Research

Original Investigation

Effect of Endobronchial Coils vs Usual Care on Exercise

Tolerance in Patients With Severe Emphysema
The RENEW Randomized Clinical Trial
Frank C. Sciurba, MD; Gerard J. Criner, MD; Charlie Strange, MD; Pallav L. Shah, MD; Gaetane Michaud, MD; Timothy A. Connolly, MD;
Gaëtan Deslée, MD; William P. Tillis, MD; Antoine Delage, MD; Charles-Hugo Marquette, MD, PhD; Ganesh Krishna, MD;
Ravi Kalhan, MD; J. Scott Ferguson, MD; Michael Jantz, MD; Fabien Maldonado, MD; Robert McKenna, MD; Adnan Majid, MD;
Navdeep Rai, MD; Steven Gay, MD; Mark T. Dransfield, MD; Luis Angel, MD; Roger Maxfield, MD; Felix J. F. Herth, MD;
Momen M. Wahidi, MD; Atul Mehta, MD; Dirk-Jan Slebos, MD, PhD; for the RENEW Study Research Group

Supplemental content at
IMPORTANCE Preliminary clinical trials have demonstrated that endobronchial coils compress jama.com
emphysematous lung tissue and may improve lung function, exercise tolerance, and
symptoms in patients with emphysema and severe lung hyperinflation.

OBJECTIVE To determine the effectiveness and safety of endobronchial coil treatment.

DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted among 315 patients
with emphysema and severe air trapping recruited from 21 North American and 5 European
sites from December 2012 through November 2015.

INTERVENTIONS Participants were randomly assigned to continue usual care alone (guideline
based, including pulmonary rehabilitation and bronchodilators; n = 157) vs usual care plus
bilateral coil treatment (n = 158) involving 2 sequential procedures 4 months apart in which
10 to 14 coils were bronchoscopically placed in a single lobe of each lung.

MAIN OUTCOMES AND MEASURES The primary effectiveness outcome was difference in
absolute change in 6-minute-walk distance between baseline and 12 months (minimal
clinically important difference [MCID], 25 m). Secondary end points included the difference
between groups in 6-minute walk distance responder rate, absolute change in quality of life
using the St George’s Respiratory Questionnaire (MCID, 4) and change in forced expiratory
volume in the first second (FEV1; MCID, 10%). The primary safety analysis compared the
proportion of participants experiencing at least 1 of 7 prespecified major complications.

RESULTS Among 315 participants (mean age, 64 years; 52% women), 90% completed the
12-month follow-up. Median change in 6-minute walk distance at 12 months was 10.3 m with
coil treatment vs −7.6 m with usual care, with a between-group difference of 14.6 m
(Hodges-Lehmann 97.5% CI, 0.4 m to ⬁; 1-sided P = .02). Improvement of at least 25 m
occurred in 40.0% of patients in the coil group vs 26.9% with usual care (odds ratio, 1.8 [97.5%
CI, 1.1 to ⬁]; unadjusted between-group difference, 11.8% [97.5% CI, 1.0% to ⬁]; 1-sided P = .01).
The between-group difference in median change in FEV1 was 7.0% (97.5% CI, 3.4% to ⬁; 1-sided
P < .001), and the between-group St George’s Respiratory Questionnaire score improved −8.9
points (97.5% CI, −⬁ to −6.3 points; 1-sided P < .001), each favoring the coil group. Major
complications (including pneumonia requiring hospitalization and other potentially
life-threatening or fatal events) occurred in 34.8% of coil participants vs 19.1% of usual care
(P = .002). Other serious adverse events including pneumonia (20% coil vs 4.5% usual care)
and pneumothorax (9.7% vs 0.6%, respectively) occurred more frequently in the coil group.

CONCLUSIONS AND RELEVANCE Among patients with emphysema and severe hyperinflation Author Affiliations: Author
affiliations are listed at the end of this
treated for 12 months, the use of endobronchial coils compared with usual care resulted in an
article.
improvement in median exercise tolerance that was modest and of uncertain clinical
Group Information: The members of
importance, with a higher likelihood of major complications. Further follow-up is needed to the RENEW Study Research Group
assess long-term effects on health outcomes. are listed at the end of the article.
Corresponding Author: Frank C.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01608490
Sciurba, MD, University of Pittsburgh,
3471 Fifth Ave, Ste 1211, Kaufmann
JAMA. 2016;315(20):2178-2189. doi:10.1001/jama.2016.6261 Bldg, Pittsburgh, PA 15213
Published online May 15, 2016. (sciurbafc@upmc.edu).

2178 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema Original Investigation Research

P
atients with advanced emphysema and severe lung hy- former smokers who recently completed pulmonary reha-
perinflation have few treatment options to relieve bilitation and/or were participating in exercise mainte-
dyspnea.1,2 Lung volume reduction surgery has been nance. Self-reported ethnicity and race were collected as
shown to improve lung function, quality of life, and survival fixed categories per Clinical Data Interchange Standards
in the subset of patients with advanced, heterogeneous, upper Consortium standards to appropriately adjust lung function
lobe emphysema.3 However, relatively few patients with em- and to account for any potential differences by treat-
physema undergo lung ment. Key inclusion criteria included postbronchodilator
FEV1 forced expiratory volume in the
first second
volume reduction sur- forced expiratory volume in the first second (FEV1) of 45%
gery because a minority predicted or less, total lung capacity (TLC) of more than
MCID minimal clinically important
difference have an upper lobe–domi- 100% predicted, and residual volume (RV) of at least 225%
nant heterogeneous pat- predicted. The RV threshold was lowered to at least 175%
RV residual volume
tern of destruction and predicted following enrollment of 169 patients to ad-
TLC total lung capacity
postoperative complica- dress the effectiveness and safety of endobronchial coils
tions can be severe.3-5 A less invasive bronchoscopic ap- in a broader patient population. S evere bronchitis/
proach targeting patients with heterogeneous emphysema bronchiectasis, comorbidities potentially affecting trial
involves segmental airway placement of unidirectional completion, and significant reversible airflow obstruction
valves resulting in lobar collapse and clinical improvement; (postbronchodilator response >20%) excluded patients from
however, this approach is still investigational in North enrollment (eAppendix in Supplement 2).
America and restricted to patients without interlobar collat-
eral channels. 6-8 Patients with advanced homogeneous Trial Design
emphysema and/or presence of interlobar collateral ventila- This multicenter, randomized, assessor-blinded study com-
tion have very limited treatment options, essentially lung pared outcomes between treatment and control groups at 12
transplantation or palliative support. months. A radiology core laboratory reviewed scans for eli-
Endobronchial coils, 10- to 15-cm nitinol wires that re- gibility, identified lobes for treatment, and classified the
gain their preformed shape following deployment, are de- type of emphysema (heterogeneous or homogeneous) (eFig-
signed to compress emphysematous tissue, thus restoring elas- ure 1 in Supplement 2) using a semiquantitative visual
tic properties in adjacent lung tissue and improving ventilatory assessment (Supplement 1). Upper lobes were preferentially
mechanical function. Endobronchial coils have been tested in targeted in patients with homogeneously distributed dis-
patients with both heterogeneous and homogeneous lung de- ease based on physiologic modeling, preliminary surgical
struction with or without incomplete interlobar fissures. Sev- experience, and a feasibility trial.12,15 Blinded block random-
eral small clinical trials preliminarily reported that coils may ization (block size of 4) stratified by type of emphysema
improve quality of life and exercise tolerance.7,9-14 The re- occurred on a 1:1 basis between usual care (control group)
cently published REVOLENS randomized clinical trial raised and usual care plus treatment with endobronchial coils
questions with respect to effectiveness, including durability (PneumRx Inc) using a computerized, automated system
of effect, optimal patient selection criteria, multiperformer (Datatrak IWRS) directed by an independent contractor
technical feasibility, and importance of short- and long-term (Pharm-Olam International).
adverse events including pneumonia.14 The RENEW trial was Usual care was based on the Global Initiative for Chronic
conducted to assess 1-year effectiveness and safety of endo- Obstructive Lung Disease (GOLD)2 guidelines, whereby treat-
bronchial coils on exercise tolerance, quality of life, and lung ment was optimized in cooperation with the treating physi-
function in patients with severe lung hyperinflation and ad- cian at the pretreatment visit. Each participant was encour-
vanced homogeneous or heterogeneous emphysema. aged to use inhaled long-acting bronchodilators with or without
inhaled corticosteroids. Current influenza and pneumococ-
cus vaccinations were encouraged. Participants were re-
quired to complete a pulmonary rehabilitation program within
Methods 6 months or be performing maintenance rehabilitation prior
Study Oversight and Ethics to baseline testing. During the posttreatment period, medica-
The institutional review boards at participating centers ap- tion adjustment for treatment of exacerbations was permit-
proved the study protocol (Supplement 1), which was over- ted; however, changes to the medical regimen were other-
seen by an independent data monitoring committee. Patients wise discouraged and participants were encouraged to continue
were screened only after providing written informed con- maintenance rehabilitation.
sent. This study was conducted in compliance with the prin- The treatment group, in addition to receiving usual care,
ciples enunciated in the Declaration of Helsinki, the US clini- underwent implantation of 10 to 14 coils under fluoroscopic
cal investigative laws, and those laws appropriate for guidance via bronchoscopy (eFigures 2 and 3 in Supplement
participating centers in the European Union and Canada. 2). The choice of moderate sedation or general anesthesia
was determined by the investigator. The bronchoscopist
Study Participants advanced the bronchoscope to the ostium of the target sub-
The trial enrolled patients aged 35 years or older with medi- segmental airway and then advanced a catheter with a guide
cally optimized emphysema (Figure 1). Participants were wire into the bronchial segment of the treatment lobe to

