsGroningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Median survival after endobronchial valve treatment was 8.2 years.
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Increase in exercise capacity and quality of life results in a survival benefit.
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This survival benefit is independent of improvements in pulmonary function.
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This survival benefit is also independent of the presence of a complete atelectasis.
Abstract
Background
Bronchoscopic lung volume reduction using endobronchial valves (EBV) is a treatment option for selected patients with advanced emphysema. The treatment significantly improves pulmonary function, exercise capacity, quality of life, and potentially improves survival. Our main aim was to assess whether treatment response significantly influences survival time after EBV treatment.
Methods
We evaluated treatment response at 6-week and 1-year follow-up of all patients treated with EBVs between 2008 and 2020. Survival status was retrieved on December 1, 2021. Patients were defined as responders or non-responders based on known minimal important differences for FEV1, residual volume (RV), RV/Total Lung Capacity (TLC) ratio, 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), target lobe volume reduction (TLVR), and complete lobar atelectasis. Uni- and multivariate cox regression models were used to evaluate the effect of response on survival time.
Results
A total of 428 patients were included. EBV treatment resulted in significant improvements in pulmonary function, exercise capacity and quality of life. Median survival was 8.2 years after treatment. SGRQ and 6MWD response were independent predictors for improved survival time (Hazard Ratio (HR) 0.50 [0.28–0.89], p = .02 and HR 0.54 [0.30–0.94], p = .03, respectively). The presence of a complete lobar atelectasis did not significantly affect survival, neither did pulmonary function improvements.
Conclusions
Our results suggest that improvement in exercise capacity and quality of life after EBV treatment are associated with a survival benefit, independent of improvements in pulmonary function, reduction in target lobe volume or the presence of complete lobar atelectasis.
]. Standard medical care includes smoking cessation, pharmacological therapy, and pulmonary rehabilitation aiming for symptom reduction, minimizing the burden of disease, slowing disease progression, and improving exercise tolerance [
]. However, in patients with more severe COPD these options fall short and additional treatment options, such as lung volume reduction or lung transplantation can be considered.
Lung volume reduction is a treatment option for COPD patients with a predominantly emphysematous phenotype and severely hyperinflated lungs. Currently, both surgical and bronchoscopic lung volume reduction (BLVR) approaches are performed. Due to the less invasive nature and lower morbidity, bronchoscopic lung volume reduction approaches are generally preferred over lung volume reduction surgery (LVRS), when technically possible [
]. Different BLVR approaches are available of which BLVR using endobronchial valves (EBV) is the most effective and most commonly used in clinical practice [
]. BLVR using EBVs has, in numerous randomized controlled trials, shown to improve pulmonary function, exercise capacity and health-related quality of life [
Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial.
]. Subsequently, endobronchial valve treatment also improves known predictors of survival in COPD including the BODE index and the inspiratory capacity to total lung capacity ratio [
]. Furthermore, we recently published long-term survival data suggesting that BLVR treatment also poses a survival benefit, compared to standard medical care, in patients with advanced COPD [
Two previous studies on the long-term survival after EBV treatment reported prolonged survival in patients with a complete lobar atelectasis following treatment compared to patients without, suggesting that responders to endobronchial valve treatment have a survival benefit over non-responders [
]. However, in our clinical experience, patients with a partial lobar atelectasis can also have a significant treatment response based on pulmonary function and/or exercise capacity what might also be associated with a survival benefit. This hypothesis has not yet been thoroughly investigated in a large number of patients. Therefore, our aim was to evaluate long-term survival after EBV treatment and to assess whether responders, either on pulmonary function, radiological, health-related quality of life and/or exercise capacity outcomes, have a survival benefit over non-responders.
2. Methods
2.1 Study design and patients
We collected data from all patients who underwent BLVR using EBV between June 2008 and December 2020 at the University Medical Center Groningen (UMCG), The Netherlands. Patients were treated in one of the following clinical trials: CHARTIS (NCT01101958) [
], or within our regular care program which led to the inclusion of their data in our national database: BREATHE-NL (NCT02815683). All trials were approved by the local ethics committee of the UMCG, and ethics approval was officially waived for the BREATHE-NL registry which, due to its non-invasive nature, did not fall within the scope of the WMO (Dutch Medical Research with Human Subjects Law). All patients included in this analysis provided written informed consent for the scientific usage of their data.
