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Multiple Dose Regimens* Impact on Compliance Donald P. Tashkin, MD, FCCP A new metered-dose inhaler (MDI) formulation (Combivent) combines a f2-adrenergic agonist (albuterol) and a quaternary anticholinergic compound (ipratropium bromide) for maintenance bronchodilator therapy of the reversible obstructive component of symptomatic COPD. This product was developed because of the expectation that combining two frequently prescribed regularly scheduled inhaled bronchodilator medications into one MDI would improve patient compliance with prescribed therapy by rendering the treatment regimen less complex and more convenient, thereby resulting in better disease control. The purpose of this report is to consider the evidence concerning the validity of this concept and, more broadly, to review the factors that influence compliance with prescribed medication, particularly when complex, multiple drug regimens are prescribed. While multiple drug regimens are often required for adequate or optimal management of chronic respiratory diseases, including tuberculosis, asthma, and COPD, the goals of therapy are often undermined by poor patient adherence to the prescribed regimen. For tuberculosis, the consequences of poor compliance can be dire indeed for both the patient's health (treatment failure, drug resistance, drug toxicity) and public health (failure to eliminate the disease, increased drug resistance in the community, prolonged communicability and adverse effects on high-risk populations, such as patients with AIDS).1 Compliance with prescribed treatment is also a crucially important factor in asthma management, for which more than one agent is often prescribed. Multiple drug regimens in asthma are also complicated by the need to distinguish between regularly scheduled prophylactic agents (such as inhaled antiinflammatory compounds) and drugs that are used primarily for rescue (inhaled d-agonists) or for rescue in addition to maintenance use. The consequences of poor compliance in asthma include increased morbidity and possibly mortality due to asthma and increased personal and public expense for health care.I Trom the Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles. Reprint requests: Dr. Tashkin, Dept of Medicine, UCLA School of Medicine, 10833 LeConte, Los Angeles, CA 90095-1690 176S In COPD, as in asthma, different classes of drugs are often used in combination and in regimens requiring multiple daily doses of each agent, so that the resulting dosage schedules can be quite complex. While it has been suggested that complex treatment regimens should result in poor compliance,2 few studies have specifically addressed the impact on compliance of multiple drug regimens. In COPD, compliance with prescribed treatment in general has not been well investigated, while compliance studies in asthma have focused more on the impact of the frequency of dosing of a single drug rather than on the impact of the number of different drugs. In addressing the question of the impact of multiple dose regimens on compliance, this article will define compliance, consider the different methods of assessing compliance, review data concerning the frequency of noncompliance in patients with asthma and COPD, discuss current concepts concerning the factors responsible for poor compliance, and finally consider methods of enhancing compliance. DEFINITION "Compliance" with prescribed therapy, sometimes referred to as "adherence," is defined simply as following the instructions of the health-care provider. Compliance can be total, partial, nil, or erratic. Patients can also be overcompliers or undercompliers. METHODS OF ASSESSING COMPLIANCE The definition of compliance in any given patient is dependent on the method of assessing compliance. The various methods of assessing compliance include self-report (history taking, diaries, questionnaires, self-report scales), medication measurement (interval pill counts, weighing of MDls), biochemical validation, and electronic medication monitors (pill dispensers, MDIs, eyedroppers). Self-report measures are notorious for underestimating true compliance.3'4 Pill counts and weighing of inhaler canisters are also unreliable measures of adherence,5'6 particularly if patients fail to bring their medication with them at the time of their clinic visit or if participants in a clinical trial attempt to deceive their physician by emptying their pill bottles or "dumping" the contents Innovations in Combination Bronchodilator Therapy Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21714/ on 05/11/2017 Percent 80 * NC E Self-Report N=93 706050- 4030- 20_ 100-L - 1.4 D1.5 Mean IJses Per Day FIGURE 1. Self-reported mean daily inhaler use compared with use determined