McDonald HP, Garg AX, Haynes RB. Interventions to Enhance Patient Adherence to Medication PrescriptionsScientific Review. JAMA. 2002;288(22):2868-2879. doi:10.1001/jama.288.22.2868
Author Affiliations: Health Research Methodology Program, McMaster University School of Graduate Studies (Ms McDonald and Dr Garg), and Department of Clinical Epidemiology and Biostatistics and Department of Medicine, McMaster University Faculty of Health Sciences (Dr Haynes), Hamilton, Ontario.
Scientific Review and Clinical Applications Section
Editor: Wendy Levinson, MD, Contributing Editor.
Context Low adherence with prescribed treatments is ubiquitous and undermines
Objective To systematically review published randomized controlled trials (RCTs)
of interventions to assist patients' adherence to prescribed medications.
Data Sources A search of MEDLINE, CINAHL, PSYCHLIT, SOCIOFILE, IPA, EMBASE, The Cochrane
Library databases, and bibliographies was performed for records from 1967
through August 2001 to identify relevant articles of all RCTs of interventions
intended to improve adherence to self-administered medications.
Study Selection and Data Extraction Studies were included if they reported an unconfounded RCT of an intervention
to improve adherence with prescribed medications for a medical or psychiatric
disorder; both adherence and treatment outcome were measured; follow-up of
at least 80% of each study group was reported; and the duration of follow-up
for studies with positive initial findings was at least 6 months. Information
on study design features, interventions, controls, and findings (adherence
rates and patient outcomes) were extracted for each article.
Data Synthesis Studies were too disparate to warrant meta-analysis. Forty-nine percent
of the interventions tested (19 of 39 in 33 studies) were associated with
statistically significant increases in medication adherence and only 17 reported
statistically significant improvements in treatment outcomes. Almost all the
interventions that were effective for long-term care were complex, including
combinations of more convenient care, information, counseling, reminders,
self-monitoring, reinforcement, family therapy, and other forms of additional
supervision or attention. Even the most effective interventions had modest
Conclusions Current methods of improving medication adherence for chronic health
problems are mostly complex, labor-intensive, and not predictably effective.
The full benefits of medications cannot be realized at currently achievable
levels of adherence; therefore, more studies of innovative approaches to assist
patients to follow prescriptions for medications are needed.
Adherence may be defined as the extent to which a patient's behavior
(in terms of taking medication, following a diet, modifying habits, or attending
clinics) coincides with medical or health advice.1,2 If
a patient is prescribed an antibiotic for an infection to be taken as 1 tablet
4 times a day for a week but takes only 2 tablets a day for 5 days, the adherence
would be 36% (10/28). The term adherence is intended to be nonjudgmental,
a statement of fact rather than of blame of the prescriber, patient, or treatment.
Compliance and concordance are synonyms for adherence.
This simple definition of adherence belies the difficulties that many
medical regimens present for patients. For example, the regimen described
for type 2 diabetes mellitus in a previous article3 includes
a special diet, increased exercise, smoking cessation, oral hypoglycemic drugs,
and risk factor management, usually involving additional drugs. Such regimens
fulfill theoretical, physiological, and empirical considerations about optimal
care, while ignoring practical patient-centered concerns, such as the nature,
nurture, culture, and stereotyping of the patient, and the inconvenience,
cost, and adverse effects of the treatment. Indeed, low adherence with prescribed
treatments is very common. Typical adherence rates for prescribed medications
are about 50% with a range of 0% to more than 100%.4
At a theoretical level, the nature and determinants of noncompliant
behavior are complex and not well understood, although there are interesting
models.5 The following generalizations stem
from numerous studies of the determinants of adherence.5- 7 Compliance
has little relation to sociodemographic factors such as age, sex, race, intelligence,
and education. Also, although low adherence is a problem with self-administered
treatments for all disorders, patients with psychiatric problems are less
likely to comply and those with physical disabilities caused by the disease
are more likely to comply. In addition, patients tend to miss appointments
and drop out of care when there are long waiting times at clinics or long
time lapses between appointments. Finally, adherence decreases as the complexity,
cost, and duration of the regimen increase.