2.2 Data collection
Patients attended a baseline visit and were invited for post-treatment follow-up visits at 6 weeks, 6 months, 12 months and annually thereafter. During the visits, patients performed pulmonary function tests, a 6-min walk test (except at 6-weeks follow-up) and completed the St. George's Respiratory Questionnaire (SGRQ). A high resolution chest computed tomography (CT) scan was obtained at baseline and 6-weeks follow-up and quantitatively assessed using LungQ software (Thirona, Nijmegen, The Netherlands). Survival status was retrieved from medical records and verified with the Dutch government personal records database on December 1, 2021. Patients who were alive on December 1, 2021 were categorized as ‘survivor’ and patients who died before this date were labelled as ‘non-survivor’.
2.3 Statistical analysis
Overall survival after EBV treatment was calculated using the Kaplan-Meier method. All patients treated within the study period were retained in the analysis even if EBVs were removed or when the patient underwent LVRS or a lung transplantation. We performed a univariate Cox proportional hazards analysis on predetermined potential predictors of survival and potential confounders (age at treatment, sex, and baseline body mass index [BMI]). Variables with a significance level below 0.20 were included in a multivariate Cox proportional hazards model. The presence of multicollinearity was checked using the Variation Inflation Factor (VIF). If variables had a VIF above 4, the variable with the highest VIF would be excluded until all included variables had a VIF below 4. The proportional hazards assumption was checked using Schoenfeld residuals test.
The predetermined potential predictors of survival included change in forced expiratory volume in 1 s (FEV1), change in residual volume (RV), change in RV/total lung capacity (RV/TLC) ratio, change in 6-min walk distance (6MWD), change in total score on the St. George's Respiratory Questionnaire (SGRQ), target lobe volume reduction (TLVR), and presence of complete lobar atelectasis (defined as a TLVR of 100%). For each of these variables, except atelectasis, a patient was categorized as a responder when they reached the minimal important difference (MID) threshold and as a non-responder when they did not. We used the following MID thresholds: increase in FEV1 of ≥100 mL [
]. All statistical analysis were performed using R Statistical Software version 4.1.3 (R Core Team 2021, Vienna, Austria).
3. Results
3.1 Patient characteristics and follow-up
Between June 2008 and December 2020, 428 patients underwent EBV treatment and were included in this analysis. The baseline characteristics are presented in Table 1. Six weeks follow-up was attended by 389 (91%) patients and one year follow-up by 291 (68%) patients (Fig. 1). At both follow-up visits, patients showed significant improvements in pulmonary function, exercise capacity, target lobe volume, and quality of life (Table 2). The number of responders ranged from 44% for complete lobar atelectasis to 93% for relative target lobe volume reduction (Table S2, online supplement).
Table 1Baseline patient characteristics.
Demographics
n
Sex, female
428
293 (68%)
Age, years
428
61.3 ± 8.2
BMI, kg/m2
428
23.9 ± 3.7
Pack years
411
38 (25–48)
BODE index
401
5.6 ± 1.5
Pulmonary function and blood gas
FEV1, % predicted
428
26 ± 8
RV, % predicted
424
254 ± 50
RV/TLC ratio, %
424
64 ± 8
IC/TLC ratio, %
422
22 ± 6
DLCO, % predicted
354
38 ± 12
pO2, kPa
389
9.2 ± 1.2
pCO2, kPa
389
5.3 ± 0.7
Exercise capacity and symptoms
6-min walk distance, meter
413
327 ± 97
mMRC, total score
402
3 (2–3)
SGRQ, total score
403
57.5 ± 12.6
Quantitative HRCT analysis
Target lobe inspiratory volume, mL
420
1890 ± 628
Target lobe emphysema score, %#
418
49 ± 10
Data are presented as mean ± standard deviation, median (interquartile range), or frequency (percentage). All predicted values were calculated using the global lung initiative (GLI) equations. BMI, body mass index; BODE index, combined index of body mass index, airflow obstruction, dyspnea and exercise capacity; FEV1, forced expiratory volume in 1 s; RV, residual volume; DLCO, diffusion capacity of the lung for carbon monoxide; RV/TLC ratio; residual volume to total lung volume ratio; pO2, partial pressure of oxygen; pCO2, partial pressure of carbon dioxide; SGRQ, St. George's respiratory questionnaire; HRCT, high-resolution computed tomography. #Emphysema score is the percentage of voxels below −950 Hounsfield Units on the inspiratory HRCT scan.
