Download The RePneu Coil System and Other Bronchoscopic Lung Volume

Health Policy Advisory Committee on
Technology
Extended Technology Brief
The RePneu® Coil System and other bronchoscopic lung
volume reduction treatments for advanced emphysema
July 2015
© State of Queensland (Queensland Department of Health) 2015
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DISCLAIMER: This Brief is published with the intention of providing information of interest. It is
based on information available at the time of research and cannot be expected to cover any
developments arising from subsequent improvements to health technologies. This Brief is based on
a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered.
The State of Queensland acting through Queensland Health (“Queensland Health”) does not
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This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose,
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This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy
Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by
HealthPACT. HealthPACT comprises representatives from health departments in all States and
Territories, the Australian and New Zealand governments and Medical Services Advisory Committee
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This brief was prepared by Dr Vicki Foerster from ASERNIP-S.
Summary of findings
The evidence on the RePneu Coils reviewed for this brief consisted of one small RCT
comparing lung volume reduction coils (LVRC) with best medical care26 and two case series
studies with potentially overlapping patient populations.3, 29 Due to the small patient
numbers in the included studies (123 patients in total; 99 treated with LVRC) and the
apparent loss of clinical benefit over time illustrated in a three-year follow-up study,4 the
initial favourable results for this procedure should be interpreted cautiously. The most
common adverse events (AEs) reported after LVRC treatment were chronic obstructive
pulmonary disease (COPD) exacerbation, pneumothorax, lower respiratory infection and
coughing of blood. The randomised controlled trial (RCT)26 only reported AEs that were
considered serious, but the rate did not differ significantly between study arms.
With respect to effectiveness, in the RCT26 three of four clinical outcomes (SRGQ score,
residual volume reduction and 6MWT result) showed statistically significant benefit for LVRC
patients, compared with usual care, when the degree of change was assessed against values
determined to be clinically meaningful. In the two case series studies, 3, 29 several clinical
outcomes showed statistically significant improvement over baseline at six months’ followup. Most of these benefits were sustained in the case series study that followed up 59 per
cent of its patients to 12 months.29 However, a subsequent report4 on a subset of patients
from these studies showed a gradual decline in benefit over the three years post-treatment,
with only the mMRC score showing a significant improvement over baseline values.
Only one study was located for each of the two other bronchoscopic lung volume reduction
procedures included in this report, AeriSeal (foam sealant) and InterVapor (heated water
vapour). Although AeriSeal showed benefit at three months’ follow-up,35 no recent
information was available, and it was not clear whether this technology is still being
pursued. InterVapor showed more promise, with clinical benefit at six months (that declined
by 12 months).36 An international RCT of InterVapor is underway, which includes sites in
Australia and New Zealand, and is expected to be completed in June 2015.
In summary, although the available evidence for RePneu Coils showed clinical improvement
in patients with severe emphysema, the durability of the benefits is unclear. A large, triple
arm RCT comparing LVRC with traditional lung volume reduction surgery and standard
medical care is required to determine the clinical benefit of the procedure. Additionally,
further work is required to adequately identify the patients who may benefit most from the
procedure.
It would be prudent to await the results of the large RCT (n=315 patients), which is
underway at 29 international sites and is expected to be finalised in January 2016. This will
add to the evidence base and clarify the long-term safety and effectiveness profiles of the
LVRC procedure.
RePneu® Coil System: Update July 2015
i
HealthPACT Advice
HealthPACT noted that the evidence supporting the use of the InterVapor and AeriSeal
technologies was currently lacking. In addition, it was noted that the RePneu Coils were a
costly treatment option and although the evidence demonstrated a clinical improvement in
patients with severe emphysema treated with RePneu, the durability of the benefits is
unclear. HealthPACT does not support the introduction of this technology into clinical
practice at this time and recommend that a further review of the evidence be conducted in
24 months once the results of ongoing RCTs are published.
RePneu® Coil System: Update July 2015
ii
Technology, Company and Licensing
Register ID
WP172
Technology name
RePneu® Coil System
Patient indication
Advanced emphysema
Description of the technology
RePneu® Coil System
The RePneu Coil System reduces the volume of diseased areas of the lung, tethers small
airways open to prevent their collapse during exhalation and restores elastic recoil in
healthier regions of the lung. The small nickel-titanium (nitinol) coils have shape memory
and are straightened prior to insertion. Once deployed, the coils act as springs and assume
their original shape, gathering and compressing diseased lung tissue in the process. 1
The coil insertion procedure is performed in a hospital under general anaesthesia or
conscious sedation with an endoscope and is usually completed in 30 to 50 minutes. An
overnight hospital stay is commonly required.1-3 The coils, which are 70 to 200 mm long, are
inserted using a delivery catheter, guide wire, cartridge and forceps.4 The guide wire is
advanced into the airway to within 15 mm of the pleural surface (lung membrane). A
catheter is then inserted over the guide wire and the straightened coil is fed through the
cartridge and catheter under fluoroscopic guidance. Forceps are used to pull the coil into
the cartridge and deliver it to the airway as well as to remove or reposition the coils. Ten
coils are deployed per lung lobe (personal communication, Alfred Health Victoria). The
surgery is conducted in one lung at a time; patients requiring treatment in both lungs
undergo two separate procedures.1
Figure 1
®
RePneu coil
5
AeriSeal®
AeriSeal is a liquid foam that is delivered via a catheter to the peripheral airways and air sacs
of diseased lung segments using bronchoscopy. The procedure takes about 15 minutes, but
it is unclear what type of anaesthesia is required. The foam hardens thirty minutes after
RePneu® Coil System: Update July 2015
1
placement, causing the treated lung area to collapse and allowing the healthier surrounding
lung tissue to expand.6 It is unclear whether a hospital stay is required after this procedure.
InterVapor® System
InterVapor is an endoscopic technique in which heated water vapour is administered
directly to diseased regions of the lung. This causes an inflammatory response that is
followed by contraction fibrosis and lung collapse, thereby reducing the volume of diseased
lung tissue and allowing the expansion of healthier tissue. The InterVapor System consists
of a generator, a delivery catheter and software for developing a personalised patient plan.7
The procedure is conducted under general anaesthesia and requires an overnight
postoperative hospital stay.8
Company or developer
The RePneu® Coil System was developed by PneumRx, Inc. (California, USA).
AeriSeal® is manufactured by PulmonX (California, USA).
The InterVapor® System is produced by Uptake Medical (California, USA).
Reason for assessment
Emerging treatments for severe emphysema include a range of endoscopic lung volume
reduction devices such as endobronchial blockers, airway bypass stents, endobronchial
valves, thermal vapour ablation, biological sealants and lung volume reduction coils (LVRCs).
In November 2013 a Technology Brief was completed on the RePneu Coil System for
treating patients with advanced emphysema. In light of developing evidence on the subject,
the Brief recommended that the technology be monitored. In line with the
recommendation, this Extended Brief considers evidence that has emerged since 2013 that
may inform policy decisions. Two other relevant technologies (AeriSeal and the InterVapor
System) are also briefly discussed.
Stage of development in Australia
Yet to emerge
Established
Experimental
Established but changed indication
or modification of technique
Should be taken out of use
Investigational
Nearly established
Licensing, reimbursement and other approval
The RePneu Coil received a CE mark on 13 October 2010.9 The device is currently limited to
investigational use by the United States Food and Drug Administration (FDA), although in
RePneu® Coil System: Update July 2015
2
May 2012 the FDA granted PneumRx, Inc. approval to commence a clinical trial.5 The device
has not been approved by the Australian Therapeutics Goods Administration (TGA).
AeriSeal received CE marking in 20106, but the company has since changed hands and the
CE mark is expected to be reissued in late 2015. 10 The product has not been approved by
the Australian TGA or the United States FDA.
The InterVapor System received a CE mark in 20117 and was approved for marketing as a
Class II device by the Australian TGA in December 2011. 11 There was no indication that
approval by the United States FDA has been either sought or granted.
Australian Therapeutic Goods Administration approval
Yes (InterVapor System;
RePneu Coil)
ARTG number(s) 193138 (InterVapor System);
239034, 224628 (RePneu Coil)
No (AeriSeal)
Not applicable
Technology type
Device
Technology use
Therapeutic
Patient Indication and Setting
Disease description and associated mortality and morbidity
Emphysema is a chronic obstructive pulmonary disease (COPD) in which damaged lung
tissue loses its elastic recoil, causing permanent enlargement of the air sacs (alveoli). Large,
irregular air pockets form as a result, and the airways narrow or collapse. The volume of
healthy lung tissue that can transfer oxygen to the blood is reduced and the lungs remain
hyper-inflated (filled with air) even when the patient breathes out, causing symptoms such
as dyspnoea (shortness of breath), wheezing, chest tightness, coughing and phlegm
production, particularly if chronic bronchitis is also present. Patients often present with
both emphysema and chronic bronchitis, and current definitions of COPD do not distinguish
between the two conditions.12 The Global Initiative for Chronic Obstructive Lung Disease
(GOLD) classifies COPD using the spirometric measurement of forced expiratory volume in
one second (FEV1) as follows: mild (FEV1 ≥80% of predicted); moderate (50%≤ FEV1 <80% of
predicted); severe (30%≤ FEV1 <50% of predicted); and very severe (FEV1 <30% of
predicted).12
The symptoms of emphysema progress over many years and patients who seek treatment
are often in their fifth decade of life.13 Complications include collapsed lung, right-sided
heart failure, giant bullae (air sacs), recurring chest infections and pulmonary hypertension.
Patients with emphysema have a lower quality of life (QOL) owing to their disturbed sleep,
reduced capacity for exercise and impaired ability to carry out daily activities such as
RePneu® Coil System: Update July 2015
3
walking up short flights of stairs. As the condition progresses it can lead to weight loss,
muscle wasting, respiratory failure and death.14
There is no cure for emphysema. Current treatments are palliative, and a patient’s prognosis
and QOL depend on the disease stage and presence of comorbidities such as ischaemic
heart disease and diabetes. As emphysema progresses, patients may experience acute
exacerbations (sudden worsening of symptoms) that require hospitalisation.12 The leading
cause of COPD (90% of cases) is long-term tobacco smoking. Other common causes are air
pollution and occupational exposure to various types of fumes and dust.14
Among Australians aged 55 years or older in 2011-12 who had COPD, three per cent rated
their health as excellent and 28 per cent as fair or poor, compared with 15 and 7 per cent,
respectively, in those who did not have COPD (15%).15 In 2010, COPD was the third leading
cause of disease burden in Australasia and the ninth leading cause in the world.16
Number of patients
COPD was the third leading cause of death in the world in 2012, causing 3.1 million deaths. 17
A study conducted in Australia between 2006 and 2010 found that the prevalence of
moderate to very severe COPD was 8 per cent in people aged 40 years or older and 29 per
cent in people aged 75 years or older.18 The prevalence of severe or very severe COPD was
1.5 per cent in people aged from 55 to 74 years and 2.1 per cent in people aged 75 years or
older. In 2012–13 there were 62,500 hospital separations for COPD and emphysema in
Australia.19
The 2006-07 New Zealand (NZ) Health Survey20 found that one in 15 adults aged 45 years or
older had been told by a doctor that they had COPD. This diagnosis was more common in
women (7.4%) than in men (5.6%) and was twice as likely in people of Māori origin,
compared with other ethnic groups.
Speciality
Respiratory disease and thoracic surgery
Technology setting
General hospital or specialist hospital
Impact
Additive and substitution technology
For patients who are not eligible for surgery, bronchoscopic lung volume reduction
treatments would be an addition to optimal medical therapy. In patients who are eligible for
surgery, bronchoscopic treatments may be a substitute for lung volume reduction surgery.
Current technology
Patients with severe COPD have limited treatment options. The management of COPD aims
to relieve symptoms, reduce the severity and frequency of exacerbations and slow disease
RePneu® Coil System: Update July 2015
4
progression. All patients with COPD are advised to stop smoking. Management of COPD may
include drug therapy, pulmonary rehabilitation, long-term oxygen therapy, surgical
treatments and ventilator support. Only smoking cessation and long-term oxygen therapy
are thought to confer any survival benefit.12
Pharmacological therapy consists of beta2-agonists, anticholinergics, methylxanthines,
inhaled or systemic corticosteroids and phosphodiesterase-4 inhibitors. These medications
aim to improve health and reduce the frequency and severity of exacerbations. The goal of
pulmonary rehabilitation is to reduce symptoms and to improve QOL and participation in
daily activities. At a minimum it includes six weeks of exercise training, and may also include
nutrition counselling, education and smoking cessation support. Long-term oxygen therapy
has been shown to increase the survival rate in patients who have low blood-oxygen levels
at rest.12
Surgical treatments for end-stage COPD include lung transplantation and lung volume
reduction surgery. Lung transplantation can improve pulmonary function, functional lung
capacity and QOL. However, the use of transplants is limited by cost, donor organ
availability, surgical risks and the need for lifelong immunosuppression. 21 In lung volume
reduction surgery, which is performed via median sternotomy or video-assisted
thoracoscopy, 20 to 30 per cent of the most diseased segments of each lung are removed.
Its application is limited by stringent selection criteria (restricted to patients with
heterogeneous upper lobe emphysema and low exercise capacity) and high rates of
postoperative morbidity.22 The rates of intraoperative and postoperative complications are
9 per cent and 59 per cent, respectively, and there is an elevated risk of re-intubation,
arrhythmias, pneumonia, readmission to the intensive care unit and tracheotomy. 22 In
addition, the improvement in lung function that is gained gradually declines over time,
returning to baseline three to four years after surgery.23
In addition to lung transplantation and lung volume reduction, other surgical procedures for
patients with heterogeneous emphysema include endobronchial valves and spigots. For
patients with homogeneous emphysema alternative surgical procedures include airway
fenestration and the Portero procedure (personal communication, Alfred Health Victoria).
Diffusion of technology in Australia
There are no reports of the RePneu Coil, AeriSeal or InterVapor being used in Australia,
aside from participation of Australian sites in a study on InterVapor from 2009 to 2011.
RePneu® Coil System: Update July 2015
5
International utilisation
RePneu Coil System
Country
Level of Use
Trials underway or
completed
Canada