jama.com (Reprinted) JAMA May 24/31, 2016 Volume 315, Number 20 2179

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Research Original Investigation Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema

Figure 1. Participant Flow in the RENEW Randomized Clinical Trial

685 Patients assessed for eligibility

370 Excluded
288 Did not meet inclusion criteria
168 Residual volume ≤225% of predicted
52 Disease condition or habit potentially
interfering with study completion
or outcomes
37 Diffusion capacity <20% of predicted
31 Change in forced expiratory volume
in the first second >20%
postbronchodilator response
24 Screening in process at enrollment close
58 Other reasons

315 Randomized

158 Randomized to receive intervention therapy 157 Randomized to receive control therapy
155 Received intervention as randomized 157 Received control as randomized
3 Did not receive intervention
2 Withdrawn by investigator (eligible
for lung transplant)
1 Withdrew consent

141 Completed study through 12 mo 143 Completed study through 12 mo

14 Did not complete study 14 Did not complete study
10 Died 8 Died
3 Withdrew consent 2 Lost to follow-up
1 Eligible for lung transplant 2 Had suspicious lung nodule
1 Severe chronic obstructive lung
disease exacerbation
1 Withdrew consent

23 Missing efficacy end-point dataa 18 Missing efficacy end-point dataa

21 Missing 6-minute walk distance 17 Missing 6-minute walk distance
21 Missing forced expiratory volume 17 Missing forced expiratory volume
in the first second in the first second
22 Missing residual volume 17 Missing residual volume
20 Missing St George’s Respiratory 18 Missing St George’s Respiratory
Questionnaire score Questionnaire score

a
Most patients with missing values
158 Included in primary analysis 157 Included in primary analysis
were included in all categories of
missing data.

within a minimum of 3 cm of the pleural surface. The (range, 0-100, with higher scores indicating worse quality of
selected coil length (100, 125, or 150 mm) was based on sub- life). Six-minute walk testing, spirometry, and physiologic
segmental airway length. Two sequential single-lobe treat- testing were performed using established standards, with
ments of contralateral upper or lower lobes were performed participants carrying their oxygen at the prescribed flow rate
4 months apart (based on a conservative estimate of the when necessary.18-21
recovery time needed after a bronchoscopy for this severely Other exploratory effectiveness end points included
affected patient population) (Supplement 1). St George’s Respiratory Questionnaire response, defined using
a 4-point or greater score reduction as the MCID22; mean ab-
Effectiveness Outcomes solute difference in RV (MCID, 0.35 L)23 measured by body ple-
All end points compared baseline data vs results at 12 months thysmography; and mean absolute difference in RV/TLC.
after first treatment. Participants were not blinded, although
walk and spirometry measurements were obtained using a Safety Outcome Assessment
blinded assessor. The primary safety analysis reports the proportion of partici-
The primary effectiveness variable was the difference in pants in the coil and usual care groups who experienced at least
absolute change in 6-minute walk distance between baseline 1 major complication within 12 months after baseline (eTable 1
and 12-month visit. Secondary end points included 6-minute in Supplement 2). All major complications were adjudicated by
walk distance response, defined as a 25-m minimal clinically an independent clinical events committee in an unblinded fash-
important difference (MCID)16 in 6-minute walk distance; ion to facilitate imaging review (eAppendix in Supplement 2).
mean percent change in FEV1 (MCID, 10%)17; and mean abso- Some participants experienced a focal lung tissue re-
lute difference in St George’s Respiratory Questionnaire score sponse to coil treatment, identified on chest imaging and

2180 JAMA May 24/31, 2016 Volume 315, Number 20 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema Original Investigation Research

characterized during the course of this trial as coil-

associated opacity (eFigure 4 in Supplement 2). The RENEW Results
data monitoring committee adjudicated the investigator-
reported pneumonia adverse events and determined that Participants
some of these events were misclassified and represented Study enrollment began in December 2012, and the final
coil-associated opacity. participant completed 12-month follow-up in November
2015. Six hundred eighty-five patients were screened at 34
Statistical Analysis sites; 315 patients were randomized to receive either endo-
Based on previous studies, a sample size of 315 was selected bronchial coil treatment (n = 158) or usual care (control;
to provide greater than 95% power to detect a treatment dif- n = 157) at 21 North American and 5 European sites. Twelve-
ference in effectiveness, assuming 5% lost to follow-up and month follow-up was completed by 90.2% of participants
treatment difference in change in 6-minute walk distance of (Figure 1). Three participants randomized to coil treatment
59 m (SD, 80 m) (the difference from baseline observed in withdrew before the intervention. Baseline characteristics
early feasibility trials) and in FEV 1 of 0.05 L (SD, 0.10 L) were similar between groups (Table 1). This population was
using a 1-sided t test at α = .025.6,24 Comparisons of the coil notable for the severity of airflow obstruction and hyperin-
group vs usual care in primary and secondary effectiveness flation, the high prevalence of comorbidities, and the pre-
end points were tested using analysis of covariance (or non- dominance of homogeneous emphysematous destruction
parametric rank analysis of covariance in the presence of on chest computed tomography. Seventy-six percent of coil
significant skewness) and logistic regression (for 6-minute vs 71% of usual care participants had “very severe” spiro-
walk distance responder end point) controlling for the metric disease based on the GOLD 4 guidelines. Extreme
covariates of corresponding baseline value, analysis center, hyperinflation was present, with a mean RV of 246% (SD,
and emphysema status in an intention-to-treat (ITT) analy- 39%) predicted in the coil group vs 245% (SD, 39%) pre-
sis. Missing values were imputed 50 times using the Markov dicted in usual care participants. The coil group had a
chain Monte Carlo method of multiple imputation. Mean median of 2.0 (interquartile range [IQR], 1.0-4.0) nonpul-
between-treatment differences adjusted for covariates and, monary major comorbidities vs 2.0 (IQR, 1.0-3.0) in the
for data that were significantly skewed, Hodges-Lehmann usual care group (eTable 3 and eFigure 5 in Supplement 2);
median between-treatment differences adjusted for base- 43% vs 41% received long-term oxygen and 31% vs 27% had
line were reported with associated 97.5% confidence inter- been hospitalized in the year prior to enrollment in the coil
vals. The proportion of responders, odds ratios (ORs), and and usual care groups, respectively. Emphysema distribu-
97.5% CIs adjusted for covariates are reported for responder tion on computed tomography was similar between groups
end points. This study was designed as a pivotal study to (77% with homogeneous and 23% with heterogeneous pat-
support regulatory product registration by testing the supe- terns) (eFigure 1 in Supplement 2).
riority in effectiveness of the coil group over usual care
against the null hypothesis of equality or inferiority. There- Procedures
fore, all effectiveness analyses were 1-sided tests of superi- Bilateral treatment was completed in 144 of 158 participants
ority at the α = .025 significance level comparing endobron- assigned to coil treatment; 11 participants completed only uni-
chial coil treatment vs usual care. The Hochberg step-up lateral treatment due to death (n = 3) or clinical worsening
procedure was used to control the study-wise α for multiple (n = 8). Among the treatments, 84.2% were in upper lobes and
comparisons in secondary end points.25-28 15.8% were in lower lobes, with a median insertion of 10 and
Other effectiveness end points tested for statistical sig- 12 to 13 coils, respectively (eTable 4 in Supplement 2). Proce-
nificance included St George’s Respiratory Questionnaire dure duration was 42 minutes (SD, 16 minutes) with a median
response analysis and mean absolute differences in RV and hospital stay of 1 night (range, 0-15 nights).
RV/TLC and were not adjusted for multiple comparisons.
Post hoc analyses compared effectiveness between the coil Primary and Secondary 6-Minute Walk Distance
group and usual care separately by prespecified subgroups Effectiveness End Points (ITT Population)
for type of emphysema and baseline RV measurement using The median prespecified primary effectiveness end point of
the same methods as the primary and secondary effective- change in 6-minute walk distance at 12 months was 10.3 m
ness analyses. (IQR, −33.0 to 45.0 m) in coil-treated patients vs −7.6 m (IQR,
Between-group comparisons at baseline were based on −40.0 to 26.0 m) for usual care, with a median between-
analysis of variance with a factor for investigational site, group difference of 14.6 m (Hodges-Lehmann 97.5% CI, 0.4 m
stratified Cochran-Mantel-Haenszel test, or Fisher exact to ⬁; 1-sided P = .02) (Table 2, Figure 2, and eTable 5A in
test. Between-treatment comparison of proportions of par- Supplement 2). The secondary effectiveness end point of
ticipants experiencing at least 1 major complication were 6-minute walk distance response rate revealed 40.0% vs 26.9%
analyzed using a 2-sided Fisher exact test. All analyses were favoring the coil group (OR, 1.8 [97.5% CI, 1.1 to ⬁]; unad-
conducted using SAS version 9.3 (SAS Institute Inc). For justed between-group difference, 11.8% [97.5% CI, 1.0% to ⬁];
detailed information about study methods, see the eAppen- 1-sided P = .01) A small subset of 12 participants in the coil group
dix in Supplement 2 and the statistical analysis plan in and 8 participants in the usual care group reported a 12-
Supplement 3. month decline of greater than 100 m (4 times the MCID).

