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Do fixed-dose pills or unit-of-use packaging improve adherence?
A systematic review
Connor J, Rafter NJ, Rodgers A.
School of Population Health, University of Auckland
Problem Statement: Low adherence to medication regimens is common and
contributes to reduced effectiveness of treatment, increased secondary health care
costs, medication wastage, and increased antimicrobial resistance in
communicable diseases. Poor adherence is multifactorial and difficult to address,
but the complexity of the medication regimen has been identified as an important
contributor, and is amenable to passive intervention.
Objective: To quantify the advantages of fixed-dose combination pills and unit-of-use
packaging compared with medications in their usual presentation, in terms of
adherence to treatment and improved outcomes.
Design: Systematic review of randomized and quasi-randomized controlled trials.
Setting and Population: Trials were included if they involved adults taking more
than one oral self-administered medication, an intervention consisting of a
combination pill or unit-of-use packaging system compared with separate pills in
usual containers, and at least one outcome measure relating to adherence, the
pharmacological goal of medication, or the cost of therapy.
Outcome Measures: 1. Adherence to the regimens under study; by pill counting, selfreport, or biological markers. 2. Clinical or intermediate end-point relevant to
condition being treated; blood pressure, HbA1c, HIV viral load, CD4+, TB
sputum conversion.
Results: Fourteen trials met the inclusion criteria, three using fixed-dose combination
pills, and 11 with unit-of-use packaging. The trials involved treatments for
communicable diseases (n=5), combinations of blood pressure–lowering
medications (n=3), diabetic patients with multiple medications (n=1), and
management of multiple medications by the elderly (n=5). There were trends to
improved adherence and/or clinical outcomes in all but two of the trials, which
reached statistical significance in 4 of 7 trials reporting a clinically relevant or
intermediate endpoint, and 7 of 12 studies reporting medication adherence.
However, outcome measures and settings were heterogeneous. Methodological
issues, particularly trial size and length and losses to follow-up, further limited
interpretation.
Conclusions: Combination pills and unit-of-use packaging are likely to improve
adherence in a range of clinical conditions and settings. However, almost all the
trials have been too small or have other limitations; important uncertainty about
the size of these benefits remains. Large simple trials are needed to provide
quantitative information so that the cost-benefit of these interventions can be
determined.
Poor adherence to medication…
• Is extremely common even in affluent countries
(estimated at 50% for long term therapy)
• Leads to reduced effectiveness or treatment
failure
• Increases secondary healthcare costs
• Contributes to antimicrobial resistance in
communicable disease
• Is multifactorial: the complexity of the medication
regimen is an important contributor
Five interacting dimensions affecting adherence
Social and economic factors
Health care team/system factors
Condition-related factors
Therapy-related factors
Patient-related factors
(from “Adherence to long-term therapies: evidence for action” WHO, 2003)
FDCs and unit-of-use packaging
• Fixed dose combinations (FDC) combine two or
more medications for the same indication in a
single pill
• Unit-of-use packaging includes methods of prepackaging multiple medications intended to be
taken together, and includes blister packing and
medication organisers, with or without calendar
labeling
• Both reduce the complexity of medication dosing
• FDCs also reduce the number of pills taken
• Blister packaging allows for calendar labeling to
prompt the user
• For example oral contraceptive pills
– combined advantages of FDC (single pill)
and blister calendar pack (reminder system).
Also portability, preservation, storage
benefits
Study aims
To quantify the advantages of
fixed dose combination pills
and unit-of-use packaging,
compared with medications in
their usual presentation,
in terms of adherence to
treatment and improved
outcomes
Methods
A systematic review of randomised and quasirandomised controlled trials
Inclusion criteria:
• Adult participants taking more than one oral
self-administered medication
• Intervention consisting of FDC or unit-of-use
packaging
• Comparison group taking same medications in
usual presentation (free combinations)
• At least one outcome measure related to
adherence, the pharmacological goal of
medication (e.g. BP, HIV viral load), or cost of
therapy
Search: electronic databases, bibliographies of
relevant publications, websites of conferences
and institutions involved in research, policy
and regulation relating to pharmaceuticals
Review: 2 independent reviewers judged eligibilty
for inclusion, extracted data, and assessed
methods
• No quantitative combination of findings (metaanalysis) due to substantial variation in
settings, conditions studied, interventions,
adherence and outcome measures, and study
quality
Results: studies included
14 trials met inclusion criteria,
conducted between 1980 and 2002
Interventions: 3 FDC, 11 packaging
Conditions: Tuberculosis x 2, HIV,
Leprosy, Malaria, Hypertension x 3,
Diabetes x 1, Multiple medications in
geriatric patients x 5
Outcome measures: 7 reported
clinically relevant endpoints, 12
reported at least one adherence
measure, one reported cost
Adherence measures: pill counting,
self-report, diary cards, patient
medication adherence questionnaire
(PMAQ), urine testing, composite
measures
Slides 7 and 8 (landscape)
Results: evidence of effect
on adherence and treatment
Of 12 studies measuring adherence, 7 reported a
statistically significant improvement, but
measures of adherence varied
Four out of seven studies measuring clinical
outcomes found a significant improvement:
sputum conversion in TB, reduction in blood
pressure x3, and improved diabetic control
Study quality was generally poor: many trials were
too small, too short to assess long term
adherence, had high losses to follow-up, or did
not report intention-to-treat analysis. Methods
of measurement of adherence were usually
unvalidated and sometimes unclear
The two trials using the most robust methods both
showed significant improvements with the
intervention: Eron et al (2000) and Simmons et
al (2000)
Yeboah-Antwi et al (2001) showed that
prepackaging of unit doses anti-malarial drugs
not only improved adherence, but also reduced
cost and waiting time by 50%
Very few trials have been conducted in
developing countries.
Conclusions
Combination pills and unit-of-use
packaging are likely to improve
adherence to medication and
treatment outcomes in a range of
clinical conditions and settings.
However, direct evidence of the size
of any benefit is weak as few trials
have been carried out,and most have
been too small or have other
significant limitations. The small
number of good quality trials show
benefits, but important uncertainty
remains.
Implications
FDCs and co-blistering of medications have
important applications in both communicable
and non-communicable disease. In particular,
the prevention of cardiovascular disease and
the treatment of HIV, tuberculosis and malaria
all employ multiple medications and are
hampered by poor adherence to therapy
Evidence of the size of adherence benefits and
therefore cost-effectiveness of this approach is
poor and large trials are required.
Important questions remain about the most
appropriate ways to measure adherence to
medication
The effect of using FDCs and co-blistering will
be modified by many other factors including:
– Appropriate training for health workers
– Simple written/pictorial instructions for
patients to accompany medication
– Cost-effective and culturally appropriate
modes of communication with families and
communities
Research needs
Trials
• Knowing the comparative benefits of different
modes of delivery is important for allocative
efficiency
• There is an ethical responsibility to evaluate
effectiveness, adverse events, and cost-benefit
when interventions are introduced
• Trials can be conducted in an appropriate
context as interventions are being introduced.
This opportunity is lost once the interventions
are established.
New trials must
• Be big enough for sufficient power
• Be long enough to determine long term effects
• Use reliable adherence and outcome measures
• Use intention to treat analysis
New trials can
• Compare FDCs, co-blistering and free
combinations, with no placebo arm
• Also measure patient safety and development of
resistance in communicable disease