Perhaps You Already Suspected This...

Abstract & Commentary

By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips is a consultant to Cephalon and Ventus and serves on the speakers bureaus of Cephalon and Boehringer Ingelheim.

Synopsis: A significant proportion of patients with difficult- to-control asthma are non-adherent to both inhaled and oral corticosteroid therapy.

Source: Gamble J, et al. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med 2009;180:817-822.

This report is the result of a retrospective cross-sectional analysis of data in Northern Ireland Regional Difficult Asthma Service. The hypothesis was that medication non-adherence is a significant contributing factor in difficult-to-control asthma. For this report, data were obtained on 182 of 188 patients in the cohort. None of the patients included in this study had non-adherence suspected as a major clinical issue at the time of referral to the difficult asthma service, and all subjects denied non-adherence at the time of first clinical assessment at the clinic.

Difficult asthma was defined as persistent symptoms despite treatment at the Global Initiative for Asthma (GINA) at step 4/5.1 (After a look a the GINA web site, I concluded that GINA 4/5 treatment would include a medium- or high-dose inhaled corticosteroid [ICS], plus a long-acting beta agonist, plus a leukotriene modifier, plus sustained release theophylline, and perhaps an oral glucocorticoid. This is a lot of medication.)

The investigators assessed adherence both to inhaled and to oral corticosteroid treatment in this cohort of individuals who met criteria for difficult asthma. Adherence is easier to measure in Northern Ireland than in the United States. In Northern Ireland, all prescribed medication is obtained via prescription from a single source, which allows use of prescription refill information as a measure of adherence. Combination inhaled steroids/long-acting beta agonist (ICT) is basically a universal part of the treatment for asthma in Northern Ireland and was prescribed in all subjects in this study. General practitioner prescription records were obtained for the previous 6 months for prescription refill rates and were compared with prescribed medication, taking into consideration the number of doses per inhaler and the daily doses prescribed. This was expressed as a percentage of prescribed medication. To assess adherence to oral corticosteroid treatment, plasma prednisolone and cortisol assay levels were used to identify non-adherence when patients were supposed to be taking prednisolone. Non-adherence to oral steroids was defined as undetectable blood plasma prednisolone with detectable plasma cortisol, and the investigators confirmed their assessment of oral corticosteroid non-adherence by discussing their suspicion of it with patients when it was suggested by testing.

Patient demographics, hospital admissions, lung function, outpatient steroid treatment, courses, and quality of life (QoL) data were obtained retrospectively from clinic notes. QoL scores were measured using a generic QoL instrument, the EuroQol EQ-5D,2 and the disease-specific Asthma Quality of Life Questionnaire.3 Anxiety and depression were measured using the Hospital Anxiety and Depression Scale.4

One hundred eighty-two consecutive referrals to the difficult asthma clinic were assessed. Of these, 63 patients (35%) filled 50% or fewer prescriptions for ICT (defined as the non-adherent group), 21% of patients filled more than 100%, and 45% of subjects filled between 51% and 100% of prescribed medication. Patients filling 50% or fewer of prescriptions for ICT were more likely to have been admitted to the hospital on three or more occasions in the previous year. Women were significantly more likely to be non-adherent to ICT than men (42% female; 23% male). There were no age differences between the groups. There was a tendency for the non-adherent group to have been prescribed higher and more frequent doses of daily inhaled steroid and higher total beta-agonist inhaler doses than the adherent group, although this failed to reach statistical significance. Non-adherent patients were more likely to have been prescribed a nebulizer and used significantly more nebulized beta agonist over the 6-month study period. There were no statistical differences between adherent and non-adherent groups for anxiety and depression scores. Subjects filling 50% or fewer of prescriptions for ICT scored significantly lower in asthma-specific QoL scores for symptoms, activity, and overall score, as well as scoring lower in the general QoL scale. Linear multivariate stepwise regression analysis with percent adherence to ICT as a continuous variable demonstrated three variables to be significantly related to low adherence: female sex (P = 0.001), EuroQoL score (P = 0.02), and hospital admission in the preceding 12 months (P = 0.02).

