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Arschang Valipour, MD, on Targeted Lung Denervation for Patients With COPD

Targeted lung denervation (TLD) plus optimal pharmacotherapy reduces respiratory adverse events among symptomatic patients with chronic obstructive pulmonary disease (COPD), according to results from the AIRFLOW-2 trial.1

TLD is a minimally invasive procedure for treating COPD in which a bronchoscope is used to complete circumferential ablation of the mainstream bronchus.

The research team was led by Arschang Valipour, MD, who is director of the Karl-Landsteiner Institute for Lung Research Oncology in Vienna, Austria.

Pulmonology Consultant caught up with Dr Valipour to find out more about his team’s research.

PULM CON: For your study, you and your colleagues aimed to better understand the safety and impact of TLD on respiratory adverse events. Can you tell us about your findings? How did TLD affect COPD outcomes?

Arschang Valipour: The AIRFLOW trial2 was an extended safety trial that evaluated energy dose through a comparative and a confirmatory phase in 46 patients. We learned that energy could be safely and reliably delivered to the lungs, and we also evaluated procedure modifications that improved the safety profile further. One-year follow-up data were published in 2018, and in 2020, we anticipate publication of 3-year follow-up in these patients, demonstrating longer-term safety, which is very important for any novel therapy. We then enrolled 82 patients in a randomized, sham-controlled, double-blinded trial to confirm the safety results under tightly controlled protocol. Patients were randomly assigned to a sham bronchoscopy or to TLD bronchoscopic treatment. Both the patients and their follow-up study teams remained blinded to their cohort allocation for a full year. We found a striking reduction in the risk of COPD exacerbations requiring hospitalization in patients with TLD vs patients in the sham group, which was statistically significant despite the small study size. Importantly, these were patients already on optimal medical management at trial inclusion, with more than 95% of participants taking dual or triple therapy. This observation cannot be explained by baseline differences or prior exacerbation history, and we believe this is a true treatment effect that is now being evaluated in the AIRFLOW-3 trial.

PULM CON: Do you think duration of treatment impacted COPD outcomes? That is to say, do you think longer-term use of TLD beyond 12.5 months would further reduce exacerbations requiring hospitalization?

AV: Exacerbations are seminal events in the lives of patients with COPD. COPD exacerbations worsen clinical prognosis and are linked to increased risk of mortality, as well as to increased risk of major cardiovascular events such as acute myocardial infarction and stroke. The strongest predictor of a future acute exacerbation of COPD is history of prior events, and mortality risk associated with severe COPD exacerbation drops by nearly 4-fold if a subsequent hospitalization is delayed by even a year. Therefore, reducing or delaying COPD exacerbations, especially severe events, has the extraordinary potential to alter disease trajectory. I believe we will be able to show longer-term positive impact of TLD in the two-year follow-up of AIRFLOW-2, expected later this year.

PULM CON: What knowledge gaps related to TLD still exist?

AV: As with any permanent intervention, we must carefully evaluate longer-term safety data and ensure that trial design will provide confidence in study results. We are also still learning about the dose-response effects of lung denervation, and the trade-offs between more conservative treatment strategies and potential therapeutic effects. Finally, we do not fully understand the mechanisms of action of bronchoscopic lung denervation and are exploring potential mechanisms in hypothesis-generating AIRFLOW substudies. There are no biomarkers that could plausibly define best responders to TLD, and we are currently studying TLD impact in the “at-risk” COPD population defined by exacerbation history and persistent symptom burden. We hope these substudies provide direction toward additional populations who may benefit from TLD treatment.

PULM CON: What is the clinical take-home message from your study?

AV: Despite advances in pharmacologic therapies targeting reduction in COPD exacerbations, there remains a large population of patients with persistent symptoms and exacerbation history who remain at-risk for future events. Bronchoscopic lung denervation is a logical therapeutic concept that represents a potential breakthrough in our ability to durably mitigate exacerbation risk independent of the challenges of patient compliance. Encouraging data in a well-designed, well-executed, randomized, and sham-controlled trial has provided evidence of TLD safety and potential clinical impact. If successful, the AIRFLOW-3 trial will confirm that targeted lung denervation can reduce moderate to severe exacerbations among patients with COPD and will address a large unmet medical need.

Reference:

  1. Slebos DJ, Shah PL, Herth FJF, et al; AIRFLOW-2 Study Group. Safety and adverse events after targeted lung denervation for symptomatic moderate to severe chronic obstructive pulmonary disease (AIRFLOW): a multicenter randomized controlled clinical trial. Am J Respir Crit Care Med. 2019;200(12):1477-1486. https://doi.org/10.1164/rccm.201903-0624oc.
  2. Targeted Lung Denervation for Patients With Moderate to Severe COPD (AIRFLOW). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02058459. Accessed January 22, 2020. ClinicalTrials.gov Identifier: NCT02058459.