To calculate the BODE index at one-year follow-up baseline BMI was used since BMI data at follow-up was not available.
–
–
–
253
−1.0 ± 1.4
<.001
Target lobe volume, mL
371
−1360 ± 700
<.001
–
–
–
Data are reported as mean change ± standard deviation from baseline. P-values were derived using a paired sample t-test. FEV1, forced expiratory volume in 1 s; RV, residual volume; RV/TLC ratio; residual volume to total lung volume ratio; IC/TLC ratio, inspiratory capacity to total lung capacity ratio; 6MWD, 6-min walk distance; SGRQ, St. George's respiratory questionnaire; MMRC, modified medical research council; BODE index, combined index of body mass index, airflow obstruction, dyspnea and exercise capacity.
a To calculate the BODE index at one-year follow-up baseline BMI was used since BMI data at follow-up was not available.
During the study period, valves were permanently removed in 64 (15%) patients. In total, 20 (5%) patients received a lung transplantation (of which 8 after EBV removal in an earlier stage) and 29 (7%) patients underwent LVRS (of which 10 after EBV removal in an earlier stage).
3.2 Overall survival
Patients were followed for a median of 43 months (range 1–158) until death or censoring. In total, 130 (30%) patients died during the study period. The cause of death was unknown in the majority (75%) of patients since this is not retrievable from the Dutch government personal records database. The known causes of death are reported in Table S3 (online supplement).
Median overall survival time after EBV treatment was 8.2 years (95%CI 6.7 to 10.0) and survival rates at 1, 3 and 5 years post-treatment were 96%, 86%, and 68%, respectively (Fig. 2). Non-survivors were more often male, had a significantly higher age at treatment and a higher burden of disease at baseline with significantly lower FEV1 and 6MWD, and a significantly higher mMRC and SGRQ total score (Table S1, online supplement).
Fig. 2Kaplan-Meier curve for overall survival after endobronchial valve treatment. The dotted black line indicates median survival (8.2 year).
Both the univariate and multivariate analysis indicated a significant survival benefit for 6MWD- and SGRQ-responders (increase of ≥26 m and decrease of ≥8.3 points, respectively). There was no significant survival benefit for patients that were responders on RV, RV/TLC, TLVR, or patients that had a complete lobar atelectasis (Table 3, Fig. 3). Adjusting the univariate model for baseline differences between survivors and non-survivors also showed a significant survival benefit for 6MWD- and SGRQ-responders, but did also show a significant benefit for FEV1-responders (Table S4, online supplement). Using continuous variables in a Cox proportional hazards model adjusted for age at treatment, baseline body mass index and sex, also showed a positive significant association between increase in 6MWD or decrease in SGRQ total score and survival (Table S5, online supplement).
Table 3Univariate and multivariate Cox proportional hazards analysis models for survival after endobronchial valve treatment.
A patient was defined a ‘responder’ when change from baseline to 1-year follow-up (or 6-weeks follow-up for TLVR and atelectasis) reached the minimal important difference (MID) threshold, which were: Δ (delta) FEV1 ≥100 mL, ΔRV ≤ -400 mL (absolute), ΔRV ≤ -8% (relative), ΔRV/TLC ≤ -3.7%, Δ6MWD ≥26 m, TLVR ≥563 mL (absolute) or ≥22.4% (relative), ΔSGRQ ≤ −8.4 points. Complete lobar atelectasis was defined as a TLVR of 100%. Significant p-values are highlighted in bold. FEV1, forced expiratory volume in 1 s; RV, residual volume; RV/TLC, residual volume to total lung volume; 6MWD, 6-min walk distance; TLVR, target lobe volume reduction; SGRQ, St. George's Respiratory Questionnaire.
