chronic obstructive pulmonary disease ( copd ) is now the third leading cause of death in the united states.1 in 2007 , the economic burden of copd in the us was $ 42.6 billion in health care costs and lost productivity.2 although different pharmacological treatments have shown improvement in lung functions in general copd patients , the predominantly emphysema phenotypes with poor lung functions are often considered for additional surgical procedures . these include the bullectomy,3 single and double lung transplantation,4 and , more recently , lung volume reduction ( lvr ) surgery ( lvrs).5 the latter is based on the concept that targeted resection of the damaged tissue that causes hyperinflation allows more space for the residual lung , which results in improvement of chest wall mechanics and transpulmonary recoil pressures . this and other factors appear to contribute to the physiological and symptomatic improvements that follow lvrs . the national emphysema treatment trial ( nett ) showed that the patients who benefited the most from lvrs in terms of survival and functional improvement were those who had predominantly upper lobe emphysema and poor exercise capacity.5,6 however , significant short - term morbidity and mortality have been associated with lvrs.7 furthermore , the associated costs of lvrs are almost prohibitive and make this a less attractive option for lvr.8 different methods of bronchoscopic lvr ( blvr ) have been studied , and more alternatives to lvrs are being studied in clinical trials . most of the evidence in literature exists for one - way valves , sealants / hydrogels ( from here on , collectively referred to as biolvr ) , coil implants ( lvr coils [ lvrcs ] ) , airway bypass stents , and bronchial thermal vapor ablation ( btva ) therapy . the valves work by preventing inspired air from entering target airways and allow exit of trapped air from distal airways . biolvr therapy involves administration of a fibrinogen suspension and thrombin solution into the airways separately . once in contact , these products polymerize into a hydrogel in situ . a localized inflammatory reaction ensues , causing atelectasis and remodeling , as well as a volume reduction over a 4- to 6-week period . btva uses heated water to produce thermal injury of the target tissue , which is followed by permanent fibrosis and atelectasis . airway bypass stents have been used to create and maintain passages between the bronchi and emphysematous lobes . in the lvrc method , once deployed , a coil conforms to its predetermined shape , by bending in the airway and causing compression of adjacent lung tissue , thereby creating local lvr . since the advent of these new blvr techniques , there has been no head - to - head comparison of one versus another . in this meta - analysis , we sought to analyze the comparative efficacy of each blvr technique . we used combinations of the following keywords :  endobronchial valves  ,  one way valves  ,  lung sealants  ,  coils  ,  lung volume reduction surgery  ,  bronchial thermal vapor ablation  , and  emphysema  . the search from pubmed yielded all the studies included in this meta - analysis . to ensure a thorough search of the literature , we handsearched the reference lists of the included studies and previously published meta - analyses . for inclusion in our meta - analysis , we considered only those studies that reported the pre- and post - lvr data on lung functions ( in specific , the forced expiratory volume in 1 second [ fev1 ] , forced vital capacity [ fvc ] , total lung capacity [ tlc ] , residual volume [ rv ] , and diffusion lung capacity of carbon monoxide [ dlco ] ) , the 6-minute walk distance ( 6 mwd ) , and the st george s respiratory questionnaire ( sgrq ) . prospective nonrandomized and randomized controlled trials ( rcts ) were included , provided pre- and post - intervention data ( absolute numbers ) or mean difference ( between pre- and post - intervention ) were available . we included prospective nonrandomized consecutive case series but excluded case reports . prospectively conducted multicenter cohort studies with retrospective analyses were also considered eligible for inclusion . however , retrospective cohort studies , as well as studies that reported data in median and interquartile range , were excluded . figure 1 summarizes the results of the selection process . as a general rule , for multiple publications of the