The cost and effectiveness of adherence-improving interventions for antihypertensive and lipid-lowering

R. H. Chapman,1 C. P. Ferrufino,1 S.L. Kowal,1 P. Classi,2 C. S. Roberts,2


Aims: Adherence to cardiovascular medications is poor. Accordingly, interventions have been proposed to improve adherence. However, as intervention-associated costs are rarely considered in full, we sought to review the effectiveness and costs associated with different adherence-improving interventions for cardiovascular dis- ease therapies. Methods: We reviewed MEDLINE to update a prior review of interventions to improve adherence with antihypertensive and ⁄ or lipid-lowering therapy covering January 1972 to June 2002, to add studies published from July 2002 to October 2007. Eligible studies evaluated ‡ 1 intervention compared with a control, used measures other than self-report, reported significant improvement in adherence and followed patients for ‡ 6 months. Effectiveness was measured as relative improvement (RI), the ratio of adherence in the intervention group to the control group. Costs were calculated based on those reported in the analysis, if available or estimated based on resource use described. All costs were truncated to 6 months and adjusted to 2007 US$. Results: Of 755 new articles, five met all eligibility criteria. Combining with the prior review gave 23 interventions from 18 studies. RI in adherence ranged from 1.11 to 4.65. Six-month intervention costs ranged from $10 to $142 per patient. Reminders had the lowest effectiveness (RI:
1.11–1.14), but were least costly ($10 ⁄ 6 months). Case management was most effective (RI: 1.23–4.65), but the most costly ($90–$130 ⁄ 6 months). Conclu- sions: Generally, we found a positive association between intervention costs and effectiveness. Therefore, consideration of intervention costs, along with the benefits afforded to adherence, may help guide the design and implementation of adher- ence-improving programs.

Introduction Relatively little is known about the net balance between increased medication costs vs. reduced

1U.S. Health Economics and Outcomes Research, IMS Health, Falls Church, VA, USA 2Pfizer Inc, New York, NY, USA

Correspondence to:
R. H. Chapman,
Senior Director, U.S. Health Economics and Outcomes Research, IMS Health, 300 N. Washington Street, Suite 303, Falls Church, VA 22046, USA Tel.: + 1 703 286 2869
Fax: + 1 703 286 2899
Email: [email protected]

Dr R. H. Chapman, Ms C. P. Ferrufino, and Ms S. L. Kowal of IMS Health were paid consultants to Pfizer Inc in connection with the development of the manuscript. Mr P. Classi was a paid consultant to Pfizer Inc. when this study was conducted, and Dr C. S. Roberts is an employee of Pfizer Inc.

*Parts of these data were presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 13th Annual International Meeting, Toronto, Canada, Tuesday, 6 May 2008.

Numerous studies have demonstrated that patients’ adherence with antihypertensive and lipid-lowering medications is poor (1–5). For example, one retrospec- tive study reported just 36% of patients with concomi- tant hypertension and dyslipidaemia were adherent with both their antihypertensive and lipid-lowering therapy 12 months after initiating these medications (4). Optimising medication adherence is important, as low adherence is associated with poor clinical out- comes in comparison with full adherence (2,6–8). Fur- thermore, increasing adherence to cardiovascular disease (CVD) medications improves clinical out- comes and may reduce overall healthcare costs (9–11).

total healthcare costs that may be observed as a result of an improvement in adherence (12). One study reported a net overall reduction in healthcare costs achieved by improving adherence with medi- cations for hypercholesterolaemia and diabetes (9). Conversely, other evidence suggests overall health- care costs were similar between non-adherent and adherent patients taking statin therapy over several years of follow-up (12,13). These data outline the importance of considering overall per-patient costs when optimising adherence, particularly when designing or implementing adherence-improving interventions.

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, January 2010, 64, 2, 169–181
doi: 10.1111/j.1742-1241.2009.02196.x 169

A variety of techniques have been devised to help improve adherence with medications to levels seen in clinical trials, including cardiovascular (CV) medica- tions (14). These have included modifications to dos- ing regimens or packaging (15); reminder systems (15,16); intensive case management by a pharmacist or nurse (17–21); patient education or counselling (22–24); other interventions such as home blood pressure (BP) monitoring to improve adherence to hypertension medications (25) or the Medication Event Monitoring System (MEMS®; Aprex Corpora- tion, Fremont, CA, USA) (25–27); and combinations of the above approaches.
The positive results of the high-profile Federal study of Adherence to Medications in the Elderly (FAME) (28), a three-phase study that demonstrated the effec- tiveness of a comprehensive pharmacy care program on adherence in older patients (‡ 65 years of age) tak- ing four or more chronic medications daily, has rekin- dled interest in the use of interventions to improve adherence. Despite the interest in adherence-improv- ing interventions, few large-scale interventions have been adopted by the healthcare system.
One barrier to widespread adoption of adherence programs may be the real or perceived cost associated with their implementation. As outlined above, the costs of adherence programs need to be considered in addition to increased medication costs, and weighted against the overall net per-patient healthcare benefits achieved through improving adherence. Accordingly, comparison of methods for improving adherence may benefit from the inclusion of an analysis of overall per- patient costs as well as adherence benefits.
Petrilla et al. (14) conducted a critical review screening 79 adherence-enhancing interventions for antihypertensive and lipid-lowering therapy to deter- mine which interventions could be recommended based on available evidence. The greatest improve- ments in adherence were seen with the most inten- sive and personalised programs. But, such methods are time-consuming and potentially more expensive compared with less intensive interventions. However, Petrilla et al. (14) did not examine cost elements, as the review focused solely on effectiveness outcomes. We updated this previous literature reviews and extended the analyses to include an assessment of both the effectiveness and costs of interventions designed to improve patient adherence with antihy- pertensive and lipid-lowering medications.

