The Prevalence of Nonadherence in Difficult Asthma Jacqueline Gamble1,2, Michael Stevenson3, Elizabeth McClean4, and Liam G. Heaney1 1 Centre for Infection and Immunity, Queen’s University of Belfast; 2Regional Respiratory Centre, Belfast City Hospital; 3Department of Epidemiology and Public Health, Queen’s University of Belfast; and 4Department of Clinical Chemistry, Belfast City Hospital, Belfast, Northern Ireland
Rationale: With the advent of new and expensive therapies for severe refractory asthma, targeting the appropriate patients is important. An important issue is identifying nonadherence with current therapies. The extent of nonadherence in a population with difficult asthma has not been previously reported. Objectives: To examine the prevalence of nonadherence to corticosteroid medication in a population with difficult asthma referred to a Specialist Clinic and to examine the relationship of poor adherence to asthma outcome. Methods: General practitioner prescription refill records for the previous 6 months for inhaled combination therapy and short-acting b-agonists were compared with initial prescriptions and expressed as a percentage. Blood plasma prednisolone and cortisol assay levels were used to examine the utility of these measures in assessing adherence to oral prednisolone. Patient demographics, hospital admissions, lung function, oral prednisolone courses, and quality of life data were analyzed to indentify the variables associated with reduced medication adherence. Measurements and Main Results: A total of 182 patients were assessed. Sixty-three patients (35%) filled 50% or fewer inhaled medication prescriptions; 88% admitted poor adherence with inhaled therapy after initial denial. Twenty-one percent of patients filled more than 100% of presciptions, and 45% of subjects filled between 51 and 100% of prescriptions. Twenty-three of 51 patients (45%) prescribed oral steroids were found to be nonadherent. Conclusions: A significant proportion of patients with difficult-tocontrol asthma remained nonadherent to corticosteroid therapy. Objective surrogate and direct measures of adherence should be performed as part of a difficult asthma assessment and are important before prescibing expensive novel biological therapies. Keywords: adherence; objective measures; medication
Asthma affects an estimated 300 million people worldwide (1, 2) and is estimated to account for 1 in every 250 deaths and 15 million disability-adjusted life years lost annually (2). Suboptimal adherence to medication regimens is a recognized but incompletely understood problem (3) seen in all severities of asthma and contributes to poor asthma control, increased mortality and hospitalization rates, decreased quality of life (QoL), and reduced lung function (4–11). Despite treatment with high-dose therapy, approximately 5% of adult patients remain difficult to control, with persisting symptoms and frequent exacerbations (12). This subgroup of patients is a cause for concern because of the potential consequences of uncontrolled disease, including fatal or near fatal asthma (8, 13–15). Systematic evaluation of subjects with difficult-to-control asthma identifies reasons for persisting symptoms, which are unrelated to disease severity (9, 16). Non-
(Received in original form February 3, 2009; accepted in final form July 29, 2009) Supported by a fellowship from the Research and Development Office, Northern Ireland. Correspondence and requests for reprints should be addressed to Dr. Liam Heaney, M.D., Regional Respiratory Centre, Belfast City Hospital, Lisburn Road, Belfast, Northern Ireland, UK BT9 7AB. E-mail:
[email protected] Am J Respir Crit Care Med Vol 180. pp 817–822, 2009 Originally Published in Press as DOI: 10.1164/rccm.200902-0166OC on July 30, 2009 Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY Scientific Knowledge on the Subject
Nonadherence with medication in subjects with different severities of asthma, including subjects with mild and moderate disease has been consistently demonstrated to be common with concomitant asthma morbidity. Data on the degree of nonadherence in a difficult asthma population (symptomatic despite treatment GINA step 4/5) assessed in a specialist service has not been previously presented. What This Study Adds to the Field
A significant proportion of patients with difficult-to-control asthma are nonadherent to inhaled and oral corticosteroid therapy. This study supports the importance of using objective, surrogate, and direct measures of adherence. Identifying non-adherence in this population is crucially important, given currently available (and imminent) expensive biological therapies but is also central to research efforts to define mechanisms and phenotypes of refractory asthma.
adherence with treatment is likely to be a reason for poor control in this group. A retrospective case control survey identified poor adherence in 22% in 57 children with difficultto-control asthma (17). The prevalence of poor adherence in adults with difficult asthma (persistent symptoms despite prescribed treatment at GINA step 4/5) (18) remains unclear, and a recent evidence review found little information available in this group (19). Furthermore, the ATS definition of refractory asthma includes the statement ‘‘subjects are felt to be generally adherent with therapy’’ (20), but assessing adherence with asthma therapy can be difficult. Various methods to measure medication adherence have been studied, but none can be considered the ‘‘gold standard.’’ Direct or objective measures, such as drug assays, pill counts, or electronic monitoring, may be more reliable but have problems with regard to accuracy, cost, and convenience and therefore are not always practical in the clinical setting (4, 21–23). Surrogate measures (e.g., pharmacy refill records) have been found to be a useful and convenient method of measuring and identifying poor adherence and are unobtrusive and inexpensive (24–30). In patients on oral prednisolone (OP) or high-dose inhaled steroids, it has been suggested that the absence of cortisol suppression in the presence of poor asthma control may potentially identify poor adherence in this group (31). One study identified that approximately 50% of subjects on maintenance oral steroids undergoing detailed inpatient assessment for difficult to control asthma were nonadherent to oral corticosteroids (9). We hypothesized that nonadherence to medication would be a significant contributing factor in subjects referred to a specialist clinic with difficult-to-control asthma and examined the prevalence of nonadherence to combination inhaled com-
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bination therapy (ICT) and OP in sequential patients referred to a Regional Difficult Asthma Service. Some of the results of this study have been previously reported in the form of an abstract (32).