To the extent that treatment response is related to the dose and schedule
of a therapy, nonadherence reduces treatment benefits8 and
can bias assessment of the effectiveness of treatments.5,9 In
addition to its potential for undermining the effectiveness of any treatment,
nonadherence is associated with poorer prognosis.10 With
increasing numbers of effective self-administered treatments, the need is
apparent for better understanding and management of nonadherence. We review
evidence from randomized controlled trials (RCTs) of interventions to assist
patients to follow prescribed medications for medical or mental disorders
but not for addictions.
Literature searches were completed from 1967 to August 2001 without
language restrictions through MEDLINE, CINAHL, PSYCHLIT, SOCIOFILE, IPA, EMBASE,
and The Cochrane Library databases to identify all articles of RCTs involving
interventions intended to improve adherence to self-administered medications.
At least 2 of the 3 reviewers independently screened all citations, index
terms, abstracts if available, and any article considered potentially relevant
by either reviewer was retrieved. Bibliographies of other reviews and original
trial publications were also screened for potentially relevant studies. Authors
of included trials were contacted to suggest other published or unpublished
trials that had been missed.
Studies were selected for inclusion from potentially relevant full-text
articles if they reported an unconfounded RCT (ie, having no baseline variables
or interventions that are extraneous to the study question but potentially
related to the outcome and differentially applied to the intervention and
control groups) of an intervention to improve adherence with prescribed medications
for a medical or psychiatric disorder, measuring both medication adherence
and treatment outcome, with at least 80% follow-up of each group studied and,
for long-term treatments, at least 6 months follow-up for studies with positive
initial findings. Negative trials with shorter follow-up periods were included
on the grounds that initial failure was unlikely to be followed by success.4 The criterion for assessment of both adherence and
outcome was based on the observation that studies showing an increase in adherence
without an improvement in outcome provide no practical guidance for practice.
The criterion of at least 6 months follow-up for long-term treatments was
based on the premise that such interventions must have persistent effects
if they are to be of practical clinical benefit.
Each potentially relevant full-text article was reviewed independently
by at least 2 of the reviewers according to the criteria for review, reading
until at least 1 exclusionary characteristic was found or until the end of
the article, whichever came first. Disagreements about whether criteria were
met (primarily assessment of confounding and adequacy of follow-up) were resolved
by discussion. Eligible studies differed in venues, patient selection, clinical
disorders, interventions, adherence measures, reporting, and outcome measures.
Thus, there was insufficient common ground for pooling differences between
groups or calculating effect sizes that would permit quantitative summarization
(ie, meta-analysis) of findings across studies. Methods for this systematic
review have also been described in detail elsewhere.2
Because explicit criteria were used to select trials for our review,
the studies included are quite homogeneous from a methodological perspective.
Nonetheless, it is possible that there still exists a relationship between
the methodological quality of the included studies and the success of their
respective interventions. To test this hypothesis, we applied the 5-point
Jadad Scale,11 a widely used validated tool
for assessing the methodological quality of RCTs, to all of our included studies,
with 2 modifications. First, due to the nature of the interventions tested
for adherence, blinding of the patient is essentially impossible. However,
it is still possible to blind outcome assessors; therefore, for item 2 on
Jadad's scale, we allotted 1 point to studies in which those assessing the
adherence and clinical outcomes were blinded. Second, the importance of concealment
of allocation in RCTs was demonstrated after publication of the Jadad Scale;
therefore, we awarded an extra point to studies in which allocation was concealed.