jama.com (Reprinted) JAMA May 24/31, 2016 Volume 315, Number 20 2181

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Research Original Investigation Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema

Table 1. Baseline Demographics and Disease Characteristicsa

Coil Treatment Usual Care
Characteristics (n = 158) (n = 157)
Age, y 63.4 (8.05) 64.3 (7.76)
Female, No. (%) 86 (54.4) 79 (50.3)
Body mass indexb 24.9 (4.6) 24.5 (4.9)
Hispanic/Latino ethnicity, No. (%) 1 (0.6) 2 (1.3)
Race, No. (%)
Black or African American 6 (3.8) 4 (2.5)
White 151 (95.6) 152 (96.8)
Asian/other 1 (0.6) 1 (0.6)
GOLD stage 4, No. (%) 120 (75.9) 112 (71.3)
BODE score33c 5.96 (1.26) 6.03 (1.32)
Score of 7-10, No. (%) 51 (32.3) 52 (33.1)
Smoking history, pack-yearsd 50.7 (27.9) [n=157] 50.3 (23.5)
No. of nonrespiratory comorbiditiese 2.6 (2.0) 2.3 (1.8)
Median (IQR) 2.0 (1.0-4.0) 2.0 (1.0-3.0)
≥4 Baseline total nonrespiratory comorbidities, 45 (28.5) 39 (24.8)
No. (%)
Receiving continuous oxygen, No. (%) 68 (43.0) 64 (40.8)
Flow rate, L/min 2.5 (0.9) 2.3 (0.9)
Hospital visits, all causes, 0-12 mo prior to baseline, 49 (31.0) 43 (27.4)
No. (%)
Baseline inhaler category, No. (%)
Long-acting β agonist and/or long-acting muscarinic 136 (86.1) 141 (89.8)
antagonist plus inhaled corticosteroid
Long-acting β agonist and/or long-acting muscarinic 15 (9.5) 13 (8.3)
antagonist
Short-acting β agonist and/or short-acting muscarinic 2 (1.3) 2 (1.3)
antagonist alone
None 5 (3.2) 1 (0.6)
6-Minute walk distance, m 312.0 (79.1) 302.7 (79.3)
Median (IQR) 318.3 (251.5-361.0) 300.0 (244.0-356.6)
Type of emphysema, No. (%) Abbreviations: BODE, body mass
Heterogeneous 36 (22.8) 36 (22.9) index, airflow obstruction, dyspnea,
and exercise; DLCO, single-breath
Homogeneous 122 (77.2) 121 (77.1) diffusion capacity for carbon
FVC, L 2.47 (0.69) 2.46 (0.75) monoxide; GOLD, Global Initiative for
Chronic Obstructive Lung Disease;
FVC, % predicted 67.8 (14.3) 67.4 (15.0)
FEV, forced expiratory volume;
FEV1, L 0.71 (0.20) 0.72 (0.21) FEV1, forced expiratory volume in the
FEV1, % predicted 25.7 (6.3) 26.3 (6.7) first second; FVC, forced vital
capacity; mMRC, Modified Medical
FEV1/FVC, % 28.8 (6.8) 29.9 (6.8)
Research Council; RV, residual
RV, L 5.28 (1.06) 5.33 (1.15) volume; TLC, total lung capacity.
a
RV, % predicted 245.9 (39.1) 244.5 (38.7) Data are expressed as mean (SD)
unless otherwise indicated.
TLC, L 7.87 (1.35) 7.92 (1.56)
b
Calculated as weight in kilograms
TLC, % predicted 139.2 (15.6) 138.8 (16.1)
divided by height in meters
RV/TLC, % 67.1 (6.7) 67.3 (6.3) squared.
c
DLCO, mL/min/mm Hg 8.12 (2.86) 8.15 (2.80) Scores range from 0 to 10, with
DLCO, % predicted 34.1 (10.5) 34.5 (10.7) higher scores indicating worse
prognosis.
St George’s Respiratory Questionnaire total scoref 60.1 (12.8) 57.4 (14.8) d
One coil group participant had a
mMRC Dyspnea Scale score, No. (%) history of smoking but had missing
0/1 0 0 smoking pack-year data.
e
2 54 (34.2) 56 (35.7) See eTable 3 in Supplement 2 for the
list of 15 nonrespiratory
3 69 (43.7) 70 (44.6) comorbidities included in this
4 35 (22.2) 31 (19.7) calculation.
f
PaCO2, mm Hg 41.6 (5.6) 41.5 (5.3) Scores range from 0 to 100, with
higher scores indicating worse
PaO2, mm Hg 68.0 (10.5) 69.2 (10.9)
quality of life.

