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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 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/au/deed.en. For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Healthcare Improvement Unit, Clinical Excellence Division Department of Health, Queensland Level 2, 15 Butterfield St HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD 4001 Email: [email protected] Telephone: +61 7 3328 9180 For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, email [email protected], phone (07) 3328 9824. Electronic copies can be obtained from: http://www.health.qld.gov.au/healthpact 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 guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. 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 (MSAC). It is a sub-committee of the Australian Health Ministers’ Advisory Council (AHMAC), reporting to AHMAC’s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. 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. 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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 10 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. RePneu® lung volume reduction coils: November 2013 11 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 12 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 13 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 14 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 15 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 16 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 17 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 18 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 19 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 References 1. Gasparini S, Zuccatosta L, Bonifazi M& Bolliger C T. Bronchoscopic treatment of emphysema: state of the art. Respiration 2012; 84(3): 250-63. 2. PneumRx Inc. (2013). RePneu® Lung volume reduction coil. Available from: http://www.pneumrx.com/products-technology/ [Accessed 12 Aug 2013]. 3. Slebos D J, Klooster K, Ernst A, Herth F J& Kerstjens H A. Bronchoscopic lung volume reduction coil treatment of patients with severe heterogeneous emphysema. Chest 2012; 142(3): 574-82. 4. PneumRx Inc. (2012). PneumRx, Inc. Receives FDA Approval to Commence Pivotal Clinical Trial of RePneu Lung Volume Reduction System. 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