by an electronic monitoring device (Nebulizer Chronolog [NC]), calculated as NC "sets." Mean daily NC sets of -2.5 are classified as three uses per day, 1.5 to 2.4 sets are classified as two uses per day, 0.5 to 1.4 sets as one use per day, and <0.5 sets per day as less than one use per day (adapted from Rand et al,'0 with permission). < M5.e of the inhaler just prior to the clinic visit.6,7 Biochemical validation is not technically feasible with many compounds for which assays are not readily available and especially with inhaled agents which are associated with only limited systemic absorption. Moreover, results of blood and urine tests for therapeutic drug monitoring are influenced by variable drug absorption, metabolism, and clearance. Furthermore, such tests may give rise to an inaccurate impression of overall compliance with prescribed therapy because levels of short-acting drugs reflect only recent dosing and provide no information on drug-taking behavior several days before the test. Blood or urine drug assays may also overestimate compliance since patients are sometimes relatively more compliant just prior to a clinic visit than at other times (analogous to the "toothbrush effect" prior to a dental visit).8 Electronic medication monitors provide the most accurate information concerning actual compliance with prescribed drug therapy. A variety of microelectronic monitors are currently available.9 These include pill box monitors and medication event monitoring systems that record the opening of a box or a bottle to remove tablets or capsules, an eyedrop monitor that records inversion of the bottle dispensing the ophthalmic solution, and various electronic monitors that record the time and date of each actuation of an inhaler (Nebulizer Chronolog).37'10 Although these devices provide more accurate information regarding patient compliance than the other adherence measures, a drawback of most of these electronic monitors is that although they record that medication was removed from a box, bottle, or inhaler canister, they do not document that the medication was actually used, ie, ingested, applied to the eye, or inhaled. However, newer electronic devices that incorporate a flow sensor do have the capability of tracking actual inhaler use. QUANTITATION OF COMPLIANCE Quantitation of compliance with inhaled medication is possible with electronic monitoring devices. These devices allow calculation of a number of quantitative indices of adherence, such as the following: (1) the mean number of inhalations per day; (2) the average number of separate times the inhaler is used per day ("sets"); (3) the mean number of actuations per "set" (which can also be expressed as the percentage of the number of actuations prescribed); (4) the number of days on which actual use conformed with prescribed use ("compliant days") (which can also be expressed as a percentage of the total number of monitored days); and (5) the percentage of "noncompliant" days, ie, days with less than (underuse) or more than (overuse) the prescribed number of inhalations. Using these objective measures, 'overall compliance" over a given time interval can be defined as appropriate use on more than a specified percentage (eg, 75%) of monitored days. Morever, these data can be plotted against time to provide information on patterns and trends in compliance over time. A recent study'0 provides an example of the use of an electronic monitoring device (Nebulizer Chronolog, Medtrac Technologies; Lakewood, Colo) for assessing compliance with inhaled medication in a clinical trial. The study sample consisted of 95 participants (35 to 59 years of age) from two of ten clinical centers conducting a clinical trial of early intervention in COPD. Subjects were prescribed ei- Percent : :45: 50 0 Canister Wt NC Functional Wt N095 0 40 35302520- 15 10 0 Over GodStsatr or Vr oor Compliance Level FIGURE 2. Canister-weight determined compliance level compared with NC-weight-determined compliance level. Canister weight for each participant is the difference between the issue and return weights of all canisters issued to that participant. NC weight is the percentage of inhalations taken as prescribed multiplied by the measured change in canister weight. Over >11I0%; good=86 to 110%; satisfactory=50 to 85%; poor=25 to 49%; and very poor= <25% of prescribed use (adapted from Rand et al,'0 = with permission). CHEST / 107 / 5 / MAY, 1995 / Supplement Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21714/ on 05/11/2017 177S ther ipratropium bromide or placebo MDI in a dose of two inhalations three times daily. Compliance was monitored over at least the first 4 months by the electronic monitoring device, self-report, and canister weighing. Results are shown in Figures 1 and 