Review: Interventions To Improve Adherence To Self-Administered Medications For Chronic Diseases in The United States

Annals of Internal Medicine Review
Interventions to Improve Adherence to Self-administered Medications

for Chronic Diseases in the United States
A Systematic Review
Meera Viswanathan, PhD; Carol E. Golin, MD; Christine D. Jones, MD, MS; Mahima Ashok, PhD; Susan J. Blalock, MPH, PhD;
Roberta C.M. Wines, MPH; Emmanuel J.L. Coker-Schwimmer, MPH; David L. Rosen, MD, PhD; Priyanka Sista, BA; and Kathleen N. Lohr, PhD
Background: Suboptimum medication adherence is common in the copayments or improved prescription drug coverage. Clinical con-
United States and leads to serious negative health consequences ditions amenable to multiple approaches to improving adherence
but may respond to intervention. include hypertension, heart failure, depression, and asthma. Inter-
ventions that improve adherence across multiple clinical conditions
Purpose: To assess the comparative effectiveness of patient, pro- include policy interventions to reduce copayments or improve pre-
vider, systems, and policy interventions that aim to improve med- scription drug coverage, systems interventions to offer case man-
ication adherence for chronic health conditions in the United States. agement, and patient-level educational interventions with behav-
Data Sources: Eligible peer-reviewed publications from MEDLINE ioral support.
and the Cochrane Library indexed through 4 June 2012 and addi- Limitations: Studies were limited to adults with chronic conditions
tional studies from reference lists and technical experts. (excluding HIV, AIDS, severe mental illness, and substance abuse)
Study Selection: Randomized, controlled trials of patient, provider, in the United States. Clinical and methodological heterogeneity
or systems interventions to improve adherence to long-term med- hindered quantitative data pooling.
ications and nonrandomized studies of policy interventions to im- Conclusion: Reduced out-of-pocket expenses, case management,
prove medication adherence. and patient education with behavioral support all improved medi-
Data Extraction: Two investigators independently selected, ex- cation adherence for more than 1 condition. Evidence is limited on
tracted data from, and rated the risk of bias of relevant studies. whether these approaches are broadly applicable or affect long-
term medication adherence and health outcomes.
Data Synthesis: The evidence was synthesized separately for each
clinical condition; within each condition, the type of intervention Primary Funding Source: Agency for Healthcare Research and
was synthesized. Two reviewers graded the strength of evidence by Quality.
using established criteria. From 4124 eligible abstracts, 62 trials of
patient-, provider-, or systems-level interventions evaluated 18 Ann Intern Med. 2012;157:785-795. www.annals.org
types of interventions; another 4 observational studies and 1 trial of For author affiliations, see end of text.
policy interventions evaluated the effect of reduced medication This article was published at www.annals.org on 11 September 2012.
A lthough many efficacious medical treatments exist, a

recent Institute of Medicine report identified a gap
between current treatment success rates and those believed
interventions, and clinical conditions for quality improve-
ment. Our report addresses the comparative effectiveness
of interventions to improve medication adherence.
to be achievable (1). This gap has been attributed partly to
lack of patient adherence to recommended treatment (1, METHODS
2). Poor medication adherence is common (3, 4). Studies
The protocol and full review are available online at
have consistently shown that 20% to 30% of medication
http://effectivehealthcare.ahrq.gov. This article focuses on
prescriptions are never filled and that approximately 50%
2 of our key questions. First, among patients with chronic
of medications for chronic disease are not taken as pre-
diseases with self-administered medication prescribed by a
scribed (5, 6).
provider for secondary or tertiary prevention, what is the
This lack of adherence has dramatic effects on health
comparative effectiveness of interventions aimed at pa-
(5, 7–16). In the United States, it is estimated to cause
tients, providers, or systems in improving medication ad-
approximately 125 000 deaths, at least 10% of hospitaliza-
herence? Is improved medication adherence associated with
tions (5), and a substantial increase in morbidity and mor-
improved patient outcomes? Second, what is the compar-
tality (11, 12). Nonadherence has been estimated to cost
ative effectiveness of policy interventions for improving
the U.S. health care system between $100 billion and $289
billion annually (3, 5, 17–20).
This review is part of a larger initiative, Closing the
Quality Gap: Revisiting the State of the Science, and See also:
builds on an earlier Agency for Healthcare Research and
Quality (AHRQ) collection of publications, Closing the Web-Only
Quality Gap: A Critical Analysis of Quality Improvement Supplements
Strategies (21). This new series focuses on selected settings,
© 2012 American College of Physicians 785
Downloaded From: http://annals.org/ on 04/03/2014

Review Improving Adherence to Self-administered Medications for Chronic Diseases
medication adherence? Is improved medication adherence nonadherence than the reference group of patients who
associated with improved patient outcomes? were seniors receiving social assistance in Ontario, Canada
(29). Of note, in our review of 61 excluded non-U.S. stud-
Study Eligibility ies, 7 were set in developing countries (30 –36), 1 was a
We assessed medication adherence effectiveness for multicenter trial that included developing countries (37),
studies conducted in outpatient primary and specialty care, and the remaining 53 were set in 15 advanced economies
as well as community-based and home-based settings with universal coverage of various types (38 –90). Of these,
(Appendix Table 1, available at www.annals.org). We ex- more than half were set in the United Kingdom (17 stud-
cluded studies in institutional settings because medications ies) (38 –54) and Canada (10 studies) (55– 64).
are generally not self-administered there, interventions to As suggested by Norris and colleagues (91), we con-
improve antiretroviral adherence because comprehensive ducted a preliminary assessment of the availability of evi-
reviews of such interventions were only recently completed dence from randomized, controlled trials (RCTs) and the
(22, 23), interventions for adherence to medications for likelihood of selection bias and confounding from observa-
patients with severe mental illness (schizophrenia, other tional studies and accordingly focused on RCTs for pa-
psychoses, and bipolar disorder) and substance abuse be- tient, provider, and systems interventions. We expanded
cause the complex cognitive features of adherence for such the scope to include observational studies for policy inter-
conditions require specific interventions that are not appli- ventions because these studies allowed us to assess the ef-
cable to patients with other conditions, acute conditions fectiveness of policy innovations in practice settings that
because adherence for such disease differs from that for are not usually tested in trials.
chronic illness (23), studies published before 1994 because
Data Sources and Searches
of a large systematic review that included studies up to
1994 (24), and non–English-language and non-U.S. stud- To identify relevant articles, we conducted separate
ies to ensure greater applicability of our findings to the targeted literature searches for patient, provider, systems,
unique health care setting of the United States. Other sys- and policy interventions by using MEDLINE, the Co-
tematic reviews also note that adherence studies from non– chrane Library, and the Cochrane Central Register of Con-
U.S.-based health care systems are inherently different trolled Trials from 1994 through 4 June 2012. We re-
from those in the United States because of variations in the viewed our search strategy with a panel of technical experts
ways that patients procure, pay for, and monitor medica- and supplemented it as needed according to their recom-
tions (25, 26). mendations. To avoid retrieval bias, we manually searched
Adherence is a complex multifactorial behavior that is the reference lists of pertinent reviews to identify relevant
influenced by social and economic factors (for example, citations that our searches missed.
age, race, sex, and socioeconomic status), patient-related Study Selection
factors (for example, knowledge, attitude, and beliefs), Two trained researchers independently reviewed each
condition- and treatment-related factors (for example, se- title and abstract. All titles selected by at least 1 reviewer
verity of the symptoms and disease, complexity of the med- went on to full-text review by 2 independent reviewers.
ical regimen, duration of treatment, and adverse effects), Reviewers resolved conflicts by discussion and consensus or
provider characteristics (for example, communication consultation with a third reviewer as needed.
skills, training, and resources), and setting (for example,
Data Extraction and Quality Assessment
drug coverage, cost sharing of medications, and access to
For studies meeting the inclusion criteria, a trained
medication and clinical care) (27). Such factors interact to
reviewer abstracted data into structured evidence tables
influence adherence behavior. For instance, the setting may
that were then reviewed by a second trained reviewer for
influence patient and provider behavior through appoint-
completeness and accuracy.
ments that are too short to discuss adherence, fee structures
Two independent reviewers assessed risk of bias for
that do not support reimbursement for patient counseling
each study by using predefined criteria based on those de-
and education, poor continuity of care that disrupts the
veloped by AHRQ (92) and specified in the RTI Item
patient–provider relationship, and systems that impede in-
Bank (93). We resolved disagreements between reviewers
formation sharing between providers and pharmacists on
by consulting a senior member of the team.
prescription refills (27).
Hence, patient adherence behaviors in countries or Data Analysis and Synthesis
settings without the systemic characteristics of the United To make the findings as clinically useful as possible,
States are markedly different. Residents of the United we analyzed results for each key question by both clinical
States have been found to be 2 to 3 times more likely to condition and intervention type. We specified a priori the
report cost-related nonadherence than Canadian residents data to be collected for all outcomes except biomarkers and
(28, 29), even when the results were stratified by insurance morbidity. On the basis of the recommendations of the
status. Publicly or privately insured patients in the United technical expert panel, we elected to collect a comprehen-
States were more than twice as likely to report cost-related sive set of biomarkers and morbidity outcomes, rather than
786 4 December 2012 Annals of Internal Medicine Volume 157 • Number 11 www.annals.org

