Medication Adherence in Older Adults With Cognitive Impairment: A Systematic Evidence-Based Review

N.L. Campbell et al.

The American Journal of Geriatric Pharmacotherapy

Medication Adherence in Older Adults With Cognitive Impairment: A Systematic Evidence-Based Review Noll L. Campbell, PharmD1– 4; Malaz A. Boustani, MD, MPH2,3,5; Elaine N. Skopelja, MALS, AHIP6; Sujuan Gao, PhD2,3,7; Fred W. Unverzagt, PhD8; and Michael D. Murray, PharmD, MPH1,2,5 1

Department of Pharmacy Practice, Purdue University College of Pharmacy, West Lafayette, Indiana; 2Regenstrief Institute, Inc., Indianapolis, Indiana; 3Indiana University Center for Aging Research, Indianapolis, Indiana; 4Department of Pharmacy, Wishard Health Services, Indianapolis, Indiana; 5Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; 6Ruth Lilly Medical Library, Indiana University School of Medicine, Indianapolis, Indiana; 7 Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana; and 8Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana

ABSTRACT Background: Cognitive impairment challenges the ability to adhere to the complex medication regimens needed to treat multiple medical problems in older adults. Objective: Our aim was to conduct a systematic evidence-based review to identify barriers to medication adherence in cognitively impaired older adults and interventions aimed at improving medication adherence. Methods: A search of MEDLINE, EMBASE, PsycINFO, GoogleDocs, and CINAHL for articles published between 1966 and February 29, 2012 was performed. Studies included older adults with a diagnosis of cognitive impairment of any degree (mild cognitive impairment or mild, moderate, or severe dementia). To identify barriers to adherence, we reviewed observational studies. To identify relevant interventions, we reviewed clinical trials targeting medication adherence in cognitively impaired older adults. We excluded studies lacking a measure of medication adherence or lacking an assessment of cognitive function, case reports or series, reviews, and those focusing on psychiatric disorders or infectious diseases. Population demographics, baseline cognitive function, medication adherence methods, barriers to adherence, and prospective intervention methodologies were extracted. Results: The initial search identified 594 articles. Ten studies met inclusion criteria for barriers to adherence and three met inclusion criteria for interventional studies. Unique barriers to adherence included understanding new directions, living alone, scheduling medication administration into the daily routine, using potentially inappropriate medications, and uncooperative patients. Two studies evaluated reminder systems and showed no benefit in a small group of participants. One study improved adherence through telephone and televideo reminders at each dosing interval. The results of the review are limited by reviewing only published articles, missing barriers or interventions due to lack of subgroup analysis, study selection and extraction completed by 1 reviewer, and articles with at least an abstract published in English. Conclusions: The few studies identified limit the assessment of barriers to medication adherence in the cognitively impaired population. Successful interventions suggest that frequent human communication as reminder systems are more likely to improve adherence than nonhuman reminders. (Am J Geriatr Pharmacother. 2012;10:165–177) © 2012 Elsevier HS Journals, Inc. All rights reserved. Key words: cognitive impairment, medication adherence, systematic review. Accepted for publication April 19, 2012. © 2012 Elsevier HS Journals, Inc. All rights reserved.