2. Figure 1 illustrates the marked disparity between the mean number of inhaler uses per day reported by the participants vs that recorded by the electronic monitoring device. While 73% of the participants reported using the inhaler an average of three times daily, only 15% actually used their inhaler an average of 2.5 or more times per day according to the electronic monitoring device. The superiority of the electronic monitoring device over canister weighing is illustrated in Figure 2 which demonstrates that good compliance is overestimated and poor compliance is underestimated by canister weighing since only 62% of the inhaler uses detected by the electronic monitoring devices contained the prescribed two actuations. This drawback of canister weighing is that canister weights provide only a global indication of overall averaged inhaler use and fail to take into account inappropriate overuse or underuse of the inhaler at each of the specified times of the day that the inhaler is prescribed. FREQUENCY OF COMPLIANCE The frequency of poor compliance has been estimated to range from 20 to 80% ,1112 although these estimates are based largely on inaccurate adherence measures, such as self-report or pill counting. Moreover, compliance rates may differ depending on the patient population that is studied, the type and severity of disease, and the nature and complexity of the treatment regimen. DETERMINANTS OF COMPLIANCE A number of factors have been shown to influence compliance with prescribed therapy, as reviewed by Mellins et al.13 Factors not believed to be important include age (except for old age associated with impaired memory), gender, educational level or socioeconomic status, personality traits, and various disease characteristics, such as diagnosis (except for mental illness and alcoholism), severity or frequency of symptoms, medication side effects, and the physician's prediction of compliance. However, a number of factors appear to be associated with improved compliance. These include the following: (1) a relatively simple treatment regimen (ie, one in which the frequency of dosing, number of prescribed drugs, duration of treatment, and requirement for behavior change have been minimized); (2) a stable family that provides positive support for medication compliance; (3) patients' health beliefs that their disease is serious, 178S their well-being is threatened, the proposed treatment will be effective, and there are no cogent reasons not to implement the medication regimen; (4) patient understanding of the rationale for treatment and the details of the treatment plan; and (5) various aspects of the patient-physician relationship. The latter include the provision of continuity of care, written instructions concerning how and when the prescribed medication is to be used, close supervision of the patient's medication use, and patient satisfaction with the care provided. COMPLEXITY OF THE TREATMENT REGIMEN: IMPACT ON COMPLIANCE Older Studies A number of studies have evaluated the impact on compliance of more or less complex medication regimens, consisting of one or more different drugs prescribed one or more times a day. A widely cited early study14 examined the impact on noncompliance of the frequency of dosing with a tricyclic antidepressant in chronically ill medical and psychiatric outpatients who spanned a broad age range (20 to 65 years). Compliance was assessed by pill counts and self-report. Noncompliance, which was defined liberally as failure to take 25 to 50% of the prescribed dose, increased dramatically with an increase in the frequency of prescribed dosing: 70%, four times daily; 60%, three times a day; 30%, twice daily; and 20%, once daily. No differences in adherence were noted between the patients with medical and psychiatric conditions; also, side effects to medication did not appear to impact on compliance. In contrast to the inverse relationship between compliance and the number of times each day medication was prescribed, when two drugs were ingested together, compliance was similar to that for a single drug. However, as the number of drugs prescribed increased, especially if each had to be taken three or more times daily, compliance decreased proportionately. For example, more than 80% of patients prescribed four or more drugs three or more times a day did not take 25 to 60% of the prescribed dose of each drug. Older patients were noted to default most often, particularly with complex regimens. Gatley15 conducted a "pill-count" survey of the number of tablets taken as a percentage of the prescribed dosage by 86 patients with general medical conditions followed up by a single practitioner. Results were generally similar to those reported by Ayd,'4 although compliance was defined more strictly as