950726

review-article2020
AOPXXX10.1177/1060028020950726Annals of PharmacotherapyBingham et al

Review Article
Annals of Pharmacotherapy

Impact of Telehealth Interventions on

1­–13
© The Author(s) 2020
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DOI: 10.1177/1060028020950726
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Type 2 Diabetes, Hypertension, and/or journals.sagepub.com/home/aop

Dyslipidemia: A Systematic Review

Jennifer M. Bingham, PharmD, BCACP1 ,

Melissa Black, PharmD, BCGP2, Elizabeth J. Anderson, MPH3,
Yawen Li4, Natalie Toselli4, Shawna Fox4, Jennifer R. Martin, MA3,
David R. Axon, PhD, MPharm, MS3 , and
Armando Silva-Almodóvar, PharmD5

Abstract
Objective: To describe telehealth interventions and determine their effect on medication adherence for patients with
type 2 diabetes, hypertension, and/or dyslipidemia. Data Sources: PubMed/MEDLINE, EMBASE, Cochrane, CINAHL Plus,
PsycINFO, Academic Search Ultimate, International Pharmaceutical Abstracts, Scopus, Web of Science, WHO Global Index
Medicus, association websites, and gray literature were searched from January 1, 1998, to December 31, 2019. Study
Selection and Data Extraction: Eligible studies reported eHealth, mobile health, and telehealth interventions for adult
patients prescribed medications for chronic condition management (eg, type 2 diabetes, hypertension, and/or dyslipidemia).
Studies were required to evaluate medication adherence outcomes (eg, medication possession ratio [MPR], proportion of
days covered (PDC)]. Randomized controlled trials, cohort studies, and controlled before-and-after studies were included.
Multiple reviewers independently extracted data and evaluated risk of bias. Data Synthesis: Of 8693 studies identified,
13 reported either an MPR or PDC and were included in the systematic review. The systematic review demonstrated that
electronic health (eHealth) and telehealth interventions were successful at improving medication adherence, whereas mobile
health interventions did not improve medication adherence. Relevance to Patient Care and Clinical Practice: This
systematic review highlighted the available research and findings of studies assessing interventions to improve medication
nonadherence among patients with type 2 diabetes, hypertension, and/or dyslipidemia. The evaluated findings lend support to
the need for targeted medication adherence interventions based on patient population and practice settings. Conclusions:
Telehealth modalities include telephonic outreach and specialized tools designed to increase health literacy. eHealth and
telehealth medication adherence interventions were associated with improved MPR and/or PDC rates.

Keywords
telehealth, medication adherence, systematic review, dyslipidemia, hypertension, diabetes

Introduction
Medication nonadherence is associated with significant
avoidable health care costs and increased health care utili- 1
Tabula Rasa HealthCare Group, Tucson, AZ, USA
2
zation in the United States.1 Previous research estimated SinfoniaRx, Tucson, AZ, USA
3
University of Arizona College of Pharmacy, Tucson, AZ, USA
that medication nonadherence related to type 2 diabetes, 4
University of Florida College of Pharmacy, Gainesville, FL, USA
hypertension, heart failure, and dyslipidemia consequently 5
Ohio State University College of Pharmacy, Columbus, OH, USA
resulted in approximately $30 billion dollars in avoidable
Corresponding Author:
Medicare health care costs.2 A systematic review suggested Jennifer M. Bingham, Tabula Rasa HealthCare Group, 100 North Stone
that medication nonadherence may place a significant cost Ave, Suite 109, Tucson, AZ 85701, USA.
burden on the health care system.3 Discovering ways to Email: JBingham@trhc.com
2 Annals of Pharmacotherapy 00(0)
reduce medication nonadherence is one way to reduce
avoidable health care utilization, morbidity, and mortality.
To address the issues associated with medication nonad-
herence, stakeholders and health care professionals and
organizations have implemented programs and services to
address this important issue. One systematic review high-
lighted the different methods that could be used to improve
medication adherence, including the provision of patient
education, medication regimen management, clinical phar-
macist consultations, medication-taking reminders, cogni-
tive behavioral therapy, and financial incentives.4 However,
implementation of these interventions requires significant
investment at the level of the health care system. Moreover,
because some patients may be limited in how often they can
be seen within a health care setting given travel time,5 or
socioeconomic limitations,6 exploring ways to address med-
