Download Multiple Dose Regimens

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
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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
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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).
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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,
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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
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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.
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(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
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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
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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).
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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.
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Innovations in Combination Bronchodilator Therapy
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