taking 95 to 105% of the tablets prescribed. Compliance was best with once-daily dosing (67%) and fell progressively to only 22% with a four-times-a-day regimen. No difference in compliance was noted Innovations in Combination Bronchodilator Therapy Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21714/ on 05/11/2017 Table 1-Compliance Rates for Prescribed Dosing Regimens* Dosaget Patients Mean No. of Days Observed qd bid tid qid All 3 12 7 191 161 102 4 26 52 132 No. of Mean (SD) Compliance 87§ (11) 8111(17) 7711(12) 39 (24) 76 (21) Rate, % I Range, % 73-99 44-100 52-90 3-68 3-100 *From Cramer et al.20 fqd indicates once daily; bid, twice daily; tid three times a day; and qid, four times a day. 1p<0.01 by analysis of variance. §p<0.01 vs qid group by Student's t test with Bonferroni multiple comparison correction. 110.05 vs qid group by Student's t test with Bonferroni multiple comparison correction. when two tablets, instead of one, were prescribed four times daily (25% vs 22%, respectively). The latter findings are in agreement with those of Ayd'4 and suggest, at least for oral medication, that frequency of dosing during the day is a more important determinant of compliance than the number of different drugs prescribed. Conflicting results were reported by Weintraub et al'6 who used self-report and serum digoxin concentrations to assess compliance in 101 outpatients with congestive heart failure treated with either digoxin alone or digoxin plus a diuretic. Patients for whom two medications were prescribed were found to demonstrate a lower compliance rate (60%) than those for whom only a single drug was prescribed (82%), suggesting that in at least some groups of patients, the number of prescribed drugs does influence adherence. Latiolais and Berry'7 used self-report to assess compliance in a broad variety of 180 patients with medical conditions and patients who had undergone surgery among whom noncompliance was 43% overall. The average number of medications prescribed for noncompliant patients (2.7) exceeded that prescribed for the compliant outpatients (1.8). Moreover, in 800 pediatric outpatients, Francis et al'8 found that compliance was significantly less when three or more medications were prescribed com- pared with one to two medications. One of two studies comparing the antihypertensive efficacy of one-tablet combination drug therapy with the same ingredients (hydrochlorothiazide, reserpine, and hydralazine) administered as three separate tablets'9 found the combination tablet to provide significantly better control of hypertension. Although compliance was not specifically assessed, the superior outcome of the combination regimen was attributed to enhanced compliance. Taken together, these findings provide further support for the view that the number of separate drugs prescribed is an important determinant of compliance. The meaningfulness of conclusions drawn from the older studies cited above concerning the influence of dosing frequency and number of prescribed drugs on compliance may be questioned because inaccurate methods were used for assessing adherence (selfreport, pill counts). Moreover, most of these studies were retrospective, uncontrolled, and limited to a short time span and failed to take dropouts into account. Newer Studies More recent investigations have avoided some of the pitfalls of older studies by relying on microelectronic monitoring devices for a more accurate objective assessment of compliance. For example, Cramer and colleagues20 used an electronic pill bottle dispensing system (Medication Event Montoring Systems [MEMS], Aprex Corporation, Fremont, Calif) to assess compliance with one (n= 11) or two (n=13) oral antiepileptic drugs prescribed one to four times daily for 24 epileptic outpatients 18 to 68 years of age. Compliance was assessed over 1 to 37 (mean, 14) weeks and was calculated as the number of days the drug doses were taken as prescribed, expressed as a percentage of the total number of monitored days. As frequency of prescribed dosing increased, the compliance rate fell (Table 1). The major step decline in compliance occurred between the three- and four-times daily dosing schedule. Unfortunately, the authors did not investigate the influence of the prescription of one vs two drugs on compliance rates. Coutts et al2' used an electronic monitoring device Table 2-Compliance of Children With Prophylactic Inhaled Medication* No (%) of Days of Recorded Compliance No (%) of Days of No (%) of Days of Recorded Study Days Reported Compliance in Days, %t Recorded Underuse Overuse 233 80 224 96 90 69 166 (71) 27 (34) 41 (18) 63 (27) 49 (61) 181 (81) 5 (2) 4 (5) 2 (1) Prescribed Frequency No. of No. of (Times/Day) Children 2 3 4 5 3 6 *From Coutts et al.2' tExpressed as a percentage