gms | German Medical Science

In German hospitals the incidence of treating lung emphysema was two cases per 100,000 inhabitants in 2011 (age standardised). In total 2,416 patients were classified as being affected by a lung emphysema. Patients with lung emphysema are often not visible in routine data because they are usually listed as patients with a chronic obstructive pulmonary disease (COPD). Consequently, the incidence of COPD treatment is considerably higher (182 cases per 100,000 inhabitants in 2011). Based on estimations it can be assumed that currently 1,000,000 persons in Germany suffer from lung emphysema. Especially smokers over the age of 50 are affected. In 2011 1,257 deaths have been attributed to lung emphysema and 26,018 to COPD. This corresponds to the fifth most common cause of death in Germany.

The costs of a lung volume reduction (LVR) depend on the selected surgical or minimally invasive method. The reimbursement of an LVR is regulated in the German Entgeltkatalog (reimbursement catalogue) for diagnosis-related groups (DRG) for inpatient services. The LVR using endobronchial valves is the only minimally invasive endoscopic LVR that is regulated by the DRG-catalogue. Other minimally invasive techniques are currently not included in the catalogue, but hospitals can apply for reimbursement.

Lung emphysema is a chronic, progressive and irreversible destruction of the lung tissue with a hyperinflation of the alveoli distal to the bronchioli terminales. The development of a lung emphysema is influenced by endogenous (e.g. shortage of protease inhibitors, increased protease activity) and exogenous factors (e.g. tobacco smoking). The most common cause of lung emphysema is COPD, which is primarily caused by tobacco smoking and to a lesser extent by gases and vapours. Furthermore, a genetic disposition is supposed to play a role in the development of lung emphysema. In case of a suspect of lung emphysema, various pulmonary function tests are conducted to assess the condition of the lung. A high-resolution computer tomography of the lung is crucial in order to characterise the emphysema and to identify an adequate treatment strategy. Possible treatment methods for severe emphysema are non-medical therapies (e.g. tobacco smoking cessation, pulmonary rehabilitation, physiotherapy), the well-established medical treatment, as well as surgical and minimally invasive methods for LVR, such as valves, coils or hydrogel sealants. Minimally invasive methods to reduce a hyperinflated lung are continuously gaining relevance as they can avoid the complete opening of the thorax.

Lung emphysema has considerable impact on the everyday and occupational life of the patients and their social surroundings. Supporting services as well as financial and in kind services, depending on the severity of the limitations, are defined by legislation and can be claimed before and after a lung volume reduction surgery. The patient selection for a LVR is especially sensitive as the surgery is a palliative treatment for severely ill patients.

This report aims to assess the effectiveness and the costs of minimally invasive lung volume reduction surgery and discusses associated legal and ethical aspects. The following research questions are considered:

1.

What is the effectiveness of minimally invasive procedures compared to other forms of LVR in patients with emphysema?

2.

What is the cost-effectiveness of minimally invasive procedures compared to other forms of LVR in patients with emphysema?

3.

What are the legal entitlements of patients after a LVR procedure in Germany?

4.

Are there any ethical aspects that have to be considered when selecting suitable emphysema patients?

5.

Are there any further legal or ethical aspects that have to be considered when conducting a minimally invasive LVR compared to other forms of LVR?

A systematic literature search in 34 international databases (e.g. MEDLINE and EMBASE) is conducted by linking different search terms, e.g. regarding different methods of LVR, the disease (lung emphysema), economics, study types as well as ethics and law. German and English publications are considered. No limitations are defined with respect to the year of publication. Additionally, the internet and the reference lists of the identified studies are searched systematically for relevant literature. The screening and selection of the abstracts and full texts are based on criteria defined ex ante. External and internal validity of the selected studies are assessed and presented according to a predefined set of criteria. In case of a lack of studies with high evidence grade, studies with a lower evidence grade are regarded. The quality of the studies regarding legal and ethical aspects is not assessed systematically.

Based on the systematic literature search 2,257 abstracts are delivered. After the selection of relevant abstracts according to predefined selection criteria 182 full texts are ordered, of which 172 are available. Following the initial search an updated systematic search is conducted and 190 additional abstracts are delivered. From the screened abstracts 27 studies are considered relevant of which 23 full texts are available. The additional, systematic internet search adds 59 relevant publications.

After selection of the full texts, twelve publications are identified to answer the medical research question, five to assess the economic aspects and 27 to address the legal and ethical aspects.