Improving Adherence to Self-administered Medications for Chronic Diseases Review
judge which to collect in advance. We determined quanti- reported on RCTs and 4 reported on observational studies.
tative analysis to be inappropriate because of clinical or Sixty-two provided data on patient, provider, and systems
methodological heterogeneity, low numbers of similar interventions (95–162). One trial and 4 observational
studies, and insufficiency or in outcome reporting, so we studies provided information on policy interventions
synthesized data qualitatively. We grouped interventions (163–167).
into categories that reflected key intervention components. Most trials on patient, provider, or systems interven-
We graded the strength of evidence for medication tions provided information about 6 key characteristics: the
adherence, biomarkers (for example, systolic blood pressure targets, agents, methods, intensity, duration, and compo-
and hemoglobin A1c), morbidity (for example, depressive nents of the interventions. The characteristics provided a
symptoms and asthma symptoms), mortality, and other framework by which we could describe the interventions.
health outcomes (94). These grades incorporate 4 key con- For example, for the targets, slightly more than 50% of the
siderations when the strength of a stated effect is being interventions were aimed at various combinations of mul-
evaluated: risk of bias (including study design and aggre- tiple targets, whereas nearly 40% targeted only patients.
gate quality), consistency, directness, and precision (see Similarly, for delivery, a pharmacist, physician, or nurse
Appendix Table 2, available at www.annals.org, for defi- delivered approximately 50% of interventions. About half
nitions of strength-of-evidence grades). We excluded stud- of interventions involved at least some face-to-face delivery
ies with high risk of bias and found no variation in direct- of the program. Supplement 2 (available at www.annals
ness. As a result, consistency and precision were key drivers .org) presents information about each study’s intervention,
of the strength-of-evidence grades in this body of studies including its description, type, dose, and method of
with medium and low risk of bias. delivery.
Role of the Funding Source
Included trials of patient, policy, and systems interven-
tions focus on hypertension (18 trials, 9691 patients), de-
The AHRQ funded the systematic review. The key
pression (13 trials, 11 445 patients), hyperlipidemia (9 tri-
questions, protocol, and draft report were reviewed by the
als, 19 228 patients), asthma (8 trials, 4423 patients),
funder, the peer reviewers, the technical expert panel mem-
diabetes (6 trials, 1056 patients), heart failure (5 trials, 719
bers, and the public. Approval from AHRQ was required
before the manuscript could be submitted for publication, patients), multiple or unspecified chronic conditions (4 tri-
but the authors are solely responsible for its content and als, 3403 patients), musculoskeletal diseases (4 trials, 2559
the decision to submit it for publication. patients), myocardial infarction (1 trial, 907 patients),
multiple sclerosis (1 trial, 435 patients), and glaucoma (1
trial, 66 patients). Of these, 7 studies examine more than 1
RESULTS clinical condition. Fifteen studies (24%) were powered for
First, we present the results from our literature search adherence as a primary outcome (98, 107, 108, 124, 129,
and a summary of the characteristics of our included stud- 131–133, 135, 139, 153–156, 159). Of note, we found no
ies. We then present our results for patient, provider, and eligible studies for cancer, probably because we restricted
systems interventions by clinical condition and interven- this review to patient-administered medications in outpa-
tion type. Supplement 1 and Appendix Table 3 (available tient settings.
at www.annals.org) summarize our findings and give the Included studies on policy interventions focus on car-
strength-of-evidence grade for each intervention. Although diovascular disease (5 studies, ⬎70 000 patients), diabetes
we present our results separately by clinical condition and (3 studies, approximately 20 000 patients), and respiratory
intervention type, the close correlation between these 2 conditions (1 study, number of patients not reported).
factors requires that results synthesized by clinical condi-
Effect of Patient, Provider, or Systems Interventions on
tion specify intervention type. Similarly, results synthesized
Medication Adherence and Other Outcomes
by intervention type specify clinical condition. Finally, we
Overall, the evidence from 62 trials (68 articles) sug-
present results for policy interventions and summarize the
gests that many pathways provide opportunities to improve
findings in Appendix Table 4 (available at www.annals
medication adherence across clinical conditions. These ap-
.org). We generally highlight evidence of moderate or low
proaches range from low-cost, low-intensity interventions,
strength.
such as 1-time mailings, to intensive interventions, such as
Characteristics of Included Studies case management, care coordination, and collaborative
Of the 4124 citations identified (Appendix Figure, care.
available at www.annals.org), 758 published articles met Despite evidence for promising approaches to improv-
inclusion criteria at the title and abstract review. Of these, ing medication adherence, we found relatively little evi-
661 articles did not meet inclusion criteria on review of the dence linking higher adherence to improvements in other
full text. We excluded 24 additional articles with high risk outcomes, such as biomarkers, morbidity, mortality, qual-
of bias during data extraction. Of the 73 included articles ity of life, patient satisfaction, health care use, or costs. Of
(comprising 67 studies of low or medium risk of bias), 69 the 62 trials, 33 (53%) reported improvement in medica-
www.annals.org 4 December 2012 Annals of Internal Medicine Volume 157 • Number 11 787

tion adherence. Of these 33 trials, 18 (29%) reported im- its and improved patient satisfaction (129). Among pa-
provements in at least 1 health outcome, 8 (13%) reported tients with depression, case management reduced symp-
no improvements in health outcomes, and 7 (11%) did not toms of depression (95, 111, 140 –142), and collaborative
evaluate changes in health outcomes. The remaining 29 care improved depression symptoms, patient satisfaction
trials (47%) showed no improvement in medication with medications, and quality of care (144 –147). Finally,
adherence. among patients with asthma, shared decision making im-
proved symptoms, pulmonary function, health care use,
and quality of life (137). We generally graded these inter-
Findings Related to Clinical Conditions ventions as beneficial, with low to moderate strength of
Medication Adherence. We found evidence supporting evidence, depending on the specific type of intervention.
multiple effective interventions to improve medication ad- We found very little evidence supporting a relationship
herence for the following conditions: hypertension (blister between improved medication adherence and adverse
packaging, case management, education with behavioral events (data not shown).
support) (109 –112, 116, 117, 122–124), heart failure
(reminder calls; pharmacist-led, multicomponent interven-
tions; education with behavioral support; case manage-
Findings Related to Interventions
ment) (127–130), depression (case management, collabor-
Of the 18 intervention approaches, 7 had been tested
ative care) (95, 111, 140 –142, 144 –147, 152), and
across different clinical conditions (Appendix Table 3 and
asthma (self-management, shared decision making) (132–
Supplement 2): education; case management; reminders;
137). Not all interventions in these clinical areas, however,
pharmacist-led, multicomponent approaches; collaborative
provided evidence of benefit. We graded the strength of
evidence for some interventions as insufficient because of care; telephone-based counseling, care management, and
inconsistent or statistically nonsignificant results (98, 125, reminders; and decision aids. Of these, educational inter-
126, 149, 150). In addition, we found evidence of no ventions with behavioral support through continued pa-
benefit of collaborative care for hypertension (97, 114, tient contact over several weeks or months (effective for
115) or patient or provider access to patient adherence data hypertension [122–124], hyperlipidemia [104 –108], heart
for asthma (138, 139). failure [128], and myocardial infarction [131]) and case
With respect to diabetes, hyperlipidemia, and muscu- management (effective for diabetes [95–97], hypertension
loskeletal diseases, we found evidence of 1 effective inter- [111, 112], heart failure [127], and depression [95, 96,
vention for each condition. These included care coordina- 111, 140 –142]) offer the most voluminous and consist-
tion and collaborative care for diabetes (95), education ent evidence of improvements in medication adherence
with behavioral support for hyperlipidemia (104 –108), and other health outcomes across varied clinical condi-
and virtual clinic for osteoporosis (157). All other interventions. We also found moderate-strength evidence for self-
tion types studied for these clinical conditions had insuffi- management interventions for asthma, which generally
cient evidence of benefit, generally due to results that were include strong educational components. Other promising
inconsistent or not statistically significant (98, 99, 101– approaches found to be effective in more than 1 clinical
103, 109, 155, 156). area include reminders (heart failure, depression) (130,
The least evidence of improvement in medication ad- 152) and pharmacist-led, multicomponent approaches
herence, despite multiple trials testing 2 approaches, (heart failure, glaucoma) (129, 153), but this evidence is
pertained to patients with multiple chronic conditions. limited to single studies in each clinical area.
Three trials testing 1 approach—pharmacist-led case Certain intervention types may provide the most ben-
management—resulted in no benefit for medication adher- efit for patients with a specific clinical condition. Collab-
ence (159 –161). In addition, we judged evidence from orative care with in-person patient visits for education and
another trial, which tested intensive interdisciplinary as- counseling seemed to be effective primarily for patients
sessment followed by nurse-led case management, to be with depression or with depression and diabetes; for other
insufficient because the results were not statistically signif- clinical conditions (hyperlipidemia and hypertension), the
icant (162). evidence was insufficient.
Other Health Outcomes. We found the most consistent Some effective interventions, such as shared decision
evidence for improved health outcomes attributable to bet- making (137) and blister packaging (110), that were tested
ter medication adherence for patients with hypertension, in only a single clinical area with a single trial may hold
heart failure, depression, and asthma. For hypertension, promise, but without additional evidence, their widespread
both case management (96, 111, 112) and face-to-face ed- applicability is difficult to judge. Telephone counseling,
ucation by pharmacists (109, 116, 117) led to enhanced care management, and monitoring, tested under 4 clinical
adherence that decreased systolic and diastolic blood pres- conditions (diabetes [100], multiple sclerosis [154], depres-
sure. For heart failure, a pharmacist-led, multicomponent sion [149 –151], and musculoskeletal disease [158]), failed
adherence intervention reduced emergency department vis- to show statistically significant benefit for medication ad-

