Fig. 35.5  Endobronchial valves (IBV) in the right upper lobe 3 years after deployment

expected, serious adverse events were more common in the treatment group (14.1%) compared with the control group (3.7%), although most were neither procedure nor device related (Fig. 35.5). The disappointing results of the bilateral approach avoiding lobar collapse coupled with demonstrable improvements by responders with intact fssures treated with the lobar occlusion method have rendered the strategy used in the Spiration trials obsolete. Interestingly, a pilot trial seeking lobar occlusion found signifcant improvements in lung function and more impressive reductions in SGRQ scores in patients who achieved atelectasis with the IBV system [27]. The risks associated with this complication motivated the subsequent change

in treatment strategy. However, it is clear from the available evidence that while avoiding atelectasis improves safety, it does so at the expense of effcacy. The randomized EMPROVE study explored the effcacy of the IBV system using the unilateral complete occlusion approach in 172 patients with severe heterogeneous emphysema, intact fssures, and hyperin ation. Nearly 37% of those treated were considered responders with an improvement in FEV1 ≥ 15%. Six deaths were reported in the treatment arm, but only one in the standard care arm, and a 12.4% incidence of pneumothorax was also reported after valve treatment [28].

One of the most striking fndings of the initial Spiration trials was the impressive magnitude of the placebo effect. Many patients undergoing sham bronchoscopy reported signifcant benefts in quality of life. Such fndings match results from a bronchial thermoplasty trial employing sham bronchoscopy [29]. Clearly, the placebo effect has a signifcant impact in device-related interventions and should be taken into account in trials using soft endpoints such as quality of life as the primary outcome.

Airway Bypass Tracts

While most ELVR techniques are designed to promote lung volume reduction by limiting ow to the most affected region of lung parenchyma,

Broncus (Mountain View, CA) developed a technique which reduces air trapping by promoting non-anatomic collateral ow. This method of ELVR known as the Exhale™ emphysema treatment system shunned atelectasis, currently an essential goal of valve treatment, striving instead to create airway fenestrations in order to facilitate exhalation of trapped air. A Doppler system was used in order to avoid damaging major vessels and select the appropriate site for stent deployment using a needle. This approach reduced end­ -­expiratory volume without altering lung recoil and could be tested in patients with both homogeneous and heterogeneous emphysema.

Preliminary evidence treating explanted lungs was quite encouraging. Improvements in FEV1 following deployment of multiple stents in one small study of 12 explanted lungs were dramatic [30]. Outcomes in vivo, however, were frustrating, mostly as a consequence of stent occlusion by granulation tissue. Drug-eluting stents have been created to avoid this complication and seem to work in animal studies, prolonging patency [31]. An open label study of the drug-eluting stents showed that the Exhale™ system can reduce hyperin ation for a limited time in a selected group of patients with severe emphysema [32]. Unfortunately, while results at 1 month were impressive including improvements in FEV1, quality of life, and total lung capacity in more than 30 treated patients, results at 6 months were less encouraging. Post-­ procedure complications including COPD exacerbations were relatively frequent, and one patient died as a consequence of massive hemoptysis induced by stent implantation.

The Exhale™ system was used in a multicenter randomized, sham-bronchoscopy controlled trial known as EASE (Exhale Airway Stents for Emphysema) [33]. Three hundred and ffteen patients with severe hyperin ation defned as a ratio of residual volume to total lung capacity of ≥0.65 from 38 centers worldwide were enrolled. Patients were followed for 12 months. Treated patients did not achieve the co-primary endpoints of a 12% improvement in FVC and 1 point improvement in the mMRC dyspnea score when compared to controls, though the latter did

show a statistically signifcant improvement. Only 30 out of 208 treated patients met the co-­ primary endpoint, although a considerable mean reduction in residual volume averaging 0.5 L was achieved in 40% of the treated patients. This fnding predicted clinical success. The 6-month composite primary safety endpoint combining 5 severe adverse events was 14.4% for the treatment arm which compared favorably with 11.2% for the control group and was judged non-­inferior. This ELVR technique is currently not available in the US or Europe [34].

Biologic/Polymer Lung Volume

Reduction

Biologic lung volume reduction, unlike its predecessors, was not device based. This method of ELVR, developed by Aeris Therapeutics (Woburn, MA), sought to achieve its goals employing tissue engineering principles [35]. Remodeling of damaged lung parenchyma by the next generation polymer-based treatment created progressive atelectasis in treated subsegments of the upper lobes thus promoting true lung volume reduction (Figs. 35.6 and 35.7). The ability of the polymer to spread through the airway limited the impact of collateral ventilation, a major concern with endobronchial valves. Treatment was found to be irreversible and frequently associated with considerable, though relatively brief, in ammation which mandated prophylactic treatment with steroids and antibiotics, akin to a COPD exacerbation in most treated patients. A preliminary small open label phase I trial showed the treatment to be safe and moderately effective in a small group of patients [36]. Results from a phase 2 clinical trial enrolling 50 patients were subsequently reported [37]. High dose therapy was effective in that trial and yielded sustained benefts, but COPD exacerbations were frequent, occurring in 28% of treated patients. A subsequent trial enrolling patients with homogeneous emphysema also showed beneft with high dose treatment and had a similar safety profle [38]. Evidence from three separate clinical trials demonstrated the beneft of polymer treatment inde-