Denmark

France

Germany

Netherlands

Spain

Switzerland

United Kingdom

USA

Limited use
Widely diffused
May be occurring in
these countries (a
registry study is
underway in Germany,
Spain and Switzerland)
Investigational only
AeriSeal
Country
Level of Use
Trials underway or
completed
Austria

France

Germany

Italy

Limited use
Widely diffused
InterVapor System
Country
Level of Use
Trials underway or
completed
Australia

Austria

Germany

Ireland

USA

Limited use
Widely diffused
Cost infrastructure and economic consequences
RePneu® Coil System
The costs associated with the LVRC procedure include hospitalisation, anaesthesia, the
bronchoscopic delivery system and the coils. Information from the manufacturer indicated
that a single procedure costed approximately $19,436 in 2013 (personal communication,
RePneu® Coil System: Update July 2015
6
PneumRx, Inc.). The cost of 20 coils in Europe is around EUR 30,000A (personal
communication, Alfred Health Victoria). Further breakdown of the procedure cost according
to the cost of anaesthesia and other inputs was not available.24 Patients undergoing bilateral
treatment would require two procedures, one for each lung. At this point in time, it is
unclear what role LVRC surgery would play in the management of severe emphysema.
Therefore, the economic consequences of its diffusion are uncertain.
AeriSeal and InterVapor System
The cost of the interVapor system including planning, delivery of steam and the catheters is
around $11,000 (personal communication, Alfred Health Victoria). The cost of the AeriSeal
system is unknown.
Ethical, cultural, access or religious considerations
No cultural, religious or access considerations were identified.
Evidence and Policy
Iftikhar et al 201425 conducted a meta-analysis of 17 studies published up to June 2013 on
the following five bronchoscopic lung volume reduction procedures: one-way valves (eight
studies); sealants and hydrogels (four studies); airway bypass stents (two studies); LVRCs
(two studies); and bronchial thermal vapour ablation therapy (one study). The authors
noted that although all of the technologies (except airway bypass stents) produced
beneficial outcomes, there were no studies directly comparing bronchoscopic lung volume
reduction techniques with lung volume reduction surgery.
This Brief reports the most recent and largest studies available for the RePneu Coil System,
AeriSeal and the InterVapor System published up to 3 March 2015.
RePneu Coil System – Effectiveness and Safety
One randomised controlled trial26 (RCT) (level II intervention evidence) and four case series
studies3, 22-24 (level IV intervention evidence) were identified.3, 27-29 The RCT26 and the two
larger case series studies3, 29 are included in this report (Table 1). In addition, a report of
longer-term results from these two case series3, 29 was located.4 It is possible that there was
some patient overlap among the two case series studies because of common study
enrolment dates and study sites.
A
th
Approximately $45,000 (http://www.xe.com/currencyconverter/#, accessed 4 August 2015)
RePneu® Coil System: Update July 2015
7
Table 1
Included study characteristics
Study / Design
Number of
patients
Conflicts of
interest
Extensive, including
(in part): change in
FEV1 >20% postbronchodilator;
single-breath diffusion
capacity for CO <20%
predicted; history of
recurrent, clinically
significant respiratory
infection; uncontrolled
pulmonary
hypertension; inability
to walk >140 metres
in 6 minutes
LVRC: 23
Best medical care:
24
Losses to followup:
2 (one from each
arm)
Study designed
and sponsored by
PneumRx, Inc. and
lead author. Four
of eight authors
received some
form of industry
funding.
Age ≥35 years;
bilateral
heterogeneous
emphysema on CT
scan (unilateral or
bilateral); postbronchodilator FEV1
≤45% predicted; TLC
>100% of predicted;
mMRC dyspnoea
score ≥2; on optimal
medical treatment at
enrolment; ceased
smoking for ≥8 weeks
prior to enrolment
Extensive, including
(in part): change in
FEV1 >20% postbronchodilator;
TLCO <20%
predicted; history of
recurrent, clinically
significant
respiratory infection;
pulmonary
hypertension with
RVP >50 mmHg;
inability to walk >140
metres in 6 minutes;
previous LVR
surgery; lung
transplant or
lobectomy; clinically
significant
bronchiectasis
N = 60
Losses to followup:
2 by 6 months and
another 23 by 12
months (per
protocol), i.e. 35
patients were
followed up to 12
months
PneumRx, Inc.
designed the trial
with two authors
and facilitated
monitoring of
safety, audit and
data collection and
storage. Four of 13
authors received
some form of
industry funding.
Age ≥35 years;
heterogeneous
emphysema (unilateral
or bilateral); FEV1
<45%; TLC >100% of
predicted; mMRC
dyspnoea score >1;
ceased smoking for ≥8
weeks prior to
enrolment
Change in FEV1
>20% postbronchodilator; TLCO
<20% predicted; RVP
>50 mmHg; >3
hospitalisations due
to COPD
exacerbations in
previous 12 months;
clinically significant
bronchiectasis;
previous lung
surgery; giant bulla
(>1/3 of lung volume);
inability to walk >140
metres in 6 minutes;
use of clopidogrel or
coumarins; disease
that might
compromise survival
N = 16 (enrolled
17)
Losses to followup:
2 by 6 months (no
reasons given)
Study sponsored
by PneumRx, Inc.
The authors serve
as advisors to
PneumRx, Inc.
None of the
authors has a
financial interest in
the company.
Inclusion criteria
Exclusion criteria
Shah et al 2013
NCT01334307
United Kingdom
(3 centres)
Prospective RCT
(level II
evidence)
Enrolment:
January 2010 to
October 2011
26
Age ≥35 years; severe
heterogeneous or
homogeneous
emphysema (unilateral
or bilateral); FEV1
≤45% predicted; TLC
>100% of predicted;
mMRC dyspnoea
score ≥2; on optimal
medical treatment at
enrolment; ceased
smoking for ≥8 weeks
prior to enrolment
Deslee et al
29
2014
NCT01328899
France,
Germany,
Netherlands
(11 centres)
Prospective case
series (level IV
evidence)
Enrolment:
December 2009
to October 2011
3
Slebos et al
NCT01220908
Germany,
Netherlands
(5 centres)
Prospective case
series (level IV
evidence)
Enrolment: April
2009 to October
March 2010
CO: carbon monoxide; COPD: chronic obstructive pulmonary disease; CT: computed tomography; FEV 1: forced expiratory
volume in one second; TLC: total lung capacity; LVR: lung volume reduction; LVRC: lung volume reduction coil; mMRC:
modified Medical Research Council, RCT: randomised controlled trial; RVP: right ventricular pressure; TLCO: carbon monoxide
lung transfer factor; UK: United Kingdom
RePneu® Coil System: Update July 2015
8
Shah et al 201326
This RCT (level II intervention evidence) enrolled 47 patients with severe heterogeneous or
homogeneous emphysema. The definition of heterogeneous and homogenous was not
outlined in the study, other than that it was determined by computed tomography. Patients
were randomly assigned to treatment using a computer-generated randomisation
sequence. The generated codes were placed in opaque sealed envelopes and opened in
sequence when a patient fulfilled all of the eligibility criteria. Bronchoscopists and patients
were aware of treatment allocation, but assessments were conducted by nurses and
physiologists who were masked to allocation. The inclusion and exclusion criteria are shown
in Table 1. Baseline characteristics were similar between the two treatment groups
(statistical significance was not reported) except for St George’s Respiratory Questionnaire
(SGRQ) total score and modified Medical Research Council (mMRC) dyspnoea score, which
were both higher, and therefore worse, in the treatment group and indicated severe airflow
obstruction and substantial lung hyperinflation.
Patients assigned to the LVRC procedure underwent bronchoscopy under moderate
sedation or general anaesthesia, depending on local practice and patient requirements. The
23 patients received a total of 410 coils in 44 procedures. The mean procedure time was 45
minutes (standard deviation [SD] 17, range 20 to 88). Patients treated in both lungs received
an average of 19 coils. Details of treatment for the 24 patients in the usual care group were
not provided. Of the 23 patients in the LVRC arm, 21 (91%) had a second LVRC treatment in
the contralateral lung. Patients were reassessed at 30 and 90 days after the procedure.
The primary endpoint was the change in SGRQ score from baseline to 90 days after final
treatment. Secondary endpoints were the change in FEV1, total lung capacity (TLC) and
residual volume (RV), 6-minute walk test (6MWT) result and mMRC dyspnoea score. For
patients whose last results were recorded less than 90 days from the final treatment, the
last recorded values were carried forward. One patient in the LVRC group who had
improved enough to return to work withdrew from the study before the second treatment
and was not included in the 90-day analysis.
Effectiveness
After an analysis of covariance was undertaken to correct the imbalance in baseline SGRQ
scores between the treatment groups, the change in mean SGRQ score from baseline to 90
days after the final visit was greater in the LVRC group than in the usual care group,
exceeding the 4-point reduction that was considered clinically meaningful. Patients in the
LVRC group also had an improved 6MWT (mean 51 metres) result that was also greater than
the 26 metres considered to be clinically meaningful. The degree of change in FEV1 and RV
was also greater in the LVRC group than in the usual care group. No differences were
detected between the groups with respect to changes in mMRC dyspnoea score and TLC
(Table 2).
RePneu® Coil System: Update July 2015
9
Table 2
Change from baseline in QOL and lung function measures 90 days after final
26
treatment in Shah et al
Outcome
LVRC (N=23)
Change in mean
value (95% CI)
Usual care (N=23)
Change in mean
value (95% CI)
Mean difference
between groups
(95% CI)
p value
SGRQ score
-8.1 (-13.83 to -2.39)
0.3 (-5.58 to 6.07)
-8.4 (-16.24 to 0.47)*
0.04
TLC (L)
-0.2 (-0.38 to -0.10)
-0.1 (-0.27 to 0.01)
-0.1 (-0.29 to 0.07)
0.2
RV (L)
-0.5 (-0.73 to -0.30)
-0.2 (-0.42 to 0.02)
-0.31 (-0.59 to 0.04)
0.03
6MWT (metres)
51.2 (27.65 to 74.66)
-12.4 (-36.61 to
11.83)
63.6 (32.57 to
94.53)
FEV1 (%)
14.2 (6.84 to 21.55)
3.6 (-4.02 to11.17)
10.6 (1.12 to 20.12)
0.03
mMRC dyspnoea
score
-0.2 (-0.57 to 0.09)
-0.1 (-0.44 to -0.26)
-0.2 (-0.60 to 0.30)
0.5
<0.001
6MWT: 6-minute walk test; CI: confidence interval; FEV1: forced expiratory volume in one second, LVRC: lung volume
reduction coil; mMRC: modified Medical Research Council; RV: residual volume; SGRQ: St George’s Respiratory
Questionnaire; TLC: total lung capacity
*Corrected for difference between groups at baseline
The authors also conducted a responder analysis of QOL and lung function outcomes 90
days after the final treatment and found that just over half of the LVRC patients experienced
improvements that were clinically meaningful (Table 3).
Table 3
Number of patients achieving a clinically meaningful change in outcomes 90 days
26
after final treatment in Shah et al
Clinically meaningful
outcome
LVRC (N=23)
No. of patients (%)
Usual care (N=23)
No. of patients (%)
p value
SGRQ score ≥4-point
improvement
15 (65)
5 (22)
0.01
SGRQ score ≥8-point
improvement
13 (57)
3 (13)
0.01
Residual volume
reduction ≥0.35 L
13 (57)
4 (17)
0.01
6MWT improvement ≥26
metres
17 (74)
4 (17)
<0.001
≥10% improvement in
FEV1
13 (57)
6 (26)
0.07
6MWT: 6-minute walk test; LVRC: lung volume reduction coil; SGRQ: St George’s Respiratory Questionnaire; FEV 1: forced
expiratory volume in one second
RePneu® Coil System: Update July 2015
10
Safety
Most patients in the LVRC group were discharged the day after treatment (40 of 44
procedures); however, four procedures required hospital stays of two (3 procedures) or
three days (1 procedure). Adverse events (AEs) not deemed severe were not reported. The
serious AEs that occurred within 30 days of each LVRC treatment or usual care visit are
listed in Table 4. All AEs required hospitalisation. There was no statistically significant
difference in AE rates between the treatment groups. No coughing of blood, device removal
or respiratory failure occurred during the follow-up period.
Table 4
Serious AEs within 30 days of first and second visits or up to 29 days after first and
26
second treatments
Outcome
LVRC
(N=23 at 30 days; N=22 at 90 days)
No. of events* (number of patients)
Usual care (N=23)
No. of events (number of
patients)
COPD exacerbation
2 (2)
1 (1)
Lower respiratory tract
†
infection
2 (2)
0
Pneumothorax
2 (2)
0
Total
6 (6)
1 (1)
LVRC: lung volume reduction coil; COPD: chronic obstructive pulmonary disease
*Some patients experienced multiple occurrences of the same event; †Includes pneumonia
Serious AEs occurring between 30 and 90 days after treatment or the second usual care visit
were also reported (Table 5). There was no statistically significant difference in AE rates
between the two patient groups.
Table 5
Serious AEs occurring in 30 to 90 days after the second treatment or second
26
usual care treatment visit in Shah et al
Outcome
LVRC (N=22)
No. of events* (number of patients)
COPD exacerbation
Lower respiratory tract
†
infection
Total
Usual care (N=23)
No. of events (number of
patients)
3 (2)
2 (2)
0
1 (1)
3 (2)
3 (3)
LVRC: lung volume reduction coil; COPD: chronic obstructive pulmonary disease
*Some patients experienced multiple occurrences of the same event; †Includes pneumonia
Deslee et al 201429
This multicentre case series study (level IV intervention evidence) enrolled 60 patients with
bilateral heterogeneous emphysema at 11 centres in France, Germany and the Netherlands.
The inclusion and exclusion criteria are listed in Table 1. All procedures were performed
RePneu® Coil System: Update July 2015
11
under general anaesthesia, and fluoroscopy was used to visualise coil deployment.