herence, except in 1 trial for patients with multiple sclerosis total patient spending but no change in total insurer pay-
(154). ments. We concluded that evidence is insufficient to draw
conclusions about the effect of policy interventions on clin-
Effect of Policy Interventions on Medication Adherence ical and economic outcomes (Appendix Table 4).
and Other Outcomes
Five studies evaluated effects of policy interventions on
adherence to medications; all 5 addressed medications used DISCUSSION
to treat cardiovascular disease (Appendix Table 4) (163– In this systematic review of patient, provider, systems,
167). Three of the 5 studies (163, 165, 167) also assessed and policy interventions to improve medication adherence,
adherence to medications used to treat diabetes, and 1 of we found evidence of effective interventions for many
the 5 studies (163) assessed adherence to medications used chronic conditions. Among interventions to improve med-
to treat respiratory conditions. One of the 5 studies was an ication adherence at the patient, provider, or systems level,
RCT (166), whereas the other 4 were cohort studies. All 5 we found the strongest evidence for improving medication
studies measured medication adherence by using insurance adherence for self-management of asthma (in the short
claims data as either the medication possession ratio or term) and case management or collaborative care with in-
proportion of days covered. All 5 policy change interven- person patient education visits for depression. Among inter-
tions reduced patients’ out-of-pocket expenses for prescrip- ventions to improve medication adherence at the policy
tion medications through either reduced medication co- level, we found robust evidence that reduced out-of-pocket
payments or improved prescription drug coverage. expenses improved medication adherence across clinical
All 5 studies found statistically significant between- conditions. With regard to clinical outcomes, we found the
group differences in adherence to medications for cardio- strongest evidence that improved medication adherence
vascular conditions, favoring patients whose medication was accompanied by improved clinical outcomes with
copayments were reduced (163–166) or whose coverage pharmacist-led hypertension management interventions for
improved (167). In 2 of the cohort studies (163, 164), systolic blood pressure improvement and case management
however, medication adherence to cardiovascular medi- interventions for depression symptoms. We also found ev-
cines decreased over time in all groups, although the mag- idence that education with behavioral support; reminders;
nitudes of between-group differences were similar to those and pharmacist-led, multicomponent interventions en-
reported in the RCT (166). Together, these results provide hanced adherence across more than 1 clinical area.
moderate-strength evidence that policy interventions that Our review is consistent with previous medication ad-
reduce patient out-of-pocket expenses have a beneficial ef- herence reviews. A meta-analysis of intervention studies on
fect on adherence to cardiovascular medications (Appendix medication adherence published through 1994 showed
Table 4). small to moderate effects of a broad range of behavioral
All 3 studies that assessed adherence to medications interventions on medication adherence across multiple
used to treat diabetes found statistically significant conditions (24), although the reviewers identified only 3
between-group differences in adherence to those medicines broad categories of intervention types (behavioral, educa-
favoring the group that had reduced out-of-pocket ex- tional, and “affective”) and found no differences in out-
penses (163, 165, 167). In 2 of the 3 studies, medication comes by intervention type. The investigators did report
adherence decreased over time in all groups. However, the that multidimensional approaches were more effective than
magnitude of between-group differences was similar to that unidimensional approaches (24). A Cochrane review of
in the third study, which found an increase in adherence studies through 2007 also showed that medication adher-
among those with some prior coverage for prescription ence interventions can have moderate effects on adher-
medications after implementation of Medicare Part D ence and health outcomes for several common chronic (as
(167). Therefore, we found moderate-strength evidence for well as acute) medical conditions, although this review
policy interventions that reduced patient out-of-pocket ex- included only adherence studies that also assessed health
penses to improve adherence to medications used to treat outcomes (6).
diabetes (Appendix Table 4). Our review sought to broaden understanding of the
One study found no effect of a policy intervention on effect of interventions on adherence. It included studies
adherence to inhaled corticosteroids, which are usually from 1994 through 4 June 2012 with adherence interven-
used to treat reactive airway disease conditions (163). tion trials, even if they did not assess other health out-
Therefore, we concluded that evidence is insufficient to comes. Unlike other reviews, it examined intervention ef-
draw conclusions for the effectiveness of policy interven- fects for specific clinical conditions and across conditions
tions in this clinical area. in relation to intervention type to identify those programs
One trial examined the effect of policy interventions with the strongest evidence. It also included studies that
on clinical outcomes (166). It found a 14% reduction in assessed the effects of policy interventions.
the rate of first vascular events after hospital discharge for Poor medication adherence produces large down-
myocardial infarction. It also found a 26% reduction in stream health care costs. Thus, policymakers contemplat-

ing changes in health policy should take note of our dren and adolescents, and non-U.S. populations—limit its
assessment, from 5 consistent studies (moderate-strength generalizability.
evidence), that reducing patients’ out-of-pocket costs im- Although many studies were relatively small, they were
proves medication adherence. Compared with other effec- conducted across many common chronic conditions affect-
tive interventions, such as case management and collabor- ing adults. Findings from this diverse set of clinical condi-
ative care, which are relatively complex and labor-intensive, tions and interventions have not been replicated in trials
reducing copayments can potentially improve adherence with larger patient populations or multiple study sites, in
for large numbers of geographically diverse patients. groups with different sociodemographic characteristics, or
Clinicians may be encouraged that the best evidence over longer follow-up periods. These gaps in the evidence
for improved medication adherence was present for several base limit the applicability of our results.
common conditions, including depression, hypertension, We also limited our pool of included interventions to
diabetes, asthma, and hyperlipidemia. However, it is also those designed specifically to address medication adherence
noteworthy that we found no studies that directly ad- as a primary or secondary outcome. We excluded clinical
dressed polypharmacy and that we found either insufficient trials of drugs that assessed adherence to aid in the inter-
evidence or evidence of no benefit for studies of popula- pretation of safety and efficacy data. Thus, we did not
tions with multiple chronic conditions. Hence, caution address the comparative effectiveness of specific drug for-
must be used in extrapolating findings for 1 condition to mulations in improving adherence.
patients with multiple comorbid conditions. We categorized patient, provider, and systems inter-
The 18 intervention clusters and characteristics we ventions by assigning labels based on short intervention
identified provide a starting framework by which practitio- descriptions that do not fully account for heterogeneity
ners and researchers may develop, test, and report their within and across clinical conditions or patient popula-
adherence programs more explicitly and consistently. The tions. Doing so allowed us to make comparisons across
interventions we analyzed ranged from simple to complex. conditions but limited our ability to make definitive state-
Decision-makers should be cautious in trying to pick com- ments about intervention effectiveness across clinical areas.
ponents of complex interventions to enhance medication We believe our categories provide useful heuristics, but
adherence. In our judgment, and as noted in a prior ad- users should regard them more as hypothesis-generating
herence review by Simoni and colleagues (22), sufficient than as an established system of classification.
information is not yet available to guide choices among the Several reviews published over the past 2 decades, now
considerable array of program components. In our review, complemented by our systematic review, confirm that a
a lack of data about mediating relationships through which wide range of interventions can improve medication
interventions affected adherence limited the conclusions adherence. At this stage, new studies need to ask, “What
that we could draw about the effectiveness of specific in- specific elements of multicomponent interventions work
tervention components. Therefore, future studies should best for improving medication adherence?” and, “How can
strive to more clearly describe each intervention compo- we further enhance medication adherence interventions
nent, and studies should be designed to identify which to increase adherence and ultimately improve health
components are driving the effects of the intervention. For outcomes?”
instance, more studies with factorial designs would help to
assess both additive and multiplicative effects of interven- From RTI International, Durham, and University of North Carolina at
tion components. At a minimum, using guidelines from Chapel Hill, Chapel Hill, North Carolina.
the Standards for Quality Improvement Reporting Excel-
Note: RTI International is a trade name of Research Triangle Institute.
lence group (http://squire-statement.org/guidelines) will
improve the quality of reporting so that future studies of
Disclaimer: The findings and conclusions in this article are those of the
complex interventions routinely clarify the mechanisms by
authors, who are responsible for its contents; they do not necessarily
which intervention components are expected to cause represent the view of AHRQ or the Veterans Health Administration.
change, the course of the implementation, and the success Therefore, no statement in this report should be construed as an official
of tests of the mechanism of action (168). position of these entities, the U.S. Department of Health and Human
Diverse interventions and varied adherence measures Services, or the U.S. Department of Veterans Affairs.
across studies limited our ability to pool results quantita-
tively. The identification and use of standardized, objective Acknowledgment: The authors thank the Evidence-based Practice Cen-
adherence measures and definitions in future research ter (EPC) team staff at RTI International and the University of North
should enable investigators to pool data from such studies. Carolina at Chapel Hill for their considerable support, commitment, and
contributions; Timothy S. Carey, MD, MPH, Director of the Cecil G.
In addition to the heterogeneity of outcome measures
Sheps Center for Health Services Research at the University of North
noted, our review process and the evidence base both limit Carolina; Christiane Voisin, MSLS, EPC Librarian; Audrey R. Holland,
interpretations of our findings. The constraints for popu- MPH, and Elizabeth Harden, MPH, EPC Project Managers; Catherine
lations and settings that we imposed on the systematic A. Grodensky, MPH, and Andrea Yuen, BS, abstractors; Laura Small,
review—such as excluding interventions for HIV, chil- BA, EPC editor; and Loraine Monroe, EPC publications specialist.

