Asthma in the real world
Key words: Adherence, inhaled corticosteroids, long-acting inhaled β-agonists, leukotriene receptor antagonistsDespite the availability of effective and generally very safe medications to treat asthma,1 some of which have been available for use for more than 40 years, surveys of asthmatic patients suggest that asthma remains poorly controlled in the majority of patients,2, 3 and this state of affairs has not substantially improved over the past decade.4 The presence of poor asthma control is associated with poor asthma outcomes, including increased risks of severe exacerbations.5 The most widely prescribed medications to achieve asthma control include inhaled corticosteroids (ICSs), either alone or in combination (in a single inhaler) with long-acting inhaled β2-agonists (LABAs) and leukotriene receptor antagonists (LTRAs).
In some patients the lack of optimal asthma control is a reflection of severe asthma not responding to usual treatment at conventional doses. This population of patients is believed to represent 5% to 10% of all asthmatic patients,6 a relatively small proportion of all patients with poorly controlled disease. The symptoms of the majority of the remaining patients likely could be optimally controlled with the medications available, but their adherence to treatment plans is poor.7 There are many reasons for this, and these are likely similar to other chronic diseases, such as hypertension, in which adherence is also inadequate.
The problems with adherence to therapy are not identified in phase III clinical trials to evaluate the efficacy of medications. This is because in most efficacy trials there is a run-in period in which adherence is measured and because lack of adherence results in the patient not being randomized in the study. Most studies randomize less than 50% of all patients enrolled, partly for this reason. Of course, this optimizes the apparent efficacy of the treatment intervention studied under the most ideal conditions. Once a treatment is approved for use, it is possible to conduct studies to attempt to measure the “real-world” effectiveness of the treatment, and this is usually done by conducting “pragmatic” trials, in which everything possible is done to mimic the real-world environment, with no blinding or efforts to optimize adherence. One such study has compared the effectiveness of LTRAs with that of ICSs either as a first-line controller therapy or LABAs as add-on therapy in asthmatic patients already receiving ICSs in primary care practice.8 The study demonstrated that LTRAs were equivalent to an ICS as first-line controller therapy and to LABAs as add-on therapy, with no difference between the treatments over 2 years. The main reason for this result appeared to be better adherence to taking the oral LTRAs when compared with the ICSs. This suggested that although ICSs improve asthma outcomes to a greater extent than LTRAs in head-to-head efficacy trials,9 improved adherence narrows this difference in a real-world setting. Although these pragmatic studies are very useful to establish effectiveness, they do have limitations.10 Of necessity, they are often unblinded and nonrandomized, so that confounding factors can easily influence the results.
Another approach to measure effectiveness in a real-world setting is to use data collected in administrative databases. An excellent example of the value of this approach is a study reported by Sadatsafavi et al11 in this issue of the Journal. These investigators used a health service database in British Columbia, Canada, which collects health care information from all residents to access vital statistics and census information; hospital admission and discharge data, with a relative weighting of the intensity of the admission; all outpatient services; and all drugs dispensed. They used this information to compare outcomes in 2 groups of asthmatic patients aged between 12 and 45 years, all of whom were taking ICSs, required a step-up of treatment, and received either LABAs or LTRAs added to the ICS. Also, they examined resource use and asthma-related medical costs over 2 years in the 2 groups. The main outcomes were adherence to medications and rates of asthma-related resource use, such as hospitalizations, outpatient visits, and medication dispensations, as well as asthma exacerbations, as determined by the need for dispensation of oral corticosteroids. The adherence was measured as the percentage of days for which the add-on medication was dispensed over the 2 years from the index date of the initial dispensation. The results indicated that adherence to both of the add-on treatments was poor but was significantly better for ICSs when LABAs were chosen as add-on therapy (45% of days) when compared with LTRAs (36% of days). There was no difference in the adherence to the add-on component. In addition, the proportion of patients who continued to receive uninterrupted treatment by the end of the first year was shockingly low, being 9% of patients receiving ICS/LABA treatment and 3% receiving ICS/LTRA treatment. The better adherence to ICS/LABA treatment was associated with fewer asthma-related outpatient visits and medication dispensations (including short-acting inhaled β2-agonists). Also, when periods of uninterrupted treatment were analyzed, the dispensation of oral corticosteroids, presumably reflecting the rate of severe asthma exacerbations, was significantly lower in the ICS/LABA group.
This study has highlighted a number of issues. The numbers of asthmatic patients who continuously take their medication as recommended is vanishingly low, and this is an important reason for the consistent findings of lack of asthma control in many patients. However, if an add-on treatment to an ICS is needed, the proportion of time on ICSs is better when LABAs are chosen when compared with LTRAs. This might be related, in part, to the fact that ICSs/LABAs are usually dispensed as a single inhaler, and therefore the patient cannot take the one component without the other. In addition, the consistent improvement in the outcomes for ICSs/LABAs during the periods of uninterrupted treatment suggests that this combination is also a more effective choice, as the randomized controlled trials comparing these combinations have suggested.12
Asthma-related hospitalizations were very infrequent in these patients and not different between the 2 treatment approaches, but a surprising finding of this study was that non–asthma-related hospitalizations were slightly but significantly higher in the patients treated with ICSs/LABAs in the uninterrupted treatment analysis. This might have been a chance observation but requires further evaluation given the concerns about the safety of LABAs when added to ICSs in asthmatic patients.13
Although results generated from administrative databases have limitations, which have been recognized by the authors of the study, they allow conclusions that cannot be obtained from randomized controlled trials. The study reinforces the dreadfully poor adherence to regular ICS treatment in asthmatic patients, the somewhat better adherence to ICSs when LABAs are chosen as add-on therapy when compared with LTRAs, and the improvement in some asthma outcomes when this is done. There is little doubt that the greatest opportunity to further improve outcomes in asthmatic patients is to develop ways to enhance adherence to the effective treatments that are currently available.
- Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008;31:143–178
- . Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J. 2008;31:320–325
- Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol. 2004;114:40–47
- . Repeated cross-sectional survey of patient-reported asthma control in Europe in the past 5 years. Eur Respir Rev. 2012;21:66–74
- Overall asthma control: the relationship between current control and future risk. J Allergy Clin Immunol. 2010;125:600–608
- Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126:926–938
- . Non-adherence with asthma therapy: more than just forgetting. J Pediatr. 2005;146:157–159
- Leukotriene antagonists as first-line or add-on asthma-controller therapy. N Engl J Med. 2011;364:1695–1707
- . Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database Syst Rev. 2002;(3):CD002314
- . A pragmatic view on pragmatic trials. Dialogues Clin Neurosci. 2011;13:217–224
- . Comparative outcomes of leukotriene receptor antagonists and long-acting beta-agonists as add-on therapy in asthma: a population based study. J Allergy Clin Immunol. 2013;132:63–69
- . Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2006;(4):CD003137
- . Risks of long-acting beta-agonists in achieving asthma control. N Engl J Med. 2009;360:1671–1672