Contralateral procedures were performed at least one month after the first procedure.
Patients stayed at least one night in hospital, and follow-up extended to six months in the
German centres and 12 months in France and the Netherlands.
The primary efficacy endpoint was improvement in SGRQ total score from baseline. The
secondary efficacy endpoints were changes in forced vital capacity (FVC), FEV1, RV, RV/TLC
ratio, 6MWT result and mMRC dyspnoea score 6 months after treatment.
Effectiveness
Sixty patients underwent 115 procedures (55 bilateral and 5 unilateral). All patients were
meant to have bilateral procedures, but this did not occur in five cases for the following
reasons: lost to follow-up (two patients); second lung not suitable for treatment due to
bullae (one patient); and procedure declined (two patients: one was satisfied with the
improvement and one did not want to proceed with the trial). Fifty-eight patients were
available at the six-month follow-up and 34 were available at the 12-month follow-up.
Twenty-four patients from Germany left the study at six months as planned (12 months of
follow-up were required by the ethics boards in France and the Netherlands).
The average procedure time was 50 minutes (median 55 minutes, range 20 to 135) and each
patient received a median of 10 coils (range 5 to 15). The average postoperative hospital
stay was 2.3 days (median 1 day, range 0 to 19). All measures of lung function and SGRQ and
mMRC dyspnoea scores were significantly improved, compared with baseline values, at the
six-month follow-up for the group overall and at the six and 12-month time points for the 34
patients with longer term follow-up (except for the RV/TLC ratio at 12 months in the latter
group) (Table 6).
Table 6
Outcome
Change in efficacy outcomes from baseline in Deslee et al 2014
29
Change in mean values
(SD) for overall group at
6 months’ FU (N=58)
Change in mean values
(SD) for 12-month group
at 6 months’ FU (N=34)
Change in mean values
(SD) for 12-month group
at 12 months’ FU (N=34)
FVC (L)
0.2 (5.3) (p<0.001)
0.3 (5.7) (p<0.002)
0.28 (4.5) (p<0.001)
FEV1 (L)
0.1 (0.2) (p<0.001)
0.1 (0.3) (p=0.021)
0.11 (0.30) (p=0.04)
RV (L)
-0.7 (0.9) (p<0.001)
-0.8 (1.0) (p<0.001)
-0.11 (0.30) (p=0.04)
RV/TLC ratio
-4.5 (12.2) (p=0.007)
-6.1 (8.6) (p<0.001)
-3.12 (15.59) (p=0.3)
FEV1: forced expiratory volume in one second, FU: follow-up; FVC: forced vital capacity; RV: residual volume; SD: standard
deviation; TLC: total lung capacity
RePneu® Coil System: Update July 2015
12
The study also assessed improvement with respect to the smallest benefit of value to
patients, or the minimal clinically important difference (MCID), for FEV1, RV, 6MWT and
SGRQ and found significant numbers of responders at six and 12 months’ follow-up for
these endpoints (Table 7).
Table 7
Responder rates for MCIDs in Deslee et al 2014
MCID
29
Percentage of patients at 6
months’ FU (n=58)
Percentage of patients at 12 months’
FU
(n=34)
Improvement in FEV1 ≥12%
48%
41%
Residual volume reduction
≥0.35 L
65%
58%
6MWT improvement ≥26
metres
53%
60%
SGRQ ≥4-point improvement
74%
66%
SGRQ ≥8-point improvement
61%
53%
6MWT: 6-minute walk test; FEV1: forced expiratory volume in one second, FU: follow-up; MCID: minimal clinically important
difference; SGRQ: St George’s Respiratory Questionnaire
Safety
No serious peri-procedural AEs occurred in 115 bronchoscopies (60 patients). Safety
outcomes at one month, one to six months and six to 12 months are listed in Table 8. All AEs
were treated and resolved with routine medical care.
RePneu® Coil System: Update July 2015
13
Table 8
Adverse events in Deslee et al 2014
Adverse event
29
No. of events (patients)
1 month FU (N=155)
No. of events
(patients)
1 to 6 months’ FU
(N=58)
No. of events (patients)
>6 to 12 months’ FU
(N=35)
7 (7)
6 (5)
4 (4)
1 (1)
12 (10)
3 (3)
2 (2)
0
4 (3)
3 (3)
1 (1)
0
8 (7)
5 (3)
61 (35)
21 (15)
4 (3)
3 (3)
19 (15)
3 (3)
2 (2)
2 (2)
28 (20)
3 (3)
7 (6)
0
3 (3)
Serious respiratory AE:
COPD exacerbation
Pneumonia
Pneumothorax
Haemoptysis (coughing
blood)
Respiratory AE:
COPD exacerbation
Pneumonia
Mild coughing of blood
(<5 mL)
Cough
Transient chest pain
AE: adverse event; COPD: chronic obstructive pulmonary disease; FU: follow-up
Slebos et al 20123
This case series study (level IV intervention evidence) enrolled 17 patients with emphysema
at one centre in the Netherlands. One patient was excluded due to homogeneous
emphysema. It was not stated whether enrolment was consecutive. The inclusion and
exclusion criteria are listed in Table 1. Patients remained in hospital overnight following the
procedure. Efficacy endpoints included changes in SGRQ score, pulmonary function and
6MWT result.
Effectiveness
Sixteen patients underwent 28 procedures. The median procedure duration was 36 minutes
(range 20 to 60) and patients received a median of 10 coils (range 5 to 12). Chest
radiographs taken up to six months after the procedure did not show any coil migration.
Two patients were not included in the six-month follow-up analysis due to coronary artery
disease (n=1) and severe osteoporotic vertebral fracture (n=1). The authors reported that
lung function (FEV1, FVC, RV and 6MWT) and SGRQ outcomes were significantly improved at
the six-month follow-up compared, with baseline values (Table 9).
RePneu® Coil System: Update July 2015
14
Table 9
Change in efficacy outcomes from baseline in Slebos et al 2012
3
Outcome
Change in mean
values (SD) 1 month
st
after 1 treatment
(N=16)
Change in mean
values (SD) 1 month
nd
after 2 treatment
(N=12)
Change in mean
values (SD) 6
nd
months after 2
treatment (N=12)
Change in mean
values (SD) 6
nd
months after 2
treatment (N=14)
FVC (%)
11.5 (13.6) (p=0.005)
17.0 (14.9) (p=0.005)
13.3 (13.2) (p=0.007)
13.4 (12.9) (p=0.002)
FEV1 (%)
10.3 (13.1) (p=0.009)
22.6 (21.7) (p=0.004)
17.3 (19.4) (p=0.01)
14.9 (17.0) (p=0.004)
RV (%)
-9.5 (6.5) (p=0.001)
-12.4 (9.0) (p<0.001)
-10.6 (9.6) (p=0.004)
-11.4 (9.0) (p<0.001)
RV/TLC
(%)
-6.7 (4.8) (p<0.001)
-8.2 (7.1) (p=0.002)
-8.1 (5.2) (p<0.001)
-8.0 (5.5) (p<0.001)
6MWT
(metres)
12.6 (13.8) (p=0.003)
29.8 (30.4) (p=0.006)
34.4 (39.2) (p=0.01)
32.9 (36.3)
(p=<0.005)
SGRQ
score
-14.2 (11.6) (p<0.001)
-12.2 (10.8) (p=0.009)
-15.8 (12.2) (p<0.002)
-14.9 (12.1) (p<0.001)
6MWT: 6-minute walk test; FEV1: forced expiratory volume in one second, FVC: forced vital capacity; RV: residual volume; SD:
standard deviation; SGRQ: St George’s Respiratory Questionnaire; TLC: total lung capacity
The study also reported that 50 per cent of patients had a change of more than the MCID
(as sourced from peer-reviewed publications) from baseline for FEV1 and SGRQ (Table 10).
Table 10
Responder rates for MCIDs six months after treatment in Slebos et al 2012
MCID
3
Percentage of responders (N=14)
30
Improvement in FEV1 ≥12%
64%
Residual volume reduction
≥10%
64%
6MWT improvement
31
≥48 metres
32, 33
≥25 metres
64%
86%
34
SGRQ ≥4-point improvement
79%
6MWT: 6-minute walk test; FEV1: forced expiratory volume in one second, MCID: minimal clinically important difference;
SGRQ: St George’s Respiratory Questionnaire
Safety
The authors reported no intra-procedural AEs; however, one case of pneumothorax
occurred an hour after the procedure and resolved in one day with insertion of a chest tube.
AEs were reported as the number of events and some patients experienced multiple events.
Slight coughing of blood, which resolved spontaneously, occurred in 12 patients (21
RePneu® Coil System: Update July 2015
15
procedures) within the first few days after the procedure. Chest pain occurred in four
patients, but also resolved within a few days. By the one- to six-month follow-up, 16
patients had experienced 14 COPD exacerbations. Safety outcomes are detailed in Table 11.
Table 11
Respiratory AEs and antibiotic or prednisolone treatment (n=16)
Category
Respiratory AE
Antibiotic/prednisolone
treatment
Adverse event
3
No. of events within 1
month of first or
second treatment
No. of events 1 to 6
months after last
treatment
2009 influenza A (H1N1)
2
1
Chest pain
4
2
COPD exacerbation
6
14
Cough
2
2
Pneumonia
2
3
Pneumothorax
1
0
Pulmonary embolism*
0
1
Slight haemoptysis (<5
mL)
21
0
Any course of
prednisolone or antibiotics
8
†
17
AE: adverse event; COPD: chronic obstructive pulmonary disease
*Non-treated lung; †one month after first treatment
Hartman et al 2014 (long-term follow-up)4
The Dutch research group that published several earlier cohort studies3, 29 provided data on
outcomes up to three years. Of 38 patients with severe emphysema who had participated in
one of two LVRC cohort trials between April 2009 and November 2010, 35 (92%) attended
the one year follow-up (one had died and two were lost to follow-up), 27 (71%) were
available at two years (one had died, five were lost to follow-up and two had lung
transplants) and 22 (58%) attended at three years (one had died and five were lost to
follow-up).
Effectiveness
At one-year follow-up all but one of the clinical outcomes had significantly improved
compared with baseline. This was maintained two years after treatment for RV and the
mMRC dyspnoea and SGRQ scores. At the three-year follow-up, only the improvement in
mMRC dyspnoea score remained. The authors concluded that although the treatment had
demonstrated adequate safety, and the three-year survival rate was at least as good as that
reported in the literature for this patient group (84%), only about 50 per cent of patients
maintained improvement in 6MWT result, SGRQ score and mMRC dyspnoea score at three
years, and only one outcome showed a significant difference from the pre-treatment value
(Table 12).
RePneu® Coil System: Update July 2015
16
Table 12
Change in efficacy outcomes from baseline in Hartman et al 2014
4
Outcome
Change in mean values
(95% CI) at 1-year followup (N=35)
Change in mean values
(95% CI) at 2-year followup (N=27)
Change in mean values
(95% CI) at 3-year followup (N=22)
FVC (%
predicted)
3 (-12 to 4) (p=0.01)
1 (-25 to 44) (p=NS)
6 (-18 to 38) (p=NS)
FEV1 (%
predicted)
1 (-6 to 20) (p=NS)
-1 (-9 to 17) (p=NS)
0 (-14 to 19) (p=NS)
RV (%
predicted)
-21 (-91 to 32) (p<0.001)
-10 (-83 to 43) (p=0.01)
-2 (-89 to 57) (p=NS)
-3.55 (-21.3 to 5.7) (p<0.001)
-0.23 (-18.6 to 10.3) (p=NS)
1.49 (-19 to 12.5) (p=NS)
mMRC
dyspnoea score
0 (-3 to 2) (p=0.007)
0 (-3 to 1) (p=0.007)
-0.5 (-3 to 1) (p=0.04)
6MWT (metres)
31.0 (-110 to 185) (p=0.01)
-12.0 (-140 to 238) (p=NS)
-31.5 (-120 to 177) (p=NS)
-4.2 (-44.0 to 13.1) (p=0.005)
-8.0 (-39.9 to 20.4) (p=0.03)
-7.2 (-29.6 to 21.2) (p=NS)
RV/TLC ratio
SGRQ score
6MWT: 6-minute walk test; FEV1: forced expiratory volume in one second, FVC: forced vital capacity; mMRC: modified Medical
Research Council, NS: not significant, RV: residual volume; SGRQ: St George’s Respiratory Questionnaire; TLC: total lung
capacity
Safety
By three years six patients had died of causes unrelated to the treatment. Pneumonia was
common, affecting 16 patients (46%) in the first year, two (7%) in the second year and one
(5%) in the third year following treatment. Hospitalisations due to COPD exacerbations
affected 18 patients (51%) in the first year, 10 (37%) in the second year and eight (36%) in
the third postoperative year. There was one case of coughing up blood (between years two
and three) that, although severe, settled spontaneously. There were no coil migrations, late
pneumothoraces (although two occurred in the first year) or unexpected AEs.
AeriSeal – Safety and Effectiveness
The single publication available summarised three prospective case series studies,
conducted at 10 hospitals in Germany, France, Austria and Israel, that included 54 patients
with advanced upper lobe emphysema.35 On average, three lung sites were treated per
patient. Three-month efficacy data, including complete before-and-after computed
tomography results, were available for 28 patients (58%) (Table 13 ). There was no
discussion of safety or adverse effects.
RePneu® Coil System: Update July 2015
17
Table 13
Outcomes for AeriSeal treatment at 3 months compared with baseline
35
Outcome
Change in mean values (SD) at
3-months’ follow-up (N=28)
% responders
(definition of minimal response)
FEV1 (%)
19.1 (21.5) (p<0.001)
55% (+12%)
FVC (%)
11.2 (17.1) (p=0.003)
41% (+12%)
RV/TLC ratio
-6.5 (10.7) (p=0.007)
-
RV (%)
-9.3 (15.8) (p<0.001)
-
TLC (%)
-2.6 (8.8) (p<0.001)
-
mMRC dyspnoea score
-0.9 (1.09) (p=0.004)
-
6MWT (metres)
30.9 (50.2) (p=0.005)
31% (≥54 metres)
SGRQ score
-11.6 (12.4) (p<0.001)
71% (≤4 points)
6MWT: 6-minute walk test; FEV1: forced expiratory volume in one second, FVC: forced vital capacity; mMRC: modified Medical
Research Council; RV: residual volume; SD: standard deviation; SGRQ: St George’s Respiratory Questionnaire; TLC: total lung
capacity
InterVapor System – Safety and Effectiveness
One publication provided six- and 12-month follow-up data pooled from two similar
prospective, industry-funded studies conducted in Australia, Europe (Austria, Germany and
Ireland) and the USA,36 six-month data were also reported separately.8 Forty-four
consecutive patients with severe and very severe (GOLD stages III and IV) upper lobe
emphysema received the treatment in one lung. Data were reported for 40 patients (91%)
at six months and 37 patients (84%) at 12 months.
Efficacy
The study’s clinical outcomes are shown in Table 14. The authors observed that
improvements were numerically larger at six months than at 12 months after treatment,
thus supporting the need for studies to extend follow-up beyond six months. Subgroup
analyses revealed that patients with severe and very severe (GOLD stage III and IV) COPD
had similar outcomes at six months; however, improvements relative to baseline were
numerically higher in patients with greater disease severity (GOLD stage IV). Larger