same trials a total of seven studies915 from the subgroup of one - way valves , one from biolvr,16 and two from btva17,18 were affected by this rule ( see  supplementary material  for details ) . our primary outcomes included assessments of lung function ( fev1 and fvc ) measured in liters , lung volumes ( tlc and rv ) measured in liters , diffusion capacity ( dlco ) measured in ml / min / mmhg , assessment of exercise capacity ( 6 mwd ) measured in meters , and assessment of the health - related quality of life with the sgrq . analyses of secondary outcomes were related to the safety of a particular device or procedure . as the complications associated with each procedure were distinct from each other , we were not able to pool the data for a common outcome across different subgroups . for one - way valves , we included the incidence rates of pneumonia distal to valve , pneumothorax lasting more than 7 days , and migration of valves . data from the studies on airway bypass stents and btva were not sufficient enough to analyze . this included first author s name , year of publication , number of study participants , their age and sex distribution , presence of comorbidities besides copd , type of blvr , country of origin , and study design . for the analysis , we recorded the mean of pre- and post - blvr fev1 , dlco , 6 mwd , and sgrq with standard deviations ( sds ) , and , where necessary , the mean difference with sd or 95% confidence intervals ( cis ) . for any included study , where such information was not complete for a particular outcome of interest , this information was not included . in any included study , if outcomes were assessed at different time points , we obtained the data available for the longest follow - up . where dlco was available in mmol / min / kpa units , we used the conversion factor of 0.335 to obtain data in ml / min / mmhg.19 6 mwd reported in feet was converted into meters using the following formula : standard errors ( ses ) were converted into sds using the following formula : for rcts , comparing a blvr with either control or an active comparator , we extracted data only for the cohort that received blvr ( see  supplementary material  for details ) . the mean changes in the outcomes from blvr along with their 95% cis were estimated by pooling the available data using comprehensive meta - analysis software ( v 2.2.064 , biostat , englewood , nj , usa ) . we separately analyzed the pooled changes in primary and secondary outcomes for each type of blvr . random effects methods were used to account for variance between and within the studies.20 statistical heterogeneity was assessed with the i statistic.21 an i>60% indicated significant heterogeneity . where moderate - to - high heterogeneity was noticed , we reported the results in random effects model . for our analysis of safety data , we used total number of events and person years to calculate the incidence rate for a particular safety outcome . person years were calculated by multiplying the number of study participants at risk with the mean duration of follow - up ( in years ) . if the number of cases was zero , a correction factor of 0.5 was added to both the events and person years.22 data were pooled , and the results are displayed in the form of forest plots . to check for publication bias , we constructed funnel plots of effect size and standard error20,23 and also analyzed results by using the begg and mazumdar rank correlation test.24 we used combinations of the following keywords :  endobronchial valves  ,  one way valves  ,  lung sealants  ,  coils  ,  lung volume reduction surgery  ,  bronchial thermal vapor ablation  , and  emphysema  . the search from pubmed yielded all the studies included in this meta - analysis . to ensure a thorough search of the literature , we handsearched the reference lists of the included studies and previously published meta - analyses . for inclusion in our meta - analysis , we considered only those studies that reported the pre- and post - lvr data on lung functions ( in specific , the forced expiratory volume in 1 second [ fev1 ] , forced vital capacity [ fvc ] , total lung capacity [ tlc ] , residual volume [ rv ] , and diffusion lung capacity of carbon monoxide [ dlco ] ) , the 6-minute walk distance ( 6 mwd ) , and the st george s respiratory questionnaire ( sgrq ) . prospective nonrandomized and randomized controlled trials ( rcts ) were included , provided pre- and post - intervention data ( absolute numbers ) or mean difference ( between pre- and post - intervention ) were available . we included prospective nonrandomized consecutive case series but excluded case reports . prospectively conducted multicenter cohort studies with retrospective analyses were also considered eligible for inclusion . however , retrospective cohort studies , as well as studies that reported data in median and interquartile range , were excluded . figure 1 summarizes the results of the selection process . as a general rule , for multiple publications of the same trials a total of seven studies915 from the subgroup of one - way valves , one from biolvr,16 and two from btva17,18 were affected by this rule ( see  supplementary material  for details ) . our primary outcomes included assessments of lung function ( fev1 and fvc ) measured in liters , lung volumes ( tlc and rv ) measured in liters , diffusion capacity ( dlco ) measured in ml / min / mmhg , assessment of exercise capacity ( 6 mwd ) measured in meters , and assessment of the health - related quality of life with the sgrq . analyses of secondary outcomes were related to the safety of a particular device or procedure . as the complications associated with each procedure were distinct from each other , we were not able to pool the data for a common outcome across different subgroups . for one - way valves , we included the incidence rates of pneumonia distal to valve , pneumothorax lasting more than 7 days , and migration of valves . data from the studies on airway bypass stents and btva were not sufficient enough to analyze . data were extracted on a prespecified worksheet . this included first author s name , year of publication , number of study participants , their age and sex distribution , presence of comorbidities besides copd , type of blvr , country of origin , and study design . for the analysis , we recorded the mean of pre- and post - blvr fev1 , dlco , 6 mwd , and sgrq with standard deviations ( sds ) , and , where necessary , the mean difference with sd or 95% confidence intervals ( cis ) . for any included study , where such information was not complete for a particular outcome of interest , this information was not included . in any included study , if outcomes were assessed at different time points , we obtained the data available for the longest follow - up . where dlco was available in mmol / min / kpa units , we used the conversion factor of 0.335 to obtain data in ml / min / mmhg.19 6 mwd reported in feet was converted into meters using the following formula : standard errors ( ses ) were converted into sds using the following formula : for rcts , comparing a blvr with either control or an active comparator , we extracted data only for the cohort that received blvr ( see  supplementary material  for details ) . the mean changes in the outcomes from blvr along with their 95% cis were estimated by pooling the available data using comprehensive meta - analysis software ( v 2.2.064 , biostat , englewood , nj , usa ) . we separately analyzed the pooled changes in primary and secondary outcomes for each type of blvr . random effects methods were used to account for variance between and within the studies.20 statistical heterogeneity was assessed with the i statistic.21 an i>60% indicated significant heterogeneity . where moderate - to - high heterogeneity was noticed , we reported the results in random effects model . for our analysis of safety data , we used total number of events and person years to calculate the incidence rate for a particular safety outcome . person years were calculated by multiplying the number of study participants at risk with the mean duration of follow - up ( in years ) . if the number of cases was zero , a correction factor of 0.5 was added to both the events and person years.22 data were pooled , and the results are displayed in the form of forest plots . to check for publication bias , we constructed funnel plots of effect size and standard error20,23 and also analyzed results by using the begg and mazumdar rank correlation test.24 there were eight studies for one - way valves,26,29,30,3335,38,39 four for biolvr,19,27,31,32 two for lvrc,28,37 two for airway bypass stents,25,36 and one for btva.40 
