Medication adherence has a tendency to increase around the time of follow-up visits, a phenomenon known as “white coat compliance.”1 By scheduling a follow-up visit shortly after starting therapy, physicians may be able to stimulate patients to maintain an appropriate level of adherence. We performed a randomized clinical pilot study to assess the impact of an early follow-up visit as a means of improving patient adherence to topical therapy.
After receiving approval from the Wake Forest University institutional review board, we enrolled 30 subjects with moderate to severe atopic dermatitis (AD) in a randomized, open-label pilot study. Subjects, aged 2 to 15 years, were required to have AD affecting more than 5% of their body surface area and a moderate or severe rating by Investigator Global Assessment (IGA)2 (scale, 0-4). Subjects were excluded if they had used other prescription therapies for AD within 2 weeks of enrollment.
Subjects were randomized to 1 of 2 groups. Subjects in the extra visit group were scheduled follow-up visits at weeks 1 and 4. Subjects in the control group were scheduled only for a week 4 visit. All subjects were given topical tacrolimus, 0.03%, ointment (Protopic; Astellas Pharma US Inc, Deerfield, Illinois) to apply to affected body areas twice daily for 4 weeks.
Adherence was assessed by Medication Event Monitoring Systems (MEMS; Aardex Corp, Fremont, California) cap technology. The MEMS cap has a microprocessor inside that records the date and time of every tube opening. Clinical efficacy was assessed at each visit using the IGA, the Eczema Area and Severity Index (EASI),3 and a 100-mm visual analog scale (VAS) of itch intensity.
All statistics were performed using SAS statistical software, version 9.1 (SAS Institute, Cary, North Carolina).
Treatment with tacrolimus, 0.03%, ointment was well tolerated, and no serious adverse events were reported. Thirty subjects were enrolled in the 4-week study (Table). Twenty-six subjects completed the study and were evaluated for clinical efficacy, and 20 of these 26 had usable MEMS data for adherence analysis (Figure 1).
CONSORT flow diagram. Dropout rates and adverse events were similar between the 2 groups. Several of the subjects in the control group either failed to return the medication tubes or otherwise did not have usable MEMS data (Medication Event Monitoring Systems; Aardex Corp, Fremont, California). It may be that these subjects had even worse adherence.
Adherence ranged from 39% to 114% in the extra visit group and 15% to 79% in the control group. Overall, mean adherence was 69% in the extra visit group and 54% in the control group. Mean adherence in the extra visit group decreased from 88% at week 1 to 50% by week 4, while mean adherence in the control group decreased from 83% at week 1 to 43% by week 4 (Figure 2). The difference in percentage adherence between the groups did not reach statistical significance (Kruskal-Wallis test, P > .05). No correlation was found between adherence and clinical outcomes or between baseline disease severity and adherence.
Mean adherence over time. We assessed adherence behavior in the 2 study groups at each week of the study. Over 4 weeks, adherence rates decreased in both groups. While there was a large drop in adherence in the control group by week 2, this difference did not reach statistical significance at any time (Wilcoxon rank sum and Kruskal-Wallis tests, P > .05 at each time point). Adherence of 100% required twice-daily applications.
Baseline severity was similar between the 2 groups (Kruskal-Wallis test for difference in IGA, VAS, and EASI scores between groups, P > .10). Both groups had significant improvements in all assessments by week 4 (P ≤ .01). There was no difference between the groups in the percentage of subjects achieving clear or almost clear status on IGA (Fisher exact test, P > .10). The mean percentage improvement in the VAS and EASI scores for the control group were 36% and 45%, respectively (Figure 3). The mean percentage improvement in the VAS and EASI scores for the extra visit group were 65% and 76%, respectively. The extra visit group showed better improvements in outcomes than the control group, although the difference did not reach statistical significance (P = .06 for the difference in EASI outcomes).
Mean percentage improvement in objective assessments. Both groups had significant improvements in all assessments by week 4 (Wilcoxon signed rank test, P ≤ .01). There was a better mean percentage improvement in the extra visit group, but the difference did not reach statistical significance (Wilcoxon rank sum test, P = .06). Error bars indicate 95% confidence intervals, and negative improvement indicates worsening assessment.
Nonadherence rather than nonresponse is a common cause of treatment failure in children with AD. Forgetfulness, change in disease severity, lack of efficacy, and fear of potential medication adverse effects are common reasons for medication nonadherence.5- 6 In our study, it is possible that the increased adherence noted at 1 week led to disease improvement, which then suppressed adherence later in the month.
This pilot study was not powered to detect small differences in adherence or outcomes. The better adherence in the extra visit group, while not statistically significant, suggests an opportunity to improve outcomes using an extra office visit. This study provides important preliminary data that can be used to power a larger and longer trial to confirm these hypotheses.
Correspondence: Dr Yentzer, Department of Dermatology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1071 (firstname.lastname@example.org).
Accepted for Publication: June 2, 2010
Author Contributions: Dr Feldman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Clark and Feldman. Acquisition of data: Williams, Clark, Taylor, and Feldman. Analysis and interpretation of data: Sagransky, Yentzer, and Feldman. Drafting of the manuscript: Sagransky and Feldman. Critical revision of the manuscript for important intellectual content: Yentzer, Williams, Clark, Taylor, and Feldman. Statistical analysis: Yentzer and Feldman. Obtained funding: Feldman. Administrative, technical, and material support: Sagransky, Yentzer, Williams, Clark, Taylor, and Feldman. Study supervision: Feldman.
Funding/Support: Support for this study was provided by Astellas Pharma US Inc.
Financial Disclosure: Dr Feldman has received research, speaking, and/or consultant support from Galderma, Connetics Corporation, Astellas, Abbott Labs, Warner Chilcott, Centocor, Amgen, Photomedex, Genentech, Biogen Idec, Coria, Pharmaderm, Dermatology Foundation, American Society for Dermatologic Surgery, National Psoriasis Foundation, Ortho Pharmaceuticals, Roche Dermatology, 3M, Bristol-Myers Squibb Dermatology, and Novartis.
Role of the Sponsors: The sponsor had no role in the conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and
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