improvements were also observed in patients with more heterogeneous emphysema.
RePneu® Coil System: Update July 2015
18
Table 14
Outcomes for InterVapor treatment at 6 and 12 months compared with baseline
36
values
Outcome
Change in mean values (SD) at
6 months’ FU (N=40)
Change in mean values (SD) at
12 months’ FU (N=37)
FVC (mL)
271 (455) (p<0.05)
249 (429) (p<0.05 vs baseline)
FEV1/FVC ratio
0.02 (0.04) (p<0.05)
0.00 (0.05) (p<0.05 vs 6 months)
TLC (mL)
-220 (445) (p<0.05)
-65 (532) ) (p<0.05 vs 6 months)
RV/TLC
-0.03 (0.06) (p<0.05)
-0.04 (0.07) (NS vs 6 months)
FRC (mL)
-369 (615) (p<0.05)
-167 (624) (p<0.05 vs 6 months)
SGRQ score
-14.0 (15.1) (p<0.05)
-11.0 (14.0) (p<0.05 vs baseline)
6MWT: 6-minute walk test; FEV1: forced expiratory capacity in one second; FRC: functional residual capacity; FU: follow-up;
FVC: forced vital capacity; NS: not significant; RV: residual volume; SGRQ: St George’s Respiratory Questionnaire; SD:
standard deviation; TLC: total lung capacity
Safety
At the 12-month follow-up, 39 serious AEs had been reported in 23 patients. Twenty-nine
occurred in the first six months, 25 of which were respiratory: COPD exacerbation (n=9);
pneumonia (n=6); lower respiratory tract infection (n=4); coughing up blood (n=3); endstage COPD (n=1); inflammatory reaction (n=1); and Pseudomonas bacterium in the sputum
(mucous) (n=1).8 Ten serious AEs occurred between six and 12 months in eight patients as
follows: COPD exacerbation (n=5); respiratory tract infection (n=1); investigation of diabetes
(n=1); acute dyspnoea (n=1); cardiac insufficiency (n=1); and right-heart failure (n=1). One
patient died 67 days after treatment due to end-stage lung disease. A second death
occurred 350 days post-treatment due to complications following lobectomy for an
infection in the untreated lung.36 The authors interpreted the decrease in serious AEs over
time as an indication that there are no long-term safety concerns with the procedure.36
Economic evaluation
RePneu® Coil System
No economic evaluations of the LVRC procedure were identified. A press release described
successful enrolment of 100 patients in a French, government-funded cost-effectiveness
study in 2013, but results of the study could not be located.37 Also a European registry that
is under development (recruitment of 1,000 patients anticipated in Germany, France and
Switzerland) aims to collect data to serve as the foundation for a cost-effectiveness
analysis.38
RePneu® Coil System: Update July 2015
19
AeriSeal and InterVapor System
No economic evaluations were identified.
Ongoing research
RePneu Coil System
Eleven clinical trials were identified from searches of ClinicalTrials.gov (Table 15). Of these,
four are complete and included in this report,3, 26, 28, 29 one is active but not recruiting, five
are recruiting and one is not yet recruiting (Table 15). The industry-sponsored RENEW study
(NCT01608490) will be of particular interest as it is a multicentre RCT of more than 300
patients from the USA, Canada, France, Germany, the Netherlands and the United Kingdom
that will compare LVRC with standard medical care for at least 12 months after treatment.
The anticipated end dates are September 2015 for primary data collection and January 2016
for study completion.
AeriSeal
The current status of this technology is unclear. Of 10 trials listed in ClinicalTrials.gov, two
are complete,35 five have been terminated, two are “status unknown” and one has been
withdrawn.
InterVapor System
According to ClinicalTrials.gov (last verified December 2014), the international STEP-UP RCT
(NCT01719263) of InterVapor is underway at 17 sites in six countries, including four in
Australia and one in New Zealand. Sixty-nine patients with heterogeneous emphysema
(upper lobe predominance in both lungs) will be randomly assigned to either InterVapor
plus optimal medical therapy or optimal medical therapy alone. The primary outcomes are
changes in FEV1 and SGRQ scores. Study completion is planned for June 2015.
RePneu® Coil System: Update July 2015
20
Table 15
Registered clinical trial characteristics for RePneu (ClinicalTrials.gov)
Study
Design
No. of
patients
Intervention
Outcomes
Status (Estimated
completion date)
315
RePneu
LVRC
Standard
medical care
Baseline vs 12 months:
Primary: 6MWT
Secondary: SGRQ score, 6MWT
(responder analysis) and change in
FEV1
Active, not recruiting
(September 2015 for
primary data collection;
January 2016 for study
completion )
1,000
RePneu
LVRC
Primary: QOL at baseline vs 12
months
Secondary: Annual changes in
pulmonary function and exercise
capacity (5 years planned)
Recruiting (May 2015 for
primary data collection)
Strange et al (USA) “RENEW” study: USA,
Canada, France, Germany, Netherlands,
United Kingdom (29 sites)
NCT01608490
Sponsored by PneumRx, Inc.
Prospective RCT;
open label but
assessor-blinded
Hetzel & Schumann (Germany): Germany,
Spain, Switzerland (29 sites planned)
NCT01806636
Sponsored by PneumRx, Inc.
Prospective, postmarket, observational
registry
Draher & Müller (Germany): Germany
NCT02246569
Sponsored by RWTH Aachen University
Prospective case
series study
20
RePneu
LVRC
Primary: Change in breathing strength
at 3 & 9 months (maximal inspiratory
& expiratory pressure)
Secondary: SGRQ and SF-8
depression score
Recruiting (September
2015 for primary data
collection)
Lepper et al (Germany): Germany,
Denmark
NCT02273349
Sponsored by University Hospital, Saarland
(Germany)
Prospective case
series study of
patients with
emphysema due to
alpha-1 antitrypsin
deficiency
20
RePneu
LVRC
Primary: SGRQ score at 6 & 12
months
Secondary: FEV1, RV, RV/TLC,
mMRC dyspnoea score and 6MWT at
6 & 12 months
Recruiting (August 2015
for primary data
collection)
Slebos et al (Netherlands): Netherlands
NCT02012673
Sponsored by University Medical Centre,
Groningen
Prospective case
series study of
patients with failing
RePneu who need
new implants in other
lung areas
12
RePneu
LVRC
Primary: Adverse effects (device- and
procedure-related)
Secondary: FEV1, FVC, RV/TLC,
6MWT and mMRC dyspnoea score at
2 & 6 months
Recruiting (January 2016
for primary data
collection)
Franke & Domanski (Germany):
NCT02399514
Sponsored by Institut für Pneumologie
Hagen Ambrock eV and PneumRx, Inc.
Prospective case
series study
25
RePneu
LVRC
Primary: Sleep efficiency at 6 & 12
months
Secondary: SGRQ score and physical
activity level
Recruiting (November
2016 for primary data
collection; November
2017 for study
completion)
Slebos et al (Netherlands): Netherlands,
United Kingdom
NCT02179125
Prospective case
series study
40
RePneu
LVRC
Primary: Change in physical activity at
3 months
Secondary: Lung compliance,
Not yet recruiting
(September 2016 for
primary data collection)
RePneu® Coil System: July 2015
21
Sponsored by University Medical Centre,
Groningen
volumes, perfusion, small airway
function
6MWT: 6-minute walk test, FEV1: forced expiratory volume in one second, FVC: forced vital capacity; LVRC: Lung volume reduction coil; mMRC: Medical Research Council; QOL: quality of life; RV:
residual volume; SF-8: short-form 8; SGRQ: St George’s Respiratory Questionnaire; TLC: total lung capacity
RePneu® Coil System: Update July 2015
22
Other issues
All three of the included studies on RePneu were sponsored by the manufacturer. 3, 26, 29 The
single RCT compared LVRC treatment with usual care in 47 patients,26 but it was limited by
an inability to mask patients to treatment allocation (although treatment assessors were
masked), a short observation period (90 days) and differences between the patient groups
with respect to important baseline indicators of health and QOL status.
Given that LVRC treatment may be offered to patients who are not suitable for lung volume
reduction surgery, the comparison with usual care is appropriate. However, the lack of
studies comparing LVRC treatments to other lung volume reduction procedures means that
its comparative safety, efficacy and cost-effectiveness are unknown.
The results from the included trials generally showed improvement from baseline at the
follow-up points. In the longer-term examination of 38 Dutch patients,4 the benefits noted
postoperatively at six and 12 months in pulmonary function, 6MWT result and SGRQ score
had diminished until only the mMRC dyspnoea score showed statistically significant
improvement at the end of three years. However, the number of patients followed up was
low (58% at three years).
Although the LVRC procedure is performed bronchoscopically, it requires an inpatient stay
and only one lung can be treated at a time. It should also be noted that several other
endoscopic interventions for emphysema are also being developed.
Number of studies included
All evidence included for assessment in this Technology Brief has been assessed according
to the revised NHMRC levels of evidence. A document summarising these levels may be
accessed via the HealthPACT web site.
RePneu® Coil System
Total number of studies
3
Total number of Level II studies
1
Total number of Level IV studies
2
AeriSeal®
Total number of studies
1
Total number of Level IV studies
1
InterVapor® System
Total number of studies
1
Total number of Level IV studies
1
RePneu® Coil System: Update July 2015
23
Search criteria to be used (MeSH terms)
Emphysema/therapy*
Literature search date
3 March 2015
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
PneumRx Inc. (2015a). PneumRx gets CE Mark for Lung Volume Reduction Coil Syste.
Available from: http://pneumrx.com/corporate/news-press-releasesdetail/pneumrx-gets-ce-mark-for-lung-volume-reduction-coil-system [Accessed 25
March 2015
Service, N. H. (2012). RePneu™ lung volume reduction coils for emphysema. Available
from:
http://www.hsc.nihr.ac.uk/files/downloads/1903/2271.d8bb8046.PneumRxRePneuf
oremphysemaFINAL.pdf [Accessed May 1, 2015].
Slebos D. J., K. K., Ernst A., Herth F. J. F., Kerstjens A. M., (2012). 'Bronchosopic lung
bolume reduction coil treatment of patients with severe Heterogenous emphysema'.
Chest, 142 (3), 8.
Hartman, J. E., Klooster K. , (2015). 'Long-term follow-up after bronchoscopic lung
volume reduction treatment with coils in patients with severe emphysema'.
Respirology, 20 (2), 7.
PneumRx Inc. (2015c). RePneu® Lung volume reduction coil. Available from:
http://www.pneumrx.com/products-technology/ [Accessed 1 May 2015].
Stomp W. (2010). Aeris AeriSeal system receives EU approval for emphysema
treatment Available from:
http://www.medgadget.com/2010/09/aeris_aeriseal_system_receives_ce_approval.
html [Accessed 3 April 2015].
PRNewswire.com (2011). Uptake Medical receives CE mark for InterVapor Endoscopic Lung Volume Reduction for treatment of severe emphysema - and
announces positive clinical results. Available from:
http://www.prnewswire.com/news-releases/uptake-medical-receives-ce-mark-forintervapor---endoscopic-lung-volume-reduction-for-treatment-of-severeemphysema---and-announces-positive-clinical-results-130547908.html [Accessed 3
April 2015].
Snell, G., Herth, F. J., (2012). 'Bronchoscopic thermal vapour ablation therapy in the
management of heterogeneous emphysema'. Eur Respir J, 39 (6), 8.
PneumRx Inc. (2015b). PneumRx, Inc. receives FDA approval to commence pivotal
clinical trial of RePneu Lung Volume Reduction System. Available from:
http://www.pneumrx.com/blog/2012/05/15/pneumrx-inc-receives-fda-approval-tocommence-pivotal-clinical-trial-of-repneu-lung-volume-reduction-system/ [Accessed
25 March 2015].
Thomson Reuters. (2015). Pulmonx® Acquires Assets of Aeris Therapeutics,
Expanding the Company's Treatment Options for COPD Patient. Available from:
http://www.reuters.com/article/2015/01/08/ca-pulmonx-aerisidUSnBw085041a+100+BSW20150108
[Accessed 3 April 2015].
RePneu® Coil System: November 2013
24
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
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27.
28.
Uptake Medical (2015). Uptake Medical announces TGA approval of InterVapor for
patients with severe emphysema. Available from:
http://www.uptakemedical.com/uptake-medical-announces-tga-approval-ofintervapor-for-patients-with-severe-emphysema [Accessed 3 April 2015].
Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2015). Global Strategy
for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary
Disease Available from: http://www.goldcopd.org/guidelines-global-strategy-fordiagnosis-management.html [Accessed 25 March 2015].
Demirjian, B. G. (2014). Emphysema Available from:
http://emedicine.medscape.com/article/298283-clinical [Accessed 25 March 2015].
BMJ Evidence Centre (2015). COPD. Available from:
http://us.bestpractice.bmj.com/bestpractice/monograph/7/highlights/summary.html [Accessed 25 March 2015].
Australian Institute of Health and Welfare (2014a). How does COPD affect quality of
life? Available from: http://www.aihw.gov.au/copd/quality-of-life/ [Accessed 25
March 2015].
Australian Institute of Health and Welfare (2014b). What is the health burden of
COPD. Available from: http://www.aihw.gov.au/copd/quality-of-life/ [Accessed 25
March 2015].
World Health Organisation (2014). The top 10 causes of death Available from:
http://who.int/mediacentre/factsheets/fs310/en/# [Accessed 1 May 2015].
Toelle, B. G., Xuan, W., (2013). 'Respiratory symptoms and illness in older
Australians: the Burden of Obstructive Lung Disease (BOLD) study'. med J Aust,, 198
(3).
Australian Institute of Health and Welfare (2014c). Available from:
http://www.aihw.gov.au/hospitals-data/principal-diagnosis-data-cubes/ [Accessed
25 March 2015].
Ministry of Health (2008). Portrait of Health: Key results of the 2006/07 New Zealand
Health Survey. Available from: http://www.health.govt.nz/publication/portraithealth-key-results-2006-07-new-zealand-health-survey [Accessed 25 March 2015].