ication adherence within a home setting may be beneficial.
Telehealth interventions are defined by the American
Telemedicine Association as interventions that utilize tele-
communications and information technologies to deliver
health care services.7 A previous review found that tele-
phonic and text messaging interventions were commonly
used to improve medication adherence among patients with
serious mental illness.8 Another meta-analysis demon-
strated that text messaging services can significantly
improve medication adherence for certain chronic diseases.9
To date, there are no studies identifying and reviewing the
use of telehealth interventions to address medication non­
adherence for patients with type 2 diabetes, hypertension,
and/or dyslipidemia. This systematic review described the
different telehealth interventions implemented to improve
medication nonadherence across a multitude of health care
settings. The objectives of this systematic review were to
describe the types of telehealth interventions and assess the
impact of these interventions on medication nonadherence
among patients with type 2 diabetes, hypertension, and/or
dyslipidemia.
Methods
Data Sources and Searches
The review was registered in the PROSPERO international
registry of systematic reviews (CRD42019133379).10 It was
conducted in accordance with the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA)
guidelines.11 English-language studies examining eHealth,
mobile health, and telehealth interventions designed to
improve medication adherence, published within the past 20
years between January 1, 1998, and December 31, 2019,
were identified to capture recent innovative telehealth solu-
tions. A medical research librarian conducted a systematic
search using the following data sources: PubMed/MEDLINE
(National Library of Medicine), EMBASE (Elsevier),
Cochrane (Wiley), CINAHL Plus with Full Text (EbscoHost),
PsycINFO (EbscoHost), Academic Search Ultimate
(EbscoHost), International Pharmaceutical Abstracts (Ovid),
Scopus (Elsevier), Web of Science (Clarivate Analytics), and
WHO Global Index Medicus (World Health Organization).
Additional sources of gray literature included the following
professional association websites: American Pharmacists
Association, Academy of Managed Care and Specialty
Pharmacy, American College of Clinical Pharmacy, and the
American Journal of Health-System Pharmacists. Hand
searches were also conducted to identify additional studies
published in the following journals: Diabetes Technology &
Therapeutics, mHealth, Journal of Telemedicine & Telecare,
Telemedicine & E-Health, Journal of Medical Internet
Research, and Studies in Health Technology & Information.
Search terms included a combination of both controlled
vocabulary and terminology keywords, including medication
adherence, telemedicine, telecommunications, mobile appli-
cations, cell phone, text messaging, cell phone use, electronic
mail, dyslipidemia, hypertension, and type 2 diabetes. See
Table 1 for the search method utilized in PubMed/MEDLINE.
This search method was used in July of 2019 to translate the
search into all the bibliographic databases and used as a base
for conducting searches for gray literature.
Study Selection
Eligible research studies included telehealth interventions,
including telephonic, electronic health (eHealth) informa-
tion technology, or mobile health interventions, intended to
improve medication adherence for patients 18 years of age
or older with a reported medication adherence outcome.
Studies where patients did not have one of the chronic
conditions (ie, type 2 diabetes, hypertension, and/or dyslip-
idemia) were excluded. For inclusion, the intervention out-
come had to be measured using industry standards as either
the medication possession ratio (MPR) or proportion of
days covered (PDC) rate. Additional requirements for study
inclusion were the following: presence of an electronic
intervention (eg, patient education, counseling), description
of provider type, and description of the practice setting.
Identified studies were exported to EndNote.12
Data Extraction
Three reviewers (SF, NT, YL) independently assessed article
titles and abstracts for study inclusion and data extraction.
The authors involved in the initial review process (SF, NT,
YL) used standardized checklists to assess for study inclu-
sion. The standardized checklist allowed the reviewers to
select yes/no, and studies were excluded if they met any of
the following criteria: not an adult intervention, no mention
of MPR, no mention of PDC, not related to medication
adherence, not a research article, and was a review article.
Bingham et al 3