http://dx.doi.org/10.1016/j.amjopharm.2012.04.004 1543-5946/$ - see front matter

Volume 10 ● Number 3

June 2012

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INTRODUCTION In 2010, there were ⬎40 million Americans 65 years of age and older.1 This population has multiple chronic diseases requiring numerous prescribed and over-thecounter medications and is at a high risk for the development of cognitive impairment.2– 4 In a study published in the Journal of the American Medical Association in 2008, 91% of adults of ages 57 to 85 years used at least 1 medication daily, with prescription medication use being the most prevalent (81%), followed by 42% using an over-the-counter medication and 49% a dietary supplement.5 It has also been documented that ambulatory older adults use as many as 11 medications per day and 74% use prescription medications and dietary supplements.6,7 Medication management of chronic comorbid conditions requires treatment adherence, which is commonly complicated by multiple daily doses and tablet combinations. In general, adherence in the older adult appears to be influenced mostly by the number of long-term medications, cost, satisfaction with care, and transportation than age alone.8,9 Poor treatment adherence also has been associated with worse short- and long-term health outcomes.10,11 Within the older adult population, incident cognitive impairment may be less likely in those regularly using medications to control for vascular risk factors, suggesting cognitive dysfunction is less likely in those adhering to pharmacotherapy.12–14 Although observational studies have suggested that baseline cognitive abilities significantly influence medication adherence,15–23 few studies have evaluated interventions aiming to improve adherence in older adults with cognitive impairment. Adherence to medication regimens requires a variety of complex cognitive skills, including accessing medications, understanding prescribed directions, scheduling medications throughout daily activities, adjusting the medication schedule to daily activities, planning continuous access to medications through acquisition of refills, and problem solving for missed doses.24 These tasks have been evaluated in various studies as functions of verbal memory, working memory, processing speed, and reasoning.15,19,25–30 At least 50% of persons with chronic medical illness who manage long-term medication regimens have difficulty satisfactorily adhering to complex regimens.31 Depending on the method and duration of measurement among observational studies, adherence in older adults without cognitive impairment has ranged from 26% to 84%,32–34 whereas adherence rates in those with cognitive impairment have ranged from 42% to 97%, likely reflecting assistance from family

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or caregivers.35–37 Differences in these ranges may be explained by the support those with recognized cognitive impairment receive in various care environments. Several reviews or meta-analyses have been previously published describing barriers to medication adherence in the older adult population.38 – 43 Only 1 systematic review was conducted with the specific focus of identifying risk factors and interventions targeting medication adherence in the specific population of patients with cognitive impairment.44 This review searched 1 database of medical literature and did not include articles published after 2007. Among clinical trials of adherence interventions identified in this review, the majority excluded participants with cognitive impairment, limiting the ability to extrapolate results to the growing population with cognitive impairment. These reviews suggest a gap in the literature recognizing risk factors for medication adherence and interventions conducted in the specific population with cognitive impairment who may pose a unique set of barriers to medication adherence. Several interventions to improve medication adherence have been studied in the older adult population including medication education; disease education, provision of written instructions; medication reviews for inappropriate medications, doses, or interactions; and packaging and dispensing interventions.39 Despite the moderate success of various interventions to improve adherence in older adults, few studies have attempted to translate these results specifically to older adults with cognitive impairment. In an effort to better describe the current literature on this vulnerable population, we performed a systematic review of published literature to describe barriers to medication adherence and identify interventions aimed at improving medication adherence specifically in older adults with cognitive impairment.

METHODS Data Sources and Searches We searched MEDLINE (PubMed and Ovid), EMBASE, PsycINFO, CINAHL, Web of Science, Google Scholar, and GoogleDocs for eligible articles. This review includes articles published between 1966 and February 29, 2012. Search terms consisted of adult, elderly, older adult or geriatric, and cognitive impairment, cognitive impairment not dementia, mild cognitive impairment, dementia, confusion, clouded state, Alzheimer’s disease, vascular dementia, and medication adherence, medication compliance, patient compliance, patient adherence.

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Study Selection

Data Extraction and Quality Assessment

Using the above search terms and databases, titles and abstracts appearing to meet our inclusion criteria were reviewed and stratified into our 2 objectives. We first removed studies meeting our exclusion criteria for both study objectives, which consisted of case studies, case series, review articles, editorials, protocols, studies enrolling adults ⬍45 years of age, and studies focusing on psychiatric disorders or infectious diseases. The minimum age limit of 45 years was selected in recognition that cognitive impairment may be diagnosed before adults are considered to be “older adults” (commonly aged 65 years and older), with an intent to be more inclusive in capturing potential articles meeting our inclusion criteria. We next separated articles into our 2 study objectives for further review. To meet our first objective of developing a comprehensive list of barriers to medication adherence specific to the cognitively impaired population, we included any observational study describing medication adherence barriers from the perspective of the patient, caregiver, or health-care provider, as well as risk factors identified by health information technology databases. Our second objective, to identify interventions targeting medication adherence in cognitively impaired older adults, included prospective clinical trials that evaluated interventions targeting medication adherence among cognitively impaired older adults. After stratification into the 2 study objectives, remaining studies were included if they systematically measured both medication adherence and cognitive impairment. The clinical disciplines of the authors include 2 clinical pharmacists (N.L.C., M.D.M.), a geriatrician (M.A.B.), a medical librarian (E.N.S.), a biostatistician (S.G.), and a psychologist (F.U.). Concordance in study selection was not evaluated in this review because only 1 author conducted the review and data extraction. Disagreements related to either inclusion or exclusion criteria were resolved by discussions among the reviewers. References of included studies and relevant review articles were manually reviewed for eligible articles not identified in the database search. Reviewing the authors’ personal files as a manual supplement to the electronic search criteria was also performed. Corresponding authors of the eligible studies were also contacted either by telephone or e-mail when it was considered necessary for data extraction.

