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PARIS -- Use of targeted lung denervation (TLD) on top of a long-acting bronchodilator in moderate-to-severe chronic obstructive pulmonary disease (COPD) cut respiratory-related events by more than half, the sham-controlled AIRFLOW-2 trial found.

Between 3 and 6.5 months, 32% of patients randomized to TLD plus tiotropium had respiratory adverse events (AEs) compared with 71% of those getting sham procedure along with the drug (P=0.0008), reported Dirk-Jan Slebos, MD, PhD, of the University Medical Center Groningen in the Netherlands.

Events leading up to month 3 were not counted so as to exclude bronchoscopy-related events.

The study also found that while there was not a significant difference in all COPD exacerbations between the two arms in the first year of study, severe exacerbations requiring hospitalization were reduced in the TLD arm (P=0.039), suggesting the treatment could have cost-effectiveness benefits, according to data presented here at the European Respiratory Society (ERS) congress.

"The sham group at 1 year behaved a little bit like the year before, around 25% to 30% of those patients needed to be hospitalized again," said Slebos. "But the treatment group had a really big decrease in the occurrence of these events."

Numerically, efficacy and quality-of-life endpoints at 6 and 12 months mostly favored TLD over sham, but the trial was very much underpowered to detect significance, according to the investigator.

Modified Medical Research Council (mMRC) dyspnea scale:

• -0.47 with TLD versus -0.26 with sham at 6 months
• -0.46 versus -0.21 at 12 months, respectively

St. George's Respiratory Questionnaire COPD score:

• -8.31 versus -3.76 at 6 months
• -5.30 versus -2.50 at 12 months

Forced expiratory volume in 1 second (FEV₁) appeared better with TLD at the 6-month mark (128 mL versus 86 mL), but this advantage was no longer seen at 12 months (78 mL versus 104 mL). Forced vital capacity (FVC) favored TLD at both time points: 253 versus 147 at 6 months and 253 versus 211 at 12 months.

Using a cooled balloon catheter and either flexible and rigid bronchoscopes, TLD targets the parasympathetic nervous system and deactivates pulmonary nerve reflexes. This relaxes smooth muscles, decreases secretion of mucus, eases airway hyper-responsiveness, and reduces exacerbations, according to Slebos.

"The mechanism of action, that we're actually ablating these nerves, is really confirmed by the outcomes we see and the strong exacerbation reduction signal," said Slebos. "The post-hoc responder rate suggest superior outcomes in really highly symptomatic patients, so we really should treat that patient group."

ERS president-elect Tobias Welte, MD, who was not involved in the research, said he viewed this as a "step-up approach" that could play a role following first-line use of pharmaceutical treatments and non-pharmaceutical management (smoking cessation, vaccination, exercise training) for patients with uncontrolled or progressive disease. "I think this is how it should be placed," he said.

Slebos agreed, noting that the highly symptomatic patients in the trial fulfilled those criteria. A larger phase III trial is planned to test TLD, with COPD exacerbations as the primary outcome.

The double-blind study randomized 82 COPD patients at 16 sites in Europe to either sham treatment (n=41) or active treatment with TLD (n=41). Prespecified respiratory AEs included COPD exacerbation, influenza, respiratory failure or infection, pneumonia, tachypnea, wheezing, airway defects requiring intervention, and worsening bronchitis or dyspnea.

Most of the respiratory events in each arm were COPD exacerbations, followed by dyspnea, pneumonia, bronchitis, and others.

Serious AEs occurred in 17 TLD patients versus 16 sham patients, respiratory events occurred in 6 versus 15, respectively, and gastrointestinal (GI) events occurred in 6 versus 2. GI events in the TLD arm included impaired gastric emptying in three patients, and abdominal pain, GERD, dysphagia in one patient each. Adjustments had been made from an earlier TLD trial to reduce potential damage to the esophagus, which greatly reduced GI events, said Slebos.

No therapeutic interventions were required for events related to TLD treatment, and no deaths occurred in either study arm.

Patients included in the trial had mMRC dyspnea scale grade ≥2 or CAT score ≥10, had post-bronchodilator FEV₁ of 30% to 60%, post-bronchodilator FEV₁/FVC <70%, and were required to have ceased smoking at least 4 months prior to the study and to stay on tiotropium for the duration of the study.

Exclusion criteria included those with active respiratory infections or prior abdominal surgeries, those with a gastric symptom questionnaire score ≥18, and a body mass index (BMI) of <18 or >33 for men and >34 for women.

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