Financial Support: By AHRQ (contract 290200710056I). Dr. Jones is 20. Task Force for Compliance. Noncompliance with Medications: An Eco-
supported by an NIH/HRSA training grant (T32HP14001-25). nomic Tragedy with Important Implications for Health Care Reform. Washing-
ton, DC: Task Force for Compliance; 1994.
21. Shojania KG, McDonald KM, Wachter R, Owens DK. Closing the Quality
Potential Conflicts of Interest: Disclosures can be viewed at www
Gap: A Critical Analysis of Quality Improvement Strategies: Volume 1—Series
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽M12
Overview and Methodology. AHRQ publication no. 04-0051-1. (Prepared by
-1030. the Stanford University-UCSF Evidence-based Practice Center under contract
290-02-0017.) Rockville, MD: Agency for Healthcare Research and Quality;
Requests for Single Reprints: Meera Viswanathan, PhD, Social, Statis- 2004.
tical, and Environmental Sciences, RTI International, 3040 Cornwallis 22. Simoni JM, Pearson CR, Pantalone DW, Marks G, Crepaz N. Efficacy of
Road, Durham, NC 27709; e-mail, viswanathan@rti.org. interventions in improving highly active antiretroviral therapy adherence and
HIV-1 RNA viral load. A meta-analytic review of randomized controlled trials.
Current author addresses and author contributions are available at www J Acquir Immune Defic Syndr. 2006;43 Suppl 1:S23-35. [PMID: 17133201]
23. Rueda S, Park-Wyllie LY, Bayoumi AM, Tynan AM, Antoniou TA,
.annals.org.
Rourke SB, et al. Patient support and education for promoting adherence to
highly active antiretroviral therapy for HIV/AIDS. Cochrane Database Syst Rev.
2006:CD001442. [PMID: 16855968]
References 24. Roter DL, Hall JA, Merisca R, Nordstrom B, Cretin D, Svarstad B. Effec-
1. Agency for Healthcare Research and Quality. Priority Areas for National tiveness of interventions to improve patient compliance: a meta-analysis. Med
Action: Transforming Health Care Quality. Rockville, MD: Agency for Health- Care. 1998;36:1138-61. [PMID: 9708588]
care Research and Quality; 2003. 25. Gellad WF, Grenard JL, Marcum ZA. A systematic review of barriers to
2. Pathman DE, Konrad TR, Freed GL, Freeman VA, Koch GG. The medication adherence in the elderly: looking beyond cost and regimen complex-
awareness-to-adherence model of the steps to clinical guideline compliance. The ity. Am J Geriatr Pharmacother. 2011;9:11-23. [PMID: 21459305]
case of pediatric vaccine recommendations. Med Care. 1996;34:873-89. [PMID: 26. Grenard JL, Munjas BA, Adams JL, Suttorp M, Maglione M, McGlynn
8792778] EA, et al. Depression and medication adherence in the treatment of chronic
3. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353: diseases in the United States: a meta-analysis. J Gen Intern Med. 2011;26:1175-
487-97. [PMID: 16079372] 82. [PMID: 21533823]
4. World Health Organization. Noncommunicable Diseases and Mental Health: 27. Briesacher BA, Gurwitz JH, Soumerai SB. Patients at-risk for cost-related
Progress Report 2002-2003. Geneva: World Health Organization; 2003. medication nonadherence: a review of the literature. J Gen Intern Med. 2007;22:
5. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to 864-71. [PMID: 17410403]
improve medication adherence. Am J Health Syst Pharm. 2003;60:657-65. 28. Kennedy J, Morgan S. A cross-national study of prescription nonadherence
[PMID: 12701547] due to cost: data from the Joint Canada-United States Survey of Health. Clin
6. Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X. Interventions for Ther. 2006;28:1217-24. [PMID: 16982299]
enhancing medication adherence. Cochrane Database Syst Rev. 2008: 29. Kennedy J, Morgan S. Cost-related prescription nonadherence in the United
CD000011. [PMID: 18425859] States and Canada: a system-level comparison using the 2007 International
7. World Health Organization. The World Health Report 2002: Reducing Health Policy Survey in Seven Countries. Clin Ther. 2009;31:213-9. [PMID:
Risks, Promoting Healthy Life. Geneva: World Health Organization; 2002. 19243719]
8. World Health Organization. Adherence to Long-Term Therapies: Evidence 30. Bocchi EA, Cruz F, Guimarães G, Pinho Moreira LF, Issa VS, Ayub Fer-
for Action. Geneva: World Health Organization; 2003. reira SM, et al. Long-term prospective, randomized, controlled study using re-
9. Dunbar-Jacob J, Erlen JA, Schlenk EA, Ryan CM, Sereika SM, Doswell petitive education at six-month intervals and monitoring for adherence in heart
WM. Adherence in chronic disease. Annu Rev Nurs Res. 2000;18:48-90. failure outpatients: the REMADHE trial. Circ Heart Fail. 2008;1:115-24.
[PMID: 10918932] [PMID: 19808281]
10. Sarquis LM, Dellácqua MC, Gallani MC, Moreira RM, Bocchi SC, Tase 31. de Castro MS, Fuchs FD, Santos MC, Maximiliano P, Gus M, Moreira
TH, et al. [Compliance in antihypertensive therapy: analyses in scientific articles]. LB, et al. Pharmaceutical care program for patients with uncontrolled hyperten-
Rev Esc Enferm USP. 1998;32:335-53. [PMID: 10896654] sion. Report of a double-blind clinical trial with ambulatory blood pressure mon-
11. DiMatteo MR, Giordani PJ, Lepper HS, Croghan TW. Patient adherence
itoring. Am J Hypertens. 2006;19:528-33. [PMID: 16647628]
and medical treatment outcomes: a meta-analysis. Med Care. 2002;40:794-811.
32. Ponnusankar S, Surulivelrajan M, Anandamoorthy N, Suresh B. Assess-
[PMID: 12218770]
ment of impact of medication counseling on patients’ medication knowledge and
12. Schiff GD, Fung S, Speroff T, McNutt RA. Decompensated heart failure:
compliance in an outpatient clinic in South India. Patient Educ Couns. 2004;
symptoms, patterns of onset, and contributing factors. Am J Med. 2003;114:625-
54:55-60. [PMID: 15210260]
30. [PMID: 12798449]
33. Seck BC, Jackson RT. Determinants of compliance with iron supplementa-
13. Waeber B, Burnier M, Brunner HR. How to improve adherence with
prescribed treatment in hypertensive patients? J Cardiovasc Pharmacol. 2000;35 tion among pregnant women in Senegal. Public Health Nutr. 2008;11:596-605.
Suppl 3:S23-6. [PMID: 10854048] [PMID: 17764606]
14. Psaty BM, Koepsell TD, Wagner EH, LoGerfo JP, Inui TS. The relative 34. Stewart A, Noakes T, Eales C, Shepard K, Becker P, Veriawa Y. Adherence
risk of incident coronary heart disease associated with recently stopping the use of to cardiovascular risk factor modification in patients with hypertension. Cardio-
beta-blockers. JAMA. 1990;263:1653-7. [PMID: 1968518] vasc J S Afr. 2005;16:102-7. [PMID: 15915277]
15. Beckles GL, Engelgau MM, Narayan KM, Herman WH, Aubert RE, 35. Phumipamorn S, Pongwecharak J, Soorapan S, Pattharachayakul S. Effects
Williamson DF. Population-based assessment of the level of care among adults of the pharmacist’s input on glycaemic control and cardiovascular risks in Muslim
with diabetes in the U.S. Diabetes Care. 1998;21:1432-8. [PMID: 9727887] diabetes. Prim Care Diabetes. 2008;2:31-7. [PMID: 18684418]
16. Rogers PG, Bullman W. Prescription medicine compliance: review of the 36. Sookaneknun P, Richards RM, Sanguansermsri J, Teerasut C. Pharmacist
baseline of knowledge—report of the National Council on Patient Information involvement in primary care improves hypertensive patient clinical outcomes.
and Education. Journal of Pharmacoepidemiology. 1995;3:3-36. Ann Pharmacother. 2004;38:2023-8. [PMID: 15522983]
17. Mahoney JJ, Ansell BJ, Fleming WK, Butterworth SW. The unhidden cost 37. Delmas PD, Vrijens B, Eastell R, Roux C, Pols HA, Ringe JD, et al;
of noncompliance. J Manag Care Pharm. 2008;14:S1-S29. Improving Measurements of Persistence on Actonel Treatment (IMPACT)
18. New England Healthcare Institute. Thinking Outside the Pillbox: A System- Investigators. Effect of monitoring bone turnover markers on persistence with
wide Approach to Improving Patient Medication Adherence for Chronic Disease. risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab.
Cambridge, MA: New England Healthcare Institute; 2009. 2007;92:1296-304. [PMID: 17244788]
19. Showalter A. Costs of Patient Noncompliance. Crystal Lake, IL: AlignMap; 38. Sovani MP, Whale CI, Oborne J, Cooper S, Mortimer K, Ekström T, et al.
2006:1-4. Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler

containing budesonide and formoterol help? Br J Gen Pract. 2008;58:37-43. 58. Gwadry-Sridhar FH, Arnold JM, Zhang Y, Brown JE, Marchiori G, Guyatt
[PMID: 18186995] G. Pilot study to determine the impact of a multidisciplinary educational inter-
39. Perahia DG, Quail D, Gandhi P, Walker DJ, Peveler RC. A randomized, vention in patients hospitalized with heart failure. Am Heart J. 2005;150:982.
controlled trial of duloxetine alone vs. duloxetine plus a telephone intervention [PMID: 16290975]
in the treatment of depression. J Affect Disord. 2008;108:33-41. [PMID: 59. Tsuyuki RT, Fradette M, Johnson JA, Bungard TJ, Eurich DT, Ashton T,
17905442] et al. A multicenter disease management program for hospitalized patients with
40. Atherton-Naji A, Hamilton R, Riddle W, Naji S. Improving adherence to heart failure. J Card Fail. 2004;10:473-80. [PMID: 15599837]
antidepressant drug treatment in primary care: a feasibility study for a randomized 60. Rinfret S, Lussier MT, Peirce A, Duhamel F, Cossette S, Lalonde L, et al;
controlled trial of educational intervention. Primary Care Psychiatry. 2001;7: LOYAL Study Investigators. The impact of a multidisciplinary information
61-7. technology-supported program on blood pressure control in primary care. Circ
41. Claxton A, de Klerk E, Parry M, Robinson JM, Schmidt ME. Patient Cardiovasc Qual Outcomes. 2009;2:170-7. [PMID: 20031834]
compliance to a new enteric-coated weekly formulation of fluoxetine during con- 61. Edworthy SM, Baptie B, Galvin D, Brant RF, Churchill-Smith T, Manyari
tinuation treatment of major depressive disorder. J Clin Psychiatry. 2000;61:928- D, et al. Effects of an enhanced secondary prevention program for patients with
32. [PMID: 11206598] heart disease: a prospective randomized trial. Can J Cardiol. 2007;23:1066-72.
42. Peveler R, George C, Kinmonth AL, Campbell M, Thompson C. Effect of [PMID: 17985009]
antidepressant drug counselling and information leaflets on adherence to drug 62. Leenen FH, Wilson TW, Bolli P, Larochelle P, Myers M, Handa SP, et al.
treatment in primary care: randomised controlled trial. BMJ. 1999;319:612-5. Patterns of compliance with once versus twice daily antihypertensive drug therapy
[PMID: 10473477] in primary care: a randomized clinical trial using electronic monitoring. Can
43. Nazareth I, Burton A, Shulman S, Smith P, Haines A, Timberal H. A J Cardiol. 1997;13:914-20. [PMID: 9374947]
pharmacy discharge plan for hospitalized elderly patients—a randomized con- 63. Waters BM, Jensen L, Fedorak RN. Effects of formal education for patients
trolled trial. Age Ageing. 2001;30:33-40. [PMID: 11322670] with inflammatory bowel disease: a randomized controlled trial. Can J Gastroen-
44. Begley S, Livingstone C, Hodges N, Williamson V. Impact of domiciliary terol. 2005;19:235-44. [PMID: 15861266]
pharmacy visits on medication management in an elderly population. Int J Pharm 64. Sherrard H, Struthers C, Kearns SA, Wells G, Chen L, Mesana T. Using
Pract. 1997;5:111-21. technology to create a medication safety net for cardiac surgery patients: a nurse-
45. Brown I, Sheeran P, Reuber M. Enhancing antiepileptic drug adherence: a led randomized control trial. Can J Cardiovasc Nurs. 2009;19:9-15. [PMID:
randomized controlled trial. Epilepsy Behav. 2009;16:634-9. [PMID: 19864187] 19694112]
46. Goodyer LI, Miskelly F, Milligan P. Does encouraging good compliance 65. Peterson GM, Fitzmaurice KD, Naunton M, Vial JH, Stewart K, Krum H.
improve patients’ clinical condition in heart failure? Br J Clin Pract. 1995;49: Impact of pharmacist-conducted home visits on the outcomes of lipid-lowering
173-6. [PMID: 7547154] drug therapy. J Clin Pharm Ther. 2004;29:23-30. [PMID: 14748894]
47. Cooper A, Drake J, Brankin E; PERSIST Investigators. Treatment persis- 66. Vrijens B, Goetghebeur E. Comparing compliance patterns between ran-
tence with once-monthly ibandronate and patient support vs. once-weekly alen- domized treatments. Control Clin Trials. 1997;18:187-203. [PMID: 9204220]
dronate: results from the PERSIST study. Int J Clin Pract. 2006;60:896-905. 67. Rubak S, Sandbæk A, Lauritzen T, Borch-Johnsen K, Christensen B. Effect
[PMID: 16800837] of “motivational interviewing” on quality of care measures in screen detected type
48. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and 2 diabetes patients: a one-year follow-up of an RCT, ADDITION Denmark.
persistence with antiresorptive treatment for postmenopausal osteoporosis: a ran- Scand J Prim Health Care. 2011;29:92-8. [PMID: 21306296]
domized controlled trial. J Clin Endocrinol Metab. 2004;89:1117-23. [PMID: 68. Christensen A, Christrup LL, Fabricius PE, Chrostowska M, Wronka M,
15001596] Narkiewicz K, et al. The impact of an electronic monitoring and reminder device
49. Grosset KA, Grosset DG. Effect of educational intervention on medication on patient compliance with antihypertensive therapy: a randomized controlled
timing in Parkinson’s disease: a randomized controlled trial. BMC Neurol. 2007; trial. J Hypertens. 2010;28:194-200. [PMID: 19770778]
7:20. [PMID: 17634109] 69. Hornnes N, Larsen K, Boysen G. Blood pressure 1 year after stroke: the need
50. Hardstaff R, Green K, Talbot D. Measurement of compliance posttrans- to optimize secondary prevention. J Stroke Cerebrovasc Dis. 2011;20:16-23.
plantation—the results of a 12-month study using electronic monitoring. Trans- [PMID: 21187254]
plant Proc. 2003;35:796-7. [PMID: 12644142] 70. Nielsen D, Ryg J, Nielsen W, Knold B, Nissen N, Brixen K. Patient
51. Homer D, Nightingale P, Jobanputra P. Providing patients with informa- education in groups increases knowledge of osteoporosis and adherence to treat-
tion about disease-modifying anti-rheumatic drugs: Individually or in groups? ment: a two-year randomized controlled trial. Patient Educ Couns. 2010;81:155-
A pilot randomized controlled trial comparing adherence and satisfaction. Mus- 60. [PMID: 20400258]
culoskeletal Care. 2009;7:78-92. [PMID: 18792423] 71. Brus HL, van de Laar MA, Taal E, Rasker JJ, Wiegman O. Effects of
52. Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug patient education on compliance with basic treatment regimens and health in
treatment for rheumatoid arthritis: a randomised controlled trial. Ann Rheum recent onset active rheumatoid arthritis. Ann Rheum Dis. 1998;57:146-51.
Dis. 2001;60:869-75. [PMID: 11502614] [PMID: 9640129]
53. Sturgess IK, McElnay JC, Hughes CM, Crealey G. Community pharmacy 72. Elkjaer M, Shuhaibar M, Burisch J, Bailey Y, Scherfig H, Laugesen B, et al.
based provision of pharmaceutical care to older patients. Pharm World Sci. 2003; E-health empowers patients with ulcerative colitis: a randomised controlled trial
25:218-26. [PMID: 14584229] of the web-guided ‘Constant-care’ approach. Gut. 2010;59:1652-61. [PMID:
54. Varma S, McElnay JC, Hughes CM, Passmore AP, Varma M. Pharmaceu- 21071584]
tical care of patients with congestive heart failure: interventions and outcomes. 73. Billault B, Degoulet P, Devries C, Plouin PF, Chatellier G, Menard J. Use
Pharmacotherapy. 1999;19:860-9. [PMID: 10417035] of a standardized personal medical record by patients with hypertension: a ran-
55. Coté J, Cartier A, Robichaud P, Boutin H, Malo JL, Rouleau M, et al. domized controlled prospective trial. MD Comput. 1995;12:31-5. [PMID:
Influence on asthma morbidity of asthma education programs based on self- 7854076]
management plans following treatment optimization. Am J Respir Crit Care 74. Andrejak M, Genes N, Vaur L, Poncelet P, Clerson P, Carré A. Electronic
Med. 1997;155:1509-14. [PMID: 9154850] pill-boxes in the evaluation of antihypertensive treatment compliance: compari-
56. Côté J, Bowie DM, Robichaud P, Parent JG, Battisti L, Boulet LP. Eval- son of once daily versus twice daily regimen. Am J Hypertens. 2000;13:184-90.
uation of two different educational interventions for adult patients consulting [PMID: 10701819]
with an acute asthma exacerbation. Am J Respir Crit Care Med. 2001;163: 75. Boissel JP, Meillard O, Perrin-Fayolle E, Ducruet T, Alamercery Y, Sassano
1415-9. [PMID: 11371411] P, et al. Comparison between a bid and a tid regimen: improved compliance with
57. Tamblyn R, Reidel K, Huang A, Taylor L, Winslade N, Bartlett G, et al. no improved antihypertensive effect. The EOL Research Group. Eur J Clin Phar-
Increasing the detection and response to adherence problems with cardiovascular macol. 1996;50:63-7. [PMID: 8739813]
medication in primary care through computerized drug management systems: a 76. Gensichen J, von Korff M, Peitz M, Muth C, Beyer M, Güthlin C, et al;
randomized controlled trial. Med Decis Making. 2010;30:176-88. [PMID: PRoMPT (PRimary care Monitoring for depressive Patients Trial). Case man-
19675319] agement for depression by health care assistants in small primary care practices:

a cluster randomized trial. Ann Intern Med. 2009;151:369-78. [PMID: 95. Bogner HR, de Vries HF. Integrating type 2 diabetes mellitus and depression
19755362] treatment among African Americans: a randomized controlled pilot trial. Diabe-
77. Mengden T, Vetter H, Tousset E, Uen S. Management of patients with tes Educ. 2010;36:284-92. [PMID: 20040705]
uncontrolled arterial hypertension—the role of electronic compliance monitor- 96. Bogner HR, Morales KH, de Vries HF, Cappola AR. Integrated manage-
ing, 24-h ambulatory blood pressure monitoring and Candesartan/HCTZ. BMC ment of type 2 diabetes mellitus and depression treatment to improve medication
Cardiovasc Disord. 2006;6:36. [PMID: 16942618] adherence: a randomized controlled trial. Ann Fam Med. 2012;10:15-22.
78. Klein A, Otto G, Krämer I. Impact of a pharmaceutical care program on [PMID: 22230826]
liver transplant patients’ compliance with immunosuppressive medication: a pro- 97. Lin EH, Katon W, Rutter C, Simon GE, Ludman EJ, Von Korff M, et al.
spective, randomized, controlled trial using electronic monitoring. Transplanta- Effects of enhanced depression treatment on diabetes self-care. Ann Fam Med.
tion. 2009;87:839-47. [PMID: 19300186] 2006;4:46-53. [PMID: 16449396]
79. Wong FK, Chow SK, Chan TM. Evaluation of a nurse-led disease manage- 98. Pearce KA, Love MM, Shelton BJ, Schoenberg NE, Williamson MA, Bar-
ment programme for chronic kidney disease: a randomized controlled trial. Int ron MA, et al; Kentucky Ambulatory Network. Cardiovascular risk education
J Nurs Stud. 2010;47:268-78. [PMID: 19651405] and social support (CaRESS): report of a randomized controlled trial from the
80. Wu JY, Leung WY, Chang S, Lee B, Zee B, Tong PC, et al. Effectiveness Kentucky Ambulatory Network (KAN). J Am Board Fam Med. 2008;21:269-
of telephone counselling by a pharmacist in reducing mortality in patients receiv- 81. [PMID: 18612053]
ing polypharmacy: randomised controlled trial. BMJ. 2006;333:522. [PMID: 99. Wolever RQ, Dreusicke M, Fikkan J, Hawkins TV, Yeung S, Wakefield J,
16916809] et al. Integrative health coaching for patients with type 2 diabetes: a randomized
81. Vergouwen AC, Bakker A, Burger H, Verheij TJ, Koerselman F. A cluster clinical trial. Diabetes Educ. 2010;36:629-39. [PMID: 20534872]
randomized trial comparing two interventions to improve treatment of major 100. Grant RW, Devita NG, Singer DE, Meigs JB. Improving adherence and
depression in primary care. Psychol Med. 2005;35:25-33. [PMID: 15842026] reducing medication discrepancies in patients with diabetes. Ann Pharmacother.
82. Eussen SR, van der Elst ME, Klungel OH, Rompelberg CJ, Garssen J, 2003;37:962-9. [PMID: 12841801]
Oosterveld MH, et al. A pharmaceutical care program to improve adherence to 101. Mann DM, Ponieman D, Montori VM, Arciniega J, McGinn T. The
statin therapy: a randomized controlled trial. Ann Pharmacother. 2010;44:1905- Statin Choice decision aid in primary care: a randomized trial. Patient Educ
13. [PMID: 21119098] Couns. 2010;80:138-40. [PMID: 19959322]
83. Charles T, Quinn D, Weatherall M, Aldington S, Beasley R, Holt S. An 102. Weymiller AJ, Montori VM, Jones LA, Gafni A, Guyatt GH, Bryant SC,
audiovisual reminder function improves adherence with inhaled corticosteroid et al. Helping patients with type 2 diabetes mellitus make treatment decisions:
therapy in asthma. J Allergy Clin Immunol. 2007;119:811-6. [PMID: statin choice randomized trial. Arch Intern Med. 2007;167:1076-82. [PMID:
17320942] 17533211]
84. Gallefoss F, Bakke PS. How does patient education and self-management 103. Jones LA, Weymiller AJ, Shah N, Bryant SC, Christianson TJ, Guyatt
among asthmatics and patients with chronic obstructive pulmonary disease affect
GH, et al. Should clinicians deliver decision aids? Further exploration of the
medication? Am J Respir Crit Care Med. 1999;160:2000-5. [PMID: 10588620]
statin choice randomized trial results. Med Decis Making. 2009;29:468-74.
85. López-Viña A, del Castillo-Arévalo E. Influence of peak expiratory flow
[PMID: 19605885]
monitoring on an asthma self-management education programme. Respir Med.
104. Guthrie RM. The effects of postal and telephone reminders on compliance
2000;94:760-6. [PMID: 10955751]
with pravastatin therapy in a national registry: results of the first myocardial
86. López Cabezas C, Falces Salvador C, Cubı́ Quadrada D, Arnau Bartés A,
infarction risk reduction program. Clin Ther. 2001;23:970-80. [PMID:
Ylla Boré M, Muro Perea N, et al. Randomized clinical trial of a postdischarge
11440296]
pharmaceutical care program vs regular follow-up in patients with heart failure.
105. Johnson SS, Driskell MM, Johnson JL, Dyment SJ, Prochaska JO,
Farm Hosp. 2006;30:328-42. [PMID: 17298190]
Prochaska JM, et al. Transtheoretical model intervention for adherence to lipid-
87. Pladevall M, Brotons C, Gabriel R, Arnau A, Suarez C, de la Figuera M,
lowering drugs. Dis Manag. 2006;9:102-14. [PMID: 16620196]
et al; Writing Committee on behalf of the COM99 Study Group. Multicenter
106. Powell KM, Edgren B. Failure of educational videotapes to improve med-
cluster-randomized trial of a multifactorial intervention to improve antihyperten-
sive medication adherence and blood pressure control among patients at high ication compliance in a health maintenance organization. Am J Health Syst
cardiovascular risk (the COM99 study). Circulation. 2010;122:1183-91. Pharm. 1995;52:2196-9. [PMID: 8564589]
[PMID: 20823391] 107. Schectman G, Hiatt J, Hartz A. Telephone contacts do not improve ad-
88. Amado Guirado E, Pujol Ribera E, Pacheco Huergo V, Borras JM; herence to niacin or bile acid sequestrant therapy. Ann Pharmacother. 1994;28:
ADIEHTA Group. Knowledge and adherence to antihypertensive therapy in 29-35. [PMID: 8123955]
primary care: results of a randomized trial. Gac Sanit. 2011;25:62-7. [PMID: 108. Stacy JN, Schwartz SM, Ershoff D, Shreve MS. Incorporating tailored
21354671] interactive patient solutions using interactive voice response technology to im-
89. Akerblad AC, Bengtsson F, Ekselius L, von Knorring L. Effects of an prove statin adherence: results of a randomized clinical trial in a managed care
educational compliance enhancement programme and therapeutic drug monitor- setting. Popul Health Manag. 2009;12:241-54. [PMID: 19848566]
ing on treatment adherence in depressed patients managed by general practitio- 109. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on
ners. Int Clin Psychopharmacol. 2003;18:347-54. [PMID: 14571155] medication adherence and persistence, blood pressure, and low-density lipopro-
90. Chen SY, Sheu S, Chang CS, Wang TH, Huang MS. The effects of the tein cholesterol: a randomized controlled trial. JAMA. 2006;296:2563-71.
self-efficacy method on adult asthmatic patient self-care behavior. J Nurs Res. [PMID: 17101639]
2010;18:266-74. [PMID: 21139446] 110. Schneider PJ, Murphy JE, Pedersen CA. Impact of medication packaging
91. Norris SL, Atkins D, Bruening W, Fox S, Johnson E, Kane R, et al. on adherence and treatment outcomes in older ambulatory patients. J Am Pharm
Observational studies in systemic reviews of comparative effectiveness: AHRQ Assoc (2003). 2008;48:58-63. [PMID: 18192132]
and the Effective Health Care Program. J Clin Epidemiol. 2011;64:1178-86. 111. Bogner HR, de Vries HF. Integration of depression and hypertension treat-
[PMID: 21636246] ment: a pilot, randomized controlled trial. Ann Fam Med. 2008;6:295-301.
92. Agency for Healthcare Research and Quality. Methods Guide for Effective- [PMID: 18626028]
ness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Health- 112. Rudd P, Miller NH, Kaufman J, Kraemer HC, Bandura A, Greenwald G,
care Research and Quality; 2011. et al. Nurse management for hypertension. A systems approach. Am J Hypertens.
93. Viswanathan M, Berkman ND. Development of the RTI item bank on risk 2004;17:921-7. [PMID: 15485755]
of bias and precision of observational studies. J Clin Epidemiol. 2012;65:163-78. 113. Wakefield BJ, Holman JE, Ray A, Scherubel M, Adams MR, Hillis SL,
[PMID: 21959223] et al. Effectiveness of home telehealth in comorbid diabetes and hypertension: a
94. Owens DK, Lohr KN, Atkins D, Treadwell JR, Reston JT, Bass EB, et al. randomized, controlled trial. Telemed J E Health. 2011;17:254-61. [PMID:
AHRQ series paper 5: grading the strength of a body of evidence when compar- 21476945]
ing medical interventions—Agency for Healthcare Research and Quality and the 114. Carter BL, Ardery G, Dawson JD, James PA, Bergus GR, Doucette WR,
Effective Health-Care Program. J Clin Epidemiol. 2010;63:513-23. [PMID: et al. Physician and pharmacist collaboration to improve blood pressure control.
19595577] Arch Intern Med. 2009;169:1996-2002. [PMID: 19933962]