Study identification and data extraction
Petrilla et al. (14) reviewed published articles from January 1972 to June 2002 and identified 62 studies

describing 79 interventions designed to improve adherence with antihypertensive and ⁄ or lipid-lowering medications (14). These interventions were then excluded if they did not use a control group for comparison or did not demonstrate significant improvement in adherence (14).
We extended this review to identify original arti- cles published from July 2002 to October 2007 on interventions designed to improve adherence to anti- hypertensive and ⁄ or lipid-lowering therapy. The MEDLINE search terms and limits used were:
• Hypertension or hyperlipidaemia or antihypertensive agents or antilipidemic agents and patient compliance or intervention studies or reminder systems.
• Human subjects.
• Adults (‡ 18 years of age).
Additional studies were also identified using the MEDLINE ‘Related Articles’ facility.

Article screening
Article titles and abstracts were first screened to remove studies that did not report an adherence intervention or were not published in English. A sec- ond screen was undertaken to ensure each study used at least one generalisable intervention to improve adherence to antihypertensive or lipid-lowering ther- apy. As with the prior review, the intervention had to be compared with a control group receiving usual care. Also, the studies had to report an improvement in adherence. Non-randomised studies were permit- ted. Compliance and ⁄ or adherence had to be mea- sured by a method other than patient self-report after a minimum follow-up period of 6 months.

Data identification
After screening the 755 studies from the literature search, five studies which described five interventions were identified. In addition to the 18 interventions previously identified by Petrilla et al. (14), this gave a total of 23 interventions from 18 studies (Figure 1).
Each article, including those previously identified, was then reviewed to extract the following informa- tion on the interventions studied: target population; intervention type; duration of intervention and fol- low-up; resource use; costs (if reported); measure of adherence and effect on adherence.
Adherence-improving interventions were broadly classified into those that involved an active input from a healthcare professional, e.g., a physician, pharmacist or nurse, to improve adherence by the patient [case management (M)], those which involved education of the patient on the prescribed product [reminders being sent (R), dosing modifications to the packaging con-

Figure 1 Search strategy for identifying interventions designed to improve adherence to antihypertensive and ⁄ or lipid- lowering therapy

taining the medication (D), education (E)], other methods of intervention (O), or a combination of these approaches (C). Combined approaches were classified according to the primary method of intervention (i.e., C ⁄ M, C ⁄ R; C ⁄ D, C ⁄ E, C ⁄ O).

Effectiveness of interventions
Effectiveness was measured as Relative Improvement (RI), defined as the adherence outcome reported in the intervention group divided by the adherence out- come reported in the control group. Effectiveness at 6 months was used as the primary effectiveness mea- sure, as this was the most common duration of fol- low-up in the studies. The primary effectiveness

measures reported in each study were reviewed to ensure the use of consistent metrics for baseline and final adherence in both the intervention and control groups. Effectiveness measures reported in the stud- ies included medication possession ratio (MPR); number and percentage of compliant patients; change in percentage of medications taken; and number ⁄ percentage of patients taking ‡ 80% of pre- scribed medications.

Costs of interventions
An informal panel process was used to estimate resource use and costs for each intervention, with cost assumptions documented (Tables 1 and 2).

Studies were compared to identify a set of common inputs from which comparable costs could be inferred. Fixed costs at the site level, such as the cost of training staff for the intervention, were not included, as the average cost per patient would vary depending on scale. The costs of medications and CV events were also not included, as these would differ based on the particular treatment received and risk profile of the patient.
Our approach considered only direct intervention costs, using actual costs if reported in the article. If only resource use was reported, unit costs were obtained from the literature or derived by applying an estimate of labour time to standard wage rates (obtained from the Bureau of Labour Statistics) (Table 2). We compared articles to derive recom- mended blocks of time based on the tasks being per- formed. These assumptions were approved by an informal panel including an author on the prior review (Dr Joshua Benner). For example, we assumed that ‘telephone counselling’ would require 20 min of pharmacist time and used this time assumption across all articles involving telephone counselling. When articles reported time segments for activities, we used these assumptions and docu- mented the source. Non-US costs were converted to US$ using Organisation for Economic Co-operation and Development exchange rates for country and year of intervention. All costs were inflated to 2007 US$ using the medical portion of the Consumer Price Index (29). Costs were reported as the average cost per patient over 6 months, as this was the most common duration of studied interventions. To stan- dardise costs, if necessary, we estimated the antici- pated costs if the intervention was to last for 6 months. The frequency of follow-up and the cost elements were assumed to be as reported, but were truncated if the intervention was greater than 6 months.

Elements of costs
The interventions from each study were assessed so that costs could be calculated. These costs were split into four broad categories: costs per single unit of use; standardised costs; study-specific costs; and additional costs, which are detailed below (Table 1).

Cost per single unit of use
Unit of use studies evaluated single-use interventions for improving adherence. Three recent studies (25– 27) have included the MEMS® system, a medication bottle cap with a microprocessor that records the occurrence and time of each bottle opening. This tool accurately measures medication-taking behaviour, especially in patients at high risk of non-adherence,

e.g., those with conditions such as schizophrenia (30). The MEMS lids cost $18.12 per unit with additional training costs, giving an overall cost per patient over three times the expense of other single-unit use methods, principally mailed reminders, for improv- ing adherence ($6.48–$7.49).

