Asthma: Single-Inhaler Therapy May Trump Standard Care

Laurie Barclay, MD

March 04, 2013

Asthma prevention using a single combination inhaler for both prevention and relief of exacerbations is better than using guideline-based treatment, according to findings from 2 randomized trials published online March 4 in Lancet Respiratory Medicine.

Single-inhaler Maintenance and Reliever Therapy (SMART) uses a combination inhaler containing the inhaled corticosteroid (ICS) beclometasone (100 μg) and formoterol (6 μg), a rapid-onset, long-acting &betaq;2 agonist (LABA), delivered by a single inhalation twice daily for both maintenance and rescue.

Current guidelines recommend achieving asthma control with ICS plus a LABA combination inhaler and treating exacerbations with a second short-acting β2 agonist inhaler.

"These studies add to our knowledge about the use of adding anti-inflammatory therapy at the time it is needed," Alan Kaplan, MD, CCFP(EM), FCFP, chair, Family Physician Airways Group of Canada, and chair, Respiratory Medicine Special Interest Focused Practice Group of the College of Family Physicians of Canada, told Medscape Medical News in an email interview. He was not involved in either study. "Moderate asthmatics on regular maintenance therapy who develop worsenings, usually due to an inflammatory stimulus, who are treated with combination symptom control at the same time as escalating the anti-inflammatory therapy have less exacerbations, oral steroid use, and even (in 1 study) days of high use of rescue therapy."

Both trials showed that in adults with poorly controlled asthma, SMART was safe, well-tolerated, and more effective at reducing attacks than guideline-based treatment.

The first study, led by Alberto Papi, MD, from the University of Ferrara, Italy, and funded by manufacturer Chiesi Pharmaceuticals, was a randomized controlled trial enrolling 1714 adults with moderate persistent asthma from 14 European countries. Compared with current best practice, SMART was associated with a significantly lower risk for severe exacerbations and of hospitalization or urgent medical care. The primary outcome measure, time to first exacerbation, also favored SMART at 209 days vs 134 days with standard therapy (36% risk reduction; P = .0005).

The second study, led by Mitesh Patel, BMBS, from the Medical Research Institute of New Zealand, Wellington, the Capital and Coast District Health Board, Wellington, and the Division of Respiratory Medicine, School of Clinical Sciences, University of Nottingham, United Kingdom, and funded by the Health Research Council of New Zealand, enrolled 303 adults aged 16 to 65 years who were at increased risk for exacerbations and high use of rescue therapy. Patients receiving SMART had lower risk for severe asthma exacerbations without greater risk for beta-agonist overuse or increased long-term corticosteroid exposure.

Using electronic medication monitoring, Dr. Patel and colleagues found about a 40% reduction with SMART vs standard therapy in number of days of high use of beta-agonists. Participants receiving SMART had higher average daily ICS exposure than those receiving standard therapy, but similar overall systemic corticosteroid exposure, as reduced frequency of severe attacks allowed lower oral corticosteroid exposure. Weighted mean annual rate per year of severe asthma exacerbations was 35 in the SMART group and 66 with standard therapy (relative rate, 0.54; 95% confidence interval, 0.36 - 0.82; P = .004).

Aim for Full Control

"Combination therapy has certainly improved asthma symptoms and decreased exacerbations," Dr. Kaplan said. "We now have tools in primary care to manage asthma well and aim for full control. Despite this, there will be times of asthma worsenings, and early intervention will make a difference in preventing a worsening from becoming a full-blown exacerbation, with its attendant risks."

An accompanying comment from René Aalbers, MD, PhD, from Martini Hospital in Groningen, the Netherlands, notes 4 options for a patient-specific strategy of ICS and LABA. Because it is still unclear which patients will benefit most from which options, Dr. Aalbers recommends a post hoc analysis of data from previous controlled trials with SMART, as well as real-life studies involving electronic monitoring.

Strengths identified by Dr. Kaplan were that both studies had large numbers of adults with well-defined moderate asthma, well-defined intervention over the course of 48 or 24 weeks, and clear outcomes. The second study also used electronic dosing surveillance for adherence and was not funded by a pharmaceutical company.

Weaknesses of the manufacturer's study were that patients were put on high doses of ICS with reversibility, likely uncontrolled, and were then put on an essentially lower dose of maintenance steroids, which would almost guarantee symptoms to occur.

"This was likely necessary, however, to allow outcomes to be measured, but may not be what we actually do in practice," Dr. Kaplan said. "The Patel study [was] open label. Some researchers feel that only double blinded [randomized controlled studies] are valuable research, but in reality, a practical, well-done, real-world study gives the respiratory community significant useful information."

Manufacturer Chiesi Farmaceutici supported the first study, employs 3 of its authors, and has financial relationships with several other authors. L. Prevost of PAREXEL, University Kiel, and LungenClinic Grosshansdorf provided editorial support. The Health Research Council of New Zealand funded the second study. Two of the authors report various financial disclosures with Clinicanz, GlaxoSmithKline, Chiesi, AstraZeneca, GlaxoSmithKline, Cytos Biotechnology, Pharmaxis, Cephalon, Genentech, Novartis, Boehringer Ingelheim, Nycomed, and/or Otsuka Pharmaceuticals. Dr. Kaplan is on the advisory board or speakers bureau for Astra Zeneca, Boehringer Ingelheim, Merck, Novartis, and Takeda. Dr. Aalbers has reported providing consultancy services to AstraZeneca, Chiesi, and Mundipharma.

Lancet Respiratory Med. Published online March 4, 2013.