2182 JAMA May 24/31, 2016 Volume 315, Number 20 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema Original Investigation Research

Table 2. Effectiveness End Points for the Intention-to-Treat Populationa

Coil Treatment Usual Care Between-Group
(n = 158) (n = 157) Difference for Coil
Within-Group Change Within-Group Change Treatment vs Usual
End Point At 12 mo or Rateb At 12 mo or Rateb Care (97.5% CI)b P Valuec
Primary end point
Change in 6-minute 319.7 (242.9 to 387.7) 10.3 (−33.0 to 45.0) 300.0 (233.2 to 350.0) −7.6 (−40.0 to 26.0) 14.6 (0.4 to ⬁) .02e
walk distance,
median (IQR), md
Secondary end points
6-minute walk distance NA 63 (40.0) NA 42 (26.9) 11.8 (1.0 to ⬁)g .01i
response rate, No. (%) [31.0 to 49.0] [18.9 to 35.0] OR: 1.8 (1.1 to ⬁)h
[95% CI]f
Change in FEV1, 0.71 (0.58 to 0.88) 3.8 (−6.3 to 16.1) 0.68 (0.54 to 0.82) −2.5 (−8.9 to 4.4) 7.0 (3.4 to ⬁) <.001e
median (IQR), %d
Change in St George’s 51.9 (49.5 to 54.4) −8.1 (−10.2 to −6.0) 58.4 (55.9 to 60.9) 0.8 (−1.2 to 2.9) −8.9 (−⬁ to −6.3) <.001
Respiratory
Questionnaire score,
mean (95% CI)j
Other end points
St George’s Respiratory NA 97 (61.2) NA 43 (27.7) 31.6 (20.5 to ⬁)g <.001i
Questionnaire response [50.9 to 71.4] [18.6 to 36.8] OR: 4.1 (2.4 to ⬁)h
rate, No. (%) [95% CI]f
Change in RV, mean 4.95 (4.75 to 5.14) −0.41 (0.57 to −0.25) 5.28 (5.07 to 5.49) −0.10 (−0.26 to 0.06) −0.31 (−⬁ to −0.11) .001
(95% CI), Lj
Change in RV/TLC, 63.6 (62.4 to 64.8) −4.0 (−5.1 to −2.9) 67.3 (66.2 to 68.4) −0.5 (−1.6 to 0.6) −3.5 (−⬁ to −2.1) <.001
mean (95% CI), %j
e
Abbreviations: FEV1, forced expiratory volume in the first second; By nonparametric rank analysis of covariance with factors of treatment,
IQR, interquartile range; NA, not applicable; OR, odds ratio; RV, residual volume; emphysema status, analysis center, and corresponding baseline value.
TLC, total lung capacity. The Shapiro-Wilk test indicated nonnormality of residuals (P < .001).
a f
The full intention-to-treat analysis set comprised all patients who were Response in 6-minute walk distance was defined as an increase of at least 25
randomized, with multiple imputation for missing values using the Markov meters. Response in St George’s Respiratory Questionnaire score was defined
Chain Monte Carlo method. as a decrease of at least 4 points. The response rate represents the proportion
b
Response rates are adjusted for emphysema status and analysis center, and of patients achieving these minimal clinically important differences.
g
corresponding baseline values from logistic regression are presented as No. (%) Unadjusted between-treatment difference in response rate.
of patients and odds ratios between treatment groups. The frequency of h
Adjusted OR.
responders was estimated from multiple imputation results. For 6-minute walk i
By logistic regression with factors of treatment, emphysema status, analysis
distance, response rates are not adjusted for analysis center because of
center, and corresponding baseline value. For 6-minute walk distance
incomplete model convergence (eAppendix in Supplement 2).
response, analysis center was not included as a factor because of incomplete
Between-treatment differences in response rates are not adjusted for covariates.
model convergence (eAppendix in Supplement 2).
c
By analysis of covariance with factors of treatment, emphysema status, j
Mean within-group change and between-treatment difference adjusted for
analysis center, and corresponding baseline value, unless otherwise specified.
covariates from analysis of covariance.
d
Median between-treatment differences adjusted for baseline using the
Hodges-Lehmann estimator. The nonparametric median between-treatment
difference is not the simple between-treatment difference in medians.

Other Secondary Effectiveness End Points (ITT Population) −0.11 L; 1-sided P = .001) and for RV/TLC of −3.5% (97.5% CI,
The mean between-group difference in absolute change in the −⬁ to −2.1%; 1-sided P < .001) (Table 2 and Figure 2). Descrip-
St George’s Respiratory Questionnaire total score was −8.9 tive results of primary, secondary, and exploratory outcome
points (97.5% CI, −⬁ to −6.3 points; 1-sided P < .001), predomi- end points at interim time points are presented in eTable 6 in
nantly achieved through improvement in the coil group. The Supplement 2.
change in FEV1 was 3.8% (IQR, −6.3% to 16.1%) in coil-treated Prespecified subgroup analyses were performed to as-
patients vs −2.5% (IQR, −8.9% to 4.4%) for usual care, with a sess response stratified by degree of air trapping (RV ≥225%
between-group difference estimate of 7.0% (Hodges- vs <225% predicted) and by heterogeneous vs homogeneous
Lehmann 97.5% CI, 3.4% to ⬁; 1-sided P < .001) (Table 2, emphysema distribution. The RV ≥225% group and the hetero-
Figure 2, and eTable 5B in Supplement 2). geneous emphysema group each had greater magnitudes of
treatment response in all primary and secondary effective-
Exploratory Effectiveness End Points (ITT Population) ness end points compared with respective groups with RV of
The St George’s Respiratory Questionnaire response analysis less than 225% and homogeneous destruction, although the
demonstrated significantly more participants with meaning- study was not powered to test differences between sub-
ful improvement in the coil group (61.2%) vs usual care (27.7%); groups.
for an unadjusted between-group difference of 31.6% (97.5%
CI, 20.5% to ⬁; P < .001). Resting lung hyperinflation de- Post Hoc Analyses (ITT Population)
creased in the coil group relative to usual care, represented by Participants were stratified into 4 subgroups based on the
between-group differences for RV of −0.31 L (97.5% CI, −⬁ to prespecified characteristics associated with lung hyperinfla-

jama.com (Reprinted) JAMA May 24/31, 2016 Volume 315, Number 20 2183

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Research Original Investigation Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema

Figure 2. Distribution of Effectiveness End Points for the Intention-to-Treat Analysis for Key Outcome Measures

MCID threshold
Improved Declined
6-Minute walk distance, m ≥25 ≤–25
St George’s Respiratory
Questionnaire, points ≤–4 ≥+4
FEV1, % predicted ≥+10% ≤–10%
Residual volume, L ≤–0.35 ≥+0.35

6-Minute walk distance St George’s Respiratory Questionnaire

Coil Control Coil Control
(n = 158) (n = 157) (n = 158) (n = 157)
200 50
Change in 6-Minute Walk Distance, m

Change in St George’s Respiratory

100
25

Questionnaire Score
0

-100

-25
-200

-300 -50
40 30 20 10 0 10 20 30 40 40 30 20 10 0 10 20 30 40
Number Number

FEV1,, predicted Residual volume

Coil Control Coil Control
(n = 158) (n = 157) (n = 158) (n = 155)
80 3.0

60 2.0
Change in Residual Volume, L
Change in FEV1, % Predicted

40 1.0

20 0

0 -1.0

-20 -2.0

-40 -3.0
40 30 20 10 0 10 20 30 40 40 30 20 10 0 10 20 30 40
Number Number

For all measures, the response rates were higher in the endobronchial coil group intention-to-treat analysis set, with multiple imputation. For each histogram,
based on reported minimal clinically important differences (MCIDs).16,17,19,23 the bin interval was set at half of the MCID for that measure. In each bin, the
In contrast, the proportion of participants declining an MCID equivalent was data are equal to or greater than the lower limit and less than the upper limit of
numerically greater for all measures in the usual care group. Note the small the bin. The bin widths for each histogram are for residual volume, 175 mL;
number of very significant 6-minute walk distance decliners, particularly forced expiratory volume in the first second (FEV1), 5%; 6-minute walk
in the coil group, that lowered the mean response. All improver and decliner distance, 12.5 m; and St George’s Respiratory Questionnaire, 2 points.
rates were calculated with logistic regression with data from the full

tion and emphysema distribution (Figure 3 and eTable 7 in Respiratory Questionnaire change of−3.3 points. The sub-
Supplement 2). Participants with both favorable attributes group with homogeneous disease but greater air trapping
(RV ≥225% predicted and heterogeneous distribution) (RV ≥225% predicted) had a favorable treatment response in
exhibited superior treatment responses (median 6-minute all end points (median 6-minute walk distance, +20.7 m;
walk distance, +29.1 m, FEV 1 change +12.3%, and mean median FEV1 change, +8.3%; and mean St George’s Respira-
St George’s Respiratory Questionnaire change, −10.1-point tory Questionnaire change, −10.0-point difference in the
difference in the coil group relative to usual care), while coil group relative to usual care). The group expressing
those with less air trapping (RV <225% predicted) and heterogeneous disease with RV of less than 225% predicted
homogeneous disease exhibited between-treatment dif- was too small for data to be interpreted but demonstrated a
ferences of a median −16.7 m for 6-minute walk distance, mixed response. The RV threshold used, albeit prespecified,
a median FEV 1 change of 3.5%, and a mean St George’s was arbitrarily chosen, and a post hoc sensitivity analysis