Herth, F. J. F., Gompelmann, D., (2010a). 'Endoscopic lung volume reduction'.
Respiration, 79 (1), 8.
Ernst, A. A., D., (2011). 'Bronchoscopic lung volume reduction'. Pulm Med.
Munro, P. E., Bailey, M. J., (2003). 'Lung volume reduction surgery in Australia and
New Zealand. Six years on: registry reporT'. Chest, 124 (4), 7.
Delporte. PneumRx web contact us form submission. In: Lambert R, editor.2013.
Iftikhar, I. H., McGuire, F. R., Musani, A. I., (2014). 'Efficacy of bronchoscopic lung
volume reduction: a meta-analysis'. Int J Chron Obstruct Pulmon Dis, 9, 10.
Shah, P., Zoumot, Z., (2013). 'Endobronchial coils for the treatment of severe
emphysema with hyperinflation (RESET): a randomised controlled trial'. The Lancet
Respiratory Medicine, 1 (3), 7.
Herth, F. J., Eberhard, R., (2010b). 'Bronchoscopic lung volume reduction with a
dedicated coil: a clinical pilot study'. Ther Adv Respir Dis, 4 (4), 6.
Klooster, K., Ten Hacken, N. H., (2014). 'Lung volume reduction coil treatment in
chronic obstructive pulmonary disease patients with homogeneous emphysema: a
prospective feasibility trial'. Respiration, 88 (2), 9.
RePneu® Coil System: November 2013
25
29.
30.
31.
32.
33.
34.
35.
36.
Deslee, G., Klooster, K., (2014). ''Lung volume reduction coil treatment for patients
with severe emphysema: a European multicentre trial'. Thorax, 69 (11), 7.
Donohue, J. F. (2005). 'Minimal clinically important differences in COPD lung
function'. COPD, 2 (1), 111-24.
Wise, R. A.& Brown, C. D. (2005). 'Minimal clinically important differences in the sixminute walk test and the incremental shuttle walking test'. COPD, 2 (1), 125-9.
Holland, A. E., Hill, C. J. et al (2010). 'Updating the minimal important difference for
six-minute walk distance in patients with chronic obstructive pulmonary disease'.
Arch Phys Med Rehabil, 91 (2), 221-5.
Puhan, M. A., Chandra, D. et al (2011). 'The minimal important difference of exercise
tests in severe COPD'. Eur Respir J, 37 (4), 784-90.
Jones, P. W. (2005). 'St. George's Respiratory Questionnaire: MCID'. COPD, 2 (1), 759.
Magnussen, H., Kramer, M. R. (2012). 'Effect of fissure integrity on lung volume
reduction using a polymer sealant in advanced emphysema'. Thorax, 67 (4), 6.
Herth, F. J., Ernst, A., (2012). 'Characterization of outcomes 1 year after endoscopic
thermal vapor ablation for patients with heterogeneous emphysema'. Int J Chron
Obstruct Pulmon Dis, 7, 8.
37.
PRNewswire.com (2013). French cost-effectiveness trial of PneumRx RePneu LVR coil
fully enrolled in record time. Available from: http://www.prnewswire.com/newsreleases/french-cost-effectiveness-trial-of-pneumrx-repneu-lvr-coil-fully-enrolled-inrecord-time-229516371.html [Accessed 25 March 2015].
38.
ClinicalTrials.gov. (2014). Post Market Observational, Prospective Multi-centre study.
Available from: https://clinicaltrials.gov/ct2/show/NCT01806636 [Accessed 25
March 2015].
RePneu® Coil System: November 2013
26
Technology Brief 2013
Technology, Company and Licensing
Register ID
WP172
Technology name
RePneu® Lung Volume Reduction Coils
Patient indication
Patients with advanced emphysema
Description of the technology
The RePneu® Lung Volume Reduction Coil (LVRC) is composed of nitinol, a nickel/titanium
alloy. The coils, which have shape memory, are straightened for insertion into the airways.
Once deployed, they assume their predetermined shape and act as a spring, gathering and
retracting diseased lung tissue (Figure 1). This bundling of the surrounding lung tissue
reduces the volume of highly diseased areas, restores elastic recoil in healthier regions of
the lung and makes breathing easier in patients with advanced emphysema. 1
Figure 1
®
RePneu coil
2
The LVRC procedure is performed endoscopically under general anaesthesia or conscious
sedation in a hospital and is usually completed in 30 to 50 minutes.3,3 The coils, which are
100, 125 or 150 mm long, are inserted using a delivery system which consists of a delivery
catheter, guidewire, cartridge and forceps. The guidewire is advanced into the airway up to
15 mm from the surface of the pleura and a catheter is inserted over the guidewire. The
straightened coil is inserted through the cartridge and catheter under fluoroscopic
guidance; forceps are used to pull the coil into the cartridge and deliver the coil to the
airway. Forceps may also be used to remove or reposition the coils. Multiple coils are
deployed per lung lobe. The surgery is conducted in one lung at a time; patients requiring
treatment in both lungs undergo two separate procedures.2
Company or developer
The RePneu® LVRC was developed by PneumRx, Inc. (Mountain View, California, USA).
Reason for assessment
The RePneu® LVRC is a novel bronchoscopic lung volume reduction device for patients with
advanced emphysema.
RePneu® lung volume reduction coils: November 2013
1
Stage of development in Australia
Yet to emerge
Established
Experimental
Established but changed indication
or modification of technique
Should be taken out of use
Investigational
Nearly established
Licensing, reimbursement and other approval
The RePneu® coil received CE mark approval on 13 October 2010. On 15 May 2012, the US
Food and Drug Administration (FDA) granted PneumRx, Inc. approval to commence a clinical
trial.4, 5 No Australian Therapeutic Goods Administration approval (ARTG) or Health Canada
approval of the technology was identified.
Australian Therapeutic Goods Administration approval
Yes
ARTG number (s)
No
Not applicable
Technology type
Device
Technology use
Therapeutic
Patient Indication and Setting
Disease description and associated mortality and morbidity
Emphysema is a chronic obstructive pulmonary disease (COPD) characterised by permanent
enlargement of the air sacs (alveoli) in the lungs. The damaged lung tissue loses its elastic
recoil leading to the formation of large irregular air pockets and narrowing or collapse of the
airways. In addition, the damaged tissue reduces alveolar-capillary interface resulting in a
reduction in gas transfer. Thus, the lungs remain filled with air even when the patient
breathes out (hyperinflation), causing symptoms such as shortness of breath (dyspnea),
wheezing, chest tightness, coughing and phlegm production (particularly if chronic
bronchitis co-exists). Patients often present with both emphysema and chronic bronchitis
and current definitions of COPD do not distinguish between the conditions. 6 COPD is
characterised by progressive airflow limitation that is not fully reversible. The Global
Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD, using spirometric
measurement of forced expiratory volume in one second (FEV1), as mild (FEV1 ≥ 80% of
predicted), moderate (50% ≤ FEV1 < 80% of predicted), severe (30% ≤ FEV1 < 50% of
predicted) or very severe (FEV1 < 30% of predicted).6
RePneu® lung volume reduction coils: November 2013
2
The symptoms of emphysema progress over many years and patients seeking treatment are
often in their fifth decade of life.7 Complications associated with emphysema include
collapsed lung, cor pulmonale, giant bullae, recurring chest infections and pulmonary
hypertension. The quality of life in patients with COPD is negatively affected by the
interruption of daily activities and sleep and the reduced capacity for exercise. As the
condition advances, patients may become progressively less able to carry out daily activities
such as walking up short flights of stairs. Patients with advanced emphysema may
experience weight loss and muscle wasting and may use purse-lipped breathing (as a means
of reducing the amount of gas breathing).8
There is no cure for emphysema; current treatments are palliative and a patient’s prognosis
and quality of life depends on the stage of disease and extant comorbidities. Patients with
COPD often have comorbidities and COPD can contribute to or exacerbate comorbidities
such as ischaemic heart disease and diabetes. COPD may also increase the risk of developing
other diseases, such as lung cancer.6 As the disease progresses, patients may experience a
sudden worsening of symptoms (acute exacerbation) that requires hospitalisation. These
hospitalised patients have an increased risk of death due to progressive respiratory failure,
cardiovascular disease, cancer and other diseases.6
The prevalence of COPD increases with age and is most common among individuals older
than 60 years.6 The leading cause of COPD is long-term tobacco smoking. Other risk factors
for the disease include a family history of chronic lung disease and exposure to air
pollutants, and coal and silica dust.8
In Australia the 2007–08 National Health Survey revealed that in people aged 55 years and
over, people with COPD generally rated their health worse than people without COPD. Very
few people with COPD rated their health as excellent (2%) compared with those without
COPD (9%) and people with COPD had a greater propensity to rate their health as fair or
poor as compared to people without COPD. COPD contributes substantially to the burden of
disease in Australia and worldwide; in terms of disability-adjusted life years, COPD was the
sixth leading cause of male burden of disease and the seventh leading cause of female
burden of disease in Australia in 2003.9
Number of patients
According to the World Health Organization (WHO), COPD was the fourth leading cause of
death in 2011.10 The WHO predicts that COPD will become the third leading cause of death
worldwide by 2030.11 A study conducted in Australia between 2006 and 2010 found that the
prevalence of moderate to very severe COPD was 8 per cent in people aged 40 years or
older and 29 per cent in people aged 75 years or older.12 The prevalence of severe or very
severe COPD was 1.5 per cent in people aged from 55 to 74 years and 2.1 per cent in people
aged 75 or older. The 2006–07 New Zealand Health Survey13 found that one in 15 adults
RePneu® lung volume reduction coils: November 2013
3
aged 45 years or older had been told by a doctor that they had COPD. This diagnosis is more
common in women (7.4%) than in men (5.6%) and twice as likely in people of Māori origin
compared with other ethnic groups.
In 2009–10 there were 56,534 hospital separations for COPD in Australia and 418
separations for emphysema (total 56,952 separations).14
Speciality
Respiratory disease and thoracic surgery
Technology setting
General hospital
Impact
Alternative and/or complementary technology
The LVRC procedure is an adjunct treatment as patients receiving RePneu® coils will
continue to be managed with optimal medical therapy; it may be considered as an
alternative to other lung volume reduction procedures and devices. The device has the
potential to treat more patients than lung volume reduction surgery as it may be offered to
those who are considered unfit for such a procedure.
Current technology
All patients with COPD are advised to stop smoking. Patients with severe emphysema have
limited treatment options and the management of COPD is aimed at reducing the severity
and frequency of exacerbations and symptoms as well as slowing disease progression.
Management of COPD may include pharmacological therapy, pulmonary rehabilitation,
long-term oxygen therapy and ventilator support, and surgical treatments. Only smoking
cessation and long-term oxygen therapy are thought to confer any survival benefit.6
Pharmacological therapy consists of beta2-agonists, anticholinergics, methylxanthines,
inhaled corticosteroids, systemic corticosteroids and phosphodiesterase-4 inhibitors. These
medications aim to reduce the frequency and severity of exacerbations and to improve
health.6
Pulmonary rehabilitation aims to reduce symptoms and to improve quality of life and
participation in everyday activities. It includes, at a minimum, six weeks of exercise training
and may also include nutrition counselling, education and smoking cessation support. 6
Long-term oxygen therapy, which involves the administration of oxygen to patients with
chronic respiratory failure, has been shown to increase survival in patients who have low
resting oxygen saturation (<88% breathing room air).6
Surgical treatments for end-stage COPD include lung transplantation and lung volume
reduction surgery. Lung transplantation can improve pulmonary function, functional
capacity and quality of life. However, the procedure is costly and is limited by organ
RePneu® lung volume reduction coils: November 2013
4
availability, the surgical risks and the need for lifelong immunosuppression.15 In lung volume
reduction surgery, which is performed via median sternotomy or video-assisted
thoracoscopy, 20 to 30 percent of the most emphysematous segments of each lung are
removed. Its application in clinical practice is limited by stringent selection criteria
(restricted to patients with heterogeneous upper lobe emphysema and a low baseline
exercise capacity) and high postoperative morbidity.16 The reported rate of intraoperative
complications is nine per cent and postoperative complications is 58.7 per cent, with
elevated risks of reintubation, arrthymias, pneumonia, readmission to the intensive care
unit and tracheotomy.16 In addition, the improvement in lung function gradually declines
over time, returning to baseline three to four years after surgery.17
Emerging treatments for severe emphysema include a range of endoscopic lung volume
reduction devices such as endobronchial blockers, airway bypass stents, endobronchial
valves, thermal vapour ablation, biological sealants and LVRCs.15 These devices aim to
reduce symptoms and improve lung function but with fewer adverse events than for lung
volume reduction surgery.
Diffusion of technology in Australia
The RePneu® coil has not been used in Australia.
International utilisation
Country
Level of Use
Trials underway or
completed
France