Studies describing barriers to nonadherence were reviewed to extract factors relating to medication adherence as well as the source reporting those factors. From each study reporting results of interventions aimed at improving medication adherence, we extracted demographics and baseline cognitive performance from the target study population, delivery and content of each intervention, the method of assessment of medication adherence, and study results from published studies meeting all inclusion criteria. The methodological quality of studies reporting prospective interventions was independently assessed using the Jadad scale.45 This scale assesses parameters that are critical to the scientific credibility of a clinical trial. The scale evaluates 5 parameters of scientific rigor and allocates a score to each study between 0 and 5, with higher scores indicating a higher quality in the conduct and/or reporting of the trial.45 Intervention studies were reviewed for randomization procedures, blinding of intervention and assessment procedures, appropriate handling of confounders, and existence of conflict of interest. The authors have previously used this method to evaluate study credibility in other systematic reviews.46,47

RESULTS Our search considered a total of 597 articles meeting our primary search criteria. Articles meeting exclusion criteria were initially discarded for identified reasons (Figure). Remaining articles were then stratified into 2 review pathways; the first included 189 observational studies potentially identifying barriers to adherence, and the second identified 108 potential articles studying interventions aimed at improving medication adherence in cognitively impaired older adults.

Barriers to Adherence in Cognitively Impaired Older Adults Ten studies provided barriers to medication adherence in cognitively impaired older adults. Barriers were reported by patients (n ⫽ 2), caregivers (n ⫽ 2), the patient– caregiver dyad (n ⫽ 2), or health information technology databases (n ⫽ 4).35–37,48 –54

Barriers Reported by Patients Two studies identified barriers to medication adherence reported from the patient perspective. Nikolaus et al48 and Kripalani et al49 described patientreported barriers to medication adherence as identified by a population that included those with

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597 Articles identified in initial literature search

Stratified by Study Objective Identification of Barriers to Medication Adherence (189)

300 Articles excluded after reviewing titles and abstracts 130 Reviews 52 Psych population 50 Editorial 31 ID population 27 Survey 10 Protocol

Identification of Prospective Interventions (108)

179 Observational Articles excluded:

105 Articles excluded: 52 No assessment of CI 38 Excluded CI 15 No assessment of MA

107 Descriptive studies 41 No assessment of CI 28 No assessment of MA 3 Excluded CI

10 Articles included in final review

3 Articles included in final review

Figure. Flow diagram of search results. CI ⫽ cognitive impairment; ID ⫽ infectious disease; MA ⫽ medication adherence. and without mild cognitive dysfunction after hospital discharge. Although several barriers were identified in these 2 studies, only 2 were unique to participants with cognitive impairment: difficulty understanding how to take new medications and knowledge of treatment indication and directions.