Fisher exact tests and univariate and multivariate logistic regression were
used to compare study quality, based on the Jadad score, with success in achieving
an improvement in adherence or clinical outcomes. All analyses were conducted
with SPSS version 10.0 (SPSS Institute, Chicago, Ill) and P<.05 was considered significant. Statistical analyses showed that
there was no relationship between Jadad score and success in clinical or adherence
We also hypothesized that interventions involving a greater number of
components or categories, compared with interventions with fewer components
or categories, would have greater success in improving adherence and clinical
outcomes. Success in improving adherence or clinical outcomes was defined
as an improvement of at least 50% of the adherence or clinical outcomes that
were measured in a particular study. Interventions for eligible studies were
independently classified by 2 reviewers in at least 1 of 3 categories: behavioral,
cognitive, or social/environmental,12 and the
number of components within each category was recorded. For example, an intervention
consisting of written instructions and a reminder telephone call would be
classified as having 2 components, with 1 component in each of the cognitive
and behavioral categories. Because of the prior demonstration that patients
with psychiatric disorders have lower adherence levels than those with other
long-term disorders,5 we also analyzed results
with vs without those for psychiatric problems. Two-by-two tables were constructed
for each study characteristic and adherence or clinical outcome. Unweighted
Fisher exact tests and univariate and multivariate logistic regression were
used to compare numbers and types of interventions with success in achieving
an improvement in adherence or clinical outcomes. Because these analyses failed
to show a relationship between the numbers and types of interventions and
adherence or clinical outcomes, we opted to organize the description of studies
according to the type of medical regimen (short-term vs long-term) and according
to disease (within the categories of medical and psychiatric).
Our review was restricted to adherence with prescribed medications.
Numerous other reviews refer to issues of adherence for various problems including
obesity,13 tuberculosis,14 smoking,15- 17 and asthma.18
Searches retrieved 6568 citations (including 101 review articles), 549
of which were judged to merit scrutiny of the full article. Some of the latter
trials did not meet our inclusion criteria because of confounding, making
it impossible to separate out independent effects of the interventions. Other
reasons for exclusion included insufficient duration of follow-up, follow-up
for less than 80% of randomized patients, and measurement of adherence to
medications that are not self-administered (ie, chemotherapy and vaccinations).
Of the initial 549 trials, 34 citations19- 52 of
33 trials (with 1 study described twice29,52)
met all review criteria. These trials tested 39 unconfounded interventions.
Many different interventions, alone and in combination, were tested
with common themes such as more instruction for patients (oral and written
material and programmed learning); increased communication and counseling
(compliance therapy; automated telephone, computer-assisted patient monitoring
and counseling; manual telephone follow-up; family intervention); various
ways to increase the convenience of care (provision at the worksite, simplified
dosing); involving patients more in their care through self-monitoring of
their blood pressure, seizures, or respiratory function; reminders (tailoring
the regimen to daily habits; special reminder pill packaging; dose-dispensing
units of medication and medication charts; appointment and prescription refill
reminders); and reinforcement or rewards for both improved adherence and treatment
response (eg, reduced frequency of visits and partial payment for blood pressure
A narrow range of disorders were targeted in the eligible trials. The
most common conditions studied were hypertension (8 studies), schizophrenia
or acute psychosis (8 studies), and asthma, chronic obstructive pulmonary
disease, or both (5 studies). Other conditions included depression (2 studies),
human immunodeficiency virus (2 studies), diabetes (2 studies), rheumatoid
arthritis (1 study), epilepsy (1 study), and hyperlipidemia and cardiovascular
disease (1 study). Only 3 eligible studies were of short-term conditions and
all of these were acute infections.
For short-term treatments (Table 1), Colcher and Bass25 reported increased
adherence with an antibiotic regimen for streptococcal pharyngitis with a
relatively simple maneuver of counseling patients about the importance of
full adherence, reinforced by written instructions. A second study32 attempted to assess whether providing patients with
information about adverse effects of their antibiotic treatment might cause
lower adherence or increased perception of adverse effects; neither was found.