Table 1.  Example Search Method for PubMed/MEDLINE.a

PubMed/MEDLINE, National Library of Medicine

(“Medication Adherence”[Mesh] OR “Medication adherence”[ALL] OR “medication compliance”[ALL] OR Persistence[ALL]
OR “Medication taking behavior”[ALL] OR PDC[ALL] OR “proportion of days covered”[ALL] OR MPR[ALL] OR “medication
possession ratio”[ALL] OR “Patient Compliance”[ALL] OR “drug compliance”[ALL] OR “dosage adherence”[ALL] OR “dosage
compliance”[ALL] OR “dose adherence”[ALL] OR “dose compliance”[ALL] OR “dosing compliance”[ALL] OR “dosing
adherence”[ALL] OR “dosing compliance”[ALL] OR “drug adherence”[ALL] OR “drug compliance”[ALL] OR “drug intake
compliance”[ALL] OR “drug regimen adherence”[ALL] OR “medication intake adherence”[ALL] OR compliance[ALL] OR
Comply[ALL] OR complied[ALL] OR adherence[ALL]) AND (“Telemedicine”[Mesh] OR “Telecommunications”[Mesh] OR “Mobile
Applications”[Mesh] OR “Cell Phone”[Mesh] OR “Text Messaging”[Mesh] OR “Cell Phone Use”[Mesh] OR “Electronic Mail”[Mesh]
OR cell phone*[ALL] OR cellphone*[ALL] OR “cellular phone”[ALL] OR “cellular telephone”[ALL] OR “mobile phone”[ALL]
OR “mobile telephone”[ALL] OR Telemedicine[ALL] OR Telecommunication*[ALL] OR mobile application*[ALL] OR “mobile
app”[ALL] OR portable software app*[ALL] OR portable software application*[ALL] OR Electronic intervention*[ALL] OR
Ehealth[ALL] OR “e-health”[ALL] OR “tele-health”[ALL] OR telehealth[ALL] OR Web-based trial*[ALL] OR E-health[ALL] OR
e-learning[ALL] OR elearning[ALL] OR “electronic-mail”[ALL] OR email[ALL] OR e-mail[ALL] OR “electronic messaging”[ALL]
OR “electronic mail”[ALL] OR “electronic mailing”[ALL] OR mhealth[ALL] OR m-health[ALL] OR mms[ALL] OR mobile[ALL]
OR “mobile health”[ALL] OR “mobile health technology”[ALL] OR mobile health application*[ALL] OR web-based[ALL]
OR “web based intervention”[ALL]) AND (“Dyslipidemias”[Mesh] OR “Hypertension”[Mesh] OR “Diabetes Mellitus, Type
2”[Mesh] OR Dyslipidemia[ALL] OR Dyslipoproteinemias[ALL] OR Dyslipoproteinemia[ALL] OR High Blood Pressure*[ALL]
OR hypertension[ALL] OR acute hypertension[ALL] OR arterial hypertension[ALL] OR cardiovascular hypertension[ALL] OR
controlled hypertension[ALL] OR endocrine hypertension[ALL] OR “high renin hypertension”[ALL] OR hypertension[ALL] OR
“hypertensive disease”[ALL] OR “hypertensive effect”[ALL] OR “hypertensive response”[ALL] OR “neurogenic hypertension”[ALL]
OR “preexistent hypertension”[ALL] OR “refractory hypertension”[ALL] OR “salt high blood pressure”[ALL] OR “salt
hypertension”[ALL] OR “secondary hypertension”[ALL] OR “systemic hypertension”[ALL] OR “Hydroxymethylglutaryl CoA
Reductases”[Mesh] OR Hydroxymethylglutaryl CoA Reductase Inhibitor*[ALL] OR HMG-CoA Reductase Inhibitor*[ALL] OR
HMG-CoA Statin*[ALL] OR Statin*[ALL] OR Hydroxymethylglutaryl-Coenzyme A Inhibitor*[ALL] OR Hydroxymethylglutaryl
Coenzyme A Inhibitor*[ALL] OR “hydroxymethylglutaryl-coa reductase inhibitors”[ALL] OR “Antihypertensive Agents”[Mesh] OR
Antihypertensive Agent*[ALL] OR Anti-Hypertensive Agent*[ALL] OR Anti Hypertensive Agent*[ALL] OR Antihypertensive*[ALL]
OR Anti-Hypertensive*[ALL] OR Anti Hypertensive*[ALL] OR Antihypertensive Drug*[ALL] OR Anti-Hypertensive Drug*[ALL]
OR Anti Hypertensive Drug*[ALL] OR antihypertension agent*[ALL] OR antihypertensive[ALL] OR antihypertensive drug[ALL] OR
antihypertensive*[ALL] OR antihypertonic agent[ALL] OR hypotensiva[ALL] OR hypotensive[ALL] OR hypotensive agent*[ALL]
OR hypotensive drug[ALL] OR Diabetes Mellitus Type 2[ALL] OR “Noninsulin-Dependent Diabetes Mellitus”[ALL] OR “Ketosis-
Resistant Diabetes Mellitus”[ALL] OR “Ketosis Resistant Diabetes Mellitus”[ALL] OR “Non Insulin Dependent Diabetes
Mellitus”[ALL] OR “Noninsulin Dependent Diabetes Mellitus”[ALL] OR “Non-Insulin-Dependent Diabetes Mellitus”[ALL] OR
“Non-Insulin-Dependent Diabetes Mellitus”[ALL] OR “Noninsulin-Dependent Diabetes Mellitus”[ALL] OR “Noninsulin Dependent
Diabetes”[ALL] OR “Mellitus”[ALL] OR “Stable Diabetes Mellitus”[ALL] OR “Type II Diabetes Mellitus”[ALL] OR NIDDM[ALL] OR
“Maturity-Onset Diabetes Mellitus”[ALL] OR “Maturity Onset Diabetes Mellitus”[ALL] OR MODY[ALL] OR “Slow Onset Diabetes
Mellitus”[ALL] OR “Slow-Onset Diabetes Mellitus”[ALL] OR “Type 2 Diabetes Mellitus”[ALL] OR “Maturity-Onset Diabetes”[ALL]
OR “Maturity Onset Diabetes”[ALL] OR “Type 2 Diabetes”[ALL] OR “Adult-Onset Diabetes Mellitus”[ALL] OR “Adult Onset
Diabetes Mellitus”[ALL] OR diabetic[ALL] OR diabetes[ALL] OR “Hypoglycemic Agents”[Mesh] OR Hypoglycemic Agent*[ALL]
OR Antihyperglycemic*[ALL] OR Antihyperglycemic Agent*[ALL] OR Hypoglycemic Drug*[ALL] OR Hypoglycemic*[ALL] OR
Hypoglycemic Effect*[ALL] OR Antidiabetic*[ALL] OR Antidiabetic Drug*[ALL] OR antidiabetes drug[ALL] OR antidiabeticum[ALL]
OR Antidiabetic Agent*[ALL] OR Alpha-glucosidase inhibitor*[ALL] OR Biguanide*[ALL] OR Bile Acid Sequestrant*[ALL] OR
Dopamine-2 Agonist*[ALL] OR Dipeptidyl peptidase-4 inhibitor*[ALL] OR Meglitinide*[ALL] OR Sodium-glucose Cotransporter-2
Inhibitor*[ALL] OR Sulfonylurea*[ALL] OR Thiazolidinedione*)
a
Limited to English language and search dates of January 1, 1998, through December 31, 2019. This strategy was used to translate into the other
bibliographic databases and served as a base for searching the gray literature.

