Trends in Compliance With Bronchodilator Inhaler Use Between Follow-up Visits in a Clinical Trial

Abstract

Study objectiveTo assess objectively measured, long-term trends in compliance with physician-prescribed metered-dose inhaler (MDI) use during a clinical trial.DesignA prospective study.SettingThe Lung Health Study, a 5-year clinical trial to determine the effect of special intervention with an intensive smoking cessation program and bronchodilator therapy in cigarette smokers 35 to 60 years of age with minimal to moderate airflow limitation due to COPD.ParticipantsTwo hundred thirty-one participants who were issued an MDI with an attached Nebulizer Chronolog (NC) (Forefront Technologies Inc; Lakewood, Colo) which electronically records the date and time of each MDI actuation. One hundred two participants were not informed of the recording capabilities of the attached NC, while 129 participants were aware of the NC's monitoring function.InterventionFollowing an initial 12-week period of counseling, participants returned to the clinic every 4 months.Measurements and resultsAnalysis of the data from the NC collected over a period of 2 years indicates that compliance with the prescribed medication regimen was best immediately following each follow-up visit and gradually declined during the interval between follow-up visits. The level of compliance after each visit was lower for each successive follow-up. These trends could not be observed from self-report or weighing the medication canisters at follow-up visits. The participants who were informed of the NC's function and who were provided with detailed feedback about their inhaler use generally showed better compliance. To assess objectively measured, long-term trends in compliance with physician-prescribed metered-dose inhaler (MDI) use during a clinical trial. A prospective study. The Lung Health Study, a 5-year clinical trial to determine the effect of special intervention with an intensive smoking cessation program and bronchodilator therapy in cigarette smokers 35 to 60 years of age with minimal to moderate airflow limitation due to COPD. Two hundred thirty-one participants who were issued an MDI with an attached Nebulizer Chronolog (NC) (Forefront Technologies Inc; Lakewood, Colo) which electronically records the date and time of each MDI actuation. One hundred two participants were not informed of the recording capabilities of the attached NC, while 129 participants were aware of the NC's monitoring function. Following an initial 12-week period of counseling, participants returned to the clinic every 4 months. Analysis of the data from the NC collected over a period of 2 years indicates that compliance with the prescribed medication regimen was best immediately following each follow-up visit and gradually declined during the interval between follow-up visits. The level of compliance after each visit was lower for each successive follow-up. These trends could not be observed from self-report or weighing the medication canisters at follow-up visits. The participants who were informed of the NC's function and who were provided with detailed feedback about their inhaler use generally showed better compliance. analysis of variance Johns Hopkins University metered-dose inhaler Nebulizer Chronolog special intervention usual care University of California, Los Angeles Clinical trials to determine the efficacy of new treatments or to test novel applications of established treatments depend not only on a rigorous, carefully executed protocol, but also on the full cooperation of the trial subjects. Participants are responsible for daily self-administration of the study treatment at the prescribed intervals and for reporting of adverse events. It is well known that patient compliance with prescribed medication regimens is frequently less than optimal.1Cramer JA Overview of methods to measure and enhance patient compliance.in: Cramer JA Spilker B Patient compliance in medical practice and clinical trials. Raven Press, New York1991: 3-10Google Scholar Poor compliance can affect the outcome of long-term clinical trials, possibly leading to inaccurate assessment of the treatment under investigation. However, self-report, the most commonly used method of assessing compliance, is frequently misleading, even among honest, well-intentioned study subjects.2Spector SL Kinsman R Mawhinney H et al.Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials.J Allergy Clin Immunol. 1986; 77: 65-70Abstract Full Text PDF PubMed Scopus (159) Google Scholar, 3Waterhouse DM Calzone KA Mele C et al.Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring.J Clin Oncol. 1993; 11: 1189-1197Crossref PubMed Scopus (286) Google Scholar Some objective methods of monitoring compliance, such as pill counts and inhaler canister weighings, are not only frequently inaccurate but also are not sensitive to trends in compliance over time and do not indicate whether the medication was taken at the prescribed times during the day.3Waterhouse DM Calzone KA Mele C et al.Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring.J Clin Oncol. 1993; 11: 1189-1197Crossref PubMed Scopus (286) Google Scholar, 4Cramer JA Mattson RH Prevey ML et al.How often is medication taken as prescribed?: a novel assessment technique.JAMA. 1989; 261: 3273-3277Crossref PubMed Scopus (983) Google Scholar, 5Rudd P Byyny RL Zachary V et al.The natural history of medication compliance in a drug trial: limitations of pill counts.Clin Pharmacol Ther. 1989; 46: 169-176Crossref PubMed Scopus (182) Google Scholar, 6Rand CS Wise RA Nides M et al.Metered-dose inhaler adherence in a clinical trial.Am Rev Respir Dis. 1992; 146: 1559-1564Crossref PubMed Scopus (295) Google Scholar Using a Nebulizer Chronolog (NC) (Forefront Technologies Inc; Lakewood, Colo)2Spector SL Kinsman R Mawhinney H et al.Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials.J Allergy Clin Immunol. 1986; 77: 65-70Abstract Full Text PDF PubMed Scopus (159) Google Scholar, 7Gong H Simmons MS Clark VA et al.Metered-dose inhaler usage in subjects with asthma: comparison of Nebulizer Chronolog and daily diary recordings.J Allergy Clin Immunol. 1988; 82: 5-10Abstract Full Text PDF PubMed Scopus (54) Google Scholar attached to metered-dose inhalers (MDIs), we electronically recorded each use of inhaled medication in a 5-year clinical trial (the Lung Health Study) in order to examine the patterns of use of the medication and objectively measure compliance with the prescribed medication protocol over the entire duration of the trial. Each individual in a subgroup of the study participants was provided with feedback of his/her actual inhaler usage data to permit us to examine the effect of such detailed feedback on deviations from the prescribed medication protocol as compared to a control group. Data collected over the first 24 months of the clinical trial are included in this report. Because of the large size of the study sample and the long period of data collection, this study provides a unique opportunity to investigate objectively measured patterns of medication usage in a clinical trial. The aims of the current study were to determine (1) whether and to what extent compliance drops off over the interval between study visits, (2) whether follow-up visits improve compliance, (3) whether follow-up visits later in the study are more or less effective in improving compliance, and (4) whether any such changes in compliance are affected by feedback on the participant's inhaler use. The Lung Health Study, sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health, is a 5-year clinical trial to determine the effect of special intervention with an intensive smoking cessation program and bronchodilator therapy in cigarette smokers 35 to 60 years of age with minimal to moderate airflow limitation due to COPD.8Anthonisen NR Connett JE Kiley JP et al.Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1-the Lung Health Study.JAMA. 1994; 272: 1497-1505Crossref PubMed Scopus (1762) Google Scholar, 9Connett JE Kusek JW Bailey WC et al.Design of the Lung Health Study: a randomized clinical trial of early intervention for chronic obstructive pulmonary disease.Control Clin Trials. 1993; 14: 3-19Abstract Full Text PDF PubMed Scopus (106) Google Scholar The subject population and study procedures have been described previously.8Anthonisen NR Connett JE Kiley JP et al.Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1-the Lung Health Study.JAMA. 1994; 272: 1497-1505Crossref PubMed Scopus (1762) Google Scholar Participants were randomly assigned to either of two groups: “usual care” (UC) or “special intervention” (SI). UC subjects (n=1,964) were contacted annually for repeated pulmonary function testing and determination of smoking status. SI subjects (n=3,923) were entered into an intensive group smoking cessation program with frequent contacts and follow-up visits to the study clinic every 4 months. At each follow-up visit, a questionnaire was administered that included questions about smoking status and inhaler use, and the inhaler canisters returned by the participants were weighed to determine the amount of medication that was used. Pulmonary function testing was repeated annually. SI subjects were also given an MDI containing either ipratropium bromide, an anticholinergic bronchodilator, or placebo by double-blind random assignment in order to evaluate the effect of such medication on the progression of COPD. They were instructed to use the MDI two inhalations three times per day. Two of the ten centers, the University of California, Los Angeles (UCLA) and Johns Hopkins University (JHU), participated in this ancillary study of inhaler compliance. A total of 1,117 participants were enrolled in the Lung Health Study at these two centers, 500 participants at UCLA (167 UC and 333 SI participants), and 617 participants at JHU (206 UC and 411 SI participants). Two hundred forty-one consecutively enrolled SI participants at both centers (91 at UCLA and 