Henry and Batey31 found no significant improvements
in adherence or rate of Helicobacter pylori eradication
between patients receiving an intervention consisting of an information sheet
on treatment, medication in dose-dispensing units, and a medication chart
vs controls. However, adherence was very high in both groups and was likely
stimulated by an initial 20-minute consultation given to all patients that
emphasized the importance of adherence.
Implementing changes in dosing schedules was the only relatively simple
intervention that could be easily categorized (Table 2). The remaining interventions were generally too complex
and multifaceted to categorize satisfactorily and were simply grouped by disease
(Table 3). Because adherence rates
are generally lower for patients with psychiatric conditions,5 studies
evaluating interventions for these disorders are presented separately (Table 4).
Baird et al20 reported significant improvements
in adherence measured by pill count but no differences in urine drug levels
or in blood pressure between patients receiving once-daily vs twice-daily
metoprolol (Table 2).
Girvin et al28 compared the effects of
taking enalapril 20 mg once daily vs enalapril 10 mg twice daily for the treatment
of high blood pressure. Although a trend toward greater reduction in blood
pressure occurred in the twice daily group, treatment outcomes were not significantly
different. Furthermore, the adherence results are not considered because the
follow-up was less than 6 months in duration (ie, the study was included because
the results were negative for the clinical outcome).
Brown et al22 reported improved medication
adherence and treatment outcome in patients receiving controlled-release niacin
twice daily vs regular niacin 4 times daily for the treatment of hyperlipidemia
and coronary artery disease. This intervention would be generalizable to those
situations where a reduction in the dosing frequency is possible, while also
maintaining the same total dose.
Hypertension. Sackett et al45 reported no significant
differences in adherence or clinical outcomes between hypertensive patients
receiving care at the worksite from occupational health physicians, patients
receiving programmed instructions about hypertension and adherence, or patients
receiving a combination of both strategies (Table 3).
Two studies of complex intervention programs, involving provision of
care at the worksite, special pill containers, counseling, reminders, self-monitoring,
support groups, and feedback and reinforcement, reported positive effects
on both adherence and clinical outcomes in patients with hypertension.30,39 The investigators for 1 of these
studies provided evidence in another study that benefits outweighed costs.53
Becker et al21 found no significant differences
in adherence or blood pressure between patients receiving reminder medication
packaging, in which all medicines taken together were packaged in a single
plastic blister sealed with a foil backing on which was printed the days of
the week and the time of day at which each medication was to be taken, and
those receiving separate vials labeled with drug name, dosage, and instructions
for each medication.
Friedman et al27 tested a telephone-linked
computer system for monitoring and counseling patients with hypertension.
When adjusted for age, sex, and baseline adherence, the patients using the
telephone-linked computer system demonstrated a greater improvement in medication
adherence than those receiving usual care. Further adjustment for baseline
blood pressure resulted in a significant improvement in diastolic blood pressure
in the telephone-linked computer group but no difference between the groups
for systolic blood pressure. Subgroup analysis showed that improvements in
medication adherence and diastolic blood pressure were confined to patients
who were nonadherent at baseline (<10% of all patients).
Asthma. Bailey et al19 reported positive effects
on adherence and patient outcomes with a complex intervention for asthmatic
patients. Patients in the intervention groups were provided with a standardized
set of asthma information pamphlets; a skill-oriented, self-help workbook;
a one-to-one counseling session; and additional adherence strategies such
as an asthma support group and telephone calls from a health care educator.
Patients in the control group were simply provided with the standardized asthma
Cote et al26 studied a complex intervention
involving an asthma education program, written self-management action plan,
and symptom monitoring; this failed to improve medication adherence or clinical
Gallefoss and Bakke29 tested a complex
intervention in patients with asthma and chronic obstructive pulmonary disease.
This intervention consisted of a patient brochure and 2 group education sessions
(2 hours each) with 1 session delivered by a physician and the other by a
pharmacist. In addition, 1 or 2 individual sessions (40 minutes) were supplied
by a nurse and another 1 or 2 educational sessions (40 minutes) by a physiotherapist.