Barriers Reported by Caregivers and/or the Patient–Caregiver Dyad Ownby et al50 identified caregiver-reported barriers to adherence in a population receiving care in a memory disorders clinic. Their results suggest that poorer adherence was a result of adverse events caused by medications. A second study,54 published in February 2012, pursued risk factors for medication nonadherence among a population of ambulatory older adults with cognitive impairment. Logistic regression models revealed that, besides poorer cognitive function, a history of medication nonadherence (odds ratio [OR] ⫽ 2.61; 95% CI: 1.18 –5.62) and taking four or more medications daily (OR ⫽ 2.58; 95% CI: 1.31–5.29) increased the risk of medication nonadherence. Caregiver-reported barriers to medication adherence were also reported in 2 other studies.36,51 Boucher et al36 reported that a caregiver with cognitive impairment was likely to negatively influence the medication adher-

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ence of dementia patients who were dependent on that caregiver for medication administration. Several responses were identified from caregivers of patients with cognitive and/or functional deficiencies making them dependent on medication administration. Twenty-three family caregivers identified 122 accounts of medication administration “hassles” encountered during daily medication administration practices. Barriers of scheduling logistics, administration procedures, and safety concerns were evenly distributed among caregivers, with the domain of safety concerns encompassing a slightly higher percentage of all accounts (scheduling: 29.5%, administration: 32%, safety: 38.5%).51 Table I identifies specific barriers encountered by caregivers as reported by Travis et al.51

Barriers Reported by Administrative or Dispensing Databases Administrative and pharmacy dispensing databases were also used to identify barriers of adherence in the cognitively impaired population, as listed in Table I. Herrmann et al52 used an administrative database that captured medication dispensing information to identify the impact of the dose frequency of cholinesterase inhibitors on treatment persistence. Although 1-year persistence rates to this class of medications was low

Table I. Barriers to nonadherence derived from patients, caregivers, or administrative databases of patients with cognitive impairment. Source for Barrier Identification Patient

Patient

Patient–caregiver dyad Patient–caregiver dyad Caregiver Caregiver

Method of Assessment of Adherence

Specific Reason for Nonadherence

Reference

MMSE: no absolute value given for CI; numerical comparison of MMSE scores MMSE score ⬍25

Self-report; adherence defined as following all directions of prescription labels

Lack of sufficient knowledge about medication indication and directions

Nikolaus et al, 199648

Self-report and pharmacy dispensing data; overall values not specific for those with cognitive impairment Self-report by patient and caregiver on barriers to adherence

Difficulty understanding how to take new medications after hospital discharge

Kripalani et al, 200849

Relying on patient to remember medications; presence of adverse effects

Ownby et al, 200650

At least 1 episode of over- or underdosing as reported by either the caregiver or physician at 3-mo intervals Pill counts; adherence not defined, assumed to be 100% Pill counts; adherence not defined, assumed to be 100%

Having a history of medication nonadherence; taking ⬎4 medications daily

Thiruchselvam et al, 201254

Caregiver with cognitive impairment

Boucher et al, 199636

Difficulty working administration schedules into care routine, managing complex regimens requiring multiple doses throughout the day, scheduling medications at appropriate times, keeping prescriptions filled, coordinating personal medication schedules with those of the care recipient Giving medication to a confused/uncooperative person Lack of sufficient knowledge of when to hold, alter, or discontinue a medication; how to make up missed doses; how to administer a painful, embarrassing, or noxious medication; lack of ability to recognize adverse or toxic effects; lack of knowledge of how to recognize an emergency; lack of ability to identify medication-related problems; lack of understanding of how to give medications safely; lack of knowledge of how to react if an emergency occurs More frequent doses

Travis et al, 200051

Receiving care in a memory disorders clinic; mean (SD) MMSE score of 19.8 (8.0) Dementia Rating Scale score 130 NINCDS-ADRDA criteria for dementia NINCDS-ADRDA criteria for dementia

ICD-9 diagnosis code for dementia

Administrative database Administrative database Administrative database

ICD-9 diagnosis code for dementia ICD-9 diagnosis code for dementia and hypertension Medicaid recipients with a prescription for a cholinesterase inhibitor

Claims database; persistence defined as (1) allowed missed days less than twice the number of days of the previous prescription; (2) breaks in prescriptions not exceeding 30 days at one time; (3) total number of missed days allowed per year not exceeding 120 days Pharmacy claims data; adherence defined as MPR ⱖ0.80 Pharmacy dispensing data; adherence defined as MPR ⱖ0.80 Dispensing database

Female sex, age ⱕ75 y more likely to be nonadherent, higher level of comorbidity, higher formulary tier status Minorities more likely to be nonadherent (African Americans and Hispanics compared with Caucasians) Minorities more likely to be nonadherent (African Americans and Hispanics compared with Caucasians), living in community more likely to be nonadherent (compared with those living in a long-term care environment), using potentially inappropriate medications

Herrmann et al, 200952

Borah et al, 201037 Poon et al, 200935 Kogut et al, 200553

CI ⫽ cognitive impairment; ICD-9 ⫽ International Classification of Diseases, 9th Revision; MMSE ⫽ Mini-Mental Status Examination; MPR ⫽ medication possession ratio; NINCDS-ADRDA ⫽ National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders.

