To the Editor: Inhaled long-acting beta 2-agonists (LABA) are the main pharmacological therapy recommended for stable chronic obstructive pulmonary disease (COPD) in the Global Initiative for Chronic Obstructive Lung Disease, whereas lower adherence to inhaled drugs than to oral medications has been pointed out.1–3 Elderly patients with COPD have compromised coordination and thus find it harder to use inhaled devices than do younger people with asthma.4,5 Because adherence to treatment is a critical component of treatment response, it is important to consider this factor when prescribing inhaled medications for elderly patients.4–6 The transdermal tulobuterol patch (TP) is the first transdermal patch preparation for LABA and is designed to provide and sustain beta 2-agonistic effects for 24 hours when applied once daily.7–9 Treatment adherence to TP has been reported to be significantly better than with inhaled salmeterol, although measurement of adherence and treatment efficacy was not based on a rigorous protocol.9 To compare drug-specific adherence and efficacy of LABA of inhaled salmeterol and TP and to identify certain risk factors of underuse of inhaled LABA in elderly patients, a randomized crossover study was conducted at a single center. Twenty-six patients (aged 77.1±1.1, 21 male) with moderate to severe COPD were enrolled in a study that compared the effects of 12 weeks of treatment with a TP (2 mg, Hokunalin tape, Maruho Phamaceutical, Inc., Osaka, Japan) once daily with the effects of inhalation of salmeterol 50 μg (Serevent Diskus, GlaxoSmithKline, Tokyo, Japan) twice daily. Thirteen patients each were randomly allocated to group A (TP to salmeterol) and group B (salmeterol to TP). After the first 12 weeks of treatment (Phase 1), the subjects entered into a second 12-week period with the alternate treatment (Phase 2). All patients visited the outpatient clinic every 4 weeks to confirm their medical condition and adherence to treatment. Spirometry and a 6-minute walk test were performed before Phase 1 and at the end of 12 and 24 weeks. The Mini-Mental State Examination (MMSE) was administered before entry to evaluate the cognition level of patients. Adherence was defined as the duration for which a patient took a given medication as prescribed. There were no significant differences between the two groups in age, sex, MMSE score, pulmonary function data, or 6-minute walk distance (6MWD) at entry. Overall drug-specific adherence rate was 87.7±2.6% for TP and 72.3±4.8% for salmeterol (P<.001). Adherence varied according to patient age and MMSE score. Adherence to TP was greater than to salmeterol in patients aged 80 and older (P<.05) and in those with a MMSE score of 25 or less (P=.06) but not in patients younger than 80 or with a MMSE score greater than 25 (Figure 1). There was a significant improvement from baseline in percentage vital capacity, percentage forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), percentage FEV1, and percentage mean expiratory flow between 25% and 75% of FVC after treatment with TP and salmeterol (P<.05). 6MWD was significantly longer after treatment with TP (21±2.0 m) and salmeterol (19±2.1 m) (P<.01). There were no significant differences in any of the functional parameters between TP and salmeterol. Comparison of adherence according to patient age and Mini-Mental State Examination (MMSE) score. (A) Comparison of adherence to transdermal tulobuterol patch (TP) and to salmeterol in subjects younger than 80. There was no significant difference in adherence between the two medications. (B) Comparison of adherence in subjects aged 80 and older. Adherence to salmeterol was significantly lower than to TP (P<.05). (C) Comparison of adherence to TP and to salmeterol in subjects with a MMSE score higher than 25. There was no significant difference in adherence between the two medications. (D) Comparison of adherence in subjects with a MMSE score of 25 or lower. Again, adherence to salmeterol tended to be lower than to TP (P=.06). Data represent means ± standard errors of the mean. No serious adverse events were reported, although three events of mild contact dermatitis were observed in the TP treatment. After the study protocols were completed, more than 60% of patients wished to switch from the inhaled salmeterol to TP or continue taking TP. This study demonstrated that adherence to TP was greater than to inhaled salmeterol in elderly patients with COPD and showed that older age and impaired cognitive levels lower adherence to inhalation therapy. Treatment with TP was as effective as inhaled salmeterol to improve airflow limitation and exercise tolerance in these patients. The good rate of adherence to TP appears to be related to the simple procedure for using the drug and a lesser frequency of administration than with inhaled medications.8,9 Poor adherence to inhaled salmeterol was associated with older age and impaired cognitive levels, whereas these factors affected adherence to TP less. Because the bronchodilator effect of salmeterol was equivalent to that of TP despite the poorer adherence, the pharmacological efficacy of salmeterol may be better than that of TP at the doses used in the present study. Therefore inhaled salmeterol is more favorable than TP if patient adherence is good. In contrast, TP appears to be more useful in patients with poor compliance such as persons who are elderly or cognitively impaired. In conclusion, this study provides new information that transdermal LABA may be a favorable treatment for patients with COPD with poor adherence to inhaled LABA. The authors thank Dr. K. Uchida for recruiting the patients with COPD and Dr. N. Maruyama and Ms. S. Kubo (Department of Molecular Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo) for their helpful discussion. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this letter. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Author Contributions: Study design and concept: TS, HT. Acquisition of subjects and data: TS, YN, MY, KH, YT, HM, TN, HT. Analysis and interpretation of data: YN, HT. Preparation of manuscript: HT. TS and YN contributed equally to this study. Sponsor's Role: The authors did not have any financial sponsor for the present research.
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Sugawara et al. (2009) studied this question.
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