Fig. 3Kaplan-Meier curves for overall survival after endobronchial valve treatment by the variables included in the multivariate analysis: (A) 6-min walk distance, (B) St. George's Respiratory Questionnaire, (C) atelectasis, and (D) FEV1. The hazard ratio (HR) is reported as responder compared to non-responder from the univariate analysis. The adjusted HR is adjusted for sex, age at treatment, baseline BMI and the three other variables displayed in this figure.
Data on both the 6MWD and SGRQ total score at baseline and one-year follow-up, were available for 252 patients. Of these, 113 (45%) patients were responders on both 6MWD and SGRQ, 49 (19%) patients were only a responder on 6MWD, 31 (12%) patients only on SGRQ, and 59 (23%) were non-responders on both. Non-responders had a significantly worse survival than patients that were responders on 6MWD, SGRQ or on both 6MWD and SGRQ (Fig. 4).
Fig. 4Kaplan-Meier curve showing overall survival after endobronchial valve for 6MWD responders, SGRQ responders, SGRQ & 6MWD responders, and non-responders to both SGRQ and 6MWD. For all reported hazard ratios non-responders were used as reference. 6MWD, 6-min walk distance; SGRQ, St. George's Respiratory Questionnaire; HR, hazard ratio; 95%CI, 95% confidence interval.
The results of this study showed a median survival time of 8.2 years after bronchoscopic lung volume reduction using endobronchial valves. The main finding of this study is that patients whose improvement in 6MWD or SGRQ total score reached the MID threshold (responders) had a significantly longer survival time compared to patients whose improvement did not reach the MID threshold (non-responders). Interestingly, we did not find a survival benefit for patients who developed a complete lobar atelectasis after treatment or for patients that were defined as responders based on their decrease in RV or target lobe volume.
We found that 6MWD responders have a significant survival benefit over non-responders which is independent of their improvement in pulmonary function or the presence of a complete lobar atelectasis. The 6-min walk test is a measure to objectify functional exercise capacity. In line with our results, previous studies also showed an association between the (change in) 6MWD and survival in patients with COPD [
]. A possible explanation for why change in 6MWD is a better predictor for survival after EBV treatment than the change in pulmonary function and hyperinflation, might be that the 6MWD not only reflects the pulmonary limitation of these patients, but also captures the extra-pulmonary manifestations of COPD, such as cardiac dysfunction, musculoskeletal disorders, fatigue and psychological symptoms, all of which can impact survival [
Furthermore, our results also showed that SGRQ responders have a significantly longer survival time compared to non-responders. This finding is in line with previous studies that have found a significant association between survival and health-related quality of life in patients with COPD [
]. The SGRQ is designed to measure the impact of COPD on perceived overall well-being in patients with COPD and has shown significant associations with lung function, exercise capacity, oxygen saturation and dyspnoea severity [
]. The SGRQ total score, therefore, seems to be a good reflection of the overall impact of COPD on the patient. It could be hypothesized that patients themselves are able to give a better estimate of their overall health status than that can be reflected by specific tests such as pulmonary functions tests. However, it should be noted that the association between SGRQ response and survival might be related to the change in 6MWD, since we found that 78% of the SGRQ responders was also a 6MWD responder and because we found a significant correlation between absolute change in 6MWD and SGRQ total score (r = −0.56).
In contrast to the previous studies that have assessed survival time after EBV treatment, we did not find a significant difference in survival time between patients who developed a complete lobar atelectasis and patients who did not [
]. These contradictory findings might be explained by the higher rate of patients with a complete lobar atelectasis in this study (44%) compared to the rates found in the previous studies (26–29%) [
]. For all patients in our study, fissure integrity was assessed using quantitative CT-analysis and in 95% of all patients the Chartis measurement system (PulmonX, CA, USA) was used before valve implantation to definitively confirm the absence of collateral ventilation. All previous studies have included patients that were treated with EBVs before it was known that the absence of collateral ventilation is the key feature for treatment success. Therefore, it is possible that the previous studies mainly showed the effect of EBV treatment on survival rather than the effect of lobar atelectasis. This in turn would correspond with the finding of Hartman et al. that patients that receive a BLVR treatment have a significant survival benefit over patients that are found ineligible for a BLVR treatment [
Another explanation could be that in this study quantitative CT-analysis was used to determine whether patients developed a complete lobar atelectasis after treatment. Patients were classified as having a complete lobar atelectasis when the rounded relative target lobe volume reduction was 100%. Therefore, in our non-atelectasis group there are a number of patients that have a partial atelectasis but with a substantial reduction in target lobe volume (median −987 mL). The previous studies have used visual assessment for the determination of atelectasis, which might result in a different non-atelectasis populations and might further explain the different findings with regards to the effect of atelectasis on survival after EBV treatment [
]. However, when a cut off value of 90% or 95% relative TLVR was used to define patients with a complete lobar atelectasis, it was still not significantly associated with survival (data not shown).