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Administrative database

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Method and Degree of CI

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(40%–54%), these results suggest that the type of medication and frequency of administration may have a role in adherence.52 Similarly, Borah et al37 used data from a large managed-care plan in the United States to measure adherence using a medication possession ratio (MPR); an MPR ⬎0.80 was considered adherent. The authors found that, among patients with a diagnosis of Alzheimer’s disease, those patients who were ⱖ86 years old compared with those ⱕ75 years old (OR ⫽ 1.40, 95% CI: 1.13–1.74; P ⬍ 0.001), male (OR ⫽ 1.18, 95% CI: 1.00 –1.38; P ⬍ 0.05) had a higher overall pill burden (OR ⫽ 1.19, 95% CI: 1.16 –1.22; P ⬍ 0.001) and used a medication for Alzheimer’s disease that was a lower formulary tier status (OR ⫽ 1.33, 95% CI: 1.13–1.57; P ⬍ 0.001) were more likely to adhere to Alzheimer’s medications.37 The authors also found that those with higher baseline Charlson comorbidity scores were less likely to be adherent to oral Alzheimer’s therapies (OR ⫽ 0.90, 95% CI: 0.86 – 0.95; no P value given).37 Using the Veterans Health Administration database of over 56,000 beneficiaries, Poon et al35 evaluated adherence rates also using an MPR of ⱖ0.8 to classify adherent patients. The authors found that minorities were less likely to adhere to antihypertensive and Alzheimer’s medications than Caucasians (African Americans had lower MPRs for 11/13 classes of antihypertensive or Alzheimer’s medications; Hispanics were less adherent in 1 class of antihypertensive and 1 class of Alzheimer’s medications, but neither group was more likely to be adherent than Caucasians for any drug class).35 Kogut et al53, using data from a state Medicaid program, identified Caucasian patients to be more likely to persist with Alzheimer’s medications than non-Caucasians (74% vs 52%, P ⫽ 0.001). Additionally, this study identified that community-dwelling beneficiaries were less likely to continue Alzheimer’s medications than those living in long-term care facilities (58% vs 76%, P ⬍ 0.001). Those prescribed medications thought to impair cognition (including benzodiazepines, anticholinergics, antipsychotics, and opioid analgesics) were also less likely to persist with Alzheimer’s medications (71% vs 78%, P ⫽ 0.007).53

Interventions Targeting Medication Adherence in Cognitively Impaired Older Adults Search results pursuing our second objective of identifying interventions attempting to improve medication adherence in cognitively impaired older adults revealed 108 articles from our original search criteria. Three stud-