2184 JAMA May 24/31, 2016 Volume 315, Number 20 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema Original Investigation Research

Figure 3. Intention-to-Treat Analysis Response Rates for 4 Effectiveness Measures in Subgroups Stratified
by Emphysema Distribution and Degree of Air Trapping

Coil Control
Responder criteria
6-Minute walk distance, m ≥25
St George’s Respiratory
Questionnaire, points ≤–4
FEV1, % predicted ≥+10%
Residual volume, L ≤–0.35

Residual volume ≥225% predicted, Residual volume ≥225% predicted,

heterogeneous emphysema homogeneous emphysema
80 80
Coil, n = 27 Coil, n = 88
Control, n = 31 Control, n = 89
70 70

60 60
Responders, %

Responders, %
50 50

40 40

30 30

20 20

10 10

0 0
6-Minute St George’s FEV1 Residual 6-Minute St George’s FEV1 Residual
Walk Respiratory Volume Walk Respiratory Volume
Distance Questionnaire Distance Questionnaire

Residual volume <225% predicted, Residual volume <225% predicted,

heterogeneous emphysema homogeneous emphysema
80 80
Coil, n = 9 Coil, n = 34
Control, n = 5 Control, n = 32
70 70

60 60
Responders, %

Responders, %

50 50

40 40
The greatest and most consistent
30 30 improvements occurred in the
residual volume ⱖ225% subgroups,
20 20 particularly those with
heterogeneous disease. Response
10 10 rates were calculated with logistic
regression with data from the full
0 0
6-Minute St George’s FEV1 Residual 6-Minute St George’s FEV1 Residual intention-to-treat analysis set, with
Walk Respiratory Volume Walk Respiratory Volume multiple imputation. FEV1 indicates
Distance Questionnaire Distance Questionnaire forced expiratory volume in
the first second.

(eTable 8 in Supplement 2) indicated that 200% predicted group with greater severity of air trapping (RV ≥225%)
may be a more sensitive response threshold. (eTable 11 in Supplement 2).
The presence of comorbidities reduced the 12-month
6-minute walk distance outcome despite lung function Safety End Points
improvements. Compared with usual care, coil-treated par- There was no difference in deaths in the coil group (n = 10;
ticipants with 4 or more comorbidities (eTable 9 in Supplement 6.5%) vs the usual care group (n = 8; 5.1%) at 1 year (eTable 12
2) had a 1.1-m relative decline in 6-minute walk distance in Supplement 2). Total major complications occurred more
despite significant reduction in RV, in contrast to partici- frequently in the coil group (n = 54; 34.8%) vs the usual care
pants with 3 or fewer comorbidities, who had a relative group (n = 30; 19.1%; P = .002) (Table 3). This difference was
21.0-m improvement in 6-minute walk distance. Partici- largely due to increased lower respiratory tract infections
pants who exhibited cardiac-related comorbidity also dem- (18.7% vs 4.5%; P < .001). There were 2 cases of hemoptysis
onstrated a decline in 6-minute walk distance despite requiring intervention in the coil group.
improvements in lung function (eTable 10 in Supplement 2). There were 2 direct procedure-associated deaths; one
The RV <225% subgroup had the greatest prevalence of car- patient died during the initial coil procedure because of
diac disease and averaged more comorbidities than the sub- pulmonary hemorrhage and respiratory failure leading to

jama.com (Reprinted) JAMA May 24/31, 2016 Volume 315, Number 20 2185

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Research Original Investigation Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema

Table 3. Major Complications and Important Serious Adverse Events Through 12 Months in the Safety Population

No. (%) of Patientsa

Coil Treatment Usual Care
(n = 155) (n = 157) Difference, % (95% CI)b P Valuec
Major complications
Any 54 (34.8) 30 (19.1) 15.7 (5.9 to 25.2) .002
Death 10 (6.5) 8 (5.1) 1.4 (−4.1 to 7.0) .64
Pneumothorax requiring extended chest tube 1 (0.6) 1 (0.6) 0.0 (−2.9 to 3.0) >.99
drainage >7 d
Hemoptysis requiring intervention 2 (1.3) 0 1.3 (−1.3 to 4.6) .25
COPD exacerbation requiring extended 18 (11.6) 13 (8.3) 3.3 (−3.4 to 10.2) .35
hospitalization >7 d
Lower respiratory tract infection, including 29 (18.7) 7 (4.5) 14.3 (7.3 to 21.5) <.001
pneumonia, requiring intravenous antibiotics and/or
corticosteroids
Respiratory failure requiring mechanical ventilation 6 (3.9) 6 (3.8) 0.0 (−4.7 to 4.8) >.99
Unanticipated bronchoscopy 0 0 NA
Other important serious adverse eventsd
Pneumoniae 31 (20.0) 7 (4.5) 15.5 (8.4 to 22.9) <.001
COPD exacerbation 43 (27.7) 32 (20.4) 7.4 (−2.1 to 16.7) .15
Hemoptysis 4 (2.6) 0 2.6 (−0.3 to 6.4)
Pneumothoraxf 15 (9.7)f 1 (0.6) 9.0 (4.3 to 14.7) <.001
Abbreviations: COPD, chronic obstructive pulmonary disease; NA, not disability/incapacity; or require intervention to prevent permanent
applicable. impairment or damage.
a e
Patients were counted once at most for an event type. This category combines infectious pneumonia and a localized, noninfectious
b
Confidence intervals calculated using the Newcombe method. tissue response identified during the study and adjudicated by the data
c
monitoring committee to be a coil-associated opacity.
Difference in proportions compared using the Fisher exact test.
f
d
Three additional pneumothorax events were reported but did not meet
The standard definition of serious adverse events includes events that are
serious adverse event criteria; thus, the total pneumothorax rate in the
life-threatening or result in death; require patient hospitalization or
treatment group was 11.6%.
prolongation of existing hospitalization; result in persistent or significant

cardiac arrest, and another patient died of respiratory fail- with a median 6-minute walk distance decline of −25 m
ure 6 days following the second coil procedure. Overall, (IQR, −66 to −0.6 m) and a median FEV1 change of −2.9%
serious adverse events were similar between the 2 study (IQR, −11.5% to −1.6%) (eTable 16B in Supplement 2).
groups except with respect to pneumonia (coil group, n = 31
[20%] vs usual care, n = 7 [4.5%]; P < .001) and pneumotho-
rax (coil group, n = 15 [9.7%] vs usual care, n = 1 [0.6%];
P < .001). Serious adverse events related to chronic obstruc-
Discussion
tive pulmonary disease exacerbations tended to be more In a multicenter trial, bilateral endobronchial coil treatment
frequent with coil treatment (n = 43; 27.7%) vs usual care in patients with severe lung hyperinflation and homoge-
(n = 32; 20.4%; P = .15) but returned to the level of the usual neous or heterogeneous emphysema resulted in durable but
care group in the 9- to 12-month window (eTables 13 and 14 modest increases in 6-minute walk distance of uncertain clini-
in Supplement 2). cal importance, along with improved expiratory flow rate av-
eraging less than a clinically important difference, reduced air
Post Hoc Safety Analysis trapping, and overall clinically important improvements in
Reported pneumonia events adjudicated by the data moni- quality of life. These improvements were associated with a
toring committee were determined to be noninfectious coil- higher rate of pneumothorax, pneumonia, hemoptysis, and
associated opacity in 14 of 40 adjudicable cases (35%) chronic obstructive pulmonary disease exacerbations imme-
(eTable 15 in Supplement 2). Coil participants with adjudi- diately following the coil procedure and for several months af-
cated coil-associated opacity exhibited superior 12-month ter coil implantation.
effectiveness outcomes compared with patients without This study addresses a group of patients with advanced
coil-associated opacities or pneumonia; the median predominantly homogenous emphysema who have few
6-minute walk distance response rate was 47.8% (95% CI, treatment options. More than 75% of participants had a
20.1%-75.6%) vs 38.9% (95% CI, 27.6%-50.2%) and the homogeneous emphysema distribution that would exclude
median FEV 1 change was 10.8% (IQR, 3.5%-22.7%) vs them from consideration for surgical lung reduction and
2.2% (IQR, −7.8% to 14.5%), respectively (eTable 16A in from investigational endobronchial valve treatment
Supplement 2). This contrasts with usual care participants options.3,6,8,29 The improvement in lung function associ-
with pneumonia (n=13), who had worsening of all measures, ated with quality-of-life improvement greater than 2 times
specifically a 7.8% 6-minute walk distance response rate, the established MCID at 1-year follow-up was consistent