Standardised costs
Some costs were standardised as measured on an annual basis. The most expensive overall standar- dised cost was associated with pharmacist’s man- agement programs (19–21,27,28,31). These interventions involved direct, repeated efforts by a pharmacist ($44.95 ⁄ h) or pharmacy technician ($12.75 ⁄ h). Blister packs involved costs associated with pharmacists’ time to tailor the packs, giving costs of $49.52 per patient. Mailed refill reminders were commonly used and had cheaper annual costs of $19.18 per patient. Costs associated with refill reminders included postage and printing costs ($16.12) and pharmacy technician time to prepare and send the letters ($12.75).

Study-specific costs
Study-specific costs ranged from less than $1 per patient, for patients being given a copy of their med- ical records to encourage home tracking of their medication and health, to $129.78 per patient for a pharmacist management program involving dedi- cated pharmacist time of up to 16 h ⁄ week to improve drug documentation, decrease the duplica- tion of prescriptions and improve adherence to pre- scribed drugs (19).

Additional costs
The general assumption was made that a follow-up visit lasted 30 min and cost $22.48, based on the FAME study (28). These cost assumptions were applied to other studies that involved a follow-up visit. A face-to-face follow-up visit was nearly $15 more expensive per patient than follow-up telephone counselling ($22.48 per patient vs. $7.49 per patient, respectively), which was considered to take 10 min and enabled patients to discuss any questions they had concerning healthcare.

Relative Improvement, defined as the adherence out- come reported in the intervention group divided by the adherence outcome reported in the control group, ranged from 1.11 for monthly mailed prescription reminders (15) to 4.65 for a pharmacist management program that involved a 30-min scheduled monthly meeting with a community pharmacist, including a

Table 1 Costs of specific interventions

Cost element Components Assumptions

Total cost per patient (US$)

Cost per single unit of use

MEMS lids (26)* MEMS lid cost ($18.12), initial training of patients
(15 min: $7.18) and staff
(45 min ⁄ 164 patients: $0.13)

Divide staff training by number of patients in Brunenberg study; OECD 2002 exchange rate; adjust to 2007 US$; staff time for nurses


Counselling calls
from pharmacist (35,40)*

Preparation time for the call and time spent on the call by the pharmacist

Assumed 10 min pharmacist time $7.49

Educational materials (36,40)* Printed educational materials (e.g., drug information & lifestyle changes)

Newsletter (36,40)* Newsletter developed ⁄ packed at pharmacy
and sent to patient’s homes

Cost of producing initial educational materials is assumed equivalent
for all interventions; adjusted to 2007 US$ O’Loughlin et al. provide cost of developing
and mailing monthly health education newsletters (research,
production, printing); adjusted to 2007 US$



Pharmacist management (19,20,27,40)*

Ongoing management time (both if adherent (refill, communication) and if
non-adherent (follow-up)

Telephone counselling was 10 min while in-depth guided consultations were reported as 30 min; estimated 20 min per month per patient


Standardised Costs

Blister pack (15,16,40)* Unit-of-use packaging materials and pharmacist production time

Pharmacist time needed to tailor blister packs assumed to be unchanged since 1991; per patient annual cost of packaging adjusted to 2007 US$


Mailed refill reminders (15,32,40,41)*

Pharmacist management (ambulatory care)(19)*

Postage; printing; programming of computerised refill system; pharmacy technician time
to prepare ⁄ send letters

Cost of the pharmacist’s time (management role not related to Rx refill)

Postage and printing costs from Benner ($6.12), 5 min pharmacy tech time ($12.75) and programming cost adjusted to 2007 US$ ($0.31)
Monson et al. state 16 h pharmacist time needed per week for 133 patients



Study-Specific Costs

Home visit (22)* Coordinator time (check condition [e.g., BP],
gather history, check adherence, travel time)

Only home visits reported in Haynes et al. with all workers from same company location: travel (20 min); administration (10 min);
follow-up visit (30 min)


Home visit when Rx refill missed (22,34)*

Visit from field team when Rx refill missed;
assumed similar in length to general study follow-up

Assumed monthly number receiving home visits could be approximated
by number non-adherent in intervention (18 patients). 30 min general


Copy of patient records (34)*

Additional Costs Follow-up visits

Telephone reinforcement & counselling (22,24,35,40)*

patient’s concerns

Time of healthcare professional for call to reinforce need for adherence
and address patient’s questions

(28) similar to initial assessments in other articles
Telephone counselling and reinforcement assumed to be 10 min on average


*BLS, Bureau of Labour Statistics. MEMS, Medication Event Monitoring System; OECD, Organisation for Economic and Co-operative Development; BP, blood pressure; Rx, prescription; FL, Florida; SC, South Carolina.

Table 2 Additional costs included in calculations
U.S. Bureau of Labour Statistics – 2007 wage rates
Occupation Mean hourly (US$) Mean annual (US$)
Pharmacist $44.95 $93,500.00
Pharmacy technician $12.75 $26,510.00
Registered nurse $28.71 $59,730.00
Technical worker* $16.90 $35,140.00
General costs

patient education element and discussion of problems during the follow-up (21) (Table 3 and Figure 2). Overall, after adjustments were made to standardise follow-up time, the 6-month intervention costs ran- ged from $9.59 per patient for mailed prescription reminders to $142.22 per patient for a combined pro- gram of management by pharmacists, patient diaries and educational materials (Table 3 and Figure 2).