Fig. 35.6  Before (a) and after (b) coronal CT images of a patient with heterogenous upper-lobe predominant emphysema treated with AeriSeal. The patient’s FEV1

improved by 69%, his SGRQ score diminished by 8.3 units, and the RV/TLC ratio dropped by 9% (courtesy of Dr. Ingenito)

Fig. 35.7  Before (a) and after (b) coronal CT images of a patient with homogenous emphysema treated with AeriSeal. The patient’s FEV1 improved by 29%, his

SGRQ score diminished by 8.5 units, and the RV/TLC ratio dropped by 8% (courtesy of Dr. Ingenito)

Fig. 35.8  Chest x rays of a patient with upper lobe predominant emphysema and collateral ventilation treated with AeriSeal, immediately following ELVR (a) and after

3 years of follow up (b). Radiographic changes persist and evolve overt time complicating radiographic surveillance

pendent of fssure integrity, rendering it a promising option for ELVR in patients with signifcant collateral ventilation [39]. A prospective multicenter randomized trial of polymer induced lung volume reduction known as the ASPIRE trial was initiated, but terminated prematurely for lack of funding. Ninety-fve patients had been randomized prior to study termination. FEV1, dyspnea scores, and quality of life showed improvements at 3 months following treatment. The beneft was sustained at 6 months, but unfortunately 44% of treated patients required hospitalization and 2 deaths were reported (p = 0.01) [40]. The premature termination of the study was a blow to the technique, but following the acquisition of Aeris Therapeutics by Pulmonx, AeriSeal® received CE Mark approval at the end of 2015 (Fig. 35.8). A subsequent trial known as the AeriSeal-STAGE Trial demonstrated signifcant volume reduction on computed tomography, but a lack of clinical beneft of administering a much lower dose and staged delivery of AeriSeal (NCT02877459). Future-intended uses of the AeriSeal system include sequential treatment for patients with collateral ventilation using the

AeriSeal system to eliminate collateral ventilation prior to valve treatment in the aptly named CONVERT prospective trial.

Coils

Nitinol self-actuating reduction coils (PneumRx Inc.; Mountain View, CA) have been developed as an alternative method of ELVR. Nitinol’s shape memory is ideally suited for this application since it facilitates deployment of the coils using a small caliber catheter (Fig. 35.9). Once deployed, the coils recover their pre-formed shape, retracting the surrounding lung tissue and therefore reducing lung volumes. Initial reports demonstrated the feasibility and relative safety of the procedure [41, 42]. The RESET trial, a randomized controlled trial enrolling 47 patients, reported coil-related statistically signifcant improvements in quality of life [43]. A subsequent multicenter trial enrolling 60 patients confrmed sustained beneft at 1 year following ELVR with coils [44]. The treatment strategy was bilateral in most patients deploying

Fig. 35.9  Chest radiograph of a patient treated with the PneumRx coils (a). The coil in more detail (b)

a

b

a median of 10 coils per treated lobe. Serious adverse events were common, however, occurring in 18 patients (30%) including COPD exacerbations, pneumonia, pneumothorax, and hemoptysis (Fig. 35.10). Clinically relevant improvements in SGRQ scores (−11.1 ± 13.3 points) and 6 min walk tests (+51.4 ± 76 m) were observed at 12 months. Lung function improvement was not as impressive with FEV1 improving marginally at 1 year (+0.11 ± 0.30 L) despite an impressive reduction in residual volumes (−0.71 ± 0.81 L).

Evidence from two randomized controlled trials is available. The REVOLENS trial reported a 36% responder rate for patients treated with coils based on changes in 6 min walk distance as compared to an 18% responder rate in the usual care group (P = 0.03) [45]. However, no difference in FEV1 was found comparing both groups and only a slight difference in quality of life, which accounted for a disappointing cost-effectiveness

assessment of $782,598 per additional quality-­ adjusted life-year. The RENEW trial enrolled 315 volunteers, including two-thirds of patients with homogeneous emphysema [46]. Those treated with coils showed a statistically signifcant though clinically underwhelming improvement of 10 m in the 6 min walk test (6MWT) at 12 months when compared to a control group. Clinically meaningful improvements in SGRQ scores and lung function were reported. The authors concluded that the use of endobronchial coils compared with usual care achieved only a modest improvement in median exercise tolerance with a higher likelihood of major complications. A post-hoc analysis of the RENEW data found that a residual volume ≥ 200% predicted and CT analysis are critical for successful endobronchial coil therapy. CT analysis can exclude patients who are unlikely to beneft with less severe emphysema, while identifying those with worse outcomes [47].