115. Hunt JS, Siemienczuk J, Pape G, Rozenfeld Y, MacKay J, LeBlanc BH, 135. Janson SL, McGrath KW, Covington JK, Cheng SC, Boushey HA.
et al. A randomized controlled trial of team-based care: impact of physician- Individualized asthma self-management improves medication adherence and
pharmacist collaboration on uncontrolled hypertension. J Gen Intern Med. 2008; markers of asthma control. J Allergy Clin Immunol. 2009;123:840-6. [PMID:
23:1966-72. [PMID: 18815843] 19348923]
116. Solomon DK, Portner TS, Bass GE, Gourley DR, Gourley GA, Holt JM, 136. Schaffer SD, Tian L. Promoting adherence: effects of theory-based asthma
et al. Clinical and economic outcomes in the hypertension and COPD arms of a education. Clin Nurs Res. 2004;13:69-89. [PMID: 14768768]
multicenter outcomes study. J Am Pharm Assoc (Wash). 1998;38:574-85. 137. Wilson SR, Strub P, Buist AS, Knowles SB, Lavori PW, Lapidus J, et al;
[PMID: 9782691] Better Outcomes of Asthma Treatment (BOAT) Study Group. Shared treat-
117. Gourley GA, Portner TS, Gourley DR, Rigolosi EL, Holt JM, Solomon ment decision making improves adherence and outcomes in poorly controlled
DK, et al. Humanistic outcomes in the hypertension and COPD arms of a asthma. Am J Respir Crit Care Med. 2010;181:566-77. [PMID: 20019345]
multicenter outcomes study. J Am Pharm Assoc (Wash). 1998;38:586-97. 138. Williams LK, Peterson EL, Wells K, Campbell J, Wang M, Chowdhry
[PMID: 9782692] VK, et al. A cluster-randomized trial to provide clinicians inhaled corticosteroid
118. Vivian EM. Improving blood pressure control in a pharmacist-managed adherence information for their patients with asthma. J Allergy Clin Immunol.
hypertension clinic. Pharmacotherapy. 2002;22:1533-40. [PMID: 12495164] 2010;126:225-31, 231.e1-4. [PMID: 20569973]
119. Bosworth HB, Olsen MK, Neary A, Orr M, Grubber J, Svetkey L, et al. 139. Weinberger M, Murray MD, Marrero DG, Brewer N, Lykens M, Harris
Take Control of Your Blood Pressure (TCYB) study: a multifactorial tailored LE, et al. Effectiveness of pharmacist care for patients with reactive airways
behavioral and educational intervention for achieving blood pressure control. disease: a randomized controlled trial. JAMA. 2002;288:1594-602. [PMID:
Patient Educ Couns. 2008;70:338-47. [PMID: 18164894] 12350190]
120. Bosworth HB, Olsen MK, Dudley T, Orr M, Neary A, Harrelson M, 140. Katon W, Rutter C, Ludman EJ, Von Korff M, Lin E, Simon G, et al. A
et al. The Take Control of Your Blood Pressure (TCYB) study: study design and randomized trial of relapse prevention of depression in primary care. Arch Gen
methodology. Contemp Clin Trials. 2007;28:33-47. [PMID: 16996808] Psychiatry. 2001;58:241-7. [PMID: 11231831]
121. Bosworth HB, Olsen MK, Gentry P, Orr M, Dudley T, McCant F, et al. 141. Ludman E, Katon W, Bush T, Rutter C, Lin E, Simon G, et al. Behav-
Nurse administered telephone intervention for blood pressure control: a patient- ioural factors associated with symptom outcomes in a primary care-based depres-
tailored multifactorial intervention. Patient Educ Couns. 2005;57:5-14. [PMID: sion prevention intervention trial. Psychol Med. 2003;33:1061-70. [PMID:
15797147] 12946090]
122. Friedman RH, Kazis LE, Jette A, Smith MB, Stollerman J, Torgerson J, 142. Von Korff M, Katon W, Rutter C, Ludman E, Simon G, Lin E, et al.
et al. A telecommunications system for monitoring and counseling patients with Effect on disability outcomes of a depression relapse prevention program. Psy-
hypertension. Impact on medication adherence and blood pressure control. Am chosom Med. 2003;65:938-43. [PMID: 14645770]
J Hypertens. 1996;9:285-92. [PMID: 8722429] 143. Capoccia KL, Boudreau DM, Blough DK, Ellsworth AJ, Clark DR, Ste-
vens NG, et al. Randomized trial of pharmacist interventions to improve depres-
123. Johnson SS, Driskell MM, Johnson JL, Prochaska JM, Zwick W,
sion care and outcomes in primary care. Am J Health Syst Pharm. 2004;61:364-
Prochaska JO. Efficacy of a transtheoretical model-based expert system for anti-
72. [PMID: 15011764]
hypertensive adherence. Dis Manag. 2006;9:291-301. [PMID: 17044763]
144. Katon W, Von Korff M, Lin E, Walker E, Simon GE, Bush T, et al.
124. Ogedegbe GO, Boutin-Foster C, Wells MT, Allegrante JP, Isen AM, Jobe
Collaborative management to achieve treatment guidelines. Impact on depression
JB, et al. A randomized controlled trial of positive-affect intervention and med-
in primary care. JAMA. 1995;273:1026-31. [PMID: 7897786]
ication adherence in hypertensive African Americans. Arch Intern Med. 2012;
145. Katon W, Robinson P, Von Korff M, Lin E, Bush T, Ludman E, et al. A
172:322-6. [PMID: 22269592]
multifaceted intervention to improve treatment of depression in primary care.
125. Powers BJ, Danus S, Grubber JM, Olsen MK, Oddone EZ, Bosworth
Arch Gen Psychiatry. 1996;53:924-32. [PMID: 8857869]
HB. The effectiveness of personalized coronary heart disease and stroke risk com-
146. Katon W, Von Korff M, Lin E, Simon G, Walker E, Unützer J, et al.
munication. Am Heart J. 2011;161:673-80. [PMID: 21473965]
Stepped collaborative care for primary care patients with persistent symptoms of
126. Ross SE, Moore LA, Earnest MA, Wittevrongel L, Lin CT. Providing a
depression: a randomized trial. Arch Gen Psychiatry. 1999;56:1109-15. [PMID:
web-based online medical record with electronic communication capabilities to 10591288]
patients with congestive heart failure: randomized trial. J Med Internet Res. 2004; 147. Katon W, Russo J, Von Korff M, Lin E, Simon G, Bush T, et al. Long-
6:e12. [PMID: 15249261] term effects of a collaborative care intervention in persistently depressed primary
127. Rich MW, Gray DB, Beckham V, Wittenberg C, Luther P. Effect of a care patients. J Gen Intern Med. 2002;17:741-8. [PMID: 12390549]
multidisciplinary intervention on medication compliance in elderly patients with 148. Pyne JM, Fortney JC, Curran GM, Tripathi S, Atkinson JH, Kilbourne
congestive heart failure. Am J Med. 1996;101:270-6. [PMID: 8873488] AM, et al. Effectiveness of collaborative care for depression in human immuno-
128. Wu JR, Corley DJ, Lennie TA, Moser DK. Effect of a medication-taking deficiency virus clinics. Arch Intern Med. 2011;171:23-31. [PMID: 21220657]
behavior feedback theory-based intervention on outcomes in patients with heart 149. Rickles NM, Svarstad BL, Statz-Paynter JL, Taylor LV, Kobak KA. Phar-
failure. J Card Fail. 2012;18:1-9. [PMID: 22196835] macist telemonitoring of antidepressant use: effects on pharmacist-patient collab-
129. Murray MD, Young J, Hoke S, Tu W, Weiner M, Morrow D, et al. oration. J Am Pharm Assoc (2003). 2005;45:344-53. [PMID: 15991756]
Pharmacist intervention to improve medication adherence in heart failure: a ran- 150. Simon GE, Ludman EJ, Operskalski BH. Randomized trial of a telephone
domized trial. Ann Intern Med. 2007;146:714-25. [PMID: 17502632] care management program for outpatients starting antidepressant treatment. Psy-
130. Fulmer TT, Feldman PH, Kim TS, Carty B, Beers M, Molina M, et al. chiatr Serv. 2006;57:1441-5. [PMID: 17035563]
An intervention study to enhance medication compliance in community- 151. Simon GE, Ludman EJ, Tutty S, Operskalski B, Von Korff M. Telephone
dwelling elderly individuals. J Gerontol Nurs. 1999;25:6-14. [PMID: 10711101] psychotherapy and telephone care management for primary care patients starting
131. Smith DH, Kramer JM, Perrin N, Platt R, Roblin DW, Lane K, et al. A antidepressant treatment: a randomized controlled trial. JAMA. 2004;292:935-
randomized trial of direct-to-patient communication to enhance adherence to 42. [PMID: 15328325]
beta-blocker therapy following myocardial infarction. Arch Intern Med. 2008; 152. Hoffman L, Enders J, Luo J, Segal R, Pippins J, Kimberlin C. Impact of
168:477-83; discussion 483; quiz 447. [PMID: 18332291] an antidepressant management program on medication adherence. Am J Manag
132. Bender BG, Apter A, Bogen DK, Dickinson P, Fisher L, Wamboldt FS, Care. 2003;9:70-80. [PMID: 12549816]
et al. Test of an interactive voice response intervention to improve adherence to 153. Okeke CO, Quigley HA, Jampel HD, Ying GS, Plyler RJ, Jiang Y, et al.
controller medications in adults with asthma. J Am Board Fam Med. 2010;23: Interventions improve poor adherence with once daily glaucoma medications in
159-65. [PMID: 20207925] electronically monitored patients. Ophthalmology. 2009;116:2286-93. [PMID:
133. Berg J, Dunbar-Jacob J, Sereika SM. An evaluation of a self-management 19815286]
program for adults with asthma. Clin Nurs Res. 1997;6:225-38. [PMID: 154. Berger BA, Liang H, Hudmon KS. Evaluation of software-based telephone
9281927] counseling to enhance medication persistency among patients with multiple scle-
134. Janson SL, Fahy JV, Covington JK, Paul SM, Gold WM, Boushey HA. rosis. J Am Pharm Assoc (2003). 2005;45:466-72. [PMID: 16128502]
Effects of individual self-management education on clinical, biological, and ad- 155. Montori VM, Shah ND, Pencille LJ, Branda ME, Van Houten HK,
herence outcomes in asthma. Am J Med. 2003;115:620-6. [PMID: 14656614] Swiglo BA, et al. Use of a decision aid to improve treatment decisions in osteo-

porosis: the osteoporosis choice randomized trial. Am J Med. 2011;124:549-56. missions in patients with high utilization of inpatient services. Dis Manag. 2006;
[PMID: 21605732] 9:328-38. [PMID: 17115880]
156. Rudd RE, Blanch DC, Gall V, Chibnik LB, Wright EA, Reichmann W, 163. Chernew ME, Shah MR, Wegh A, Rosenberg SN, Juster IA, Rosen AB,
et al. A randomized controlled trial of an intervention to reduce low literacy et al. Impact of decreasing copayments on medication adherence within a disease
barriers in inflammatory arthritis management. Patient Educ Couns. 2009;75: management environment. Health Aff (Millwood). 2008;27:103-12. [PMID:
334-9. [PMID: 19345053] 18180484]
157. Waalen J, Bruning AL, Peters MJ, Blau EM. A telephone-based interven- 164. Choudhry NK, Fischer MA, Avorn J, Schneeweiss S, Solomon DH, Ber-
tion for increasing the use of osteoporosis medication: a randomized controlled man C, et al. At Pitney Bowes, value-based insurance design cut copayments and
trial. Am J Manag Care. 2009;15:e60-70. [PMID: 19659407] increased drug adherence. Health Aff (Millwood). 2010;29:1995-2001. [PMID:
158. Solomon DH, Iversen MD, Avorn J, Gleeson T, Brookhart MA, Patrick 21041738]
AR, et al. Osteoporosis telephonic intervention to improve medication regimen 165. Maciejewski ML, Farley JF, Parker J, Wansink D. Copayment reductions
adherence: a large, pragmatic, randomized controlled trial. Arch Intern Med. generate greater medication adherence in targeted patients. Health Aff (Mill-
2012;172:477-83. [PMID: 22371876] wood). 2010;29:2002-8. [PMID: 21041739]
159. Nietert PJ, Tilley BC, Zhao W, Edwards PF, Wessell AM, Mauldin PD, 166. Choudhry NK, Avorn J, Glynn RJ, Antman EM, Schneeweiss S, Toscano
et al. Two pharmacy interventions to improve refill persistence for chronic disease M, et al; Post-Myocardial Infarction Free Rx Event and Economic Evaluation
medications: a randomized, controlled trial. Med Care. 2009;47:32-40. [PMID: (MI FREEE) Trial. Full coverage for preventive medications after myocardial
19106728] infarction. N Engl J Med. 2011;365:2088-97. [PMID: 22080794]
160. Schnipper JL, Kirwin JL, Cotugno MC, Wahlstrom SA, Brown BA, 167. Zhang Y, Lave JR, Donohue JM, Fischer MA, Chernew ME, Newhouse
Tarvin E, et al. Role of pharmacist counseling in preventing adverse drug events JP. The impact of Medicare Part D on medication adherence among older adults
after hospitalization. Arch Intern Med. 2006;166:565-71. [PMID: 16534045] enrolled in Medicare-Advantage products. Med Care. 2010;48:409-17. [PMID:
161. Taylor CT, Byrd DC, Krueger K. Improving primary care in rural Alabama 20393360]
with a pharmacy initiative. Am J Health Syst Pharm. 2003;60:1123-9. [PMID: 168. Davidoff F, Batalden P, Stevens D, Ogrinc G, Mooney S; SQUIRE
12816022] Development Group. Publication guidelines for quality improvement in health
162. Sledge WH, Brown KE, Levine JM, Fiellin DA, Chawarski M, White care: evolution of the SQUIRE project. Qual Saf Health Care. 2008;17 Suppl
WD, et al. A randomized trial of primary intensive care to reduce hospital ad- 1:i3-9. [PMID: 18836063]
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Annals of Internal Medicine
Current Author Addresses: Drs. Viswanathan and Lohr: Social, Statis- Author Contributions: Conception and design: M. Viswanathan, C.E.
tical, and Environmental Sciences, RTI International, 3040 Cornwallis Golin, C.D. Jones, M. Ashok, S.J. Blalock.
Road, Durham, NC 27709. Analysis and interpretation of the data: M. Viswanathan, C.E. Golin,
Dr. Golin, Ms. Wines, and Mr. Coker-Schwimmer: Cecil G. Sheps C.D. Jones, M. Ashok, S.J. Blalock, E.J.L. Coker-Schwimmer, D.L.
Center for Health Services Research, University of North Carolina, Cha- Rosen, K.N. Lohr.
pel Hill, 725 Martin Luther King Jr. Boulevard, CB #7590, Chapel Hill, Drafting of the article: M. Viswanathan, C.E. Golin, M. Ashok, S.J.
NC 27599-7590. Blalock, D.L. Rosen, K.N. Lohr.
Dr. Jones: UNC General Medicine, 5034 Old Clinic Building, CB Critical revision of the article for important intellectual content: M.
#7110, Chapel Hill, NC 27599-7110. Viswanathan, C.E. Golin, C.D. Jones, M. Ashok, S.J. Blalock, K.N.
Dr. Ashok: Social, Statistical, and Environmental Sciences, RTI Interna- Lohr.
tional, 1440 Main Street, Suite 310, Waltham, MA 02451. Final approval of the article: M. Viswanathan, C.E. Golin, C.D. Jones,
Dr. Blalock: Eshelman School of Pharmacy, University of North Caro- M. Ashok, S.J. Blalock, D.L. Rosen, K.N. Lohr.
lina, 2213 Kerr Hall, Chapel Hill, NC 27599-7573. Statistical expertise: M. Viswanathan, D.L. Rosen.
Dr. Rosen: University of North Carolina at Chapel Hill, 130 Mason Obtaining of funding: M. Viswanathan, C.E. Golin.
Farm Road, CB #7215, Chapel Hill, NC 27599-7215. Administrative, technical, or logistic support: M. Viswanathan, C.E.
Ms. Sista: UNC at Chapel Hill School of Medicine, 1001 Bondurant Golin, R.C.M. Wines, E.J.L. Coker-Schwimmer, P. Sista, K.N. Lohr.
Hall, CB #9535, Chapel Hill, NC 27599-9535. Collection and assembly of data: M. Viswanathan, C.E. Golin, C.D.
Jones, M. Ashok, R.C.M. Wines, E.J.L. Coker-Schwimmer, D.L. Rosen,
P. Sista.
Appendix Table 1. Inclusion and Exclusion Criteria
Category Inclusion Criteria Exclusion Criteria