Case management
Intensive case management provided the most effec- tive method of improving adherence, although the range was wide. The RIs for case management ranged from 1.23 [Logan rt al. (17,18)], which was amongst the lowest of the interventions studied, to the highest RI of 4.65 [McKenney et al. (21)]. These manage- ment programs were also more costly per-patient rather than other non-combined interventions ($89.90–$129.78 ⁄ 6 months) (19,20). The case man- agement studies with the lowest RI (1.23) were two nurse-led programs with biweekly meetings with the patient. This intervention also had increased costs per patient ($114.84 ⁄ 6 months) (17,18) in compari- son with the monthly follow-up visits in the McKen- ney study ($112.38 ⁄ 6 months) (21).

Reminders, packaging modifications and education interventions
Five studies were identified that evaluated a range of simple methods for improving adherence such as mailed reminders, changes to medication packaging and telephone contact to encourage adherence. Mailed reminders tended to have the lowest effective-

ness (RI = 1.11–1.14), but were the least costly per patient ($9.59 ⁄ 6 months) (32,33). Customising pack- aging had higher per-patient costs of $24.76 and resulted in an RI of 1.17–1.20, depending on the study (15,16).
Education via telephone counselling with patients involved the additional cost of professional’s time. For example, the study described by Faulkner et al. (24), in which weekly telephone consultation with the pharmacist yielded standardised costs of
$89.90 ⁄ 6 months per patient, resulted in an RI of
2.22. Friedman et al. (23) described a study using a telephone-linked computer system to monitor patients’ adherence with BP medication; this inter- vention resulted in an RI of 1.51 (with cost of
$50.89 ⁄ 6 months per patient).
Overall, these remote interventions did not gener- ally yield RIs as high (Reminders: RI = 1.11–1.14; Dose modifications: RI = 1.17–1.20; Education: RI = 1.51–2.22) (15,16,22–24) as those observed with intensive management programs (RI = 1.23–4.65) that involved direct contact with a health-care pro- fessional (17–21).

Combined interventions
Using a combined approach gave RI estimates between 1.15 for the study described by Sookanek- nun et al. (31), undertaken in Thailand and which utilised patient diaries, increased pharmacy care and educational materials, to 2.07 for new patients described in the study by Saunders et al. (34), under- taken in a polyclinic for black patients in Soweto, South Africa. The Saunders et al. study in Soweto

Table 3 Total per-patient costs of interventions and Relative Improvement (RI) in adherence (results adjusted to 6 months to allow comparison)
Total cost RI*
per patient
Source Intervention Intervention type Cost elements (US$)
McKenney et al. (21) Community pharmacist M Monthly scheduled follow-up $112.38 4.65
management to improve meeting with community
patient medication compliance pharmacist for patient education,
problem identification
(30 min ⁄ month for 5 months: $112.38)
Monson et al. (19) Pharmacist management of patient M Pharmacist management time $129.78 3.60
Rx in ambulatory care setting (sole responsibility to manage
records and meet with
patients – no refill responsibilities)
Bond et al. (20) Effect of pharmacy management M Cost of pharmacy management ($89.90) $89.90 3.16
on patient compliance
Logan et al. (17,18) Worksite-based nurse management M Nurse management $114.84 1.23
of adherence with (same resource time
antihypertensive medication assumptions as pharmacist
management; adjustment to
biweekly meetings as opposed
to monthly: $114.84)
Skaer et al. (FL) (15) (reminders) Mailed Rx refill reminders R Cost of monthly mailed Rx $9.59 1.14
reminders for 6 months ($9.59)
Skaer et al. (SC) reminders) (16) Mailed Rx refill reminders R Cost of monthly mailed Rx $9.59 1.11
reminders for 6 months ($9.59)
Skaer et al. (FL) (unit-of-use) (15) Customised packaging (unit-of-use) D Cost of the unit-of-use $24.76 1.20
packaging for 6 months ($24.76)
Skaer et al. (SC) (unit-of-use) (16) Customised packaging (unit-of-use) D Cost of the unit-of-use $24.76 1.17

Faulkner et al. (colestipol) (24)
Weekly telephone counselling ⁄
E packaging for 6 months ($24.76)
12 weekly telephone calls to
reinforcement by pharmacist patients (10 min of pharmacist

Faulkner et al. (lovastatin) (24)
Weekly telephone counselling ⁄
E time: $89.90)
12 weekly telephone calls to patients
reinforcement by pharmacist (10 min of pharmacist time: $89.90)
Haynes et al. (22) Behaviourally oriented strategies
(diary, home monitoring) and education E Home BP kit ($26.00); initial
education ⁄ data gathering with $102.60 1.53
nurse (30 min; $14.36); compliance
coupon ($4); patient diary ($7.50);
coordinator – fortnightly calls
(10 min $33.84) & final home
visit ($16.90)
Friedman et al. (23) Telephone-linked computer (TLC) system E Annual cost of the TLC system $50.89 1.51
for patient monitoring and counselling per patient was reported by
Haynes et al. in 1996 US$
($65.00) – adjusted to 2007

Saunders et al. (34)
Self-monitoring, reminders and educational
C ⁄ R US$ (6 months: $50.89)
Initial health education packet
(new patients) materials in Soweto, South Africa ($7.36); 6-monthly reminder
letters ($9.59); home visits for
non-adherent ($16.90);

Saunders et al. (34)
Self-monitoring, reminders and
C ⁄ R copy of records ($1.20)
Initial health education packet
(non-compliant patients) educational materials in Soweto, South Africa ($7.36); 6-monthly reminder
letters ($9.59); home visits for
non-adherent ($16.90); copy
of records ($1.20)

