Add-on Medications for Improved Asthma Control

If, despite use of standard doses of inhaled corticosteroids, there are still breakthrough symptoms, consideration of add-on therapy is the next step. For adults, the first line add-on would be long-acting bronchodilator (LABA). The use of a leukotriene receptor antagonist would be a second line add-on. There has recently been some controversy in the literature with regards to long-acting bronchodilators. The Salmeterol Multicenter Asthma Research Trial (SMART) followed more than 26000 participants for 6 months treated with salmererol vs. placebo in addition to their standard medications (Nelson H. et al, Chest 2006;129:15-26 - level 1 evidence). There was a four-fold increased risk for asthma-related deaths in African-American males. There were no overall differences between the two populations as a whole treated with salmeterol or placebo.

Unfortunately, the use of inhaled corticosteroids was not assessed in this trial, so it is difficult to assess whether those patients with adverse effects were using inhaled corticosteroids or not.

This study reflects use of LABA's as monotherapy for asthma in the US. Less than 50% of the patients enrolled were on ICS and continued compliance with ICS was not assessed during the study. LABA's have never been advocated as monotherapy in Canada.

A recent Meta-analysis of published studies of LABA vs. placebo showed similar results (Salpeter, S. et. al., Annals Intern Med 2006; 144:904-912 Ð level 1 evidence). Unfortunately, this study was not able to address potential contribution of disease severity, co-treatments, adherence and race to serious adverse outcomes. The editorial accompanying this article (Glasworth J., Annals Intern Med; 144:936-37) suggested that physicians must be aware of factors that predict unfavourable reactions to LABAs (including race) and carefully monitor the patients receiving these drugs.

It is crucial to remember no patient with asthma should receive a LABA unless they are also on concomitant inhaled corticosteroids, preferably combined in a single inhaler.

The Canadian asthma consensus guidelines, in agreement with recommendations worldwide, emphasize the need for adequate anti-inflammatory therapy before starting add-on treatment, including long-acting ß-agonists. This was not the case in the SMART trial.

Administration of long-acting ß-agonists in combination with inhaled corticosteroids, preferably in a single inhalation device, remains the most effective strategy for prevention of severe asthma exacerbations in those with persistent disease. If we are to reduce asthma morbidity and mortality, it is critical for this message to be understood by clinicians and not confused by reports of inappropriate use. Follow-up is necessary and medication should be discontinued, and referral to an asthma specialist should be sought, if the patient's asthma remains uncontrolled.

There are few studies of long-acting beta agonists (LABAs) in children. The addition of LABAs improves pulmonary function, sometimes reduce symptoms and the use of short-acting beta agonists, and are safe (Becker 2005). A recent Cochrane systematic review included children as low as four years of age in its review, with similar results.

For children using budesonide/formoterol for their asthma control, the mean dose of inhaled corticosteroid required was significantly less than using the inhaled corticosteroid alone. Most children are easily controlled using an inhaled corticosteroid alone, so assessment of compliance, and other diseases which may aggravate or mimic asthma, (e.g. chronic sinusitis, rhinitis and gastroesophageal reflux) should be considered before adding a LABA.

- Alan Kaplan

Thanks to Andrew McIvor for reviewing the draft copy of this article. Dr. McIvor is Professor of Medicine McMaster University, Staff Respirologist Firestone Institute for Respiratory Research St Joseph's Healthcare, Hamilton, Ontario.

References:

Ni Chroinin M, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD005535. (Level 1 evidence)

O'Byrne PM et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005:129-36 (Level 1 evidence)

You can search for abstracts of the above references by following this link: PubMed