At the final teaching session the patients received an individual treatment
plan and 2 weeks of peak flow monitoring. Gallefoss and Bakke29 reported
a statistically significant increase in the proportion of intervention group
asthma patients who collected at least 75% of prescribed steroid inhaler doses
from the pharmacy compared with asthma controls, but the difference in adherence
was not quite significant when based on median adherence. Furthermore, a flaw
in the study design undermined the credibility of even these marginally positive
results: participants assigned to the educational program but not attending
all sessions were withdrawn.52 Thus, the results
for compliance were based on follow-up of 38 of 39 control participants but
only 30 of 39 intervention participants (Fisher exact test, 2-tailed, P = .01). Data obtained from the authors (F. Gallefoss,
written communication, January 2002) on forced expiratory volume in 1 second
outcomes for patients at 12 months follow-up indicated that there was a significant
improvement for asthmatic intervention patients in forced expiratory volume
in 1 second scores compared with the control. However, this statistical analysis
was also based on per-protocol methods (including only those following the
recommended protocol). This result was not considered as a clinical improvement
because omitting noncompliers from the analyses clearly biases the results.
Finally, there were no improvements in adherence or clinical outcomes for
patients with chronic obstructive pulmonary disease, even based on the per
Levy et al38 reported that an intervention
involving asthma education from hospital-based specialist asthma nurses improved
adherence and clinical outcomes in asthmatic patients. Self-reported adherence
was significantly higher in the intervention group for use of inhaled corticosteroids
and rescue medication for severe asthmatic attacks, although there was no
significant difference between the groups for use of these medications for
mild attacks. Intervention patients also had significantly higher peak expiratory
flow values and significantly fewer symptoms at 6 months than patients in
the control group, accompanied by fewer days off work and fewer consultations
with health care professionals.
Van Es et al48 tested the effectiveness
of a 1-year intervention involving individual instruction and review of asthma
control from a pediatrician, individual and group educational sessions with
an asthma nurse, and written summaries of group sessions. At 12 months, there
were no significant improvements in adherence to prophylactic medications
or in clinical outcomes.
Diabetes. Piette et al43 evaluated the effect of
biweekly automated telephone assessment and self-care education calls with
nurse follow-up on the management of diabetes. Patients were considered to
have a problem with medication adherence if they reported that they "sometimes
forget to take their medication," "sometimes stop taking their medication
when they feel better," or "sometimes stop taking their medication when they
feel worse." Compared with usual care, patients in the intervention group
reported fewer problems with medication adherence. Patients in the intervention
group also had lower glycosylated hemoglobin levels, lower serum glucose levels,
and fewer diabetic symptoms than those in the control group.
Wysocki et al49 compared Behavioral-Family
Systems Therapy and Education and Support with current therapy for adolescents
with diabetes. Behavioral-Family Systems Therapy included group instruction
about diabetes and problem-solving training, communication skills training,
cognitive restructuring, and functional and structural family therapy. Education
and Support included group instruction about diabetes and social support but
not family communication and communication skills. Patients from both groups
also received a monetary incentive (US $100) for attending all sessions. Behavorial-Family
Systems Therapy resulted in an improvement in medication adherence at 6 and
12 months; however, had no effect on major clinical outcomes such as adjustment
to diabetes or diabetic control. Education and Support was not associated
with any improvements in adherence or clinical outcomes.
Human Immunodeficiency Virus. Knobel et al34 reported significant improvements
in adherence to highly active antiretroviral therapy (HAART) and a significant
reduction of viral loads in patients receiving individualized counseling vs
patients receiving conventional care.
