Bronchodilators added to inhaled corticosteroids
ACP J Club. 1993 Mar-April;118:48. doi:10.7326/ACPJC-1993-118-2-048
Kerstjens HA, Brand PL, Hughes MD, et al. A comparison of bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. N Engl J Med. Nov
To compare the effects of anti-inflammatory therapy with an inhaled corticosteroid and a β2-agonist (beclomethasone plus terbutaline) with maximal bronchodilatation therapy (anticholinergic-bronchodilator ipratropium bromide plus terbutaline) and with terbutaline alone in patients with asthma or chronic obstructive pulmonary disease for reduction of morbidity, hyper-responsiveness, and airways obstruction.
2.5-year, randomized, double-blind, placebo-controlled trial.
6 university pulmonary outpatient clinics in the Netherlands.
274 patients (mean age 39, 176 men) with a clinical diagnosis of asthma or chronic obstructive pulmonary disease were included meeting these criteria: 1) a forced expiratory volume in 1 second (FEV1) or the ratio of FEV1 to inspiratory vital capacity < the 95% confidence interval of normal, provided that the FEV1 was > 1.2 L; 2) a concentration of histamine causing a 20% decline in FEV1 (PC20) of ≤ 8 mg/mL; and 3) no other major illnesses.
All patients took albuterol as needed, inhaled as a dry powder, and terbutaline, 250 µg/puff. 92 patients were randomized to beclomethasone, 100 µg/puff; 91 patients, to ipratropium, 20 µg/puff; and 91 patients, to placebo. All medication except albuterol was taken in 2 puffs, 4 times/d.
Main outcome measures
Patients came to the clinic every 3 months to measure FEV1 and score symptoms, exacerbations, and adverse effects. Reversibility of airways obstruction and PC20 were measured every 6 months.
The corticosteroid group compared with the anticholinergic and the placebo groups had fewer withdrawals (12 vs. 45 and 44); fewer exacerbations (0.25 vs. 0.76 and 0.72 per patient/y); greater increase in mean FEV1 starting after 3 months (7.5% vs. -0.6% and -1.2%); and a greater increase in PC20 (1.27 vs. 0.28 and 0.15 doubling concentration) (P < 0.001 for the corticosteroid group vs. both other groups). No major adverse effects occurred, and the groups did not differ for minor adverse effects. Improvements were the same for men and women. Benefit of steroid was greater in patients with asthma and features associated with asthma: age < 40 years, nonsmokers, allergies, and increased bronchial reactivity.
The combination of beclomethasone and terbutaline reduced respiratory symptoms, exacerbation rates, airway obstruction, and hyper-responsiveness in comparison with ipratropium bromide and terbutaline or terbutaline alone in patients with airflow obstruction.
Source of funding: Netherlands Health Research Promotion Program.
For article reprint: Dr. D.S. Postma, Department of Pulmonary Medicine, University Hospital Groningen, Oostersingel 59, 9713 EZ Groningen, Netherlands. FAX 31-50-361-9320.
Recent data indicating that inhaled cortico-steroids have short-term benefit in the treatment of acute exacerbations of asthma are substantial. These inhaled agents may have long-term benefit in obstructive airways disease. Their incremental efficacy in combination with β-agonists for the treatment of asthma, however, has not been established nor has their long-term efficacy for chronic obstructive pulmonary disease been studied.
The design of the study by Kerstjens and colleagues mirrors the realistic clinical situation in which combinations of agents are used and in which patients with chronic obstructive pulmonary disease are difficult to distinguish. Limits to its generalizability, however, are that patients had no major medical illnesses and had at least moderate but not extremely severe obstructive disease.
The beneficial effect of inhaled corticosteroids plus β2-agonists was more pronounced in patients with a diagnosis of asthma and in whom that diagnosis would be more likely on the basis of age (< 40 y), nonsmoking, allergies, and baseline PC20. It was also apparent, although not always significant, in patients with chronic obstructive pulmonary disease.
It is not surprising that in patients with asthma corticosteroids provide incrementally greater pulmonary improvement when added to a regimen consisting of β2-agonists. The confirmation of this point in a carefully done, double-blind, placebo-controlled, randomized trial is comforting. On the other hand, the suggestion that inhaled corticosteroids may have a substantial incremental effect on patients with baseline characteristics consistent with chronic obstructive pulmonary disease (albeit less than for patients with asthma) is news. Because these patients were identified a posteriori, composed a relatively small group, and did not always show statistically significant effects, the use of inhaled corticosteroids in this group as first-line agents awaits further study. Additionally, in patients with chronic obstructive pulmonary disease, a comparison of oral and inhaled corticosteroids will be of substantial interest.
Roberta B. Ness, MD, MPH
University of Pennsylvania Philadelphia, Pennsylvania, USA