150 at JHU) received an inhaler with an attached NC, which electronically records the date and time of each MDI actuation. Ten participants were subsequently dropped from the analysis because they had no usable NC readings throughout the study due to technical problems, primarily battery failure and other electronic problems, and missed visits (three at UCLA and seven at JHU), leaving 231 participants in the study. One hundred two of these participants (46 at UCLA and 56 at JHU) were not informed of the date- and time-recording capabilities of the attached NC (“control” group), although they were aware that the NC would be monitoring the total amount of medication used. One hundred twenty-nine participants (42 at UCLA and 87 at JHU) were aware of the NC's exact monitoring function (“feedback” group). In the feedback group, the readings of actuation dates and times from the NC were used for feedback during the first and tenth weeks following their smoking cessation group's “quit” date and at each 4-month follow-up in an effort to enhance compliance with the prescribed medication regimen. Assignment to the NC study groups (control or feedback) was made by smoking cessation class; an entire class was assigned to either the control or feedback condition in order to avoid inadvertent unblinding of participants through interactions with classmates. Classes were first assigned to the control condition until all control participants were enrolled, with all subsequent enrollments to the feedback condition. This article reports on the first 2 years of data collection.The subjects were instructed to use their inhalers three times each day, taking two inhalations each time 1 to 5 min apart. To evaluate the pattern of inhaler use, all NC actuations were divided into daily sets of use, which is a measure of the number of separate times that the inhaler is used each day, with each day considered to begin at 4 AMto account for late-night inhaler use before going to bed. Starting with the first inhaler actuation, any actuation that occurs within a 3-h period is counted as a part of the same set. Mean sets per day for each 2-week interval following initial issuance of the NC and following each follow-up visit were calculated. In both the control and feedback groups, changes in patterns of use following each follow-up visit were evaluated by changes in the mean sets per day. The difference between the first and last 2-week period of each follow-up interval was used to assess the change during the intervisit interval, while the effect of the follow-up visit on compliance was evaluated within and between both groups by comparing the compliance during the last 2-week period before the follow-up visit with compliance during the first 2-week period after the follow-up visit. Unpaired t tests were used to compare the means of the control and feedback groups at each comparable follow-up period. Comparisons of the means of 2-week intervals within groups were made using paired Student's t tests. In the subset of participants who returned to the clinic and had usable data for every follow-up visit, repeated measures analysis of variance (ANOVA) was used to compare the means of the control and feedback groups (between-subject effect), the means of all of the follow-up effect), and the between these tests were used to compare the feedback and control groups with to the number of participants compliance or after each follow-up visit from the compliance measured during the with a less than were considered to be were using a 1 and Scholar The participants who were issued an NC were in follow-up visits during the study period. follow-up visits were from analysis due to technical the data from the NC or failure of participants to the NC to the clinic for the NC 35 follow-up visits for which the interval between visits from the interval by the study protocol or were also A of follow-up visits were from analysis for both the feedback and Ten participants had no usable NC leaving 231 participants for participants in the control group and 129 in the feedback group. participants who had data for analysis from all visits were included in the repeated measures comparing the compliance and decline between participants had data for the of in compliance, which the NC in order to assess the effect of the follow-up visit. of the 231 participants used in the analysis were for follow-up before their follow-up visit, in the feedback group and in the control group The of subjects in each group who were for follow-up were not SL Kinsman R Mawhinney H et al.Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials.J Allergy Clin Immunol. 1986; 77: 65-70Abstract Full Text PDF PubMed Scopus (159) Google Scholar of the between the feedback and control groups that the control group was than the feedback group Student's t had a lower of Student's t and was more to a bronchodilator SL Kinsman R Mawhinney H et al.Compliance of patients with asthma with an experimental aerosolized medication: implications for controlled clinical trials.J Allergy Clin Immunol. 