2186 JAMA May 24/31, 2016 Volume 315, Number 20 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema Original Investigation Research

with reports from several smaller observational and ran- care participants with pneumonia, who did very poorly, sug-
domized studies.7,9-14 On the other hand, the difference in gesting a causal and mechanistic difference between the study
6-minute walk distance of 14.6 m, while statistically signifi- groups (eTable 16 in Supplement 2). The planned follow-up of
cant, was modest and less than the established MCID of the RENEW cohort for 5 years will better elucidate the long-
25 m. Furthermore, the lower confidence limit suggests the term response and safety profile of treatment.
responder difference between the 2 groups could be as low We have identified prespecified and mechanistically plau-
as 1%. Our results compare with the 21-m 6-minute walk sible subgroups defined by degree of air trapping and disease
distance improvement reported in the recent REVOLENS distribution that associate with greater treatment response
randomized trial at the primary 6-month end point and con- (Figure 3 and eTable 7 in Supplement 2). The variation in re-
trast with greater responses observed in previous observa- sponse within these subgroups, given the exploratory nature
tional studies.24 In this trial, the 6-minute walk distance of this analysis, must be interpreted with caution but offers
response was skewed such that a significantly greater pro- preliminary evidence to support future validation of these mea-
portion of clinically important responses in the coil group sures to enhance patient selection.
relative to usual care was balanced by a small proportion of There are limitations in the interpretation of this
severe declines in both the coil and usual care groups that study’s results. The difficulty in implementing a sham con-
lowered the mean and median response differences trol group prevented effective blinding of participants
(Figure 2). The variable improvement in walk distance was and may have influenced subjective outcomes such as the
in part related to this study’s less restrictive inclusion crite- St George’s Respiratory Questionnaire. On the other hand,
ria; participants with less air trapping (RV <220% predicted) the St George’s Respiratory Questionnaire, which was the most
were excluded from REVOLENS. The baseline walk dis- responsive of this study’s effectiveness measures, tracked with
tance, degree of hyperinflation, prevalence of prior hospi- more objective physiologic measures in the subgroup analy-
talization, and long-term oxygen use in this trial reflect sis (Figure 3). Another limitation was the use of 6-minute walk
greater impairment than in those enrolled in prior surgical distance as the primary outcome measure. While 6-minute
and endobronchial volume reduction trials.3,6,8 One third of walk distance can integrate the functional effects of complex
this study’s participants would qualify for lung transplanta- physiologic changes in lung mechanics such as reductions in
tion based on their BODE ( body mass index, airflow hyperinflation and air trapping, which may not always be re-
obstruction, dyspnea, and exercise) scores of 7 or higher.30 flected in more conventional expiratory flow measures, the
Furthermore, the inclusion of participants with multiple variance in the measure and ceiling effect can limit the re-
comorbidities in this study’s cohort (eTable 3 and eFigure 5 sponsiveness of the tool. Inclusion of a practice walk at all
in Supplement 2) and in REVOLENS likely attenuated the evaluation time points or greater vigilance to maintaining re-
6-minute walk distance response in both studies despite habilitation following randomization might have increased the
improvements in lung function. responsiveness of 6-minute walk distance and lessened the
Although adverse events including pneumothorax and he- baseline decline across study groups.32 Despite these limita-
moptysis were more common in the coil group, the events gen- tions, however, the broadness of this study’s inclusion crite-
erally occurred in the periprocedural and postprocedural pe- ria, the large number of enrolled patients, the longer duration
riods and events returned toward baseline in the months of follow-up, and the inclusion of multiple centers and coil im-
following the second procedure, as has been described in pre- planters provide insights regarding the potential clinical util-
vious series.31 The 15% excess incidence of pneumonia in the ity of this therapy.
coil group vs usual care was nearly identical to that reported
in the REVOLENS trial.14 This study has expanded the under-
standing of these pneumonia-classified events by identifying
noninfectious coil-associated opacities that represent more
Conclusions
than one-third of events. These coil-associated opacities ap- Among patients with emphysema and severe hyperinflation
pear to represent coil-induced inflammatory or lung struc- treated for 12 months, the use of an endobronchial coil com-
tural changes induced by stress forces from the coils on lung pared with usual care resulted in an improvement in median
parenchyma. exercise tolerance that was modest and of uncertain clinical
Treated participants reporting a pneumonia or coil- importance, with a higher likelihood of major complications.
associated opacity event had better outcomes at 12 months than Further follow-up is needed to assess long-term effects on
participants not experiencing these events, in contrast to usual health outcomes.

ARTICLE INFORMATION National Institute for Health Research Unit, Royal Critical Care Institute, Peoria (Tillis); Quebec Heart
Published Online: May 15, 2016. Brompton and Harefield NHS Foundation Trust, and Lung Institute, Quebec City, Quebec, Canada
doi:10.1001/jama.2016.6261. Imperial College, London, England (Shah); Chelsea (Delage); University Nice Sophia Antipolis, IRCAN,
and Westminster Hospital, London, England (Shah); ONCOAGE, Nice, France (Marquette); Palo Alto
Author Affiliations: University of Pittsburgh School New York University School of Medicine, New York, Medical Foundation/El Camino Hospital, Mountain
of Medicine, Pittsburgh, Pennsylvania (Sciurba); New York (Michaud); Pulmonary, Critical Care, and View, California (Krishna); Northwestern University,
Lewis Katz School of Medicine at Temple University, Sleep Medicine, Houston, Texas (Connolly); Chicago, Illinois (Kalhan); University of Wisconsin
Philadelphia, Pennsylvania (Criner); Medical University Hospital of Reims, INSERM U903, Reims, School of Medicine, Madison (Ferguson); University
University of South Carolina, Charleston (Strange); France (Deslée); OSF HealthCare–Illinois Lung and of Florida, Gainesville (Jantz); Mayo Clinic,

jama.com (Reprinted) JAMA May 24/31, 2016 Volume 315, Number 20 2187

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Research Original Investigation Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema

Rochester, Minnesota (Maldonado); Cedars-Sinai Pulmonx, Uptake Medical, Olympus, Novartis, P. LeBlanc, F. Maltais, Y. Lacasse, N. Lampron,
Medical Center, Los Angeles, California (McKenna); Grifols, Berlin-Chemie, and Teva. Dr Wahidi reports F. Laberge, J. Milot, J. Picard, M.-J. Breton;
Beth Israel Deaconess Medical Center, Boston, receipt of personal fees from PneumRx. Dr Slebos University of Alabama at Birmingham:
Massachusetts (Majid); Franciscan Research Center, reports receipt of grants, personal fees, and other M. Dransfield, J. M. Wells, S. Bhatt, P. Smith,
Tacoma, Washington (Rai); University of Michigan, support from Aeris, Holairo, Olympus, CSA Medical, E. N. Seabron-Harris; National Jewish Health:
Ann Arbor (Gay); University of Alabama at and Pulmonx. No other disclosures were reported. K. Hammond, C. Egidio.
Birmingham, Birmingham (Dransfield); University Group Information: The members of the RENEW Funding/Support: This study was supported by
of Texas, San Antonio (Angel); New York Study Research Group include: Thoraxklinik/ PneumRx Inc, a BTG International group company.
Presbyterian Hospital/Columbia University, University of Heidelberg: F. J. F. Herth, Drs Sciurba, Criner, and Slebos receive institutional
New York, New York (Maxfield); Thoraxklinik at the D. Gompelmann, M. Schuhmann, R. Eberhardt, support from Pulmonx.
University of Heidelberg, Heidelberg, Germany D. Harzheim, B. Rump; University Medical Center,
(Herth); Duke University Medical Center, Durham, Role of the Sponsor/Funder: The investigators,
Groningen: D.-J. Slebos, N. ten Hacken, K. Klooster; sponsor (PneumRx Inc), and representatives of the
North Carolina (Wahidi); Cleveland Clinic Royal Brompton and Chelsea Westminster Hospitals:
Foundation, Cleveland, Ohio (Mehta); University of US Food and Drug Administration designed the
P. Shah, S. Singh, W. McNulty, J. Garner; CHU de trial. The sponsor funded the study, assisted in the
Groningen, University Medical Center Groningen, Reims–Hôpital Maison Blanche: G. Deslée,
Groningen, the Netherlands (Slebos). design and conduct of the study, collected the data,
H. Vallerand, S. Dury, D. Gras, M. Verdier; CHU de managed site selection and trial operations,
Author Contributions: Dr Sciurba had full access to Nice–Hôpital Pasteur: C.-H. Marquette, analyzed the data per the prespecified statistical
all of the data in the study and takes responsibility C. Sanfiorenzo, C. Clary, C. Leheron, J. Pradelli, analysis plan, supported additional analyses
for the integrity of the data and the accuracy of the S. Korzeniewski, P. Wolter, T. Arfi, F. Macone, requested by the authors and reviewed and
data analysis. M. Poudenx, S. Leroy, A. Guillemart, J. Griffonnet; approved the final manuscript from a regulatory
Study concept and design: Sciurba, Strange, Shah, Medical University of South Carolina (MUSC): perspective and approved of the decision to submit
Marquette, Krishna, McKenna, Herth, Slebos. C. Strange, R. Argula, G. Silvestri, J. T. Huggins, the manuscript for publication. Independent from
Acquisition, analysis, or interpretation of data: N. Pastis, D. Woodford, L. Schwarz, D. Walker; the sponsor, the authors interpreted the data,
Sciurba, Criner, Strange, Shah, Michaud, Connolly, Temple University Hospital: G. Criner, A. J. Mamary, prepared the manuscript, and made the decision to
Deslée, Tillis, Delage, Marquette, Krishna, Kalhan, N. Marchetti, P. Desai, K. Shenoy, J. L. Garfield, submit the manuscript for publication. The lead
Ferguson, Jantz, Maldonado, Majid, Rai, Gay, J. Travaline, H. Criner, S. Srivastava-Malhotra, investigators and writing committee had
Dransfield, Angel, Maxfield, Herth, Wahidi, V. Tauch; NYPH/CUMC, New York: R. Maxfield, unrestricted access to the data, had control of
Mehta, Slebos. K. Brenner, W. Bulman, B. A. Whippo, P. A. Jellen; manuscript preparation, and assume responsibility
Drafting of the manuscript: Sciurba, Strange, Shah, Northwestern University Feinberg School of for the accuracy and completeness of all reported
Michaud, Slebos. Medicine: R. Kalhan, C. T. Gillespie, S. Rosenberg, data. All authors received institutional funding from
Critical revision of the manuscript for important M. McAvoy DeCamp, A. S. Rogowski, J. Hixon; PneumRx Inc in support of the conduct of this trial.
intellectual content: All authors. University of Texas Health Sciences Center at Drs Sciurba and Criner participated in medical and
Statistical analysis: Sciurba, Michaud, Gay. San Antonio: L. F. Angel, O. Dib; University of scientific advisory board meetings for BTG
Obtained funding: Sciurba. Pittsburgh Medical Center: F. C. Sciurba, D. Chandra, International and have received travel fees but no
Administrative, technical, or material support: M. Crespo, J. Bon Field, J. Rahul Tedrow, consulting fees for this service totaling less than
Sciurba, Strange, Shah, Deslée, Tillis, Krishna, C. Ledezma, P. Consolaro, M. Beckner; Beth Israel $5000. Drs Strange, Michaud, Mehta, and Slebos
McKenna, Dransfield, Herth, Slebos. Deaconess Medical Center: A. Majid, G. Cheng, received travel and consulting fees totaling less
Study supervision: Sciurba, Strange, Maldonado, J. Cardenas-Garcia, D. Beach, E. Folch, A. Agnew, than $5000. Drs Shah, Mehta, and Marquette
Majid, Dransfield, Mehta, Slebos. W. Hori, A. Nathanson; Duke University Medical received travel reimbursement and speaker fees
Conflict of Interest Disclosures: All authors have Center: M. Wahidi, S. Shofer, M. Hartwig, from BTG International.
completed and submitted the ICMJE Form for K. Mahmood, E. Smathers; Illinois Lung and Critical
Care Institute (OSF Healthcare Systems): W. Tillis, Additional Contributions: Statistical support for
Disclosure of Potential Conflicts of Interest. this study was provided by Brett Bannan, MS, and
Dr Strange reports personal fees and/or grants from K. Verma, D. Taneja, M. Peil, S. Chittivelu,
P. Doloszycki, P. E. Whitten, B. Aulakh, O. Ikadios, Claire Daugherty, MS, who are BTG International
AstraZeneca, Grifols, CSL Behring, Baxter, employees and thus compensated for their
PlasmaTech, Entera Health, PneumRx, Pulmonx, J. Michel, J. Crabb, B. McVay, A. Scott, E. A. Pautler;
Pulmonary, Critical Care and Sleep Medicine contributions to the analyses.
Alpha-1 Foundation, the National Institutes of
Health, and Uptake Medical. Dr Shah reports Consultants PLLC: T. A. Connolly, J. F. Santacruz,
L. Kopas, R. Parham, B. Solis; Pulmonary and Critical REFERENCES
receipt of personal fees or clinical trial
reimbursement from Olympus, Broncus, Care Associates of Baltimore: W. Krimsky, 1. Carlucci A, Guerrieri A, Nava S. Palliative care in
Medtronic, PneumRx/BTG, Pulmonx, Holairo, F. Gregoire, S. King; Cleveland Clinic Foundation: COPD patients: is it only an end-of-life issue? Eur
Uptake Medical, and CSA Medical and sponsorship A. Mehta, F. Almeida, T. Gildea, J. Cicenia, Respir Rev. 2012;21(126):347-354.
of a bronchoscopy course from ERBE, Cook M. Machuzak, S. Sethi, Y. M. Meli, J. Baran, R. Rice, 2. Global Initiative for Chronic Obstructive Lung
Medical, Medtronic, Boston Scientific, Aquilant, D. Faile; Franciscan Research Center: N. Rai, Disease. Global Strategy for the Diagnosis,
Broncus, Pulmonx, Olympus, and PneumRx. K. Jensen, R. Kahlstrom, A. Haroon, R. Ionita, Management, and Prevention of Chronic
Dr Michaud reports receipt of consulting fees from F. White, D. Watkins, B. Moore; Cedars Sinai Medical Obstructive Pulmonary Disease. http://www
Olympus. Dr Deslée reports receipt of personal fees Center: H. Soukiasian, H. Merry, Z. Mosenifar, .goldcopd.org. Accessed May 2, 2016.
from PneumRx. Dr Delage reports receipt of S. Ghandehari, D. Balfe, J. Park, R. Mardirosian;
University of Wisconsin School of Medicine and 3. Fishman A, Martinez F, Naunheim K, et al;
speaker honoraria from Novartis and Boehringer National Emphysema Treatment Trial Research
Ingelheim. Dr Marquette reports receipt of personal Public Health: J. S. Ferguson, J. Kanne, D. Sonetti,
D. Modi, M. Regan, J. Maloney, M. Hackbarth, Group. A randomized trial comparing
fees from PneumRx/BTG. Dr Kalhan reports receipt lung-volume-reduction surgery with medical
of personal fees and/or grants from Boehringer M. Gilles, A. Harris, A. Maser; Yale University School
of Medicine: J. T. Puchalski, C. Rochester, J. Possick, therapy for severe emphysema. N Engl J Med.
Ingelheim, Forest Laboratories, AstraZeneca, 2003;348(21):2059-2073.
GlaxoSmithKline, and Sunovian. Dr Ferguson K. Johnson, Z. Dabre; University of Illinois Hospital
reports receipt of grants and/or personal fees and Health Sciences System: K. Kovitz, M. Joo, 4. Decker MR, Leverson GE, Jaoude WA,
from Uptake Medical and Allegro Diagnostics. J. DeLisa; El Camino Hospital/ Palo Alto Medical Maloney JD. Lung volume reduction surgery since
Dr Dransfield reports receipt of personal fees, Foundation/Sutter Health: S. V. Villalan, G. Krishna, the National Emphysema Treatment Trial: study of
grants, and/or clinical trial contracts from J. Canfield, A. Marfatia, E. Seeley, S. V. Villalan; Society of Thoracic Surgeons Database. J Thorac
AstraZeneca, Boehringer Ingelheim, Boston Mayo Clinic: J. Utz, D. Midthun, R. Kern, E. S. Edell, Cardiovasc Surg. 2014;148(6):2651-8.e1.
Scientific, GlaxoSmithKline, Ikaria, Skyepharma, the L. L. Boras (née Kosok); University of Michigan: 5. Valipour A, Shah PL, Gesierich W, et al. Patterns
National Institutes of Health, the US Department of S. Gay, K. A. Bauman, M. King Han, R. L. Sagana, of emphysema heterogeneity. Respiration. 2015;90
Defense, the American Heart Association, Aeris, K. Nelson, C. Meldrum; University of (5):402-411.
Otsuka, Pearl, Pfizer, Pulmonx, and Yungjin. Florida–Gainesville: M. Jantz, H. J. Mehta, C. Eagan,
Dr Herth reports receipt of personal fees from BTG, J. West; Hôpital Laval: A. Delage, S. Martel,