Table 3 (continued)
Total cost RI*
per patient
Source Intervention Intervention type Cost elements (US$)
Sclar et al. (32,33) (new cases)† Newsletters, reminders and educational C ⁄ R Initial health education packet $57.96 1.79
materials for HMO patients
(new hypertensive patients) ($7.36); follow-up telephone call
to check receipt ⁄ understanding of
materials (10 min pharmacy tech:
$2.13); reminder letters ($9.59);

Sclar et al. (32,33)
Newsletters, reminders and educational
C ⁄ R monthly newsletters ($38.88)
Initial health education packet
(existing cases)† materials for HMO patients
(existing hypertensive patients) ($7.36); follow-up telephone
call to check receipt ⁄ understanding
of materials (10 min pharmacy tech:
$2.13); reminder letters ($9.59);

Ali et al. (35)
Education and bimonthly telephone calls
C ⁄ E monthly newsletters ($38.88)
Bi-monthly counselling calls from
for reinforcement and Rx management pharmacist ($22.47); initial 30
min education with pharmacist
($22.48); printed educational

Skaer et al. (FL) (15)
Both unit-of-use packaging
C ⁄ D materials at start ($7.36)
Cost of unit-of-use packaging ($24.76)
(combination) and mailed Rx reminders and mailed refill reminders

Skaer et al. (SC) (16)
Both unit-of-use packaging
C ⁄ D ($9.59) for 6 months
Cost of unit-of-use packaging
(combination) and mailed Rx reminders ($24.76) and mailed refill

Ma´rquez-Contreras et al. (25)
Home BP monitoring (patient awareness)
C ⁄ O reminders ($9.59) for 6 months
MEMS lid and training ($25.43);
to improve compliance cost of the OMRON monitor
($33.95); cost of OMRON telephone
training (assumed 30 min nurse
time: $14.36); 4 · 30 min

Lee et al. (28)
FAME study: blister packs and patient
C ⁄ M follow-up visit with tech ($25.50)
Unit-of-use packaging ($24.76);
education to improve initial 1-h education ($44.95)
adherence and persistence and bimonthly 30-min sessions

Murray et al. (27)
MEMS tracking and pharmacist
C ⁄ M with pharmacist ($67.43)
MEMS lids and training ($25.43);
management of patient Rx initial education materials

Sookaneknun et al. (31)
Increased pharmacy care, patient diaries
C ⁄ M ($7.36); pharmacist management ($89.90)
Patient diary ($7.50); initial
and educational materials interview and communication
with pharmacist (50-min pharmacist
time: $37.46); initial educational
materials ($7.36); monthly BP
measure ⁄ check-in with pharmacist
(20 min: $89.90)
*Intervention ⁄ control; †six-month study. MEMS, Medication Event Monitoring system; BP, blood pressure; D, modifications to dosing regimens or packaging, R, reminders; M, intensive case management by a pharmacist or nurse; E, patient education or counselling; HMO, health maintenance organisation; O, other interven- tions; C, combinations of the approaches; Rx, prescription; FL, Florida; SC, South Carolina.

did not involve a home visit unless the patient was non-adherent, giving costs of $35.05 per patient in comparison with $142.22 per patient for the study by Sookaneknun et al. (31).

Some of the differences in calculated RI among other combined intervention studies could have been because of the number of professional follow-up vis- its as well as other factors, including the provision of

Figure 2 Costs vs. Relative Improvement in adherence, by type of intervention. *Relative Improvement = risk of the event occurring in the intervention group divided by the risk of the event occurring in the control group.
C ⁄ D, combination ⁄ dosing modification; C ⁄ E, combination ⁄ education; C ⁄ M, combination ⁄ case management; C ⁄ O, combination ⁄ other; C ⁄ R, combination ⁄ reminders; D, dosing modification; E, education; M, case management; R, reminders

home monitoring kits. For example, the Sookanek- nun et al. (31) study in Thailand (RI = 1.15) com- bined primarily a management program involving only one initial consultation and one follow-up con- sultation, and gave costs of $142.22 per patient; in contrast, Ali et al. (35) conducted a study in Canada (RI = 1.65) to evaluate a combined education and management intervention that involved two tele- phone consultations with the pharmacist in addition to a follow-up visit, and gave lower per-patient costs of $52.31 [savings of $89.91 per patient compared with Sookaneknun et al. (31)]. This difference is at least in part because of the additional costs of the home monitoring kit provided by Sookaneknun et al. (31). However, the potential for comparison among these studies is somewhat limited given the differ- ences in the healthcare systems in developing coun- tries, such as South Africa and Thailand, in comparison with those in the US, Canada and Eur- ope where most of the other studies we identified were undertaken.
Ma´rquez-Contreras’ study (25) had an RI of
1.24 for a combination intervention using home BP monitoring kits and MEMS. Murray and col- leagues (27) also discussed the use of a combined approach including the MEMS system, and had a lower RI (1.16) than that in Ma´rquez-Contreras’

study. Murray et al. had estimated costs of $122.69 per patient compared with $99.24 per patient in the Ma´rquez-Contreras and colleagues study, where follow-up was carried out by the pharmacists’ assistant rather than involving pharmacist’s man- agement directly (difference in per-patient costs of
$23.45 ⁄ 6 months).