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ies met our inclusion criterion of evaluating an intervention aimed at improving medication adherence in older adults with cognitive impairment.55–57 In 2005, Insel and Cole55 described a nurse-based intervention in which medication reminder cues and organization boxes were instituted in the participant’s home environment. Participants included 27 community-dwelling older adults with a mean age of 78 years. Administration of only 1 medication was assessed using the Medication Event Monitoring System (MEMS Aardex Group, Ltd) in a pre-post experimental design. Participants were more likely to adhere to the single study medication correctly after exposure to the intervention than in the control period before the intervention, (preintervention adherence: 65%, postintervention adherence: 78%), although this difference was not statistically significant. However, when those participants with lower Mini-Mental State Examination scores (defined as ⱖ1 SD below an age and education matched normal score, n ⫽ 6) were separated from the study group, adherence improved from 71% before the intervention to 86% after the intervention (P ⬍ 0.01 on Wilcoxon signed-rank test). These results suggest the population with cognitive impairment would not likely benefit from such an intervention. However, it is important to note that the study included an insufficient number of cognitively impaired elderly subjects to adequately evaluate this reminder method.55 A second study evaluated the impact of a telephone or televideo medication reminder program provided to community-dwelling older adults with a diagnosis of either mild cognitive impairment or Alzheimer’s disease identified by Diagnostic and Statistical Manual Fourth Edition criteria. Participants received either a telephone or televideo communication at each intended dosing interval to remind the participant to take each dose. The study enrolled 14 participants, with the interventions resulting in ⬎4500 telephone or televideo contacts during a 6-month intervention period. Medication adherence, evaluated by pill count at monthly intervals, showed that those receiving either the telephone or televideo intervention maintained medication adherence throughout the study period better than those not receiving the intervention (81% televideo vs 80% telephone vs 62% no intervention). Although this population had a relatively high adherence rate at baseline, the intervention suggested a benefit in maintaining the adherence rate over time.56 Finally, Kripalani, and Jacobson57 compared the impact of refill reminder postcards, an illustrated medication schedule, both, or usual care on refill adherence in a

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population of 420 older adults that included participants with or without cognitive impairment. Refill adherence was measured using medication dispensing data and evaluated adherence to cardiovascular medications over a 12-month intervention period. Adherence was calculated by a cumulative medication gap (CMG), defined as the portion of the intervention period that participants did not have medication available. A CMG ⱕ0.20 for the 12-month intervention period was used to define the number of participants considered adherent for the study period. Although more participants in the group receiving both refill reminder postcards and the illustrated medication schedule were considered adherent (n ⫽ 36.9%), there was neither a statistically significant difference between intervention arms nor a benefit in the subgroup with cognitive impairment (defined as MMSE score ⬍24; unpublished at the time of submission, direct communication with primary author).57

DISCUSSION In summary, results from this systematic review indicate that a variety of barriers to medication adherence have been identified in the literature by patients, caregivers, and database sources within the cognitively impaired population. These results reveal a disconnect between barriers identified by patients, caregivers, and administrative databases and those identified by health-care practitioners and researchers. Although the common clinical perspective that cognitively impaired individuals would have difficulty with remembering to take medications is apparent, there remain other important barriers and concerns unique to this population. Results from this systematic review identified several barriers to medication adherence that were recognized by previously published literature in populations with and without cognitive impairment. Barriers identified by both population groups include memory,58 – 61 medication knowledge,61,62 health literacy,63– 66 concern for adverse effects,61,65,67 and cost.68,69 The unique barriers to adherence in the cognitively impaired population include understanding new directions,49,50 living alone in the community,53 and factors related to the patient– caregiver relationship: the concern for recognizing emergency situations, administration concerns for agitated or uncooperative patients, caregiver burden, and scheduling logistics within care routines.51 An expected barrier identified within several previous publications including older adults without cognitive impairment is inadequate communication with providers and poor patient– caregiver relationships.60,61,64,66,67,70,71 The abbreviated interactions that many patients have with pro-

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viders in the existing health-care system become an inherent barrier to medication adherence for cognitively impaired patients when considering the cognitive function required to retain new information regarding new medications or any changes to an existing regimen. Few studies quantified the frequency of barriers to medication adherence in either the cognitively impaired or cognitively normal populations. In the cognitively impaired population, only 1 study measured the frequency with which caregivers identified barriers to medication adherence.51 Travis et al51 categorized these complaints from caregivers into 3 common domains, with each domain accounting for approximately one third of all caregiver complaints (Table II). In the cognitively normal population, Spiers et al72 reported that 34% of participants indicated memory as the reason for nonadherence, with perceived adverse events and perception that the drug was no longer needed also reported. Being distracted from one’s regular routine is another reported barrier to medication adherence cited by patients.73,74 A special component to adherence is the additional layer of complexity introduced in the cognitively impaired population who require a caregiver (usually a family member or spouse) to assist with or manage the administration of medications. Here caregivers are often responsible for remembering to administer medications and also adopt the responsibility of monitoring for adverse events and other serious events. This responsibility was suggested to result in a significant degree of perceived responsibility as recognized by both Travis et al51 and Ranelli and Aversa.75 Perhaps of equal concern to the health-care system perspective is that as many as one third of employed caregivers (not family members or spouses) have a low level of health literacy and 60% made errors in a test of competency for medication organization.76 Similarly, Boucher et al36 found that a number of familial caregivers, often automatically assumed as caregivers for patients with known cognitive impairment, may also suffer from cognitive dysfunction and have difficulty with the complexity of medication organization and administration. The interventions identified in this review, aimed at improving medication adherence in the cognitively impaired population, focused primarily on reminders and cueing systems to improve medication adherence. Although studies identified in this systematic review targeting behavioral and nonhuman reminder systems were not powered to study subgroups of participants with cognitive impairment, results of the included inter-