The available evidence (two randomized controlled multi-centre trials, RCT) shows that the use of unilateral endobronchial valves versus standard medical care achieves better results for the endpoints forced expiratory volume (FEV₁), physical ability measured by cycle ergometry, and self-assessed quality of life for patients with valve implantation (six and twelve months after intervention). The strength of evidence of these results is moderate. The effect on the six-minute walking test is unclear, as the study reports have contradicting results. The evidence strength for this endpoint is graded as low. One of the multi-center-RCT reports more favourable results regarding subjective dyspnoea after six months among patients undergoing LVR by endobronchial valves. The strength of evidence for this endpoint is graded as moderate. Study results regarding complications of endobronchial-valve therapy versus standard medical care are inconsistent and the grad of evidence is low. Contradictory results occur in patients with heterogenous emphysema, as patients with heterogenous emphysema benefit more from implantation of endobronchial valves in one trial, whereas in the other trial the heterogeneity does not influence the results considerably. This aspect has to be clarified in further trials. In conclusion, the bronchoscopic unilateral insertion of endobronchial valves is a safe treatment option, but the patient relevant added-value cannot be shown unambiguously as the results of the trials are contradictory.

One RCT comparing bronchoscopy with bilateral placement of valves in the upper lobe of the lung versus bronchoscopy without valve placement showed no significant differences regarding the lung function parameters (FEV₁ and total lung capacity), diffusion capacity of the lung for carbon monoxide, carbon dioxide tension, dyspnoea, complications, self-assessed quality of life, health status and physical capacity (six-minute walking test) three months after the intervention. The evidence shows benefits of the valve implantation regarding oxygen tension, but disadvantages regarding residual volume, the ratio of the residual volume and the total lung capacity after three months. The strength of evidence is graded as moderate. In conclusion, bronchoscopy with bilateral implantation of valves in the upper lobe does not involve a higher risk than a bronchoscopy without implantation of valves. Neither does it however show any significant effects for the majority of the study population on the reported endpoints of the trial.

The available evidence (one RCT) on bronchoscopy with bilateral insertion of transbronchial stents (airway bypass) in the upper and lower lobe of the lung in patients with severe homogeneous emphysema does not give sufficient proof of positive medium- and long-term effects. If and how the observed results are a direct outcome of the intervention is unclear, as from one day after the surgery until six months after, the majority of the patients expectorated the stents, and the inserted stents lost their patency. Further research should aim to increase the durability and the retention period of the stents.

No sufficient evidence is available to evaluate the efficacy and safety of bronchoscopic thermal vapour ablation. Results from one uncontrolled intervention study show an improvement in FEV₁, residual volume, six-minute walking test, self-assessed quality of life and subjective dyspnoea after six and twelve months. However, due to the missing control group, evidence is graded as low. Regarding the safety of the procedure, severe complications (mainly COPD exacerbations, pneumonia, acute respiratory disease, dyspnoea and cardiac insufficiency) occurred in about half of the patients within one year following the intervention. The strength of evidence for these safety endpoints is low as well.

Available evidence (one RCT and two prospective controlled intervention studies) does not show significant differences in the endpoints of length of surgery, complications, post-surgery pain, length of stay in intensive care unit, mortality after one and three months, need for mechanical ventilation after one month, FEV₁ after 24 months, living independently after four, twelve and 24 months and six-minute walking test after twelve and 24 months when comparing video-assisted thoracoscopic surgery (VATS) with median sternotomy (MS). VATS is associated with benefits regarding the endpoints hospital length of stay and living independently one month after the surgery. However, after twelve months the MS shows benefits regarding the endpoints need to reoperate for air leaks, hypoxemia and FEV₁. The strength of evidence of the above mentioned endpoints is graded as moderate. In conclusion, safety and efficacy of video-assisted thoracoscopic surgery (VATS) and MS in bilateral severe emphysema patients are similar. No general advantage of one method over the other can be reported based on the investigated endpoints as the intervention effects of both methods are heterogeneous.

The effectiveness of a staged thoracoscopy (two separately conducted VATS) regarding the endpoints FEV₁, residual volume, six-minute walking test, oxygen partial pressure (pO₂), diffusion capacity of the lung for carbon monoxide was not higher than that of a single bilateral LVR by MS. The same holds for the complications (mortality, air leaks, pneumonia, pneumothorax, need for ventilation) one year after the intervention. The evidence grade is regarded as low. Based on the identified literature, no relevant benefit of a staged VATS compared to a single bilateral LVR can be reported.

The interventions LVR using an endoscopic stapler (without resection of lung tissue) and LVR with resection of lung tissues (standard procedure) show similar effects on FEV₁, six-minute walking test and subjective dyspnoea as well as prevalence of air leaks lasting more than seven days and two-year-survival rate in a non-randomized, controlled intervention study. The non-resectional method shortens the length of the surgery, of the anesthesia and of the hospital stay. The evidence grade for all endpoints is rated as low. Only one study on LVR with application of an endoscopic stapler without resection exists which shows no benefits compared to an LVR with resection. Hence, there is a need for further research on this subject.