Germany

Netherlands

United Kingdom

USA

Limited use
Widely diffused
Cost infrastructure and economic consequences
Costs associated with bronchoscopic LVRC include hospitalisation, anaesthesia, the
bronchoscopic delivery system and the coils. Information from the manufacturer indicates
that the procedure costs approximately A$19,436 (personal communication).18 Patients
undergoing bilateral treatment would require two procedures. The breakdown of this cost
according to the cost of device, anaesthesia and other inputs is not available.
At this point in time, it is unclear what role LVRC surgery would play in the management of
severe emphysema and, thus, the economic consequences of its diffusion are uncertain.
RePneu® lung volume reduction coils: November 2013
5
Ethical, cultural or religious considerations
None identified.
Evidence and Policy
Safety and effectiveness
One randomised controlled trial (Level II evidence) and two case series (Level IV evidence)
studies were identified for inclusion in this brief (Table 16). It is possible that there was
some patient overlap among the two case series studies because of common study
enrolment dates and study sites. No other peer reviewed literature was identified.
RePneu® lung volume reduction coils: November 2013
6
Table 16
Included studies
Shah et al 2013
19
Slebos et al 2012
3
Herth et al 2010
20
Level of evidence
Prospective randomised
controlled trial (multicentre)
Prospective case series
(single centre)
Prospective case series
(single centre)
Number of
patients
LVRC: 23
Usual care: 24
Enrolled 17, treated 16
Enrolled and treated 11
patients
Patient details
Severe heterogeneous or
homogeneous emphysema
(unilateral or bilateral); FEV1
≤ 45% predicted; TLC >
100% of predicted; mMRC
dyspnoea score ≥2; on
optimal medical treatment at
enrollment; ceased smoking
for a minimum of 8 weeks
prior to enrollment
Heterogeneous emphysema
(unilateral or bilateral); FEV1
< 45%; TLC > 100% of
predicted; mMRC dyspnoea
score >1; ceased smoking
for a minimum of 8 weeks
prior to enrollment
Heterogeneous or
homogeneous
emphysema (unilateral or
bilateral); FEV1 < 45%;
TLC > 100% of predicted;
mMRC dyspnoea score
≥2; ceased smoking for a
minimum of 8 weeks prior
to enrollment
Mean age: 58 SD 7.3 years
12 women and 4 men
Age: ≥35 years
Mean age: 62.5 SD 4.0
years
8 women and 3 men
LVRC
Unilateral: 2
Bilateral: 21
Unilateral: 4
Bilateral: 12
Unilateral: 1
Bilateral: 6 patients
Second treatment in
same lung: 4
Follow-up
LVRC: 1 week, 1 month and
90 days after second
treatment
6 months, with follow-up
assessments at 1, 3 and 6
months after the final
treatment
7 days, 1 month and 3
months after each
treatment
Study sponsored by
PneumRx Inc. The authors
serve as advisors to
PneumRx, Inc. None of the
authors has a financial
interest in the company.
Study sponsored by
PneumRx, Inc. The
authors serve as advisors
to the company and were
reimbursed for studyrelated travel expenses.
None of the authors has
a financial interest in the
company
Usual care: coincided with
LVRC assessments
Conflict of interest
Lead author received an
honoraria from PneumRx,
Inc. Both second and third
authors received travel
grants from PneumRx, Inc.,
and another author received
financial support from
PneumRx, Inc., as a
consultant.
Minimum follow-up of 7
months
FEV1: forced expiratory volume; TLC: total lung capacity; LVRC: lung volume reduction coil; mMRC: modified Medical
Research Council.
RePneu® lung volume reduction coils: November 2013
7
Shah et al 201319
This randomised controlled trial enrolled 47 patients with severe heterogeneous or
homogeneous emphysema. Patients were randomised using a computer-generated
randomisation sequence. The generated codes were placed in opaque sealed envelopes and
opened in sequence when a patient fulfilled all the eligibility criteria. Bronchoscopists and
patients were aware of treatment allocation but assessments were conducted by nurses and
physiologists who were masked to treatment allocation. Exclusion criteria were a change in
FEV1 of more than 20 per cent post-bronchodilator; single-breath diffusing capacity for
carbon monoxide less than 20 per cent of predicted; history of recurrent, clinically
significant respiratory infection; uncontrolled pulmonary hypertension; inability to walk
more than 140 metres in six minutes; evidence of other diseases that could compromise
survival; pregnancy or lactation; inability to tolerate bronchoscopy under heavy sedation or
anaesthesia; clinically significant bronchiectasis; giant bullae greater than a third of lung
volume; previous lung volume reduction surgery, lung transplant or lobectomy;
participation in pulmonary drug studies within 30 days of enrolment; taking greater than 20
mg prednisone (or similar steroid) daily; on clopidogrel or unable to stop treatment for one
week prior to procedure; or other disease that would interfere with completion of the study
or follow-up assessments.
Patients assigned to the LVRC procedure underwent bronchoscopy under moderate
sedation or general anaesthesia depending on local practice and patient requirements. A
total of 410 coils were inserted in 44 procedures (23 patients). The mean procedure time
was 45 minutes (SD 17, range 20 to 88) and patients treated bilaterally received an average
of 19 coils. Details of treatment in the usual care group were not provided. Of the 23
patients in the LVRC arm, 21 received a second LVRC treatment in the contralateral lung.
Follow-up assessments included quality of life measured by the St George’s Respiratory
Questionnaire (SGRQ), pulmonary function tests including plethysmography, a 6-minute
walk test, high resolution computed tomography scans and modified Medical Research
Council (mMRC) dypsnoea scores. The primary endpoint was the difference in the change in
SGRQ scores from baseline to 90 days after final treatment. The change in FEV 1, total lung
capacity, residual volume, 6-minute walk test results and mMRC scores were secondary
endpoints. For patients whose last results were recorded less than 90 days from the final
treatment, their last recorded values were carried forward. The authors reported that the
study was powered at 84 per cent with a one-sided t test. One patient in the LVRC group
withdrew during the follow-up period and was not included in the analysis.
RePneu® lung volume reduction coils: November 2013
8
Safety
The authors report that most patients in the LVRC group were discharged the day after
treatment (40 of 44 procedures); however, four procedures necessitated hospital stays of
two (3 procedures) or three days (1 procedure). Adverse events that were not deemed
severe were not reported. The serious adverse events occurring within 30 days of each LVRC
treatment or usual care visit are listed in Table 17. All adverse events were associated with
hospitalisation; no haemoptysis, device removal or respiratory failure occurred during the
follow-up periods. There was no statistically significant difference in adverse event rates
between the treatment groups.
Table 17
Serious adverse events occurring within first and second visit or up to 29 days
19
after first and second treatments
Outcomes
LVRC group
Usual care group
23 patients
23 patients
Number of events
†
Number of events
(number of patients)
(number of patients)
2 (2)
1 (1)
2 (2)
0
Pneumothorax
2 (2)
0
Total
6 (6)
1 (1)
COPD exacerbation
Lower respiratory tract infection
§
LVRC: lung volume reduction coil; COPD: chronic obstructive pulmonary disease; †some patients experienced multiple
occurrences of the same event; §includes pneumonia.
Serious adverse events occurring between 30 and 90 days after treatment or the second
usual care visit were also reported (Table 18). There was no statistically significant
difference in adverse event rates between the treatment groups.
Table 18
Serious adverse events occurring within 30 to 90 days after the second
19
treatment or second usual care treatment visit
Outcomes
LVRC group
Usual care group
23 patients
23 patients
Number of events
COPD exacerbation
Lower respiratory tract infection
Total
§
†
Number of events
(number of patients)
(number of patients)
3 (2)
2 (2)
0
1 (1)
3 (2)
3 (3)
†
LVRC: lung volume reduction coil; COPD: chronic obstructive pulmonary disease; some patients experienced multiple
occurrences of the same event; §includes pneumonia.
Efficacy
After an analysis of covariance was undertaken to correct the imbalance in baseline SGRQ
scores between the treatment groups, the mean change in SGRQ score from baseline to 90
RePneu® lung volume reduction coils: November 2013
9
days after the final visit was greater in the LVRC group than in the usual care group,
exceeding the 4-point reduction considered clinically meaningful by the authors.19 Patients
in the LVRC group also showed an improvement (mean 51 metres) in the 6-minute walk
test, which was also greater than the distance considered clinically meaningful (26 metres).
The percentage change in FEV1 and reduction in residual volume were also greater in the
LVRC group than in the usual care group. No differences were detected between the groups
for the change in mMRC or total lung capacity (Table 19).
Table 19
Mean change from baseline in quality of life and lung function measures 90
19
days after final treatments
Outcomes
LVRC group, N=23
Mean change from
baseline (95% CI)
Usual care group,
N=23
Between group
difference
P
value
Mean change from
baseline (95% CI)
Mean difference
between groups (95%
CI)
†
St George’s Respiratory
Questionnaire
-8.11 (-13.83, -2.39)
0.25 (-5.58, 6.07)
-8.36 (-16.24,-0.47)
0.04
Total lung capacity (L)
-0.24 (-0.38, -0.10)
-0.13 (-0.27, 0.01)
-0.11 (-0.29, 0.07)
0.22
Residual volume (L)
-0.51 (-0.73, -0.30)
-0.20 (-0.42, 0.02)
-0.31 (-0.59, -0.04)
0.03
6-minute walk test (m)
51.15 (27.65, 74.66)
-12.39 (-36.61, 11.83)
63.55 (32.57, 94.53)
<0.001
% change in FEV1
14.19 (6.84, 21.55)
3.57 (-4.02, 11.17)
10.62 (1.12, 20.12)
0.03
mMRC dyspnoea score
-0.24 (-0.57, 0.09)
-0.09 (-0.44, -0.26)
-0.15 (-0.60, 0.30)
0.5
LVRC: lung volume reduction coil
†
Corrected for difference between groups at baseline; mMRC: modified Medical Research Council; CI: confidence interval;
FEV1: forced expiratory volume in one second.
The authors also conducted a responder analysis of quality of life and lung function
outcomes 90 days after the final treatment and found that just over half of the LVRC
patients treated experienced improvements that were considered clinically meaningful
(Table 20).
Table 20
Number of patients achieving a clinically meaningful change in outcomes 90
19
days after final treatment
Clinically meaningful outcomes
LVRC group, N=23
n (%)
Usual care group,
N=23
p value
n (%)
SGRQ ≥ 4 point improvement
15 (65)
5 (22)
0.01
SGRQ ≥ 8 point improvement
13 (57)
3 (13)
0.01
Respiratory volume reduction of
0.35 L
13 (57)
4 (17)
0.01
Six-minute walk test improvement
of 26 m
17 (74)
4 (17)
<0.001
10% improvement in FEV1
13 (57)
6 (26)
0.07
LVRC: lung volume reduction coil; SGRQ: St George’s Respiratory Questionnaire; FEV1: forced expiratory volume in 1 second
RePneu® lung volume reduction coils: November 2013
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Slebos et al 2012 3
Slebos et al.3 conducted a case series study that enrolled 17 patients with emphysema. It