2188 JAMA May 24/31, 2016 Volume 315, Number 20 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016

 Effect of Endobronchial Coils on Exercise Tolerance in Severe Emphysema Original Investigation Research

6. Sciurba FC, Ernst A, Herth FJF, et al; VENT Study 14. Deslée G, Mal H, Dutau H, et al; REVOLENS 24. Slebos DJ, Hartman JE, Klooster K, et al.
Research Group. A randomized study of Study Group. Lung volume reduction coil treatment Bronchoscopic coil treatment for patients with
endobronchial valves for advanced emphysema. vs usual care in patients with severe emphysema: severe emphysema: a meta-analysis. Respiration.
N Engl J Med. 2010;363(13):1233-1244. the REVOLENS randomized clinical trial. JAMA. 2015;90(2):136-145.
7. Sciurba FC, Chandra D, Bon J. Bronchoscopic 2016;315(2):175-184. 25. Conover WJ, Iman RL. Analysis of covariance
lung volume reduction in COPD: lessons in 15. Valipour A, Kramer MR, Stanzel F, et al. using the rank transformation. Biometrics. 1982;38
implementing clinically based precision medicine. Physiological modeling of responses to upper vs (3):715-724.
JAMA. 2016;315(2):139-141. lower lobe lung volume reduction in homogeneous 26. LaVange LM, Koch GG. Rank score tests.
8. Klooster K, ten Hacken NH, Hartman JE, emphysema. Front Physiol. 2012;3:387. Circulation. 2006;114(23):2528-2533.
Kerstjens HA, van Rikxoort EM, Slebos DJ. 16. Puhan MA, Chandra D, Mosenifar Z, et al; 27. Little RJA, Rubin DB. Statistical Analysis With
Endobronchial valves for emphysema without National Emphysema Treatment Trial Research Missing Data. New York, NY: John Wiley & Sons; 1987.
interlobar collateral ventilation. N Engl J Med. 2015; Group. The minimal important difference of
373(24):2325-2335. exercise tests in severe COPD. Eur Respir J. 2011;37 28. Hodges JL, Lehmann EL. Rank methods for
(4):784-790. combination of independent experiments in
9. Slebos DJ, Klooster K, Ernst A, Herth FJ, analysis of variance. Ann Math Stat. 1962;33(2):482.
Kerstjens HA. Bronchoscopic lung volume 17. Donohue JF. Minimal clinically important
reduction coil treatment of patients with severe differences in COPD lung function. COPD. 2005;2 29. Ginsburg ME, Thomashow BM, Bulman WA,
heterogeneous emphysema. Chest. 2012;142(3): (1):111-124. et al. The safety, efficacy, and durability of
574-582. lung-volume reduction surgery: a 10-year
18. Miller MR, Crapo R, Hankinson J, et al; ATS/ERS experience. J Thorac Cardiovasc Surg. 2016;151(3):
10. Shah PL, Zoumot Z, Singh S, et al; RESET Trial Task Force. General considerations for lung function 717-724.e1.
Study Group. Endobronchial coils for the treatment testing. Eur Respir J. 2005;26(1):153-161.
of severe emphysema with hyperinflation (RESET): 30. Kreider M, Kotloff RM. Selection of candidates
19. Miller MR, Hankinson J, Brusasco V, et al; for lung transplantation. Proc Am Thorac Soc. 2009;
a randomised controlled trial. Lancet Respir Med. ATS/ERS Task Force. Standardisation of spirometry.
2013;1(3):233-240. 6(1):20-27.
Eur Respir J. 2005;26(2):319-338.
11. Kontogianni K, Gerovasili V, Gompelmann D, 31. Hartman JE, Klooster K, Gortzak K, ten Hacken
20. Hankinson JL, Odencrantz JR, Fedan KB. NHT, Slebos DJ. Long-term follow-up after
et al. Effectiveness of endobronchial coil treatment Spirometric reference values from a sample of the
for lung volume reduction in patients with severe bronchoscopic lung volume reduction treatment
general US population. Am J Respir Crit Care Med. with coils in patients with severe emphysema.
heterogeneous emphysema and bilateral 1999;159(1):179-187.
incomplete fissures: a six-month follow-up. Respirology. 2015;20(2):319-326.
Respiration. 2014;88(1):52-60. 21. Holland AE, Spruit MA, Troosters T, et al. An 32. Chandra D, Wise RA, Kulkarni HS, et al; NETT
official European Respiratory Society/American Research Group. Optimizing the 6-min walk test as
12. Klooster K, Ten Hacken NH, Franz I, Kerstjens Thoracic Society technical standard: field walking
HA, van Rikxoort EM, Slebos DJ. Lung volume a measure of exercise capacity in COPD. Chest.
tests in chronic respiratory disease. Eur Respir J. 2012;142(6):1545-1552.
reduction coil treatment in chronic obstructive 2014;44(6):1428-1446.
pulmonary disease patients with homogeneous 33. Celli BR, Cote CG, Marin JM, et al. The body-mass
emphysema: a prospective feasibility trial. 22. Jones PW. Interpreting thresholds for a index, airflow obstruction, dyspnea, and exercise
Respiration. 2014;88(2):116-125. clinically significant change in health status in capacity index in chronic obstructive pulmonary
asthma and COPD. Eur Respir J. 2002;19(3):398-404. disease. N Engl J Med. 2004;350(10):1005-1012.
13. Deslee G, Klooster K, Hetzel M, et al. Lung
volume reduction coil treatment for patients with 23. Hartman JE, Ten Hacken NH, Klooster K,
severe emphysema: a European multicentre trial. Boezen HM, de Greef MH, Slebos DJ. The minimal
Thorax. 2014;69(11):980-986. important difference for residual volume in patients
with severe emphysema. Eur Respir J. 2012;40(5):
1137-1141.

jama.com (Reprinted) JAMA May 24/31, 2016 Volume 315, Number 20 2189

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Sussex Library User on 05/24/2016