 table 1 outlines the baseline characteristics of the study population . on average , study participants were > 58 years old . the duration of follow - up lasted between 1 and 12 months . there were a total of four rcts . for the studies using the biolvr method , the pooled mean change in fev1 was 0.18 l ( 95% ci : 0.09 to 0.26 ; p<0.001 ( figure 2 ) , in 6 mwd was 23.98 m ( 95% ci : 12.08 to 35.88 ; p<0.01 ) ( figure 3 ) , and in sgrq was 8.88 points ( 95% ci : 12.12 to 5.64 ; p<0.001 ) ( figure 4 ) . the studies that used one - way valves showed a pooled mean change in fev1 of 0.10 l ( 95% ci : 0.00 to 0.19 ; p=0.04 ) ( figure 2 ) , in 6 mwd of 23.27 m ( 9.06 to 37.48 ; p=0.001 ) ( figure 3 ) , and in sgrq of 13.53 points ( 24.38 to 2.23 ; p=0.01 ) ( figure 4 ) . studies on btva showed a pooled mean change in fev1 of 0.07 l ( 95% ci : 0.02 to 0.12 ; p<0.01 ) ( figure 2 ) , in 6 mwd of 16.24 m ( 95% ci : 1.92 to 34.41 ; p=0.08 ) ( figure 3 ) , and in sgrq of 10.82 points ( 95% ci : 14.95 to 6.70 ; p<0.001 ) ( figure 4 ) . only 6 mwd and sgrq data were analyzed for lvrc studies , which showed a pooled mean change of 84.4 m ( 95% ci : 48.43 to 120.36 ; p<0.001 ) ( figure 3 ) and 10.79 points ( 95% ci : 17.66 to 3.92 ; p<0.01 ) ( figure 4 ) , respectively . table 2 and figures s1s4 summarize the results of all other primary outcomes , including fvc , tlc , rv , and dlco . the effects on secondary outcomes , defined a priori , are shown in supplementary material . one - way valves were associated with an increased incidence of pneumonia distal to the valves ( incidence rate of 0.05 ; p<0.001 ) , pneumothorax > 7 days ( incidence rate of 0.06 ; p<0.001 ) , and with valve migration ( incidence rate of 0.01 ; p=0.03 ) . biolvr and lvrcs had a unique association with treatment - related copd exacerbations with an incidence rate of 0.07 ( p=0.04 ) and 1.30 ( p=0.01 ) , respectively ( figures s8 and s9 ) . biolvr was also associated with an increase in treatment - related pneumonias ( figure s10 ) . the begg and mazumdar rank correlation tests24 did not show evidence of publication bias for the data on primary outcomes ( see tables s1 and s2 ) . we separately analyzed studies from the subgroups of one - way valves , biolvr , and lvrcs that studied participants for a minimum of 6 months . there were eight studies for one - way valves,26,29,30,3335,38,39 four for biolvr,19,27,31,32 two for lvrc,28,37 two for airway bypass stents,25,36 and one for btva.40 
 table 1 outlines the baseline characteristics of the study population . on average , study participants were > 58 years old . the duration of follow - up lasted between 1 and 12 months . there were a total of four rcts for the studies using the biolvr method , the pooled mean change in fev1 was 0.18 l ( 95% ci : 0.09 to 0.26 ; p<0.001 ( figure 2 ) , in 6 mwd was 23.98 m ( 95% ci : 12.08 to 35.88 ; p<0.01 ) ( figure 3 ) , and in sgrq was 8.88 points ( 95% ci : 12.12 to 5.64 ; p<0.001 ) ( figure 4 ) . the studies that used one - way valves showed a pooled mean change in fev1 of 0.10 l ( 95% ci : 0.00 to 0.19 ; p=0.04 ) ( figure 2 ) , in 6 mwd of 23.27 m ( 9.06 to 37.48 ; p=0.001 ) ( figure 3 ) , and in sgrq of 13.53 points ( 24.38 to 2.23 ; p=0.01 ) ( figure 4 ) . studies on btva showed a pooled mean change in fev1 of 0.07 l ( 95% ci : 0.02 to 0.12 ; p<0.01 ) ( figure 2 ) , in 6 mwd of 16.24 m ( 95% ci : 1.92 to 34.41 ; p=0.08 ) ( figure 3 ) , and in sgrq of 10.82 points ( 95% ci : 14.95 to 6.70 ; only 6 mwd and sgrq data were analyzed for lvrc studies , which showed a pooled mean change of 84.4 m ( 95% ci : 48.43 to 120.36 ; p<0.001 ) ( figure 3 ) and 10.79 points ( 95% ci : 17.66 to 3.92 ; p<0.01 ) ( figure 4 ) , respectively . table 2 and figures s1s4 summarize the results of all other primary outcomes , including fvc , tlc , rv , and dlco . the effects on secondary outcomes , defined a priori , are shown in supplementary material . one - way valves were associated with an increased incidence of pneumonia distal to the valves ( incidence rate of 0.05 ; p<0.001 ) , pneumothorax > 7 days ( incidence rate of 0.06 ; p<0.001 ) , and with valve migration ( incidence rate of 0.01 ; p=0.03 ) . biolvr and lvrcs had a unique association with treatment - related copd exacerbations with an incidence rate of 0.07 ( p=0.04 ) and 1.30 ( p=0.01 ) , respectively ( figures s8 and s9 ) . biolvr was also associated with an increase in treatment - related pneumonias ( figure s10 ) . the begg and mazumdar rank correlation tests24 did not show evidence of publication bias for the data on primary outcomes ( see tables s1 and s2 ) . we separately analyzed studies from the subgroups of one - way valves , biolvr , and lvrcs that studied participants for a minimum of 6 months . to the best of our knowledge , this is the first meta - analysis that has systematically analyzed the effects of different forms of blvr . although our meta - analysis was designed to compare different methods used for blvr , most of the studies included in our meta - analysis studied one - way valves . consequently , this subgroup had the largest number of study participants compared to the other methods ( biolvr , lvrcs , airway bypass stents , and btva ) . overall , the findings of our meta - analysis favor biolvr as the most efficacious method of blvr . this is because not only did this subgroup show a statistically significant difference in the assessment of lung functions ( fev1 , fvc , tlc , rv , and dlco ) , but also showed the most increase in exercise capacity ( as assessed by the 6 mwd ) . it also seemed paradoxical that this subgroup , in fact , showed a decrease in the fev1 . direct comparison of the different blvr methods for our secondary outcomes was not possible , since each method had a unique and different side effect profile . however , there did seem to be more procedure-/device - related complications associated with the one - way valves than with the lvrcs or biolvr . data from the nett research group5 indicate that , at 6 months post - lvrs , the change in fev1 was 8.1%9.3% predicted at 6 months and 6.0%8.9% predicted at 12 months . this corresponds to an improvement of approximately 30% from baseline at 6 months and 22% from baseline at 12 months . the dominant finding of the nett was an increase in the exercise capacity ( defined as an increase in the maximal workload by more than 10 watts from baseline ) and health - related quality of life , as measured by sgrq , in those with predominantly upper lobe emphysema , in the surgical group versus the group that received medical therapy.5 the pre- to post - surgery data from the same study indicated that the change in 6 mwd at 6 months and 12 months was 47.3232.7 m and 14.4275.1 m , respectively.5 this corresponds to an improvement of 3.88% and 1.18% , respectively , compared to baseline . this study also showed that 68% of the 508 study participants randomized to surgery achieved an overall reduction in sgrq scores . most of the studies included in our meta - analysis had a shorter duration of follow - up and a much lower number of study participants compared to the nett . however , results of our post hoc analysis correspond to an improvement in fev1 of 43% and 31.2% in the subgroups of one - way valves and biolvr , respectively . similarly , for 6 mwd , results of our post hoc analysis correspond to an approximate 13.14% improvement in the subgroup of one - way valves and 5.34% in the subgroup of biolvr . thus , a comparison of our findings , in particular for fev1 , 6 mwd , and sgrq , with the data from nett , at the same duration of follow - up ( 612 months ) , suggests noninferiority , if not equivalence , for blvr . indeed , the long - term follow - up data of 5 years from the nett showed an overall survival advantage in the lvrs group compared to medical treatment.6 this data also showed significant improvements in exercise capacity and health - related quality of life ( as measured by sgrq ) at 3 and 4 years post - surgery , respectively . while similar long - term data do not exist for most methods of blvr , more recent data report that the 5-year survival rates in patients treated with one - way valves exceeded 80%.12 however , in terms of the overall safety profile , if lvrs is associated with approximately 5.5% ( 5.5% in nett and between 5% and 20% in others ) 90-day mortality , then , in comparison , current published literature shows that one - way valve therapy is associated with 1% , airway bypass stents with 3% , and biolvr with 0% 90-day mortality.15,25,27,41 the mechanism of lvr differs between one - way valves , biolvr , lvrcs , airway bypass stents , and btva . from a historical perspective the first in line were the proximal obstructing devices.42,43 however , because of their failure in producing effective lvr and the high incidence of procedural pneumothoraces , these devices soon fell out of favor . it was thought that flow from the extensive collateral ventilation ( cv ) pathways between and within the emphysematous