was not stated whether enrolment was consecutive and one patient was excluded as they
had homogeneous emphysema. Exclusion criteria were a change in FEV1 greater than 20 per
cent post-bronchodilator, more than 75 per cent destruction of the upper lobes of the lung,
smoking within eight weeks of treatment, carbon monoxide diffusion capacity of less than
20 per cent of predicted, right ventricular pressure of more than 50 mm Hg, more than
three hospitalisations due to COPD in the previous 12 months, clinically significant
bronchiectasis, previous lung surgery or a giant bulla (more than a third of lung volume),
inability to walk 140 metres in six minutes, use of clopidogrel or coumarins, or any disease
which might compromise survival or interfere with completion of study or follow-up
assessments.
The procedure was performed as described by Herth et al.20; patients remained in the
hospital overnight following the procedure. Efficacy endpoints included changes in
respiratory-related quality of life (SGRQ score), pulmonary function and 6-minute walk test
results. The mean destruction scores were 54 per cent (SD 13.8) and 21 per cent (SD 10.4)
for the right upper and lower lobes, and 48 per cent (SD 14.5) and 18 per cent (SD 9.9) for
the left upper and lower lobes.
Safety
The authors reported no intraprocedural adverse events; however, one case of
pneumothorax occurred one hour after the bronchoscopy procedure and was resolved
within one day with a chest tube. Adverse events were reported as the number of events
and, therefore, at least some patients experienced multiple adverse events. Slight
haemoptysis (spitting of blood), which resolved spontaneously, occurred in a total of 12
patients (21 procedures) within the first few days following the procedure. Chest pain
occurred in four cases, also resolving within a few days post-procedure. Within the 1- to 6month follow-up, 16 patients experienced 14 COPD exacerbations. Adverse events were
categorised as respiratory adverse events, any course of antibiotics, anaesthesia-related
events and adverse events due to other causes. Safety outcomes are detailed in Table 21
and Table 22.
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Table 21
(n=16)
Respiratory adverse events and antibiotic or prednisolone treatment
2
Category
Adverse event
Number of events one
month after first or
second treatment
Number of events one
to six months after last
treatment
Respiratory adverse
events
2009 influenza A (H1N1)
2
1
Chest pain
4
2
COPD exacerbation
6
14
Cough
2
2
Pneumonia
2
3
Pneumothorax
1
0
0
1
Slight haemoptysis < 5
mL
21
0
Any course of
prednisolone or antibiotics
8
Pulmonary embolism
Antibiotic/prednisolone
treatment
†
‡
17
COPD: chronic obstructive pulmonary disease; †non-treated lung; ‡one month after first treatment
Table 22
Adverse events related to anaesthesia or due to other causes (n=16)
2
Category
Adverse event
Number of adverse events
Anaesthesia-related adverse
events
Bronchospasm
1
Headache
2
Hoarseness
3
Paroxysmal atrial fibrillation
1
Phlebitis
1
Anaemia
1
Azathioprine-induced thrombopenia
1
Consolidation around coil
1
Diarrhoea
1
Gout
1
Hypertension
1
Nasal congestion
1
Oral candidiasis
3
Osteoporotic thoracic vertebral fracture
1
Symptomatic coronary artery disease
1
Tonsillar angina
3
Traumatic rib contusion
2
Urinary tract infection
3
Wrist fracture
1
Adverse events due to other
causes
RePneu® lung volume reduction coils: November 2013
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Effectiveness
Slebos et al. 3 report that the procedure had a median duration of 36 minutes (range 20 to
60) and a total of 260 coils were placed. The median number of coils placed per subject was
10 (range 5 to 12). Follow-up chest radiographs made on day one and at one, three and six
months post-procedure did not show any migration of the coils. Sixteen patients underwent
28 procedures. Two patients were not included in the 6-month follow-up analysis due to
coronary artery disease (n=1) and severe osteoporotic vertebral fracture (n=1).
The authors reported that lung function (FEV1, forced vital capacity, residual volume and sixminute walk test) and quality of life outcomes were significantly improved at the six month
follow-up compared with baseline values (Table 23).
Table 23
Outcome
Change from baseline in efficacy outcomes
3
One month
after first
treatment
(N=16)
One month
after second
treatment
(N=12)
Three months
after second
treatment
(N=12)
Six months
after second
treatment
(N=12)
Six months
after final
treatment
(N=14)
Forced vital
capacity, %
11.5 ± 13.6
17.0 ± 14.9
10.7 ± 11.9
13.3 ± 13.2
13.4 ± 12.9
p value
0.005
0.002
0.01
0.007
0.002
Forced expiratory
volume in 1
second, %
10.3 ± 13.1
22.6 ± 21.7
19.9 ± 20.0
17.3 ± 19.4
14.9 ± 17
p value
0.009
0.004
0.005
0.01
0.004
Residual volume,
%
-9.5 ± 6.5
-12.4 ± 9.0
-11.1 ± 9.9
-10.6 ± 9.6
-11.4 ± 9.0
p value
0.001
<.001
0.003
0.004
<.001
Residual volume/
Total lung capacity,
%
-6.7 ± 4.8
-8.2 ± 71
-6.6 ± 6.7
-8.1 ± 5.2
-8.0 ± 5.5
p value
<.001
0.002
0.006
<.001
<.001
6 minute walk test,
m
12.6 ± 13.8
29.8 ± 30.4
27.1 ± 36.6
34.4 ± 39.2
32.9 ± 36.3
p value
0.003
0.006
0.026
0.011
0.005
St George’s
Respiratory
Questionnaire
-14.2 ± 11.6
-12.2 ± 10.8
-12.6 ± 10.8
-15.8 ± 12.2
-14.9 ± 12.1
p value
<.001
0.009
0.002
0.002
<.001
Note: all values are reported as mean and standard deviation.
The study also reported that 50 per cent of patients had a change from baseline of more
than the minimal clinically important difference (MCID) for FEV1 and SGRQ (sourced from
peer-reviewed publications) (Table 24).
RePneu® lung volume reduction coils: November 2013
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Table 24
Number of patients achieving a clinically meaningful change in outcomes six
3
months after treatment
Outcome
Minimal clinically important
difference
Forced expiratory volume in 1
second
≥12%
Residual volume
≥10%
6 minute walk test
≥48 metres
21
9 (64%)
9 (64%)
22
9 (64%)
23, 24
12 (86%)
≥25 metres
St George’s Respiratory
Questionnaire
≥4 points
Responders (%)
N=14
25
11 (79%)
Herth et al 201020
The study by Herth et al.20 was a pilot trial that enrolled 11 patients with stage three or four
emphysema (GOLD criteria6). It was not stated whether enrolment was consecutive. No
blinding was undertaken. Exclusion criteria were giant bullae greater than one third of lung
volume, a 6-minute walk distance of less than 140 metres and previous lung volume
reduction surgery or lung transplantation. Patients who had a history of recurrent, clinically
significant respiratory infection; were pregnant or lactating; were unable to tolerate
bronchoscopy; had clinically significant bronchiectasis; were taking more than 20 mg of
prednisone or similar steroid daily; were on antiplatelet agents or anticoagulant therapy;
had a carbon monoxide diffusion capacity of less than 20 per cent; or had other disease that
would interfere with the completion of study were also excluded.
The procedure was performed under general anaesthesia and the coils were placed in the
most severely affected lobe as determined by a computed tomography scan. Between three
and six coils were deployed per patient, and patients remained in hospital for three days
following the procedure. The clinical follow-up included a physical exam, spirometry,
plethysmography, a 6-minute walk test, an mMRC dyspnea questionnaire and the SGRQ.
Ten of the 11 patients underwent a second coil procedure with similar follow-up. The
majority of participants (8/11) did not use oxygen supplementation and 10 of the patients
were former smokers.
Safety
The authors reported a total of 33 adverse events in 11 patients. These adverse events were
categorised as mild (36%), moderate (64%) or severe (0%) and judged whether they were
not related (42%), possibly related (58%) or probably related (0%) to the LVRC procedure.
Adverse events that were possibly related to the procedure or device included dyspnea or
increasing dyspnea (9 events: 1 mild and 8 moderate in severity), cough (5 events: 3 mild
RePneu® lung volume reduction coils: November 2013
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and 2 moderate), COPD exacerbations (2 events: all moderate) and chest pain (1 event
considered moderate).
Effectiveness
This pilot trial was intended to primarily assess safety. Hence, while the authors noted
trends in efficacy, they stated that the study was not adequately powered for an efficacy
analysis. The number of coils implanted per bronchoscopic session was 4.9 (SD 0.6). The
mean changes in effectiveness measures were small across all patients; however, the subset
of patients with predominantly heterogeneous disease showed substantial improvements in
several areas including pulmonary function, lung volumes, 6-minute walk test results and
quality of life measures (Table 25).
Table 25 Changes in lung volumes and QOL scores compared to baseline at 1- and 3-months
20
post-procedure
One month after
first treatment
Three months
after first
treatment
One month after
second treatment
Three months
after second
treatment
Forced expiratory volume in 1 second, %
All patients
6.5 ± 3.9
3.3 ± 3.2
-1.3 ± 3.2
-5.0 ± 2.9
Heterogeneous
emphysema
12.6 ± 9.9
9.6 ± 2.5
3.9 ± 5.3
-0.9 ± 4.0
Homogeneous
emphysema
4.2 ± 4.0
0.2 ± 4.2
-3.5 ± 3.8
-6.8 ± 3.8
1.6 ± 6.5
9.5 ± 5.7
1.3 ± 7.6
-1.5 ± 6
Heterogeneous
emphysema
19.7 ± 19.6
18.7 ± 10.6
25.5 ± 7.7
9.6 ± 11.3
Homogeneous
emphysema
-5.2 ± 4.2
4.9 ± 6.5
-9.1 ± 7.5
-6.3 ± 6.8
2.2 ± 0.1
-1.5 ± 4.3
11.8 ± 9.2
3.3 ± 4.6
Heterogeneous
emphysema
-9.5 ± 10.8
-9.1 ± 8.8
-13.1 ± 7.8
-8.6 ± 7.2
Homogeneous
emphysema
6.6 ± 3.4
2.3 ± 4.6
22.5 ± 10.5
9.2 ± 4.4
2.2 ± 3
-1.3 ± 2.1
5.8 ± 4.3
1.8 ± 2.4
Heterogeneous
emphysema
-6.7 ± 6.5
-6.3 ± 3.6
-7.9 ± 4.4
-3.4 ± 3.1
Homogeneous
emphysema
6.0 ± 2.2
0.9 ± 2.3
12.7 ± 3.3
4.9 ± 2.7
Forced vital capacity, %
All patients
Residual volume, %
All patients
Residual volume/ Total lung capacity, %
All patients
RePneu® lung volume reduction coils: November 2013
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6 minute walk test
All patients
2.5 ± 7.5
10.8 ± 8.8
2.9 ± 7.9
5.6 ± 8.5
Heterogeneous
emphysema
18.4 ± 16.4
32.3 ± 11.9
35.5 ± 1.4
31.9 ± 12.3
Homogeneous
emphysema
-3.5 ± 7.9
0.1 ± 9.5
-11.1 ± 5.2
-7.6 ± 6.4
St George’s Respiratory Questionnaire
All patients
-4.7 ± 3
-7.8 ± 3.7
-5.4 ± 4.2
-6.1 ± 4.4
Heterogeneous
emphysema
-6.4 2.5
-14.1 ± 2.8
-19.6 ± 3.8
-12.2 ± 11.8
Homogeneous
emphysema
-4.1 ± 4.1
-4.6 ± 5.1
0.7 ± 4.0
-3.4 ± 4.2
Modified Medical Research Council score
All patients
-0.5 ± 0.2
-0.5 ± 0.3
-0.6 ± 0.3
-0.2 ± 0.4
Heterogeneous
emphysema
-0.3 ± 0.3
-0.7 ± 0.3
-1.7 ± 0.3
-1.0 ± 0.6
Homogeneous
emphysema
-0.5 ± 0.3
-0.4 ± 0.4
-0.1 ± 0.3
0.2 ± 0.5
Note: all results are expressed as the mean and standard deviation
Economic evaluation
No economic evaluations of the LVRC procedure were identified.
Ongoing research
Five clinical trials (four ongoing and one completed) were identified from searches of the
ClinicalTrials.gov website and the Australian and New Zealand Clinical Trials Register (LVRC
with standard medical care for at least 12 months after treatment. The anticipated end
dates are September 2015 for primary data collection and January 2016 for study
completion.
AeriSeal