Surprisingly, reduction of static hyperinflation, measured as RV, RV/TLC ratio, or TLVR, had no significant effect on survival time. Previously, it has been suggested that hyperinflation is a significant predictor for mortality in patients with emphysema, but it is unknown whether reducing hyperinflation lowers the risk of death [
]. Our findings suggest that the risk of death does not significantly decreases when hyperinflation is reduced. However, in the previous study inspiratory capacity/total lung capacity (IC/TLC) ratio was used as a measure for hyperinflation. This ratio was not included in our main analysis since no MID is established so far. Nonetheless, absolute change in IC/TLC did not show a significant association with survival when included in a univariate cox analysis (HR 0.98, 95%CI 0.93 to 1.02).
Our findings suggest that improving pulmonary function or reducing hyperinflation alone does not improve survival in these patients. However, improved hyperinflation is correlated with improved health-related quality of life (r = 0.43 and r = 0.46, both p < .001, for change in RV and RV/TLC ratio, respectively) and improved exercise capacity (r = −0.50 and r = −0.56, both p < .001, for change in RV and RV/TLC ratio, respectively). But enhancing exercise capacity requires an additional active effort from the patient. Therefore, we advise all physicians, involved in the care of patients who have received EBV treatment, to evaluate the patients effort to maintain or even improve their exercise capacity and if needed timely refer the patient for a pulmonary rehabilitation program. To date, it is common practice that patients eligible for EBV treatment complete a pulmonary rehabilitation program before treatment [
]. It would be interesting to see if pulmonary rehabilitation after EBV treatment leads to a greater improvement in exercise capacity and if this, in turn, improves survival. Currently, a clinical trial (SoLVE, NCT03474471) is being conducted to study the effect of pulmonary rehabilitation and the timing on outcomes after EBV treatment, which could be helpful in answering this question.
A limitation of this study is that we have included patients that received EBV treatment at a certain timepoint in a 12-year period. Therefore, some patients reached a follow-up time of more than 10 years while others only had 1 year of follow-up. Another limitation is that we have kept patients that underwent LVRS or a lung transplantation after EBV treatment in the analysis which will likely affect the survival time of these patients which we did not account for. However, the number of patients receiving one of these additional treatments was low. Therefore, we expect that this did not have a significant effect on the reported long-term survival. Lastly, possible confounders in our analysis are the baseline differences between patients that were alive and those that died at the end of the study period. Non-survivors had a significantly higher burden of disease before treatment. However, when adjusting for these baseline imbalances, 6MWD responders and SGRQ responders still had a significant survival benefit over non-responders.
In conclusion, the findings of this study suggest that improving exercise capacity and health-related quality of life after EBV treatment are associated with a survival benefit, independent of possible improvements in pulmonary function, target lobe volume reduction or the presence of a complete lobar atelectasis. We hypothesize that improvements in pulmonary function and reduction in static hyperinflation provide the opportunity for treated patients to improve their exercise capacity, but that actually improving exercise capacity requires an active effort for which a structured training program after treatment can help.
Funding
None.
CRediT authorship contribution statement
Sharyn A. Roodenburg: Conceptualization, Methodology, Formal analysis, Data curation, Writing – original draft, and, Visualization. Dirk-Jan Slebos: Conceptualization, Investigation, Writing – review & editing, Supervision. Marlies van Dijk: Investigation, Writing – review & editing. T. David Koster: Investigation, Writing – review & editing. Karin Klooster: Investigation, Writing – review & editing, Project administration. Jorine E. Hartman: Conceptualization, Methodology, Investigation, Writing – review & editing, of the original draft, Supervision, Project administration.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial.
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