Each article identified after title and abstract screening was
reviewed in full by 2 reviewers (AS-A, MB). The 2 review-
ers (AS-A, MB) met with the study coordinator (JMB) to
resolve discrepancies. After full-text review, studies selected
for inclusion were independently reviewed by 2 reviewers
(AS-A, MB) who extracted relevant data. Studies were
included if the reviewers were able to extract the following
data: study design, description of intervention, provider
type, setting, medications assessed, adherence measure
(MPR or PDC), treatment arms, adherence measure out-
comes, P value, and overall effect.
Risk-of-Bias Assessment
Risk of bias was assessed by 2 independent reviewers
(JMB, DRA) using Cochrane tools appropriate to the study
design. Risk of bias in randomized controlled trials (RCTs)
was assessed using the Cochrane Risk of Bias 2.0 tool,
which included 5 domains: risk of bias from (1) the ran-
domization process, (2) deviations from the intended
interventions, (3) missing outcome data, (4) measurement
of the outcome, and (5) selection of the reported result as
well as an overall risk-of-bias judgment. This tool included
4 Annals of Pharmacotherapy 00(0)
Figure 1. PRISMA11 flow diagram of literature search and included studies.
Abbreviations: MPR, medication possession ratio; PDC, proportion of days covered.
signaling questions within each domain that typically
included the following options: yes, probably yes, no, prob-
ably no, no information, and not applicable. The domain-
specific and overall risk-of-bias judgment were scored as
low, some concerns, or high.13
Risk of bias in non-randomized or observational studies
was assessed using the tool for assessing risk of bias in
non-randomized studies of interventions (ROBINS-I). The
ROBINS-I contained 7 domains and an overall risk-of-bias
assessment: (1) bias caused by confounding, (2) bias in
selection of participants into the study, (3) bias in classifica-
tion of interventions, (4) bias caused by deviations from
intended interventions, (5) bias caused by missing data, (6)
bias in measurement of outcomes, and (7) bias in selection
of the reported result. The signaling questions within each
domain had response options similar to the Cochrane Risk
of Bias 2.0 tool, but the domain-specific and overall risk-
of-bias judgment could be scored low, moderate, serious,
critical, or no information.14 The 2 reviewers (JMB, DRA)
met to agree consensus after their initial independent risk-
of-bias assessments.
Data Synthesis and Analysis
Practice setting, medication related to chronic condition,
measure of adherence, and adherence outcomes were
described for all studies included in the systematic review.
Medication adherence intervention components were cate-
gorized as eHealth, mobile health, or telehealth.
Results
Systematic Review
Of 8635 studies identified, 5814 abstracts were screened
after duplicates were removed, and 55 received full-text
review for study inclusion. Also, 13 studies reported either
an MPR or PDC and were included in the systematic
review.15-27 The PRISMA flowchart of study inclusion is
shown in Figure 1. The 13 included studies were divided
into the following intervention categories: telephonic
outreach, text messaging, mobile software applications,
and miscellaneous interventions. Of these, 6 demonstrated
statistically significant improvement in medication
Bingham et al 5
adherence, whereas the other 7 found no significant change
in adherence (Table 2). To measure adherence, 2 studies
used MPR and 11 used PDC.
Telephonic Outreach
Seven studies investigated the use of telephonic outreach to
improve medication adherence.15-20 Four studies reported
positive improvement in medication adherence.16-19
To communicate with patients, some studies utilized care
managers,15 pharmacists,16,18-20 student pharmacists,17,19 or
pharmacy technicians.19 Bosworth et al,15 utilized tele-
phonic outreach to administer behavioral interventions
through 10 phone calls over 6 months designed to improve
health care literacy, provider communication, and adher-
ence to lifestyle changes and medication use relevant to
hypertension. Medication adherence appeared to improve
up to a year after the intervention in the study by Bosworth
et al; however, statistical significance was not assessed.
Other studies demonstrated that pharmacist and pharma-
cist-guided telephonic interventions utilizing call scripts
designed to identify and address barriers to medication
adherence improved medication adherence among patients
with diabetes and/or hypertension.16-19 The majority of
these studies utilized at least 1 follow-up call with patients
in their study period to assess if the initial phone call
helped address a patient’s barriers to their medication
adherence.17-19 Pawloski et al20 conducted a subanalysis of
home blood pressure measuring paired with a pharma-
cist’s telemonitoring intervention to improve blood pres-
sure control among patients with hypertension. The results
from this study demonstrated that the intervention did not
have a statistically significant effect on medication adher-
ence for the treatment of hypertension.
Text Messaging
Three investigations utilized text messaging to improve
medication adherence.21-23 Two of the 3 studies reported
positive outcomes demonstrating improved medication
adherence.21,23 Bobrow et al21 demonstrated that utilization
of text messages over one calendar year improved the aver-
age PDC by 3.8 percentage points (96% CI = 0.03-7.6) to
5.2 (95% CI = 1.5-8.9) when compared with usual care.
Whereas Foreman et al23 found that their text message
cohort saw their PDC increase by 1 percentage point over
8 months versus a matched control cohort that experienced
an average PDC decrease of 7 percentage points. All 3
studies utilized daily text messages to remind patients to
take the targeted medications as indicated.21-23 In addition
to daily reminders, each study incorporated additional
reminders regarding medication refills to promote phar-
macy services,23 or provided more detailed information to
improve medication adherence behaviors.21,22
Mobile Health
Two studies utilized mobile applications to address medica-
tion adherence.24,25 Neither study demonstrated that the use of
a mobile application significantly improved medication
adherence. The mobile application in the study by Patel et al24
included daily medication adherence reminders, medication
adherence tracking capabilities, and medication safety infor-
mation. Patients in the study by Anglada-Martinez et al25 were
already highly adherent, given an average pre-intervention
PDC of 85.5% ± 20.7%.25 This study utilized a mobile appli-
cation that included educational material, medication adher-
ence reminders, weekly motivational messages, enabled
medication reconciliation, communication with their provider,
and also permitted tracking of medication adherence.25
Miscellaneous Interventions
Two studies used interventions deemed miscellaneous.26,27
Yeung et al26 investigated the effectiveness of low health
literacy flashcards and quick response code–enabled educa-
tional videos (prepared in English and Spanish) to improve
medication adherence among patients with type 2 diabetes,
hypertension, or heart failure. The use of flashcards and
videos significantly improved average medication adher-
ence when compared with a control group in a low-health
literacy patient population (post-intervention PDC: 71% vs
44%; P = 0.007).26 Kim et al27 assessed the impact of
copayment waivers, health education material (HEM), and
telephonic nurse counseling among employees enrolled in a
disease management program utilizing a matched interven-
tion-control cohort. After controlling for unique patient
characteristics, a multivariate regression found that nurse
counseling significantly improved adherence to antihyper-
tensive, diabetes, and statin medications. This study also
demonstrated how patient receipt of HEM significantly
reduced diabetes medication cost sharing and improved
adherence to diabetes and statin medications.28
Risk-of-Bias Assessment of Included Studies
Among the randomized controlled trials (RCTs), the overall
risk of bias was typically deemed to have some concerns.
This was attributed to the inability to confirm that studies
were conducted in accordance with a prespecified analyti-
cal plan, for example, as outlined by a published proposal.
Among the non-randomized studies, the overall risk-of-bias
was typically deemed to be moderate as per ROBINS-I
guidelines—that is, although generally acceptable for a
non-randomized study, it could not be considered compa-
rable to a well-conducted RCT. Two main domains led to
this assessment: first, bias from confounding; and second,
bias in selection of reported result, again because of an
inability to consult a previously published study protocol or
6
Table 2.  Summary of Studies Assessed by Type of Intervention.
Adherence measure outcomes (MPR or
Type of Adherence PDC in decimal form) (time before or
intervention Study design Description of intervention Provider type Setting Medications assessed measure Treatment arms after intervention) P value Effect