METHODS Participants The data presented are a retrospective cross-sectional analysis of adherence and clinical data performed as part of an audit of outcome for the Northern Ireland Regional Difficult Asthma Service. At the time of data collection, there were 188 subjects attending the Service; data were obtained on 182 subjects. The Service assesses approximately 70 new patients a year, and of these approximately 40% are tertiary referrals from other respiratory specialists. The Service has a high discharge rate back to primary care or to the referring respiratory specialist after assessment through the multidisciplinary assessment protocol (16). None of the subjects had nonadherence suspected as a major clinical issue at the time of referral, and all subjects denied nonadherence at the time of first clinical assessment at the clinic. Difficult asthma was defined as persistent symptoms despite treatment at GINA step 4/5 (18).
Measuring Adherence In Northern Ireland, all prescribed medication is obtained via prescription from a single general practitioner. There is no hospital pharmacy prescribing for outpatients, and, when admitted acutely to a hospital, patients are generally advised to subsequently bring their maintenance medication to the hospital; thus, all prescribed medication is obtained via prescription from a single source, facilitating prescription refill information as a measure of prescribed drug and a surrogate measure of adherence. Single-device ICT (inhaled steroids/ long acting b2-agonist) is almost exclusively prescribed in Northern Ireland and had been 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. If a dose or inhaler had been changed during the 6-month period, the rate was adjusted accordingly. Blood plasma prednisolone and cortisol assay levels were used to examine the potential utility in identifying nonadherence to OP when patients were taking a prescribed short course of rescue prednisolone or were on maintenance prednisolone. All blood samples were taken between 2 and 4 hours after reported ingestion of prednisolone, and in all cases the time and dosage of prednisolone were recorded. Nonadherence to OP was defined as undetectable blood plasma prednisolone with detectable plasma cortisol. We determined the utility of our methods in detecting poor adherence by discussing nonadherence with patients. Patient demographics, hospital admissions, lung function, OP courses, and QoL data for between-group analyses were obtained retrospectively from clinic notes.
QoL/Anxiety and Depression Measurements QoL scores were measured using a generic QoL instrument, the EuroQol EQ-5D (33) and the disease-specific Asthma Quality of Life Questionnaire (34). Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (35).
Statistical Analysis Data were entered into a database, and statistical analysis was performed using SPSS for Windows, version 13 (SPSS, Chicago, IL). Demographic data are presented as mean 6 SD or as absolute values. For inhaled medication, we anticipated a spectrum of prescription filling; however, to facilitate the identification of factors associated with poor adherence, we compared data for groups filling prescriptions for greater than 50% of prescribed ICT with data from groups filling 50% or fewer of prescribed doses as previously described (10, 36). Group differences were examined using an independent t test for continuous variables, Chi-square analysis for dichotomous variables, and, where appropriate, Chi-square for trend and Fisher’s exact-test. We also
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analyzed % adherence as a continuous variable using multivariate stepwise linear regression, as previously described (10, 36–38) with log % adherence as the dependent variable to identify variables associated with poor adherence to ICT. A P value of less than 0.05 was considered significant.
RESULTS Adherence with ICT
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, 21% of patients filled more than 100%, and 45% of subjects filled between 51 and 100% of prescribed medication. Prescription filling by quartile is shown in Table 1. Demographic details and medication and health care utilization data for the patient population are shown in Table 2, which also shows the comparison between patients filling 50% or fewer of prescriptions for ICT and those filling more than 50% of prescriptions for ICT. One hundred thirteen (62%) of the 182 patients were female, which reflects the usual sex difference in our difficult asthma service. Women were significantly more likely to be nonadherent with ICT than men (42% female; 23% male). There were no age differences between the groups. 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 12 months. There was a trend toward higher prescribed doses of daily inhaled steroid and higher total b-agonist inhaler doses used in the 6-month period in the nonadherent group, although this failed to reach statistical significance. Nonadherent patients were more likely to own a compressor and used significantly more nebulized b-agonist over the 6-month period. Hospital Anxiety and Depression Scale and QoL scores for the entire population are summarized in Table 3, which also shows a comparison between patients filling 50% or fewer of prescriptions for ICT and those filling more than 50% of prescriptions for ICT. Psychiatric ‘‘caseness’’ (i.e., anxiety or depression score >11) was seen in 56 patients (31%) for anxiety and in 29 patients (16%) for depression. There were no statistical differences between 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. The mean difference was greater than the minimally clinical important difference of 0.5 (39). Generic QoL scores were also significantly lower using the EQ5D visual analog scale scores (Table 3). Linear multivariate stepwise regression analysis with % adherence with ICT as a continuous variable (Table 4) demonstrated three variables to be significantly related to low adherence: female sex (P 5 0.001), EURO QoL score (P 5 0.02), and hospital admission in the preceding 12 months (P 5 0.02). Adherence with Prednisolone
Blood plasma prednisolone levels and cortisol levels were obtained on 51 patients reporting current maintenance OP use TABLE 1. PRESCRIPTIONS FOR COMBINATION INHALERS FILLED BY QUARTILE Prescriptions Filled in 6 Mo 0–25% 26–50% 51–75% 76–100% .100%
Number of Patients 16 47 34 47 38
(9%) (26%) (19%) (26%) (21%)
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TABLE 2. DEMOGRAPHIC DETAILS AND MEDICATION AND HEALTHCARE UTILIZATION FOR THE ENTIRE PATIENT POPULATION AND COMPARISONS BETWEEN SUBJECTS FILLING