of completed diary card days. CHEST / 107 / 5 / MAY, 1995 / Supplement Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21714/ on 05/11/2017 179S (Nebulizer Chronolog) to measure compliance with prophylactic inhaled medication in asthma. Subjects included 14 children 9 to 16 years of age with moderate to severe asthma, all of whom were prescribed prophylactic corticosteroid MDIs to be taken 2, 3, or 4 times daily. Compliance was monitored with both the electronic monitoring device and diary cards over 1 to 3 months. Compliance was calculated in terms of "compliant days," in which a "compliant day" was defined as a day on which the prescribed number of inhaler actuations was taken at appropriate times. As with prescribed oral medication, compliance fell as the number of times per day the inhaler was prescribed (Table 2), and this decline in compliance was inaccurately reflected by self-report, which markedly underestimated true compliance. In contrast to the findings with oral agents, however, the major step decline in inhaler compliance occurred between two and three times per day, rather than between three and four times daily. The poor compliance with three times a day and four times a day inhaler dosing schedules was associated with a tendency to omit the middle dose or doses. These authors also observed that the number of times per day that the inhaler was prescribed was a more important determinant of compliance than the number of puffs prescribed at each time. The difference in the relationship between compliance and the frequency of daily dosing with inhaled vs oral medication may be due to either greater difficulty of inhaler use compared with taking medication by mouth or patient embarrassment or self-consciousness in using an inhaler device in public in the middle of the day. Comparable results were obtained by Mann and coworkers,22 who compared the effects of twice daily and four times a day dosing on compliance with an inhaled corticosteroid preparation using an electronic monitoring device. Sixteen patients with clinically stable asthma requiring regular use of inhaled steroids were asked to take four inhalations of flunisolide twice daily for 3 weeks. During the following 3 weeks, half the study group continued the same dosing schedule, while the other half were switched to two inhalations four times a day for 3 weeks. Noncompliance was calculated as the percentage of days when fewer than eight inhalations were taken. The noncompliance rate remained stable in the group that was continued on the twice daily dosing schedule (37.5 to 36.8%), while noncompliance nearly tripled in the group that was converted to the four times a day schedule (20.2 to 57.1%). These findings underscore the considerable impact of dosing frequency on adherence to prescribed therapy with prophylactic inhaled medication. The same authors23 evaluated the effect of severity of asthma on compliance with four times a day 180S prescribed dosing with inhaled beclomethasone. Ten adult outpatients with asthma who required regular use of inhaled corticosteroids and a rescue d-agonist MDI on 10 or more days of the preceding 30 days were studied. The patients were prescribed beclomethasone, two to four inhalations four times a day, and albuterol MDI, two puffs as needed. An electronic monitoring device (Nebulizer Chronolog) was used to monitor both beclomethasone and albuterol usage over 9 weeks with assessments every 3 weeks. Compliance was measured both as the ratio of the number of daily inhalations to the prescribed num- ber of inhalations of beclomethasone (in percent) and as the percentage of days when the patient took fewer (underuse) or greater (overuse) than the prescribed number of inhalations. Asthma severity was evaluated by symptom scores, morning peak flow rates, and the need for rescue albuterol, as assessed objectively by the electronic monitoring device. No significant differences were noted in any of the beclomethasone compliance measures between the lowest and highest quartiles for morning peak expiratory flow, symptom scores, or albuterol use. These findings suggest that compliance of patients with asthma with prophylactic inhaled corticosteroid therapy is not modulated by disease severity. Few studies have specifically assessed compliance with inhaled and/or oral medication in patients with symptomatic COPD. As noted previously, Rand et al'0 used an electronic monitoring device to evaluate compliance with a prophylactic inhaled bronchodilator (ipratropium) or placebo in subjects with mostly mild COPD participating in a clinical trial of early intervention. Their findings indicated that only 15% of the participants actually used their inhaler the prescribed number of times a day and that actual compliance with