Telephonic outreach
Bosworth et al, Pre-post Behavioral interventions to Care manager Patient-centered ACE inhibitor, MPRa • Control: • Preintervention (90 days) Not reported Not reported
201115 intervention address medication adherence medical home β-blocker, calcium 3992 • Control: 0.58
and lifestyle changes to improve channel blocker, • Intervention: • Intervention: 0.65
hypertension management. diuretic, α-1 blocker, 558 • Postintervention (270-359 days)
Investigators aimed to call central α-2 agonist • Control: 0.64
patients 10 times over 6 months • Intervention: 0.77
Abughosh et al, Retrospective Call script to alert patients to an Pharmacists Medicare ACE inhibitor, ARBW PDCb • Control: 65 • Postintervention (6 months) <0.001 (Results from Positive
201616 cohort overdue refill and to identify and Advantage • Intervention: • Control: 0.29 ± 0.17 multivariate linear
resolve causes of medication insurance plan 66 • Intervention: 0.58 ± 0.26 regression)
nonadherence. Patients were
called by pharmacists for 1 brief
telephone intervention that
lasted 3-5 minutes
Abughosh et al, Pre post Six motivational interview Student Medicare ACE inhibitor, ARB PDCb • Control: 495 • Preintervention (6 months) Preintervention Positive
201717 intervention phone calls using call script to Pharmacists Advantage • Intervention: • Control: 0.60 ± 0.16 (between group):
identify barriers to medication insurance plan 248 • Intervention: 0.63 ± 0.13 0.005
adherence and create a plan to • Postintervention (6 months) Postintervention
resolve them with the patient. • Control: 0.57 ± 0.38 (between group):
Investigators attempted to • Intervention: 0.66 ± 0.34 <0.001
complete 6 phone calls over 6
months (1 phone call monthly).
Odegard and Randomized Patients were contacted using Pharmacists Four community Metformin, sulfonylurea MPRa • Control: 145 • Preintervention (12 months) Postintervention Positive
Christensen, controlled a call script to identify and pharmacies • Intervention: • Control: 0.84 (between group): P
201218 trial address causes of medication 120 • Intervention: 0.86 = 0.01
nonadherence. One follow-up • Postintervention (12 months)
call was scheduled 1 week to 1 • Control: not reported
month after the initial call • Intervention: 0.90
Park et al, 201719 Matched Call scripts used to identify and Student Medicare Antihypertensives PDCb • Control: 563 • Preintervention (6 months) Difference in difference Positive
pre-post resolve potential causes of pharmacists, Advantage • Intervention: • Control: 0.62 ± 0.29 P = 0.02
intervention medication nonadherence. pharmacy insurance plan 563 • Intervention: 0.63 ± 0.29
Patients included in the analysis technicians, • Postintervention (6 months)
had at least 1 successful phone pharmacists • Control 0.76 ± 0.25
call • Intervention: 0.80 ± 0.17

(continued)
 Table 2.  (continued)
Adherence measure outcomes (MPR or
Type of Adherence PDC in decimal form) (time before or
intervention Study design Description of intervention Provider type Setting Medications assessed measure Treatment arms after intervention) P value Effect

c
Pawloski et al, Cluster One in-person visit + home blood Pharmacists 16 Primary care Antihypertensives PDC • Usual care: • Preintervention (12 months) P = 0.91 Not significant
201620 randomized pressure monitors + biweekly clinics 122 • Control: 0.91 ± 0.02
trial to bimonthly telephonic • Intervention: • Intervention: 0.95 ± 0.01
appointments emphasizing 128 • Postintervention (12 months)
medication adherence and • Control: 0.90 ± 0.01
lifestyle changes for blood • Intervention: 0.93 ± 0.01
pressure control
Text messaging
Bobrow et al, Single-blind Text messages designed to Physician, nurse Primary care clinic Antihypertensives PDCd • Control: 385 • Postintervention (12 months) • Information only Positive
201621 randomized improve medication adherence, • Information • Control: 0.79 (0.64-0.91) versus control: P
trial educate regarding hypertension, only: 395 • Information only: 0.83 (0.69-0.91) = 0.006
and remind patients to pick up • Information • Information + phone call: 0.83 • Information+
medication refills and attend + phone call: (0.66-0.91) phone call versus
clinic appointments. A second 377 control: P = 0.048
intervention group included
text messages with an option to
request a phone call to discuss
the text content
Gatwood et al, Randomized Daily individualized text messages Text messages Health system Oral diabetes PDCb • Control: 10 • Preintervention (90 days) P > 0.05 Not significant
201622 controlled using concepts derived from medications • Intervention: • Control: 0.87 ± 0.19
trial the Health Belief Model, Self 10 • Intervention: 0.84 ± 0.18
Determination Theory, or • Postintervention (180 days)
information on the medication • Control: 0.74
regimen • Intervention: 0.78
Foreman et al, Retrospective Text message alerts, including Text messages Pharmacy benefit Oral antihyperglycemic, PDCb • Control: 290 • Preintervention (242 days) Postimplementation Positive
201223 cohort notifications for availability of manager β-blocker, calcium • Intervention: • Control: 0.84 ± 0.24 between group P
medication refills, prescription channel blocker, 290 • Intervention: 0.84 ± 0.25 < 0.001
eligible for a renewal, ACE inhibitor, ARB, • Postintervention (242 days)
notification of prescription diuretic, platelet • Control: 0.77 ± 0.28
eligible to transfer to mail order, aggregation inhibitor, • Intervention: 0.85 ± 0.20
notification that medication statin, antidepressant,
was shipped, a daily reminder bisphosphonate,
to take their medication, and thyroid agent
prescription-specific dosage
reminders