The current status of this technology is unclear. Of 10 trials listed in ClinicalTrials.gov, two
are complete,35 five have been terminated, two are “status unknown” and one has been
withdrawn.
InterVapor System
According to ClinicalTrials.gov (last verified December 2014), the international STEP-UP RCT
(NCT01719263) of InterVapor is underway at 17 sites in six countries, including four in
Australia and one in New Zealand. Sixty-nine patients with heterogeneous emphysema
(upper lobe predominance in both lungs) will be randomly assigned to either InterVapor
RePneu® lung volume reduction coils: November 2013
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plus optimal medical therapy or optimal medical therapy alone. The primary outcomes are
changes in FEV1 and SGRQ scores. Study completion is planned for June 2015 (Table 26).
Table 26
Registered clinical trials underway
Trial Identifier
Country
Study
design
Trial
status
Interventions
Outcomes
assessed
Follow
up
N
Estimated
completion
date
NCT01334307
Randomised
controlled
trial
Ongoing
LVRC
compared
with standard
care
QOL (SGRQ
questionnaire)
3
months
41
September
2013
Multicentre
randomised
controlled
trial
Recruiting
LVRC
compared
with standard
medical care
Efficacy (6minute walk test
and QOL
(SGRQ
questionnaire)
12
months
315
September
2014
Multicentre
randomised
controlled
trial
Recruiting
LVRC
compared
with medical
treatment
(Safety, efficacy,
cost
effectiveness
and QOL)
6 and
12
months
100
June 2015
Multicentre
case series
Completed
LVRC
QOL (SGRQ)
questionnaire)
6
months
67
December
2012
Multicentre
case series
Recruiting
LVRC
Efficacy
(changes in
pulmonary
function and
exercise
capacity), QOL
6
months
200
February
2015
United
Kingdom
NCT01608490
Germany,
Netherlands,
United
Kingdom, USA
NCT01822795
France
NCT01328899
France,
Germany,
Netherlands
NCT01806636
Germany
QOL: quality of life; LVRC: Lung volume reduction coil; SGRQ: St George’s Respiratory Questionnaire
No literature related to the completed trial (NCT01328899) was identified. One publication 19
and one conference abstract26, reporting the results of a single ongoing trial
(NCT01334307), were identified and have been summarised in this brief. No records of
studies comparing LVRC to lung volume reduction surgery or other minimally invasive lung
volume reduction procedures were identified. The search identified one abstract indicating
that the cost effectiveness of the LVRC procedure as compared to medical management will
be assessed in a randomised multicentre study with primary outcome measures of sixmonth improvement of the six-minute walk test (NCT01822795).27
The ongoing trials include adults with bilateral emphysema (NCT01822795 and
NCT01608490) and bilateral or unilateral emphysema (NCT01334307). One registry study
will include patients over the age of 25 years diagnosed with unilateral or bilateral nonsevere homogeneous or heterogeneous emphysema (NCT01806636).
RePneu® lung volume reduction coils: November 2013
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Zoumot et al 201226
A conference abstract reporting the preliminary medium-term follow-up data from the
clinical trial NCT01334307 was also identified. The abstract reports on a subset of patients
from the Shah et al. randomised controlled trial (RCT).19 Patients who underwent LVRC were
initially treated in one lung, with many patients undergoing treatment of the other lung one
month after the initial procedure. Patients were assessed for clinical status, lung function,
exercise capacity and quality of life and the primary endpoint was the difference between
the treatment and control groups in the SGRQ at three months post the final treatment.
After this point, patients from the control group crossed over to the LVRC treatment and it is
expected that further results will become available once all patients have completed 12
months of follow-up. The abstract reported significant changes in patients’ quality of life,
exercise capacity and pulmonary function from baseline to 12 months following treatment.
The results show a trend for best outcomes at three months post treatment that reduce in
magnitude over the 12-month follow-up, although the change was still statistically
significant.
Other issues
Only one RCT was identified; the trial enrolled only a small number of patients and
compared LVRC treatment to usual care. This study was limited by an inability to mask
patients to treatment allocation (although treatment assessors were masked), the short
observation period, and the substantial differences in important baseline indicators of
health and quality of life status that occurred despite an appropriately conducted
randomisation procedure; patients in the LVRC group were in poorer health at baseline than
the patients in the usual care group.
Given that LVRC may be offered to patients who are not suitable for lung volume reduction
surgery, the comparison to usual care is appropriate and the cost effectiveness of the LVRC
to best medical care is of relevance. However, the lack of studies comparing LVRC to other
lung volume reduction procedures means the comparative safety, efficacy and cost
effectiveness of the LVRC to other lung volume reduction procedures is unknown. No
forthcoming comparisons of this nature were identified from the search of clinical trial
registries.
In the included trials, the results generally showed improvement from baseline at follow-up
points, and in the studies by Slebos et al.3 and Shah et al.19 the number of patients
experiencing changes from baseline greater than what was considered clinically meaningful
was reported. While promising, it should be noted that the maximum follow-up period of
any of the published studies is six months after the final treatment.3 The long-term effects
of the procedure are yet to be investigated.
RePneu® lung volume reduction coils: November 2013
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In both the Slebos et al.3 and Shah et al.19 studies, approximately half of the treated patients
were considered responders; in the study by Shah et al.19, the authors do not report
whether those patients had homogeneous or heterogeneous emphysema, whilst in the
study by Slebos et al.3, all patients had heterogeneous emphysema. It has been proposed 20
that patients with heterogeneous emphysema respond better to LVRC than those with
homogeneous emphysema. Thus, there are still questions around the appropriate patient
selection for the LVRC procedure.
Although the LVRC procedure is performed bronchoscopically, it requires an inpatient stay
and patients having the procedure bilaterally will need to undergo a subsequent procedure
to complete the treatment. It should also be noted that a range of other endoscopic
interventions for emphysema are being developed that also aim to provide improved quality
of life and lung function without the potential complications of lung volume reduction
surgery.
At present, it is unknown whether placement of the device may cause further pathology to
the remaining lung tissue. Furthermore, airway obstruction by these devices may increase
infection and cause segmental bronchiectasis.
Summary of findings
The evidence on LVRC included in this technical brief consisted of one randomised
controlled trial comparing LVRC to best medical care and two small case series from the
same research group, both sponsored by PneumRx, Inc. There was no evidence available
comparing LVRCs to other lung volume reduction treatments for emphysema. Due to the
small patient numbers (73 patients in total; 50 treated with LVRC) in the included studies,
limited follow-up (6 months maximum) and imbalances in baseline SGRQ scores between
treatment groups in the randomised controlled trial, the results of the included studies
should be interpreted cautiously.
Adverse events were monitored for three (Shah et al.19; Herth et al.20) to six (Slebos et al.3)
months following treatment. Those that were reported in at least two of the studies
included COPD exacerbation, pneumothorax, chest pain and cough. The randomised
controlled trial only reported adverse events that were considered serious. Those that
occurred in the LVRC treatment group (n=23) up to three months following treatment
included COPD exacerbation (five events in four patients), lower respiratory tract infection
(two events in two patients) and pneumothorax (two events in two patients). The serious
adverse event rates did not differ significantly between the LVRC treatment group and the
usual medical care group in either the 29 days following treatment or within 30 to 90 days
following treatment.
Regarding the effectiveness of LVRCs in improving lung function and symptom control in
patients with severe emphysema, the randomised controlled trial indicated that LVRC is
RePneu® lung volume reduction coils: November 2013
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associated with a greater improvement in SGRQ scores and lung function outcomes from
baseline to 90 days compared with patients in the usual care group. In all studies, patients
experienced improvements from baseline; however, the magnitude of change varied
between patients. In the randomised controlled trial by Shah et al.19, 65 per cent of the
patients treated with LVRC were categorised as experiencing changes in SGRQ scores
greater than that considered clinically meaningful. Several patients in the usual care group
also experienced changes greater than that considered clinically meaningful.
The initial trial by Herth et al.20 was not powered to analyse efficacy. The study by Slebos et
al.3 reported that approximately 50 per cent of participants experienced improvements in
baseline greater than the minimal clinically important difference for the outcomes FEV1, sixminute walk test and SGRQ. However, patients in this trial consisted of those with only
severe heterogeneous emphysema and results were based on six months follow-up; hence,
the results are taken from a small sample of highly selected patients with relatively shortterm follow-up.
The clinical impact and durability of any functional or symptomatic improvement as a result
of the LVRC procedure is unclear. Ideally, a large, triple arm randomised clinical trial
comparing LVRC to traditional lung volume reduction surgery and standard medical care is
required to determine the clinical benefit of the procedure. Additionally, further work is
required to adequately identify patients who may benefit most from the procedure.
HealthPACT assessment
Based on an expectation that several large randomised controlled trials are nearing
completion that may add to the evidence base and clarify the long-term safety and
effectiveness profile of the LVRC procedure, it is recommended that this technology be
monitored until peer-reviewed publication of the RCTs.
Number of studies included
All evidence included for assessment in this Technology Brief has been assessed according
to the revised NHMRC levels of evidence. A document summarising these levels may be
accessed via the HealthPACT web site.
Total number of studies 3
Total number of Level II studies 1
Total number of Level IV studies 2
Search criteria to be used (MeSH terms)
Emphysema/therapy*
RePneu® lung volume reduction coils: November 2013
20
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