In another study targeting adherence to HAART, Tuldra et al47 evaluated a psychoeducative intervention. Although
statistically significant improvements were not found for adherence or clinical
outcomes in the intention-to-treat analysis, improvements in compliance to
HAART at 48 weeks and an increase in the proportion of patients with a viral
load less than 400 copies/mL in the intervention group were observed when
a per-protocol analysis was conducted. The lack of statistical significance
observed using the intention-to-treat analysis may be a reflection of a low
power to detect differences due to the relatively small sample size for each
arm (n = 55 for intervention, n = 61 for control). A per-protocol analysis
is suspect in any adherence study because it ignores patients who dropped
out, which is the most severe form of nonadherence.
Rheumatoid Arthritis. Brus et al23 evaluated an intervention
involving patient education meetings focusing on compliance both with medication
therapy and with a number of physical activities in patients with rheumatoid
arthritis. The program was implemented in groups and partners were invited
to attend the meetings. Patients receiving this intervention did not demonstrate
any improvements in compliance or clinical outcomes compared with patients
in the control group, who simply received a brochure on rheumatoid arthritis.
Epilepsy. Peterson et al41 implemented a complex
intervention involving counseling, disease and drug information leaflets,
self-monitoring of medication adherence and seizures, mailed reminders for
appointments, and missed drug refills for patients with epilepsy. Although
significant improvements were observed for medication adherence and serum
drug levels, significant effects were not observed for frequency of self-reported
seizures or appointment follow-up.
Adherence interventions tested in patients with psychiatric disorders
were organized into 4 broad categories: family therapy, compliance counseling
for patients, patient education, or a combination of 2 or more of these (Table 4). The interventions studied were
diverse in nature and therefore the groupings are simply intended to serve
as a general guide. Overall, combination interventions and compliance counseling
for patients appeared to be effective for improving clinical and adherence
outcomes,35,37 followed closely
by family-oriented therapies, which were successful for both adherence and
clinical outcomes in some cases,44,46 and
less successful in other studies.50,51 The
education-oriented interventions eligible for this review24,40,42 were
The most complex of the interventions involved combining patient education
and counseling. Katon et al35 tested an intervention
in which patients received instruction (book and videotape), 2 visits to a
depression specialist, 3 telephone visits (aimed at enhancing adherence to
antidepressant medications, monitoring of symptoms, and development of a written
relapse prevention plan), personalized mailings at 2, 6, 10, and 12 months,
and telephone follow-up assessments at 3, 6, 9, and 12 months. Overall, intervention
patients demonstrated significant improvements in adherence and depressive
symptoms compared with patients receiving usual care.
Kemp et al37 evaluated the effectiveness
of a compliance counseling program in patients with psychotic disorders. Based
on the 12-month data, patients receiving compliance therapy had higher adherence
ratings and better social functioning than patients receiving nonspecific
counseling. Furthermore, 6-month data indicated that patients receiving compliance
therapy had significantly greater insight than those receiving nonspecific
Strang et al46 found that family therapy,
in which clinical staff worked closely with families of schizophrenic patients,
resulted in significant improvements in adherence and clinical outcomes compared
with individual supportive therapy. Xiong et al50 also
compared family supportive care (monthly 45-minute counseling sessions) with
usual care and reported a reduction in rehospitalization, relapse, social
dysfunction, and family social burden, with an increase in employment in the
family intervention group but found no significant differences in medication
adherence. Zhang et al51 demonstrated that,
despite a lack of improvement in adherence, there was a significant effect
of family therapy on preventing relapses among patients with schizophrenia.
In another study, Razali et al44 compared
the effects of culturally modified family therapy (intervention group) with
behavioral family therapy (control group) in the management of schizophrenia.
At 6 months and 1 year, patients in the intervention group had significantly
higher adherence than those in the control group. At 1 year, patients in the
intervention group also had significantly greater reduction of family burden,
reduction in the number of exacerbated cases (according to Brief Psychiatric
Rating Scale), and improvement in global assessment of functioning scores.