1986; 77: 65-70Abstract Full Text PDF PubMed Scopus (159) Google Scholar were no between the groups in of pulmonary and or cigarette smoking The mean of sets per day are in 1 for each subject group and each 4-month follow-up period. Data for each follow-up period inhaler usage during the 4 months. use was in the feedback group than in the control group during all follow-up considered t to or among the subset with data for all visits was between group and follow-up period. The means of the and follow-up were to from the immediately subsequent to as of of per for Each for t test comparison of control feedback in the number of subjects in data were for the follow-up in the number of subjects in data were for the follow-up for t test comparison of control feedback in the number of subjects in data were for the follow-up period. in a new during the first 4-month follow-up period sets per was for the subjects who were in the study after 24 months than for who had dropped to for their follow-up the feedback means for the first 4-month follow-up period were and sets per day for the and dropped Student's t The control subjects had means of and sets per day for the and dropped Student's t The mean number of sets per day for each 2-week interval following initial issuance of the NC and each follow-up visit is in 1 for control and feedback The means for to 24 weeks after each follow-up visit the subset of participants who were for their follow-up visit. use was to the prescribed three sets per day immediately after issuance of the NC of the 4-month the feedback subjects initial compliance than the control subjects. both groups, inhaler use the decline during the first weeks after the NC was The control group a decline in inhaler use throughout the first 4-month follow-up period than the feedback group. compliance immediately following the 4-month follow-up visit of the but group's inhaler use returned to the level of use at the of the study. subjects showed more in inhaler use following the 4-month visit than the control group. The level of compliance immediately after each follow-up visit was lower in each successive visit in both groups, the in compliance between visits to be most during the follow-up the of the two groups over the first to weeks of all but the first 4-month interval were the feedback group a level of inhaler use throughout all follow-up were the data from each were in inhaler usage from the first 2-week period after each follow-up visit to the last 2-week period before the follow-up visit are in between the first and last 2-week intervals were at all follow-up for both groups Student's t to were between groups, and no was between group and follow-up period in to the difference in sets of actuations per for paired t test comparison of first 2-week interval last 2-week for paired t test comparison of first 2-week interval last 2-week in the number of subjects in data were for the follow-up in the number of subjects in data were for the follow-up Mean difference in sets of actuations per for paired t test comparison of first 2-week interval last 2-week in the number of subjects in data were for the follow-up period. in a new The in the mean sets per day between the 2-week intervals immediately before and immediately after each follow-up visit are in for each subject group and follow-up visit. in mean sets per day were immediately following all follow-up visits for both groups Student's t to were between the in the the to the the difference in sets of actuations per for paired t test comparison of last 2-week interval before visit first 2-week interval after for paired t test comparison of last 2-week interval before visit first 2-week interval after visit. in the number of subjects in data were for the follow-up in the number of subjects in data were for the follow-up Mean difference in sets of actuations per for paired t test comparison of last 2-week interval before visit first 2-week interval after in the number of subjects in data were for the follow-up period. in a new were using mean with each daily inhaler usage as either or day was as any day that two to sets with at two of the sets of two or three were to with the analysis of mean sets per day. Using the NC to MDI usage in a clinical we that compliance with the physician-prescribed bronchodilator MDI protocol over the period. during the 4-month intervals between follow-up visits, but immediately after each of the visits. This pattern was most early in the with participants who received feedback about their actual MDI usage a level of compliance throughout the trial. These be affected by by to the long duration of the missed or visits and over the of the study. The in compliance at later times to 24 in each follow-up period in 1 be due in part to the that the participants who returned for their follow-up clinic visits after the time of the visit to be the data in the later weeks of each follow-up period are collected from a