(continued)

7
8
Table 2.  (continued)

Adherence measure outcomes (MPR or

Type of Adherence PDC in decimal form) (time before or
intervention Study design Description of intervention Provider type Setting Medications assessed measure Treatment arms after intervention) P value Effect

Mobile software applications

Patel et al, 201324 Open-label trial Patients were provided with a Mobile phone/app Renal, Antihypertensives PDCb • Intervention: • Preintervention (3 months): 0.54 ± Pairwise post hoc Not significant
smart phone preloaded with hypertension, 48 0.27 testing
software to educate on specific cardiology • During intervention (3 months): Preintervention versus
medication use along with alerts clinics 0.58 ± 0.20 during intervention
and reminders to notify when • Postintervention (3 months): 0.46 P = 0.05
to take medications ± 0.31 During intervention
versus
postintervention P
< 0.001
Anglada-Martinez Pre-post Mobile app provided patients Mobile app Primary care clinic Medications to manage PDCb • Intervention: • Preintervention (3 months): 0.86 ± P = 0.25 Not significant
et al, 201625 intervention with a medication action plan, a chronic conditions 42 0.21
medication adherence reminder, • Postintervention (3 months): 0.83
weekly motivational messages, ± 0.26
and 2-way communication
between providers and patients
MisCellaneous
Yeung et al, Prospective Patients were provided with Pharmacists Hospital system Antihyperglycemics: PDCa • Control: 34 • Preintervention (180 days) Between-group Positive
201726 matched physical flash card with linked metformin, glyburide, • Intervention: • Control: 0.34 difference P =
online informative videos glipizide, glimepiride, 34 • Intervention: 0.38 0.0069
accessible via a smartphone pioglitazone, • Postintervention (180 days)
quick response code or web saxagliptin, acarbose, • Control: 0.44
address repaglinide • Intervention:0.71
Heart failure and
hypertension:
furosemide,
torsemide, carvedilol,
metoprolol
tartrate and
succinate, lisinopril,
ramipril, captopril,
enalapril, losartan,
spironolactone,
digoxin, hydralazine,
isosorbide
mononitrate and
dinitrate

(continued)
 Table 2.  (continued)

Adherence measure outcomes (MPR or

Type of Adherence PDC in decimal form) (time before or
intervention Study design Description of intervention Provider type Setting Medications assessed measure Treatment arms after intervention) P value Effect

27
Kim et al, 2011 Retrospective Disease management service
matched case where employees received
control study reduced medication copays and
health education material (HEM)
or telephonic nurse counseling
to address therapeutic needs
b
Nurses Large retail Oral antihyperglycemic, PDC • Control: Disease management cohort •• Nurse counseling: Positive
employer intermediate- and 1276 Preintervention (1 year): antihypertensives
long-acting insulin, • Intervention: • Oral hypoglycemics: 0.80 ± 0.18 P = 0.03, diabetes
ACE inhibitor, 1276 • Insulin: 0.64 ± 0.27 medications P <
ARB, statin, • ACE inhibitor/ARB: 0.81 ± 0.24 0.001, statins P
β-blocker, inhaled • β-Blockers: 0.84 ± 0.20 = 0.02
corticosteroids • Statins: 0.79 ± 0.22 •• HEM:
HEM: antihypertensives
• Oral hypoglycemics: 0.74 ± 0.23 P = 0.96, diabetes
• Insulin: 0.65 ± 0.28 medications P
• ACE inhibitor/ARB: 0.81 ± 0.21 = 0.02, statins P
• β-Blockers: 0.76 ± 0.26 = 0.07
• Statins: 0.74 ± 0.26 •• Reduced out-
Postintervention (1 year): of-pocket cost:
• Oral hypoglycemics: 0.84 ± 0.21 antihypertensives
• Insulin: 0.67 ± 0.29 P = 0.44, diabetes
• ACE inhibitor/ARB: 0.78 ± 0.24 medications P =
• β-Blockers: 0.77 ± 0.33 0.02, statins P =
• Statins: 0.80 ± 0.28 0.004
HEM Cohort: •• (Results from
• Oral hypoglycemics: 0.71 ± 0.31 multivariate linear
• Insulin: 0.65 ± 0.33 regression)
• ACE inhibitor/ARB: 0.72 ± 0.33
• β-Blockers: 0.71 ± 0.33
• Statins: 0.72 ± 0.33
Control cohort
Preintervention (1 year):
• Oral hypoglycemics: 0.75 ± 0.21
• Insulin: 0.58 ± 0.27
• ACE inhibitor/ARB: 0.77 ± 0.24
• β-Blockers: 0.75 ± 0.25
• Statins: 0.74 ± 0.25
HEM Cohort:
• Oral hypoglycemics: 0.75 ± 0.22
• Insulin: 0.60 ± 0.26
• ACE inhibitor/ARB: 0.77 ± 0.24
• β-Blockers: 0.77 ± 0.23
• Statins: 0.72 ± 0.26
Postintervention (1 year):
• Oral hypoglycemics: 0.68 ± 0.29
• Insulin: 0.57 ± 0.29
• ACE inhibitor/ARB: 0.70 ± 0.32
• β-Blockers: 0.68 ± 0.30
• Statins: 0.67 ± 0.34
HEM:
• Oral hypoglycemics: 0.63 ± 0.32
• Insulin: 0.54 ± 0.34
• ACE inhibitor/ARB: 0.67 ± 0.33
• β-Blockers: 0.68 ± 0.33
• Statins: 0.65 ± 0.33

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; MPR, medication possession ratio; PDC, proportion of days covered; HEM, health education material; β-blocker, beta blocker.
a
Adherence measure outcomes reported as mean.
b
Adherence measure outcomes reported as mean ± SD.
c
Adherence measure outcomes reported as mean ± standard error.
d
Adherence measure outcomes reported as median (25th to 75th interquartile range).

