SAN FRANCISCO—Two randomized studies show that long-acting ß-agonists should be used in combination with inhaled corticosteroids and not as monotherapy for mild to moderate persistent asthma.[1,2] “Although guidelines have suggested that long-acting ß-agonists be used in conjunction with an anti-inflammatory, this has been based on expert opinion, not data. Our findings provide the first evidence-based support for this recommendation,” said Stephen C. Lazarus, MD, who participated in both studies.

In the first study, Dr. Lazarus and colleagues compared the effects of monotherapy with a long-acting ß2-agonist (salmeterol) or monotherapy with an inhaled corticosteroid (triamcinolone) in 164 patients (ages 12 to 65 years) with persistent asthma who were enrolled in the Salmeterol Or Inhaled Corticosteroids trial. All patients’ symptoms were well controlled during a run-in period in which they were given inhaled triamcinolone. Following the run-in period, the patients were randomized to receive placebo or one of the two study drugs.

During the 16-week treatment period, the two groups given active treatment had similar results for the following measures: morning peak expiratory flow (PEF), evening PEF, asthma symptom scores, use of albuterol as a rescue medication, and quality of life. Also, both therapies were superior to placebo in their effects on these variables. In comparison with the patients given triamcinolone, the patients receiving salmeterol had significantly higher frequencies of treatment failure and asthma exacerbations and greater increases in median sputum levels of eosinophils, eosinophil cationic protein, and tryptase (Table 1).

“If we rely solely on those outcomes that patients or clinicians might use to assess status—daytime or nighttime symptoms, need for ß-agonist rescue, peak flow measurements, etc—patients did just as well on salmeterol as on inhaled corticosteroid. But they had evidence of asymptomatic increases in markers of inflammation, associated with increased numbers of exacerbations,” Dr. Lazarus told RESPIRATORY REVIEWS. “This is somewhat analogous to [having] high blood pressure. … Patients may feel well even though their blood pressure is elevated—and that puts them at risk for complications,” explained Dr. Lazarus, who is a Professor of Medicine at the University of California in San Francisco.

The second study involved 175 patients (ages 12 to 65 years) with persistent asthma who were also enrolled in the Salmeterol ± Inhaled Corticosteroids trial. In contrast to the previous study, these patients were selected because their asthma symptoms were not adequately controlled with inhaled triamcinolone alone during a six-week run-in period.

The patients were randomized to continue taking inhaled triamcinolone with a placebo add-on or to take salmeterol in addition to the inhaled corticosteroid for 16 weeks. Half of the patients given salmeterol and all of the patients given placebo had their triamcinolone dose reduced by 50% for the first eight weeks (reduction phase) of the trial, and then the dose was eliminated for the last eight weeks (elimination phase).

During the reduction phase, the treatment failure rate was higher (although not statistically different) among the subjects randomized to salmeterol whose inhaled triamcinolone dose was halved than it was among those whose corticosteroid dose was not altered (8.3% vs 2.8%). This difference became more marked during the elimination phase (46.3% vs 13.7%). For comparison, subjects who were given placebo and had their triamcinolone dose eliminated had a treatment failure rate of 47.4% at the end of the study.

The study did show that the inhaled triamcinolone dose could be safely reduced by 50% in more than 90% of subjects randomized to salmeterol. But the corticosteroid could not be withdrawn completely: Elimination of inhaled triamcinolone was linked to a more than fourfold increase in the risk of treatment failure. “Total elimination of triamcinolone therapy results in significant deterioration in asthma control,” the researchers said “and therefore cannot be recommended.”

“Steroid phobia exists, and patients and providers have a tendency to over-utilize the long-acting ß-agonists because they do make people feel better,” said Dr. Lazarus. “We hope that the threefold to fourfold increase in asthma exacerbations and evidence for a mechanism—untreated inflammation—will convince providers that this is not a wise option.” There is the potential for adverse effects with inhaled corticosteroid use, he said, adding, “The risk is very small at low doses, and most data suggest that significant adverse effects are very uncommon, even in children.” Because the risk for adverse effects is dose- and time-related, doses should be titrated downward when patients are doing well to find the lowest possible dose that will still allow the patient to maintain control. “[NIH] guidelines[3,4] recommend such a ‘step down’ after patients have been well controlled for several months.” Further, “the current recommendation for inhaled corticosteroid in patients with even mild persistent asthma is based on the belief that untreated inflammation leads to permanent loss of lung function [through] remodeling,” Dr. Lazarus said. “The NHLBI’s Asthma Clinical Research Network is currently conducting a long-term study [IMPACT] to compare intermittent versus continuous inhaled corticosteroid treatment—versus a leukotriene receptor antagonist as an alternative anti-inflammatory. … [U]ntil these data are in, it’s clear that inhaled corticosteroids are effective therapy to decrease symptoms and reduce the risk of exacerbation, and because of their potential for preventing remodeling remain the gold standard. Salmeterol can potentiate the benefits of inhaled corticosteroids and minimize the risk, but it is not an acceptable substitute in this group of patients.”

 

Short- Versus Long-Acting ß2-Agonists for Allergic Asthma

NIJMEGEN, NETHERLANDS—Researchers from the Netherlands have found that patients with allergic asthma taking short-acting ß2-agonists have a small but significant decline in forced expiratory volume in one second (FEV1) and bronchial hyperresponsiveness over time; however, this effect was not found with use of long-acting ß2-agonists.[1] A total of 145 asthmatic patients who were allergic to house dust mites were randomized to monotherapy with a short-acting ß2-agonist, a long-acting ß2-agonist, or placebo for 12 weeks. Spirometric variables and bronchial hyperresponsiveness were measured at baseline and every four weeks during the trial. The subjects recorded peak flow values, rescue medication use, and asthma symptoms daily. In addition, dust samples from their homes were collected at the start of the trial and every six weeks thereafter. The study groups showed a similar course of FEV1 over time. However, in the short-acting ß2-agonist group, there was a marked trend over time toward a decrease in mean FEV1 as a percentage of predicted; this score dropped by 6.6 points from baseline to week 12. Neither of the other two groups demonstrated this change. Furthermore, there was a significant trend over time toward increased bronchial hyperresponsiveness in the patients given short-acting ß2-agonists. In this group, the geometric mean provocative concentration of histamine causing a 20% fall in FEV1 decreased by 1.2 mg/mL during the study period; it did not change in the other two groups. None of the groups experienced a change in peak flow parameters or asthma symptom scores. In addition, none of the variables examined were affected by allergen exposure. —Kristin Della Volpe

Reference 1. Cloosterman SG, Bijl-Hofland ID, van Herwaarden CL, et al. A placebo-controlled clinical trial of regular monotherapy with short-acting and long-acting b2-agonists in allergic asthmatic patients. Chest. 2001;119:1306-1315.