Population Adults prescribed self-administered medication for Children younger than 18 years (no adults in the study
secondary or tertiary prevention of chronic diseases or outcome of interest not stratified by child/adult);
patients administered medications in hospitals or
offices; patients undergoing primary prevention;
patients taking over-the-counter medicines not
prescribed by a provider; patients with infectious
conditions (e.g., HIV/AIDS, tuberculosis, and pelvic
inflammatory disease); patients with mental illness
involving psychosis, mania, or bipolar disorder; patients
receiving medication to treat substance abuse
Geography United States All other countries
Period 1994 to present Before 1994
Length of follow-up No limit –
Settings Outpatient primary and specialty care settings, Institutional settings (e.g., inpatient care, nursing homes,
community-based, and home-based and prisons)
Interventions Any intervention for included clinical conditions Interventions intended to improve adherence with
intended to improve adherence with prescribed, primary prevention measures (e.g., screening, diet,
self-administered medications exercise, and lifestyle changes)
Outcomes Medication adherence, biomarkers, mortality, morbidity, All other outcomes when interventions did not yield a
quality of life, patient satisfaction, health care use statistically significant improvement in medication
(and associated costs), quality of care for studies with adherence
a statistically significant improvement in medication
adherence, adverse events
Publication language English All other languages
Admissible evidence on patient-level, Original research (eligible study designs include Nonrandomized, controlled trials; observational study
provider-level, or systems-level randomized, controlled trials and systematic reviews, designs; case series; case reports; nonsystematic
interventions (study design and with or without meta-analyses) reviews; editorials; letters to the editor; articles rated
other criteria) high risk of bias; studies with historical, rather than
concurrent, control groups; studies with ⬍40
participants
Admissible evidence for policy-level Original research (eligible study designs include Cross-sectional studies; case series; case reports;
interventions (study design and randomized, controlled trials; systematic reviews, with nonsystematic reviews; editorials; letters to the editor;
other criteria) or without meta-analyses; nonrandomized, controlled articles rated high risk of bias; studies with ⬍40
trials; cohort studies; case–control studies; time series; participants
and before–after studies)
www.annals.org 4 December 2012 Annals of Internal Medicine Volume 157 • Number 11 W-285

Appendix Table 2. Definitions of Grades of Overall Strength
of Evidence
Grade Definition
High High confidence that the evidence reflects the true effect.
Further research is very unlikely to change our
confidence in the estimate of effect.
Moderate Moderate confidence that the evidence reflects the true
effect. Further research may change our confidence in
the estimate of the effect and may change the
estimate.
Low Low confidence that the evidence reflects the true effect.
Further research is likely to change our confidence in
the estimate of the effect and is likely to change the
estimate.
Insufficient Evidence either is unavailable or does not permit
estimation of an effect.
W-286 4 December 2012 Annals of Internal Medicine Volume 157 • Number 11 www.annals.org

www.annals.org
Appendix Table 3. Summary of Strength of Evidence, by Intervention Type*
Intervention Type Diabetes Hyperlipidemia Hypertension Heart Myocardial Asthma Depression Glaucoma Multiple Musculoskeletal Multiple or
Failure Infarction Sclerosis Diseases Unspecified
Conditions
Blister packaging MA, persistence†:
L (⫹)
Case management MA: L (⫹) MA: L (⫹) MA: L (⫹) MA: M (⫹) MA: I Persistence†: L (⫺)

Case management preceded by MA: I
intensive interdisciplinary
assessment
Collaborative care (telephone MA: L (⫹) MA: I MA: L (⫺) MA: M (⫹)
and in person)
Collaborative care (telephone MA: I
only)
Decision aids MA: I MA, persistence†,
initiation of
therapy: I
Education (face-to-face with MA: L (⫹)
pharmacist) Persistence†: I
Education and behavioral MA: L (⫹) MA: L (⫹) MA: L (⫹) MA: L (⫹)
support (telephone, mail, Persistence†: I
and/or video)
Education and social support MA: I MA: I
Health coaching MA: I
Multicomponent interventions MA: I MA: L (⫹) MA: L (⫹)
Pharmacist or physician access MA: L (⫺)
to patient adherence data
Patient access to medical MA: I
records
Reminders MA: L (⫹) MA: L (⫹)
Risk communication MA: I
Self-management MA: M (⫹)
Shared or clinical decision MA: L (⫹)
making
Telephone counseling, care MA: I MA: I MA: L (⫹) MA: I
management, and
monitoring
Virtual clinic MA: L (⫹)
I ⫽ insufficient; L (⫺) ⫽ low strength of evidence of no benefit; L (⫹) ⫽ low strength of evidence of benefit; M (⫹) ⫽ moderate strength of evidence of benefit; MA ⫽ medication adherence (with respect to timing, dosage,
or frequency as prescribed).
* Blank cells indicate no evidence.
† In continuing treatment for the prescribed duration.
4 December 2012 Annals of Internal Medicine Volume 157 • Number 11 W-287

Appendix Table 4. Summary of Evidence for Policy Interventions

Clinical Condition Intervention Type Strength of Evidence Studies/ Results Strength of Evidence for Studies/ Results
for Medication Individuals, Other Outcomes Individuals,
Adherence n/N n/N
Cardiovascular disease Improved prescription Moderate-strength 5/⬎70 000 Gaining coverage for cardiovascular Insufficient for death from 1/5855 Nonstatistically significant
(163–167) drug coverage* evidence of benefit medications: 13.4 to 13.5 MPR cardiovascular causes and reduction in death from
points composite outcome of cardiovascular causes and
Reduced copayment or rate of first vascular composite outcome of rate of
improvement of previous event or revascularization first vascular event or
coverage: range, ⫺0.10 to 7.3 Insufficient for rate of first revascularization
W-288 4 December 2012 Annals of Internal Medicine Volume 157 • Number 11

MPR/PDC points; median, 3.0 vascular event 14% decrease in rate of first
points (IQR, 2.5 to 4.4 points) Low for patient total vascular event
spending 26% decrease in relative spending
Low for insurer total Nonstatistically significant decrease
spending in relative spending
Diabetes (163, 165, Improved prescription Moderate-strength 3/20 000 Gaining coverage for diabetes No evidence No evidence
167) drug coverage* evidence of benefit medications: 17.9 MPR points
Reduced copayment or
improvement of previous
coverage: range, 3.6 to 4.5 MPR
points; median, 3.9 points (IQR,
3.7 to 4.3 points)
Inhaled corticosteroids† Reduced medication Insufficient 1/NR Effect not statistically significant No evidence No evidence
(163) copayment
IQR ⫽ interquartile range; MPR ⫽ medication possession ratio; NR ⫽ not reported; PDC ⫽ proportion of days covered.
* Includes all policy-level interventions that reduced patient out-of-pocket expenses for prescription drugs.
† Usually used to treat reactive airway disease conditions, such as asthma and chronic obstructive pulmonary disease.
www.annals.org
Appendix Figure. Summary of evidence search and selection.
Records found through database Additional records identified

search after duplicates removed through other sources
(n = 3979) (n = 145)
Total records after duplicates removed

(n = 4124)
Screened records
(n = 4124)
Excluded records (n = 3366)
Full-text articles assessed for eligibility

(n = 758)
Excluded full-text articles (n = 685)
Non-U.S. study: 65
Ineligible publication type/study design: 89
Sample size <40: 29
Ineligible PICOTS: 447
High risk of bias: 24
Systematic reviews with ineligible
inclusion/exclusion criteria: 31
Studies included in qualitative

synthesis of systematic review
(n = 67 [73 articles])
Studies included in quantitative

synthesis of systematic review
(NA)
NA ⫽ not applicable; PICOTS ⫽ population, intervention, comparators, outcomes, timing, setting.
www.annals.org 4 December 2012 Annals of Internal Medicine Volume 157 • Number 11 W-289

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Interventions to Improve Adherence to Self-administered Medications

A lthough many efficacious medical treatments exist, a

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Appendix Table 1. Inclusion and Exclusion Criteria

Category Inclusion Criteria Exclusion Criteria

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4 December 2012 Annals of Internal Medicine Volume 157 • Number 11 W-287

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W-288 4 December 2012 Annals of Internal Medicine Volume 157 • Number 11

Records found through database Additional records identified

Total records after duplicates removed

Excluded records (n = 3366)

Full-text articles assessed for eligibility

Studies included in qualitative

Studies included in quantitative

NA ⫽ not applicable; PICOTS ⫽ population, intervention, comparators, outcomes, timing, setting.

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