prescribed dosing frequency and the prescribed number of puffs per dosing interval was considerably overestimated by both self-report and canister weighing. In a subsequent report from the same group,7 the electronic monitoring device was found not only to provide a more accurate assessment of compliance but also to enhance compliance when the participants were given feedback of their monitoring results. Feedback consisted of a review of the pattern of inhaler use between clinic visits for appropriateness and compliance with prescribed use, praise for areas in which usage was satisfactory, and collaborative development of behavioral strategies to deal with problem areas. James and colleagues24 used questionnaires to assess compliance in 185 patients with chronic airflow obstruction due to asthma (n= 142) or chronic bronchitis and emphysema (n=43) who were prescribed a variety of inhaled and oral bronchodilator and anti-inflammatory agents (Fig 3). Patients were given Innovations in Combination Bronchodilator Therapy Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21714/ on 05/11/2017 Compliance (%) 23 100- Table 4-Number of Drugs Taken by Each Patient Related to Compliance With Therapy* 24 40 80- 183 16 123 6040- 20- 0__ Inhaled Inhaled B2.agonist corticosteroid Inhaled Oral Oral antiB2-agonist corticocholinergic steroid Oral theophylline DSG No. of Drugs No. of Patients 1 2 3 4 5 94 47 19 Compliance With Maintenance Therapy, No. (%) Full Compliance, No. (%) 9 (38) 44 (47) 26 (55) 11 (58) 6 (25) 26 (28) 15 (32) 10 (53) 1 24 1 *From James et al.24 FIGURE 3. Patient compliance in relation to the different classes of drugs prescribed. The number over each bar represents the number of patients prescribed the corresponding class of drug. DSG=disodium cromoglycate (cromolyn) (from James et al, 4 with permission). verbal advice regarding their disease and therapy. They were advised to take their maintenance drugs regularly and to increase their use of inhaled 3-agonists as needed for exacerbations of symptoms. Two measures of compliance were derived from the questionnaire: (1) compliance with maintenance therapy (ie, self-reported regular use of prescribed therapy); and (2) full compliance (ie, appropriate increases in the dose of inhaled bronchodilators, but not the doses of prophylactic agents, during exacerbations of symptoms, in addition to compliance with maintenance therapy). As shown in Table 3, compliance with maintenance therapy was similar in patients with asthma and COPD (chronic bronchitis and emphysema), whereas full compliance was higher in patients with asthma than COPD. The latter difference could be due to the fact that bronchodilator therapy is likely to be more effective in patients with reversible obstructive airways disease. Both compliance with maintenance therapy and full compliance tended to be higher in women than men. Compliance in relation to the different classes of drugs prescribed is shown in Figure 3. It is of interest that, in general, compliance tended to be higher with oral than with inhaled medication and that compliance with an inhaled anticholinergic bronchodilator was higher than that with other inhaled drugs. The relationship between the number of prescribed drugs and compliance is shown in Table 4. Although compliance appeared to increase with an increase in the number of drugs prescribed, no statistically significant differences in compliance were noted in patients taking three or more drugs compared with patients taking fewer drugs. STRATEGIES TO ENHANCE COMPLIANCE A number of strategies have been suggested to assist patients in complying with the prescribed treatment regimen.9 13 These include the following: (1) patient education about the disease and its treatment; (2) active involvement of the patient in determining the treatment plan; (3) simplification of the medication regimen to the extent possible; and (4) appropriately frequent follow-up visits to monitor compliance with the treatment plan, as well as the efficacy and side effects of the prescribed medication. With regard to methods of reducing the complexity of the medication regimen and facilitating the patient's adherence to the regimen, the following strategies Table 3-The Relationship Among Compliance, Diagnosis, and Sex* Male, No. (%) Female, No. (%) Total, No. (%) 65 29 (45) 16 (25) 77 42 (55) 34 (44) 142 71 (50) 38 17 (45) 6 (16) 5 3 (60) 2 (40) 43 20 (47) 8 (19) Asthma No. Compliance with maintenance therapy Full compliance 50(35) Chronic bronchitis and emphysema No. Compliance with maintenance therapy Full compliance All patients No. 103 82 185 45 (54) 46 (45) 91(49) Compliance with maintenance therapy 58 (31) 36 (43) 22 (21) Full compliance *From James et al.24 Full compliance was significantly higher in female