Bronchial thermoplasty: A new treatment for severe refractory asthma

A pilot study in mild to moderate asthma

Cox et al¹⁷ performed the first study of bronchial thermoplasty in patients with mild to moderate asthma. This was a prospective observational study in 16 patients who were younger than the patients in the previous study, with an average age of 30 years (range 24–58). They were given prednisone 30 or 50 mg the day before the procedure and on the day of the procedure. Three treatments were done, 3 weeks apart. The right middle lobe was not treated because the bronchus leading to it is relatively long and narrow, raising concern about damaging it.¹⁸

Results. The most frequent side effects were symptoms of airway irritation such as cough, dyspnea, wheezing, and bronchospasm. The mean time to onset was less than 1.7 days, and the mean time to resolution was 4.6 days after the most recent procedure. None of the patients needed to be hospitalized in the immediate postprocedure period.

In the 2 years after the procedure, there were 312 adverse events, mainly mild. Three (1%) of the adverse events were reported as severe, but they were deemed not related to the procedure. Yearly computed tomographic scans of the chest showed no structural changes such as bronchiectasis in the parenchyma or bronchial wall.

The FEV₁ was higher at 12 weeks and at 1 year after thermoplasty than at baseline but was not significantly different from baseline at 2 years.

At baseline, the patients reported that 50% of their days were symptom-free; this increased to 73% at 12 weeks (P = .015).

In addition, airway hyperresponsiveness decreased significantly, and the effect persisted over 2 years. The provocative concentration of methacholine that caused a 20% reduction in FEV₁ (the PC₂₀) was:

• 0.92 mg/mL at baseline (95% confidence interval 0.42–1.99)
• 4.75 mg/mL at 12 weeks (2.51–8.85)
• 5.45 mg/mL at 1 year (1.54–19.32)
• 3.40 mg/mL at 2 years (1.35–8.52).

Limitations of this study include the relatively small number of patients enrolled and their relatively stable asthma.

The AIR trial: A randomized trial in moderate or persistent asthma

The first large multicenter trial of bronchial thermoplasty, the Asthma Intervention Research (AIR) trial,⁴ was prospective and randomized but not blinded. The aim was to determine whether bronchial thermoplasty would improve asthma control after long-acting beta agonists were discontinued.

Patients could be enrolled if they were 18 to 65 years old, had moderate or persistent asthma, and needed to take an inhaled corticosteroid (beclomethasone [Qvar] 200 μg or more or an equivalent drug) and a long-acting beta agonist (salmeterol [Serevent] 100 μg or more or an equivalent drug) every day. They also needed to have FEV₁ values of 60% to 85% of predicted and airway reactivity (PC₂₀ < 8 mg/mL), and their asthma had to have been stable for 6 weeks.

At baseline, the long-acting beta agonist was withdrawn temporarily; the final criterion for entry was that their asthma had to become worse when this was done.

Then, 112 patients were randomized to receive either bronchial thermoplasty with medical care (inhaled corticosteroids and long-acting beta agonists) or usual care, ie, medical therapy alone. Treatments were done in three sessions over 9 weeks, followed by attempts to discontinue their long-acting beta agonists at 3, 6, and 9 months after the procedure without exacerbations.

An exacerbation was defined as at least one of the following for 2 consecutive days: a reduction of peak flow by 20% of baseline average, the need for more than three additional puffs of rescue inhaler, or nocturnal awakenings caused by asthma symptoms. The patients kept a daily diary of their symptoms and rescue inhaler use, and they completed the Asthma Quality of Life Questionnaire (AQLQ) and the Asthma Control Questionnaire (ACQ).

Results. The number of mild (but not severe) exacerbations per week was significantly lower at 3 and 12 months than at baseline in the thermoplasty group, with 10 fewer mild exacerbations per patient per year, but was unchanged in the control group. There were significantly greater improvements in morning peak flow at 3, 6, and 12 months from baseline in the treatment group than in the usual-care group. Rescue medication use was also significantly less at 3 and 12 months. Symptom scores, AQLQ scores, and ACQ scores were all significantly better than at baseline as well.

Not surprisingly, in this cohort with unstable asthma, there were 407 adverse events in the treatment group and 106 adverse events in the control group. Most of these occurred within 1 day and resolved within 7 days after the procedure. There were more hospitalizations in the treatment group as well, for reasons that included exacerbations of asthma, collapse of the left lower lobe, and pleurisy.⁴

Therefore, this trial found that thermoplasty improved asthma symptoms within 3 months and that the effect lasted 1 year, with an encouraging reduction in the number of mild exacerbations. However, it was not blinded, and there is a strong placebo effect in asthma. Needed was a randomized trial in which the control group would undergo a sham treatment.

The RISA trial: A randomized trial in severe asthma

The Research in Severe Asthma (RISA) trial⁵ included patients with more severe asthma than those in the AIR trial. Entry criteria were:

• Taking high doses of an inhaled corticosteroid (> 750 μg of fluticasone or its equivalent per day)
• Taking prednisone (≤ 30 mg/day)
• An FEV₁ of at least 50% of predicted without a bronchodilator
• A positive methacholine test.

Seventeen patients were randomized to undergo bronchial thermoplasty, and another 17 were randomized to receive medical treatment.

After a 2-week run-in period, the thermoplasty patients underwent three treatments, performed 3 weeks apart. For the next 16 weeks, the corticosteroid doses were kept stable in both groups, followed by a 14-week corticosteroid-weaning phase and then a 16-week reduced-corticosteroid phase. During this time, attempts were made to decrease the oral or inhaled corticosteroid doses according to a protocol (eg, a 20%–25% reduction every 2–4 weeks) unless there were mild exacerbations lasting more than 7 days.

Results. There were more adverse events in the thermoplasty group than in the medical management group in the treatment period, including seven hospitalizations for exacerbations of asthma and a partial collapse of the left lower lobe. There were no significant differences in adverse events between groups in the posttreatment period (up to 6 weeks after the last treatment). Forty-nine percent of the events were mild in each group; 10% of the events were severe in the thermoplasty group vs 4% in the control group.

During the steroid-stable phase, patients in the thermoplasty group used rescue inhalers significantly less than those in the control group, and their prebronchodilator FEV₁ and AQLQ and ACQ scores were better. The differences in rescue inhaler use and questionnaire scores remained significant at 1 year.

Comment. As expected, serious adverse events occurred more often in patients with severe asthma in the treatment group than in the control group. However, 1 year after the procedure, the adverse-event rates were similar in the treatment and control groups, suggesting that this procedure can be safely performed in similar patient populations. Although there was significant potential for a placebo effect, these patients with severe persistent asthma showed significant improvement in clinical measures of asthma compared with the control group.