For the 51 patients in the group who were supposed to be on oral prednisolone (34 patients on maintenance steroids and 17 patients on a short rescue course), 23 patients (45%) were identified as non-adherent using the criteria defined above (undetectable plasma prednisolone with detectable cortisol levels). In two patients taking maintenance oral steroids, prednisolone was detectable with concomitant detectable cortisol. When adherence to prednisolone was discussed, both patients admitted intermittent use of maintenance oral steroids. Of the 26 subjects who were adherent to prednisolone, about one-third of them were filling fewer than half of their inhaled corticosteroid prescriptions. Of the 23 subjects who were non-adherent to prednisolone, only about one-third were adherent to ICS.

When ICT non-adherence findings were discussed with the patients who continued to be followed in the Difficult Asthma Service Clinic, 88% (45/51) admitted variability in taking ICT. Of the six patients who denied non-adherence to ICT despite having a low prescription filling rate, three had undetectable levels of prednisolone/detectable cortisol or theophylline despite also reporting taking these therapies.

When non-adherence to oral prednisolone was discussed with patients, 86% (22/25) admitted variability in taking this oral steroid. Of the three patients who denied non-adherence to this therapy, two were also non-adherent to ICT. The authors concluded, "These findings indicate that nonadherence is a significant problem in an unselected group of patients attending a Difficult Asthma Service, and one could speculate that if they took regular preventative therapy (as prescribed) their asthma would probably improve substantially."


First, a clarification of terms. Sometime in the last couple of years, "adherence" has replaced "compliance" as the politically correct term for patients using prescribed treatments as recommended. The implication is that adherence is patient-driven and self-motivated, whereas compliance is somehow imposed from above.

This is the first study to evaluate adherence in a group of adult difficult asthmatics with persistent symptoms, and the findings are discouraging. Even in a cohort referred to a specialty clinic because of difficult-to-control asthma, all of whom initially claimed to be adherent, about a third were non-adherent to inhaled steroids, and about half were non-adherent to oral steroid therapy. And this report comes from a country where cost is not a barrier to treatment.

Asthma is a prevalent condition, and accounts for 1 in every 250 deaths and 15 million disability-adjusted life-years lost annually.5 Despite intensive treatment, about 5% of adult patients remain difficult to control, with persisting symptoms and frequent exacerbations.6 Although non-adherence has been suspected as a cause of this phenomenon, it has not been demonstrated so starkly before. Indeed, the American Thoracic Society (ATS) definition of refractory asthma includes the statement "subjects are felt to be generally adherent with therapy,"7 but assessing adherence to asthma therapy can be difficult.

There are some take home messages here. First, we need objective measures of adherence before undertaking expensive testing or escalating treatment to more costly or risky modalities. The authors put it this way, "Objective surrogate and direct measures of adherence should be performed as part of a difficult asthma assessment and are important before prescribing expensive novel biological therapies." This recommendation is applicable to many medical conditions, not just asthma. Those of us who routinely compare objective CPAP use downloads with patient reports have learned to focus on adherence before jumping to expensive testing or medications for persistent sleepiness on CPAP.

Who's most at risk for inadequate use of prescribed treatment? This study suggests that it is women, those with lower quality of life, and those who are more likely to be hospitalized. The gender difference has been previously reported,8 and may relate to depression, which is also more common in women.

Most of us do not have the ability to objectively measure adherence as these investigators did. But perhaps a healthy skepticism when patients are not responding well to multidrug efforts to treat chronic conditions would serve us and our patients well.


1. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention, 2008. Available at: Id=1561. Accessed Nov. 12, 2009.

2. The EuroQol Group. Euroqol: A facility for the measurement of health-related quality of life. Health Policy 1990;16:199-208.

3. Juniper EF, et al. Measuring quality of life in asthma. Am Rev Respir Dis 1993;147:832-838.

4. Zigmond AS, Snaith PR. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361-370.

5. World Health Organization. The World Health report 2002—reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002.

6. Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J 1998;12:1209-1218.

7. American Thoracic Society. Proceedings of the ATS workshop on refractory asthma: Current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 2000;162:2341-2351.

8. Smith A, et al. Depressive symptoms and adherence to asthma therapy after hospital discharge. Chest 2006; 130:1034-1038.