asthmatic patients than in male asthmatic patients, and in all female patients compared with all male patients (p<0.05). Full compliance was significantly higher in all patients with asthma than in those with chronic bronchitis and emphysema (p<0.05). CHEST / 107 / 5/ MAY, 1995/ Supplement Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21714/ on 05/11/2017 181S are likely to be helpful: decrease the number of medications, if possible; minimize the number of doses per day; tailor the dosing schedule as much as possible to the patient's lifestyle; provide written instructions; and provide a dose checklist for complex 8 9 regimens. CONCLUSION Combination products that combine individual agents that are commonly prescribed together in relatively fixed doses for maintenance therapy into a single pill or inhaler, such as the new MDI formulation (Combivent), are a pharmaceutical advance that is likely to enchance compliance by reducing the complexity and increasing the convenience of multidrug treatment regimens. Carefully designed studies using valid and reliable adherence measures, such as electronic monitoring devices, are required to confirm this concept in patients using combination inhaled medication for the maintenance treatment of obstructive pulmonary disease. REFERENCES 1 Siafakas NM, Bouros D. Consequences of poor compliance in chronic respiratory diseases. Eur Respir J 1990; 5:134-36 2 Blackwell B. Patient compliance. N EnglJ Med 1973; 289:249-52 3 Tashkin DP, Rand C, Nides M, et al. A Nebulizer Chronolog to monitor compliance with inhaler use. Am J Med 1991; 91(sup- pl 4A):335-65 4 Gordon ME, Kass MA. Validity of standard compliance measures in glaucoma compared with an electronic eye drop monitor. In: Cramer JA, Spilder B, eds. Patient compliance in medical practice and clinical trials. New York: Raven Press, 1991; 163-73 5 Cramer JA, Mattson RH. Monitoring compliance with antiepileptic drug therapy. In: Cramer JA, Spilder B, eds. Patient compliance in medical practice and clinical trials. New York: Raven Press, 1991; 123-37 6 Spector SL, Mawhinney H. Aerosol inhaler monitoring of asthmatic medication. In: Cramer JA, Spilder B, eds. Patient compliance in medical practice and clinical trials. New York: Raven Press, 1991; 149-62 7 Nides MA, Tashkin DP, Simmons MS, et al. Improving inhaler 1 82S 10 11 12 13 14 15 adherence in a clinical trial through the use of the Nebulizer Chronolog. Chest 1993; 104:501-07 Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med 1990; 150:1509-10 Cramer JA. Overview of methods to measure and enhance patient compliance. In: Cramer JA, Spilder B, eds. Patient compliance in medical practice and clinical trials. New York: Raven Press, 1991; 3-10 Rand CS, Wise RA, Nides M, et al. Inhaler adherence in a clinical trial: comparison of self-report and canister weighing to the Nebulizer Chronolog. Am Rev Respir Dis 1992; 146:1559-64 Sackett DL, Snow JC. The magnitude of compliance and noncompliance. In: Haynes RB, Taylow DW, Sackett DL, eds. Compliance in health care. Baltimore: Johns Hopkins University Press, 1979; 11-12 Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther 1984; 6:592-99 Mellins RB, Evans D, Zimmerman B, et al. Patient compliance: are we wasting our time and don't know it? [editorial]. Am Rev Respir Dis 1992; 146:1376-77 Ayd FJ Jr. Single daily dose of antidepressants [editorial]. JAMA 1974; 230:263-64 Gatley MS. To be taken as directed. J R Coll Gen Pract 1968; 16:39-44 16 Weintraub M, Au WYW, Lasagna L. Compliance as a determinant of serum digoxin concentration. JAMA 1973; 224:481-85 17 Latiolais CJ, Berry CC. Misuse of prescription medications by outpatients. Drug Intelligence Clin Pharm 1969; 3:271-77 18 Francis V, Korsch BM, Morris MJ. Gaps in doctor-patient communication: patients' response to medical advice. N Engl J Med 1969; 280:535-40 19 Clalrk CM. Troop RC. One-tablet combination drug therapv in the treatment of hypertension. J Chron Dis 1972; 25:57-64 20 Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed?: A novel assessment technique. JAMA 1989; 261:3273-77 21 Coutts JAP, Gibson NA, Paton JY. Measuring compliance with inhaled medication in asthma. Arch Dis Child 1992; 67:332-33 22 Mann M, Eliasson 0, Patel K, et al. A comparison of the effects of bid and qid dosing on compliance with inhaled flunisolide. Chest 1992; 101:496-99 23 Mann M, Eliasson 0, Patel K, et al. An evaluation of severitymodulated compliance with q.i.d. dosing of inhaled beclomethasone. Chest 1992; 102:1342-46 24 James PNE, Anderson JB, Prior JG, et al. Patterns of drug taking in patients with chronic airflow obstruction. Postgrad Med J 1985; 61:7-10 Innovations in Combination Bronchodilator Therapy Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21714/ on 05/11/2017