Because 1 psychiatrist treated all the control patients, while a second psychiatrist
treated all the intervention patients, the physicians' own styles are inseparable
from the rest of the control and intervention treatment packages to which
patients were randomized. Therefore, the generalizability of this study may
Chaplin and Kent24 found that there was
no significant difference in relapse rate or medication adherence in schizophrenic
patients receiving individual, semi-structured educational sessions compared
with patients receiving usual care. Merinder et al40 found
that an intervention consisting of family psychoeducation in patients with
schizophrenia had no effect on improving adherence or on major clinical outcomes
such as psychopathology or psychosocial functioning.
Peveler et al42 compared the effects
of treatment information leaflets, drug counseling, or a combination of both
with usual care in patients suffering from depression. The treatment leaflets
had no effect on adherence, depressive symptoms, or overall health care status.
Although counseling resulted in a significant improvement in adherence and
clinical outcomes, the results were not considered because the follow-up was
less than 6 months in duration.
The median number of components used in an adherence intervention package
was 3 (range, 1-6). The adherence intervention package was categorized as
including behavioral, cognitive, or social aspects (62%, 74%, and 24%, respectively).
None of the study intervention package characteristics (ie, used for psychiatric
disorder, >1 component, >3 components, >1 category, use of behavioral category,
use of cognitive category, use of social category) predicted improvement on
adherence or clinical outcomes.
We reviewed studies that assessed interventions designed to enhance
medication adherence and that measured the interventions' effects on both
medication adherence and health care outcomes. Forty-nine percent of the interventions
tested (19 of 39 in 33 studies) were associated with statistically significant
increases in medication adherence and only 17 reported statistically significant
improvements in treatment outcomes. For short-term treatments (<2 weeks),
1 of 3 interventions (in 3 studies) resulted in improvements in adherence
and clinical outcomes. For long-term treatments, 18 of 36 interventions reported
in 30 trials were associated with improvements in adherence but only 16 interventions
led to improvements in treatment outcomes. Major clinical outcomes such as
death, blindness, or stroke were not assessed; the studies evaluated intermediate
outcomes such as blood glucose or blood pressure control. Almost all the interventions
that were effective for long-term care were complex, including combinations
of more convenient care, information, counseling, reminders, self-monitoring,
reinforcement, family therapy, and other forms of additional supervision or
attention. Even the most effective interventions did not lead to large improvements
in adherence and treatment outcomes. We also failed to find a pattern of types
or numbers of interventions that predicted success. Current methods of improving
adherence for chronic health problems are mostly complex, labor-intensive
(and thus expensive), and not predictably effective. Nevertheless, many intervention
programs did lead to improved adherence and treatment success, and 1 study
even documented cost-effectiveness.
The existing literature on interventions to improve patient adherence
to self-administered medications has several limitations. First, studies of
adherence that focus on patients who are willing to participate in research
studies may be missing the key problems or beneficiaries of intervention,
including those who have not sought care and those who have dropped out of
care. In fact, the first task facing many physicians may be improving patient
attendance at medical appointments. Macharia et al54 found
that telephone prompting, patient reminder letters, orientation statements,
providing the patient with information about the reason for the appointment,
clinic organization, and contracting with patients to acquire their formal
agreement to attend future appointments improved attendance in both medical
and psychosocial populations. However, this analysis focused on settings where
appointment keeping ensured achievement of the intended health care objective
such as screening procedures, referral for consultation, and appointments
for counseling or administration of medications. Therefore, caution is warranted
in extrapolating the results to settings where patients attend appointments
for ongoing care that is self-administered between visits.
Second, as only published studies were considered in the review, the
findings are likely to overestimate the benefits of the interventions tested.55,56 However, some studies may have underestimated
intervention effects. As already noted, most of the measures of adherence
were imprecise, often relying on self-report, a method that is known to overestimate
could easily blur any differences between groups, particularly in unblinded
studies in which patients in an active control group might try to please the
investigators. Also, although we selected only studies that measured both
adherence and treatment outcome, the measures were not often objective and,
when subjective, the assessors were sometimes aware of the study group of
patients, increasing the possibility of biased assessments.