lobes paradoxically led to hyperinflation distal to the occlusion . the one - way valves , because of their design , are less likely to be associated with the problem of  paradoxical hyperinflation  . however , as was the case with one - way obstructing devices , certain factors such as cv and fissure integrity have a bearing on the long - term success of procedures with one - way valves.30,35 in the post hoc analyses of both the us and european endobronchial valve for emphysema palliation trial ( vent ) studies , factors such as fissure integrity on computed tomography lung scans and lobar occlusion were associated with significant lvr , and patients who exhibited these signs on computed tomography had significantly improved clinical outcomes.30 most importantly , these results were sustained at 12 months post - procedure . recently , herth et al validated the use of a method to assess cv for predicting efficacy of one - way valves.29 their results showed an accuracy of 75% . it is likely that current ongoing research trials with one - way valves using this approach would show better outcomes compared to the earlier studies . in contrast to the one - way valves , the effect of biolvr for lvr is not dependent on interlobar fissure integrity.32 the effects seem dose dependent , with the best effect produced by high - dose ( 20 ml / sub - segment ) versus low - dose ( 10 ml / sub - segment ) sealant.27 aside from some short - term complications , including treatment - related pneumonia ( figure s10 ) and copd exacerbations ( figure s8 ) , overall , as noted above , this method has been found to be very safe with no procedural mortality reported in studies.19,27,31 this is in contrast with the frequent procedure - related complications observed with one - way valves , such as pneumonia distal to valve implantation , valve- or procedure - related pneumothorax , and valve migration , as shown in figures s5s7 . we separately analyzed studies that followed participants for a minimum of 6 months to a maximum of 12 months . first , moderate - to - high heterogeneity was observed in most of the analyses . this could be because of the differences in the baseline characteristics of the study participants , procedural techniques , assessment of outcomes , and the geographic locations in which the studies were conducted . however , in order to account for the between - study variance , we used random effects model to report our results . second , excluding the subgroup of one - way valves , most of the other subgroups did not have a sufficient number of studies , hence assessment of publication bias in these subgroups was not possible . third , most of the studies included in our meta - analysis were single - arm prospective trials and not rcts and a few were pilot studies , which , as standalone studies , can not be considered powered enough to draw strong conclusions from . despite these limitations , we believe our findings are significant , as this meta - analysis provides some form of comparability between the different methods of blvr . we believe that future studies can benefit from the estimates of effect sizes provided in our meta - analysis . these preliminary findings show that , excluding airway bypass stents , most of the methods of blvr show efficacy in improving lung functions and exercise capacity . moreover , these methods could likely be noninferior , if not equivalent , to lvrs . however , it is likely that , in clinical practice , the efficacy observed for most blvr methods would be tempered with considerations of the technical peculiarities of each procedure ( such as the absence or presence of cv in the case of one - way valves ) and their associated complications . lvrs may still be considered first - line for patients with predominantly upper lobe emphysema and poor exercise capacity , and only a select number of patients could be considered for blvr . this is because , firstly , there is no trial that directly compares lvrs and blvr and , secondly , none of the bronchoscopic methods are approved by the us food and drug administration . given the preliminary nature of our findings , we believe that more trials are needed that are designed with a comparative effectiveness research model , involve a larger number of participants , with a much longer duration of follow - up , and with different markers of improvement than the ones traditionally used in earlier studies .