9
10 Annals of Pharmacotherapy 00(0)
statistical analysis plan. See Table 3 for further details about
the risk-of-bias assessment.
Discussion
Dedicated telehealth services to address medication nonad-
herence are an integral means of engaging patients beyond
geographical and socioeconomic limitations. This system-
atic review identified 13 studies that assessed the effective-
ness of telehealth interventions to improve medication
nonadherence among patients with type 2 diabetes, hyper-
tension, and/or dyslipidemia, as measured by objective mea-
sures of medication adherence (PDC or MPR).15-27 Of these
studies, 8 provided results suggesting that telehealth services
were an effective means of improving medication nonadher-
ence.16-19,21,23,26,27 Effective telehealth services included ded-
icated telephonic outreach, text messaging, and tools such as
physical flash card and short online videos.
Interventions that incorporated telephonic and text mes-
saging modalities comprised 69% (n = 9) of the studies iden-
tified.15-23 The telephonic interventions that demonstrated
statistically significant improvement in medication adher-
ence may have done so given their important focus on identi-
fying and addressing barriers to medication nonadherence.16-19
It is important to note that two interventions,17,18 used call
scripts adapted from proven methods of health behavior
modifications, such as the 5-As (Ask, Advise, Assess, Assist,
Arrange) method for smoking cessation,28 or the motiva-
tional interviewing elicit-provide-elicit approach.29 These
studies highlighted the importance of identifying specific
medication-related barriers in order to address them. The
World Health Organization (WHO) recommends that inter-
ventions are tailored to meet the needs of individual patient’s
needs to maximize the benefits of an intervention and to
ensure that it addresses barriers to medication nonadher-
ence.30 Furthermore, some studies15,17-20 utilized multiple
phone calls to follow up with patients, which may be neces-
sary to ensure that appropriate medication adherence per-
sistence occurs. The use of call scripts in these studies
highlighted that interventions designed to identify and
address barriers to medication adherence can be executed by
pharmacy technicians and student pharmacists as a means of
extending pharmacy-based care.
Although it is difficult to assess if Bosworth et al15 led to
significant improvements in medication adherence given
that statistical analyses were not performed in the study, the
results of the study illustrated a trend toward improvement
in medication adherence through telephonic outreach. It is
important to note that in the study by Pawloski et al,20 both
groups had optimal adherence (PDC > 90%) rates prior to
the start of the intervention. Thus, the benefits of an inter-
vention designed to improve medication adherence may not
be observed because of the already high adherence rates
among patients prior to the start of the intervention.
Of the text messaging studies that demonstrated success-
ful improvement of medication adherence, both utilized auto-
mated reminders to take medications and pick up medication
refills from their pharmacies.21,23 This is consistent with a
meta-analysis by Fenerty et al,31 which found that daily
reminders significantly improved medication adherence.
Among the majority of studies that did not demonstrate sig-
nificant improvement in medication adherence,20,22,23 patients’
pre-intervention medication adherence would have been con-
sidered adherent (medication adherence >80%) according to
medication adherence measures created by the Pharmacy
Quality Alliance (PQA) and adopted by The Centers for
Medicare and Medicaid Services (CMS).32 Consequently,
these interventions may be ineffective for patients who meet
certain thresholds for medication adherence. Future studies
should limit their populations to patients with poor medication
adherence.
Both mobile application interventions identified in this
study were unfortunately unable to significantly affect med-
ication adherence.24,25 Patel et al24 specifically recruited
Medicaid patients who started the study with an average
adherence of 54%. This is in contrast to the findings from
Bobrow et al,21 where daily reminders helped improve med-
ication adherence among a population where patients
receive free primary care services and medicines, and
Foreman et al,23 where patients were recruited from a large
pharmacy benefit manager serving commercial insurance
and Medicare Advantage insurance plans. It is plausible that
the intervention by Patel et al,24 which utilized daily remind-
ers and included medication information, was insufficient
in addressing the complex socioeconomic issues affecting
the medication adherence of the Medicaid cohort located
primarily in Washington, DC. Despite not improving medi-
cation adherence overall, it is noteworthy to highlight that
medication adherence significantly worsened upon inter-
vention discontinuation, which suggests that some patients
were dependent on the application as a reminder.
Finally, the use of educational tools such as flash cards
and online videos were found to significantly improve med-
ication adherence.26 Additionally, although the educational
tools developed in Yeung et al26 may be difficult to adapt to
other settings, this study does demonstrate how the success-
ful education of patients regarding their medication use can
significantly improve medication adherence.
These findings paired with the results from previous
reviews highlight telehealth interventions that can be adapted
to other health care settings to improve medication adher-
ence.8,14 Adherence interventions with a positive impact on
either MPR or PDC identified in this review included the
following: (1) interventions that engaged patients in conver-
sation to identify and resolve barriers to medication nonad-
herence,16-19 (2) adoption of a plan to help resolve their
medication adherence issues,16-19 (3) use of alerts to remind
patients to their take their medications and pick up their
Bingham et al 11