Despite the increased interest in promoting adherence with antihypertensive and lipid-lowering therapies in recent years, there are relatively few controlled studies evaluating interventions designed to improve adherence to CV medications. Among these studies, fewer still include a cost analysis, despite the importance of cost considerations in supporting the practical implementation of these programs. To allow comparisons of the relative costs and effectiveness of these interventions there- fore necessitated calculation of standardised costs for each intervention designed to improve adher- ence with CV medications. To accomplish this, we truncated all interventions to a 6-month fol- low-up period and, to the extent possible, applied a common method to estimate both costs and effects.

Our study shows a general positive relationship between the estimated cost to provide an interven- tion and its relative impact on adherence. A variety of different means of improving adherence with anti- hypertensive and lipid-lowering therapies have been identified, and can be broadly classified as those involving professional input by a doctor, nurse and ⁄ or pharmacist, and those that involved educat- ing patients regarding their therapies by providing specific information or modified packaging..
We found the most effective approaches for improving adherence are multifaceted. Personalised, intensive interventions offered the greatest improve- ments in adherence, as was found in our earlier study (14). However, these improvements in adher- ence with personalised intensive interventions must be balanced against their higher costs. Combination programs and packaging techniques were found to confer small-to-moderate improvements in adher- ence in our earlier analysis (14). The FAME study demonstrated that a pharmacy-care program could lead to increases in medication adherence, medica- tion persistence and clinically meaningful reductions in BP, whereas discontinuation of the program was associated with decreased medication adherence and persistence (28). In the current review, calculated RI was the highest for an intensive management pro- gram of monthly pharmacist monitoring during fol- low-up (21).
Another common characteristic of the most suc- cessful programs was that patients were aware that their adherence was being closely monitored, as higher RI was generally associated with studies involving more than one visit during follow-up (19– 21). However, costs were also generally higher with more intensive input from a professional (such as more follow-up visits), compared with lower costs involving consultation on medication initiation and at a single follow-up visit or by telephone.
O’Loughlin et al. (36) evaluated the effectiveness of a simple mailed leaflet compared with a more extensive information pack. Their study suggested that a simple newsletter was more cost-effective than the extensive ‘Heartfelt Kit’ (including a booklet, shopping checklist, tip-sheet on coping with stress and magnet), in part because the newsletter was more often read and remembered at follow-up. However, this study also suggests that different for- mats of media might appeal to different segments of the population.
Patients taking antihypertensive and lipid-lowering therapies may benefit from interventions such as MEMS in situations, where BP or lipid targets are not reached because of suspected non-adherence (25–27). In this situation, both the patient and

physician may be reluctant to increase the dose or add further antihypertensive drugs until the sus- pected non-adherence has been addressed. However, it should be noted that the highest RI associated with the MEMS lid system was dependent on the costly addition of ongoing pharmacist monitoring (25,27).
Brunenberg et al. (26) investigated the cost-effec- tiveness of MEMS exclusively and showed that at 5 months, 3.1% more patients had normalised BP, but only 0.003 more quality-adjusted life-years were generated using the experimental strategy vs. usual care. It was therefore concluded that additional research into the economic consequences of this intervention is warranted before large-scale imple- mentation of MEMS for monitoring adherence with antihypertensive and lipid-lowering therapies (26). These results suggest that pharmacist-led interven- tions involving MEMS for outpatients can improve adherence to CV medications and decrease healthcare use and costs, but the benefit probably requires peri- odic intervention as the effect dissipates when the intervention ceases.
The calculation of RI allowed comparison of the effectiveness of interventions across a diverse range of studies. Furthermore, the inclusion of costs or, when not available, the calculation of standardised costs, enabled comparison of the estimated per- patient costs to a healthcare system of each inter- vention. Other literature analyses have focused on either effectiveness of the intervention for improv- ing adherence or on costs caused by poor adher- ence, but not on both the cost and effectiveness of adherence interventions. For example, a literature review including diabetic medications as well as those for CVD (including antihypertensives and lipid-lowering agents) reviewed 139 studies and showed that in 73% of these studies, good adher- ence had a positive effect on clinical outcomes, although only 63% of patients continued with their medication for an entire year (37). A second review of 23 studies specifically focusing on the cost conse- quences of non-adherence with medication for CVD and related conditions showed that increased adher- ence ⁄ persistence leads to an increase in the effec- tiveness of treatment and a decrease in medical events (11).
Furthermore, increased adherence may result in longer-term savings in the overall costs of treating CVD and related conditions. Sokol et al., who eval- uated the impact of medication adherence on healthcare utilisation and costs for hypertension, hypercholesterolaemia, diabetes and congestive heart failure, suggest that increased drug utilisation, when driven by improving adherence with guideline-based

therapy, can provide a net economic benefit despite increased medication costs (9). Conversely, other evidence suggests that overall healthcare costs were similar between non-adherent and adherent patients taking statin therapy over several years of follow-up (12,13). Differences in the age or medical histories of the study populations, the time period studied and methods used could account for these divergent findings. Nevertheless, medication non-adherence is associated with poorer patient outcomes (2,6–8), which supports a clear need for interventions to improve adherence, particularly for chronic illnesses such as CVD. As such, it is also clear that further studies are needed to investigate the overall cost- effectiveness of different types of adherence inter- ventions, using a method that accounts for both the overall net cost of the intervention as well as the incremental health benefit that can be expected from its adoption.
Most of the recommended interventions were studied among newly treated patients, perhaps sug- gesting that programs should be initiated at or near the time of therapy initiation, when patients are establishing attitudes and beliefs about the impor- tance of long-term persistence (5,14,38). Indeed, when we analysed newly-treated patients separately from those who had been previously non-compliant, the RI in adherence increased (2.07 vs. 1.84) (34). Adherence is known to decrease quickly during early treatment before reaching a plateau (4,5), and as such, early interventions to improve adherence may provide the best outcomes (4,5). Further, a recent proof-of-concept study in the United King- dom among elderly (‡ 75 years of age) patients has suggested that a relatively simple intervention by a pharmacist with the aim of solving patients’ prob- lems with a new medicine in the early stages of treatment (the first 4 weeks) can improve adherence and result in an overall reduced cost to the health- care provider (38). This contrasts with a recent Cochrane review of adherence interventions across multiple medical databases, including MEDLINE (covering from database conception to January 2007), which concluded that almost all interventions that were effective for long-term care were complex, and even the most effective interventions did not lead to large improvements in adherence and treat- ment outcomes (39).