The available evidence (one RCT) on unilateral VATS using a laser to shrink the lung tissue versus unilateral VATS with resection of the lung tissue followed by stapling in patients with diffuse emphysema shows benefits of the former technique for the endpoints dyspnoea, need for oxygen and life quality after six months. The latter technique is associated with greater improvements in lung function parameters (FEV₁, forced vital capacity [FVC]) and delayed pneumothorax after four and six months. The strength of evidence is rated as moderate. No difference can be detected regarding operating time, hospital stay, air leaks persisting more than seven days, respiratory failure or deaths during the hospital stay. However, the evidence grade for these endpoints is low. Until now, the comparative effects of unilateral VATS using a laser to shrink the lung tissue and unilateral VATS with resection of the lung tissue followed by stapling have not been investigated in many studies. Direct comparison shows no clear benefit of one technique over the other. Furthermore, the complications that might occur are still undetermined.

No full economic evaluations answering the economic research question on the cost-effectiveness of methods for LVR have been published. The included studies only mention the costs of different minimally invasive LVR procedures briefly but no in-depth analysis is provided. These studies mention that the cost of an endobronchial one-way valve lies between 2,200 and 5,000 Euro. The costs of a minimally invasive endoscopic procedure in general (one-way valves, hydrogel vapour, and transbronchial stents) are estimated to range from 12,000 to 20,000 US-Dollar (around 8,800 to 14,700 Euro) per operation.

Depending on the grade of disability and/or need for care after a LVR patients are entitled to rehabilitation measures, financial benefits (sickness benefits, support sickness benefits, transitional allowance, travel allowance, reimbursement for domestic help and child care, long term care allowance) as well as benefits in kind such as extended home care.

Possible ethical considerations regarding patient selection arise from the findings of a large-scale clinical trial that shows that surgical LVR (MS and VATS) is especially effective in patients with predominantly upper lobe emphysema and low preoperative physical capability (compared to medical therapy). Based on this, a surgical LVR is mainly recommended for this patient group. A clinical trial on minimally invasive endoscopic LVR for this patient group might be ethically questionable under the assumption that a minimally invasive procedure is less risky and at least as effective as the surgical LVR. This concern is based on the need for clinical and societal equipoise when conducting a clinical trial; this means that there must be clinical and societal uncertainty about the superiority of one intervention over the other to justify a clinical trial.

Further legal and ethical aspects of minimally invasive interventions compared to other methods of LVR that should be regarded are: the duty of the physician to inform the patient, informed consent, and the issue of smoking cessation.

Currently various methods are used for LVR without an established gold standard of treatment. Further research to improve and optimise patient selection is needed in order to achieve broader effectiveness. As there is no standardised method for LVR, it should also be investigated to what extent the experience of the surgeon and/or the surgical team affects the intervention outcomes. This HTA-report could not identify relevant studies on LVR using coils or hydrogel vapour that fulfilled the inclusion criteria. Hence, there is need for further research on these two techniques.

Complete cost-effectiveness studies are to be expected only after the clinical effectiveness of minimally invasive endoscopic methods for LVR is proven. To estimate the costs and effects of minimally invasive LVR over a longer period of time, health economic modelling is necessary. Based on the currently available data on the long-term effects of the intervention these estimations are subject to great parameter uncertainty, which would lead to a low robustness of the results.

Based on the identified and included evidence no clear benefit of minimally invasive methods (VATS, valves, stents, vapour ablation) compared to surgical methods (MS) can be demonstrated. However, it should be noted that appropriate studies have only been available for the comparison of VATS (minimally invasive, surgical LVR) and MS (surgical LVR). In order to thoroughly assess the relative effectiveness and safety of different methods for LVR among patients with lung emphysema direct comparative studies are necessary.

It should be noted, that patients – depending on their disease pattern and the localisation of the emphysema – are not always suitable for all different kinds of LVR. It is possible that patients who were not considered suitable for surgical LVR might be treated with minimally invasive endoscopic methods.

Further research is needed to ascertain which intervention for LVR (surgical, minimally invasive surgical or minimally invasive endoscopic LVR) is most effective for which disease pattern (heterogeneous, homogeneous, diffuse emphysema) taking into account the localisation of the emphysema (uni- and bilateral, upper- and lower-lobe) and other patient characteristics. Current trials show promising results for minimally invasive methods, if the right patient group is selected (responders versus non-responders).

The economic evidence on minimally invasive endoscopic interventions for LVR is qualitatively and quantitatively insufficient. So far, there is a complete lack of health economic models that could depict the long-term costs and effects of these interventions.

The authors declare that they have no competing interests.