Table 3.  Summary of Risk-of-Bias Assessment for Included Studies.13,14

Randomized controlled trials

  Risk-of-bias resulting from  

Domain 2:
Domain 2: deviations deviations
from intended from intended
Domain 1: interventions (effect interventions (effect Domain Domain 4: Domain 5:
randomization of assignment to of adhering to 3: missing measurement selection of Overall risk-of-bias
Author, year process intervention) intervention) outcome data of outcome reported result judgment

Odegard and Some concerns Low Low Low Low Some concerns Some concerns
Christensen,
201218
Pawloski et al, Low Low Low Low Low Some concerns Some concerns
201620
Bobrow et al, Low Low Low Low Low Low Low
201621
Gatwood et al, Low Low Low Low Low Some concerns Some concerns
201622

Non-randomized studies

  Bias caused
Bias in selection of by deviations Bias caused Bias in Bias in selection
Bias caused by participants into the Bias in classification from intended by missing measurement of the reported Overall
confounding study of interventions interventions data of outcomes result bias

Bosworth Serious Low Low Low Low Low Moderate Serious

et al, 201115
Abughosh Moderate Low Low Low Low Low Moderate Moderate
et al, 201616
Abughosh Moderate Low Low Low Low Low Moderate Moderate
et al, 201717
Park et al, Moderate Low Low Low Low Low Moderate Moderate
201719
Foreman et al, Moderate Low Low Low Low Low Moderate Moderate
201223
Patel et al, Moderate Low Low Low Low Low Moderate Moderate
201324
Anglada- Moderate Low Low Low Moderate Low Moderate Moderate
Martinez
et al, 201625
Yeung et al, Moderate Low Low Low Low Low Moderate Moderate
201726
Kim et al, Moderate Low Low Low Low Low Moderate Moderate
201127

medication refills,21,23 and (4) use of specialized education
tools to improve a patient’s overall health literacy to better
understand the importance of their medications.26 Finding
unique ways to deliver these interventions through the use of
telehealth modalities can improve medication adherence and
consequently reduce unnecessary health care utilization and
expenditure.26
Limitations
The study only researched interventions performed on adults,
therefore, it did not include interventions that included or tar-
geted pediatric patients. Second, the study did not research
medication adherence interventions for other chronic condi-
tions, further limiting its generalizability to all adult patients.
Next, despite the inclusion of a medical research librarian, it is
possible that some studies were overlooked, with the wide
variety of terms used to describe eHealth and related technol-
ogy-facilitated health care. It is important to note that there is
heterogeneity in the execution of these studies, and the statis-
tical findings of these studies should be interpreted cautiously.
The lack of prospective evaluation,16,23,27 absence of control
cohorts,24,25 unavailability of baseline adherence rates,16,21
limitations in statistical analysis,15 low sample size,22 and hav-
ing a cohort with high baseline medication adherence18,20,22,23,25
can limit the interpretation of the findings of this review.
12 Annals of Pharmacotherapy 00(0)
Finally, researchers excluded descriptive studies because of a
particular interest in assessing the effect of the interventions
on adherence. Therefore, it is not possible to estimate the
overall prevalence of eHealth programs for medication
adherence.
Relevance to Patient Care and Clinical
Practice
Medication nonadherence is estimated to cost the health care
system approximately $30 billion in avoidable health care
expenditure among patients with type 2 diabetes, hyperten-
sion, heart failure, and dyslipidemia.2 In the current health
care climate, a vast majority of community pharmacies use
mobile reminders for refills as well as automated refill sched-
ules, given that these are easily implemented interventions.
Although effective for some patients, these interventions may
not target the direct causes for medication nonadherence. This
systematic review highlighted the available research and find-
ings of studies assessing interventions to improve medication
nonadherence among patients with type 2 diabetes, hyperten-
sion, and dyslipidemia. Furthermore, investigators have high-
lighted important details and limitations for the current body
of evidence. Thus, future investigations can be developed to
ensure better design and proper assessment of outcomes
among their targeted patient populations. Furthermore, this
review has highlighted valuable interventions that can be uti-
lized to improve medication adherence in different patient
care settings.
Conclusion
This systematic review identified 13 studies that utilized
objective measures of medication adherence to measure the
effects of telehealth interventions to improve medication
adherence among patients with type 2 diabetes, hypertension,
and/or dyslipidemia. The most successful telehealth modali-
ties included telephonic outreach, text messaging, and spe-
cialized tools designed to increase health literacy. These
interventions utilized protocols to identify and address barri-
ers to medication nonadherence or electronic alerts to remind
patients to take their medications or included tools to improve
a patient’s health literacy. The implementation of these inter-
ventions in health systems may improve overall medication
adherence among patients determined to be nonadherent to
their medication regimens. Further studies utilizing well-con-
trolled trials are needed to support the broad implementation
of these interventions on a large scale and to determine if one
intervention is better than another for certain patients.
Authors’ Note
Previous presentations at professional meeting: This original
research has not been presented at professional meetings.
Acknowledgments
The authors would like to acknowledge Ann M. Taylor for her
editorial contributions to the project.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Jennifer M. Bingham has disclosed an outside interest in
Tabula Rasa HealthCare Group. Conflicts of interest resulting
from this interest are being managed by The University of Arizona
in accordance with its policies. Elizabeth J. Anderson received
funding from Tabula Rasa HealthCare Group. David R. Axon
received funding from American Association of Colleges of
Pharmacy, Arizona Department of Health Services, Merck & Co,
Pharmacy Quality Alliance, and Tabula Rasa HealthCare Group.
Armando Silva-Almodóvar received funding from Tabula Rasa
HealthCare Group. The other authors did not receive any specific
grant from funding agencies in the public, commercial, or not-for-
profit sectors for this study.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Jennifer M. Bingham https://orcid.org/0000-0003-4892-7879
David R. Axon https://orcid.org/0000-0002-9903-5996
Armando Silva-Almodóvar https://orcid.org/0000-0002-9601-
9413
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