of who are in the pattern of compliance during the later follow-up could also be affected by the of the as by the compliance during the initial 4-month period of who in the study for the full 24 months as compared to who dropped This could compliance later in the study to than that which would have been had the participants not dropped of the NC study. this would compliance to to be with a throughout the follow-up intervals than the participants had in the study. microelectronic monitoring of the used in this study can an of the date and time of each actuation of the determine of the medication was have patterns of that have been as a to the by of study medication to clinic P Byyny RL Zachary V et al.The natural history of medication compliance in a drug trial: limitations of pill counts.Clin Pharmacol Ther. 1989; 46: 169-176Crossref PubMed Scopus (182) Google Scholar, 6Rand CS Wise RA Nides M et al.Metered-dose inhaler adherence in a clinical trial.Am Rev Respir Dis. 1992; 146: 1559-1564Crossref PubMed Scopus (295) Google Scholar, Simmons MS et inhaler adherence in a clinical trial through the use of the Nebulizer 1993; Full Text Full Text PDF PubMed Scopus Google Scholar a and pattern of inhaler actuations is that a subject would to the medication after taken the to the study Some between these two The in the study that compliance during the interval between follow-up visits in a clinical trial is with Using an electronic pill Cramer et JA Mattson RH between clinic PubMed Google Scholar that in a group of patients with the compliance with medication prescribed for control during the interval between clinic visits. et et in drug following of intervals between clinic Scopus Google Scholar observed in drug and status the interval between clinic visits was in a group of patients on regimens of that compliance had during the interval between clinic visits. The these of the patterns of compliance to a clinical trial In to the decline observed during the first 4 months of the the rate of decline during subsequent follow-up for the feedback group. In a on data from only the first 4-month follow-up interval of the Nides et Simmons MS et inhaler adherence in a clinical trial through the use of the Nebulizer 1993; Full Text Full Text PDF PubMed Scopus Google Scholar that compliance was among subjects who were aware that their MDI use was electronically and received feedback on actual MDI usage records between the follow-up visits compared to the control group. This article the of this difference during subsequent follow-up In the the effect of the follow-up visit in the subjects given feedback compared to subjects who were of the exact monitoring of the The compliance of the feedback group after the initial follow-up visit could be due at in part to in their by the feedback that they in be at for the duration of the study. for these could be that after the initial follow-up the feedback group's compliance was not because of a effect of informed of their individual MDI usage patterns at the follow-up visit, but because they were aware of the full monitoring of the Because compliance following all visits for the control group and the feedback group, the follow-up visits to have the participants to to the prescribed inhaler protocol whether or not they the full extent of the NC's monitoring It is that between follow-up visits by or also to improve compliance, but this was not by the study. The from the study have implications for the of data from long-term clinical trials. It is not to analysis to only in a study compliance in all subjects. compliance the of of compliance throughout a clinical trial on the compliance during the interval between clinic visits, this affect the of outcome measured only at the clinic visits or by the subjects throughout this period of drug The in drug use to the clinic visit by JA Mattson RH between clinic PubMed Google Scholar, M et al.Compliance with 1986; Full Text PDF PubMed Scopus Google Scholar the in a long-term study to a of The in objectively compliance over the of a clinical trial months or even in the of feedback with compliance monitoring is an of this study. to compliance in a long-term clinical be that compliance be and decline over feedback on objective compliance monitoring can improve compliance but not be The decline in compliance between clinic visits be by more frequent visits to the but this not be However, the that medication use is in be to improve compliance. also that compliance monitoring be in clinical trials, a in compliance can later in the study that is not as to be by a clinic visit. In both the feedback and control groups after the first 4-month follow-up visit, be to compliance early in the of clinical treatment or a clinical trial. However, the of data in due to missed clinic visits and technical with the NC, that not to depend on electronic for compliance These the for microelectronic and other for and monitoring compliance. The to for in the study protocol and for and the NC data at the JHU