Limitations and additional considerations
As with other literature reviews, our findings may be affected by publication bias, wherein positive findings may be more likely to be published than

negative findings. However, as we were only interested in reviewing studies that documented an adherence improvement, negative studies would have been automatically selected out during screening. In addition, our stringent inclusion criteria, which helped to standardise the studies included for this review, may have excluded other adherence-improv- ing interventions that were highly efficacious, but could not be included in the present analysis because of their study design not complying with our criteria.
The average cost of interventions that include a fixed-cost component and were greater than 6 months in length may be overestimated when trun- cated to a 6-month time period. The fixed costs of training and program roll-out, as well as indirect costs (e.g., increased medication costs resulting from improved adherence as a result of the intervention, or decreased treatment costs because of averted CV events), were not considered in this analysis.
The studies identified were highly heterogeneous with regard to the interventions assessed, adherence measurement methods, study designs and patient types. Most notably, heterogeneity in the calculation and reporting of adherence outcomes in published studies complicates comparison across interventions. Nevertheless, our approach provides an initial esti- mate from which to consider designing cost-effective and efficient adherence-improving interventions, and provides a benchmark for application and consider- ation of costs in future analyses. Future studies should thus consider reporting standard measures of adherence as well as persistence, to facilitate compar- ison among interventions. Ideally, adherence studies would include information on the distribution of MPR or proportion of days covered (PDC) as well as proportion of patients reaching an adherence thresh- old (e.g., MPR or PDC ‡ 80%). Improvements in study methodology and reporting standards will enable more robust comparisons of adherence inter- ventions and can possibly translate into more cost- effective uses of adherence-improving programs in clinical practice.

This study suggests that the most effective approaches to improving adherence with antihyper- tensive and lipid-lowering medications are both intensive and multifaceted, and are therefore likely to be expensive. Comparisons of adherence-improving interventions should therefore consider costs as well as adherence benefits to make them more relevant to medical decision-makers and acceptable for wide- scale implementation.

This study was sponsored by Pfizer Inc., New York, NY, USA. Editorial support was provided by Karen Burrows of UBC Scientific Solutions, and funded by Pfizer Inc. The authors would also like to thank Dr Joshua Benner for contributing to the study design and article review process.

Author contributions
All authors were involved in the design and conduct of the study and in the interpretation of the data. All authors contributed to revision of the article and approved the final manuscript.

1 Benner JS, Glynn RJ, Mogun H et al. Long-term persistence in use of statin therapy in elderly patients. JAMA 2002; 288: 455–61.
2 Wei L, Wang J, Thompson P et al. Adherence to statin treatment and readmission of patients after myocardial infarction: a six year follow up study. Heart 2002; 88: 229–33.
3 Cardinal H, Monfared AA, Dorais M, LeLorier J. A comparison between persistence to therapy in ALLHAT and in everyday clinical practice: a generalisability issue. Can J Cardiol 2004; 20: 417–21.
4 Chapman RH, Benner JS, Petrilla AA et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med 2005; 165: 1147–52.
5 Agarwal S, Tang SSK, Rosenberg N et al. Does synchronizing initi- ation of therapy affect adherence to concomitant use of antihyper- tensive and lipid-lowering therapy? Am J Ther 2009; 16: 119–26.
6 Blackburn DF, Dobson RT, Blackburn JL, Wilson TW. Cardiovas- cular morbidity associated with non-adherence to statin therapy. Pharmacotherapy 2005; 25: 1035–43.
7 Ho PM, Spertus JA, Masoudi FA et al. Impact of medication ther- apy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006; 166: 1842–7.
8 Ho PM, Magid DJ, Shetterly SM et al. Medication non-adherence is associated with a broad range of adverse outcomes in patients with coronary artery disease. Am Heart J 2008; 155: 772–9.
9 Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care 2005; 43: 521–30.
10 Ho PM, Rumsfeld JS, Masoudi FA et al. Effect of medication non- adherence on hospitalisation and mortality among patients with diabetes mellitus. Arch Intern Med 2006; 166: 1836–41.
11 Muszbek N, Brixner D, Benedict A et al. The economic conse- quences of noncompliance in cardiovascular disease and related conditions: a literature review. Int J Clin Pract 2008; 62: 338–51.
12 Ho PM, Bryson CL, Rumsfeld JS. Medication adherence: its importance in cardiovascular outcomes. Circulation 2009; 119: 3028–35.
13 Ho PM, Maddox TM, Shetterly SM et al. The costs of healthcare associated with medication non-adherence. Circulation 2008; 117: e460. [Abstract 228].
14 Petrilla AA, Benner JS, Battleman DS et al. Evidence-based inter- ventions to improve patient compliance with antihypertensive and lipid-lowering medications. Int J Clin Pract 2005; 59: 1441–51.
15 Skaer TL, Sclar DA, Markowski DJ, Won JK. Effect of value-added utilities on prescription refill compliance and health care expendi- tures for hypertension. J Hum Hypertens 1993; 7: 515–8.
16 Skaer TL, Sclar DA, Robison LM et al. Effect of pharmaceutical formulation for antihypertensive therapy on health service utiliza- tion. Clin Ther 1993; 15: 715–25.