Furthermore, some interventions may work well but they were not tested
well. For example, once or twice a day dosing may secure higher adherence
than 3 or 4 times a day. However, 2 studies evaluating dosing frequency only
compared once vs twice a day, finding a difference in adherence but not in
clinical effects.20,28 A study
evaluating a wider range of dosing schedules failed to meet our inclusion
criteria.58 One study22 comparing
2 vs 4 times per day dosing showed an improvement in medication adherence
and in treatment outcome in the twice per day group. However, this study was
completed by 29 men who had previously participated in a study investigating
the regression of coronary artery disease as a result of intensive lipid-lowering
therapy, and these patients may not represent those in usual care.
In addition, most of the studies had small numbers of patients and lacked
power to detect clinically important effects. As a general guide, studies
with a single intervention and control group would need to include at least
60 participants per group if they are to have at least 80% power to detect
an absolute difference of 25% in the proportion of patients judged to have
adequate adherence. Only 11 of the 33 investigations to date have met this
standard.19- 21,25,27,34,35,38,39,43,44 Interestingly,
significant improvements in both clinical and adherence measures were observed
in the intervention group in 9 of 11 studies that were sufficiently powered,
although a significant improvement in adherence but not clinical outcomes
was reported in another study.
Most studies assessing successful complex interventions did not assess
the separate effects of the components, begging the question of whether all
elements were required. Furthermore, some authors did not adequately describe
all parts of their interventions. For example, while the report might clearly
describe that patients received reminders, the person or method of administering
the reminder program was not described, or the role was described in some
part of the text other than the section on intervention. In addition, most
studies paid research staff to administer interventions, raising issues of
generalizability to usual practice settings. This also raises the issue of
attribution in many studies: if the control group received usual care, there
would be no attention control in the study and any effects observed could
be due to either the intervention proper or simply the nonspecific effects
of increased attention paid to the intervention group.
Finally, none of the studies examined major clinical end points and
the follow-up was relatively short-term in all, the longest being 24 months.
Indeed, some studies demonstrated intervention effects on adherence and/or
outcomes in the short-term but did not observe patients for a full 6 months,
thereby failing to meet the eligibility criteria. Furthermore, most studies
failed to assess adherence after the intervention had been discontinued, precluding
assessment of the durability of the effect in studies with positive findings.
Although multifaceted interventions appear to be more effective than
simple strategies for improving adherence and clinical outcomes, it is recommended
that future studies of complex interventions attempt to elicit the effects
of the individual components of the intervention in addition to the effect
of the entire intervention as a whole. Each component of a complex intervention
should be reported in sufficient detail. This would enable researchers to
pinpoint the most effective aspects of complex interventions and to determine
whether these aspects can be implemented alone or as part of the entire intervention
package proposed. Also, future studies testing adherence interventions should
use a minimum of 60 patients per study arm to achieve a satisfactory level
of power. Ideally, objective clinically relevant outcomes should be used as
the primary clinical end points and the study should be blinded at as many
levels as possible. Finally, adherence outcomes should incorporate more objective
measures such as electronic monitoring containers and blood or serum samples.
Because the results could be applied to any self-administered treatment,
effective ways to help people follow medical treatments could have far larger
effects on health care than any individual treatment. Low adherence to treatments
has been associated with poor outcomes, even when the treatment was a placebo.10 With the recent advances in medical therapeutics,
studies of nonadherence and interventions to assist patients should flourish.
However, the literature concerning interventions to improve adherence with
medications remains surprisingly weak. Compared with the large amounts of
trials for individual drugs and treatments, there are only a few relatively
rigorous trials of adherence interventions. These provide little evidence
that medication adherence can be consistently improved within the resources
usually available in clinical settings or that this will lead predictably
to improvements in important treatment outcomes.