17 Logan AG, Milne BJ, Achber C et al. Work-site treatment of hypertension by specially trained nurses. A controlled trial. Lancet 1979; 2: 1175–8.
18 Logan AG, Milne BJ, Achber C et al. Cost-effectiveness of a work- site hypertension treatment program. Hypertension 1981; 3: 211–8.
19 Monson R, Bond CA, Schuna A. Role of the clinical pharmacist in improving drug therapy. Clinical pharmacists in outpatient ther- apy. Arch Intern Med 1981; 141: 1441–4.
20 Bond CA, Monson R. Sustained improvement in drug documenta- tion, compliance, and disease control. A four-year analysis of an ambulatory care model. Arch Intern Med 1984; 144: 1159–62.
21 McKenney JM, Munroe WP, Wright JT Jr. Impact of an electronic medication compliance aid on long-term blood pressure control. J Clin Pharmacol 1992; 32: 277–83.
22 Haynes RB, Sackett DL, Gibson ES et al. Improvement of medica- tion compliance in uncontrolled hypertension. Lancet 1976; 1: 1265–8.
23 Friedman RH, Kazis LE, Jette A et al. A telecommunications sys- tem for monitoring and counseling patients with hypertension. Impact on medication adherence and blood pressure control. Am J Hypertens 1996; 9 (4 Pt. 1): 285–92.
24 Faulkner MA, Wadibia EC, Lucas BD, Hilleman DE. Impact of pharmacy counseling on compliance and effectiveness of combina- tion lipid-lowering therapy in patients undergoing coronary artery revascularization: a randomized, controlled trial. Pharmacotherapy 2000; 20: 410–6.
25 Ma´rquez-Contreras E, Martell-Claros N, Gil-Guille´n V et al. Effi-
cacy of a home blood pressure monitoring program on therapeutic compliance in hypertension: the EAPACUM-HTA study. J Hyper- tens 2006; 24: 169–75.
26 Brunenberg DE, Wetzels GE, Nelemans PJ et al. Cost effectiveness of an adherence-improving program in hypertensive patients. Pharmacoeconomics 2007; 25: 239–51.
27 Murray MD, Young J, Hoke S et al. Pharmacist intervention to improve medication adherence in heart failure: a randomized trial. Ann Intern Med 2007; 146: 714–25.
28 Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled trial. JAMA 2006; 296: 2563–71.
29 U.S. Department of Labor Bureau of Labor and Statistics. US Med- ical Care Consumer Price Index, All Urban Consumers. CUUR0000- SAM. 2006; http://data.bls.gov/cgi-bin/surveymost?cu (accessed June 2009).
30 Diaz E, Levine HB, Sullivan MC et al. Use of the Medication Event Monitoring System to estimate medication compliance in patients with schizophrenia. J Psychiatry Neurosci 2001; 26: 325–9.
31 Sookaneknun P, Richards RM, Sanguansermsri J, Teerasut C. Pharmacist involvement in primary care improves hypertensive patient clinical outcomes. Ann Pharmacother 2004; 38: 2023–8.
32 Sclar DA, Chin A, Skaer TL et al. Effect of health education in promoting prescription refill compliance among patients with hypertension. Clin Ther 1991; 13: 489–95.
33 Sclar DA, Chin A, Skaer TL et al. Effect of health education on the utilization of antihypertensive therapy: prospective trial among HMO enrolees. Drug Topics 1992; 7: 22–6.
34 Saunders LD, Irwig LM, Wilson TD. Hypertension management and patient compliance at a Soweto polyclinic. S Afr Med J 1982; 61: 147–51.
35 Ali F, Laurin MY, Lariviere C et al. The effect of pharmacist inter- vention and patient education on lipid-lowering medication com- pliance and plasma cholesterol levels. Can J Clin Pharmacol 2003; 10: 101–6.
36 O’Loughlin J, Paradis G, Meshefedjian G. Evaluation of two strate- gies for heart health promotion by direct mail in a low-income urban community. Prev Med 1997; 26 (5 Pt. 1): 745–53.
37 Cramer JA, Benedict A, Muszbek N et al. The significance of com- pliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: a review. Int J Clin Pract 2008; 62: 76–87.

38 Elliott RA, Barber N, Clifford S et al. The cost effectiveness of a telephone-based pharmacy advisory service to improve adherence to newly prescribed medicines. Pharm World Sci 2008; 30: 17–23.
39 Haynes RB, Ackloo E, Sahota N et al. Interventions for Enhancing Medication Adherence. Chichester, UK: John Wiley & Sons, Ltd, 2008.
40 Benner JS, Ganz DA, Weinstein MC et al. Cost-Effectiveness of Interventions to Improve Compliance With Lipid-Lowering Therapy

[dissertation chapter]. Cambridge, MA: Harvard University, 2000.
41 Baird TK, Broekemeier RL, Anderson MW. Effectiveness of a com- puter-supported refill reminder system. Am J Hosp Pharm 1984; 41: 2395–7.RI-1