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Reference

Population

Sample Size

Mean Age, y

Intervention

Measure of Adherence

Jadad Score45

Primary Outcome

Result Adherence improved from 64.5% to 78% in entire study group (P ⫽ 0.01); no improvement in group with CI Both intervention methods improved adherence: televideo: 81%, telephone: 80% vs control: 62% (televideo vs control, P ⬍ 0.01) Postcards: 28%, medication schedules: 34%, both: 37% Usual care: 31% No difference across overall treatment groups and no benefit of any intervention in subgroup with CI*

Insel and Cole, 200555

Ambulatory older adults

27

78

RN-driven reminder and cueing system

MEMS

MMSE ⬎1 SD below norm

3

% of days correctly taking 1 monitored medication

Smith et al, 200756

Ambulatory older adults with Alzheimer’s type dementia or mild CI

14

82

Telephone or televideo monitoring at each dosing interval

Pill count

DSM-IV of MCI or AD

2

% adherence to all medications

Kripalani and Jacobson, 201057

Ambulatory adults with CHD

420

64

Refill reminder postcards, illustrated medication schedules, or both

CMG

MMSE score ⬍24

NA

% with 1-y CMG ⬍0.20 for cardiovascular medications

AD ⫽ Alzheimer’s disease; CHD ⫽ coronary heart disease; CI ⫽ cognitive impairment; CMG ⫽ cumulative medication gap; DSM-IV ⫽ Diagnostic and Statistical Manual, Fourth Edition; MCI ⫽ mild cognitive impairment; MEMS ⫽ Medication Event Monitoring System; MMSE ⫽ Mini-Mental Status Examination; NA ⫽ not able to complete; RN ⫽ registered-nurse. *Personal communication with author; data unpublished at the time of submission.

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Measure of Cognition

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Table II. Summary of medication adherence interventions in older adults with cognitive impairment.

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ventional trials did not suggest a positive influence on medication adherence using these mechanisms.55,57 Two major themes emerged from the intervention with the most significant impact on medication adherence identified in this review.56 First, adherence interventions should provide frequent interaction on a continuous basis to have a positive impact on adherence. The study by Smith et al56 provided ⬎4500 communications with 14 patients during a 6-month intervention period, 1 contact at each dosing interval, and increased medication adherence. However, this effect on medication adherence dissipated when the study intervention was removed. Similarly, studies by Kripalani and Jacobson57 and Insel and Cole55 provided less frequent interaction and had no effect on medication adherence. Second, interventions targeting medication adherence should be delivered by a significant degree of human communication. From those studies included in our review, providing frequent human contact yielded an improvement in the outcome of adherence, whereas contact by mail did not increase adherence.55–57 Additionally, the review identified the need for medication education to assist with the medication adherence process.49 –51 Although medication administration tasks consumed only a small portion of caregiving time, Travis et al51 reported medication-related stress was present in more than half of caregiver responses. With specific attention given to the caregivers assisting cognitively impaired individuals with medication adherence, the need for medication education on dose, indication, administration with other medications, recognition of side effects, and therapeutic outcomes should be communicated not only to meet the needs of the patient, but also the caregiver. Lessons learned from this review would also indicate that this information needs to be tailored to the needs of each patient and caregiver and repeated as needed as patients interact with any component of the health-care system in a personalized manner. Six systematic reviews have been conducted evaluating adherence interventions specifically in older adults.38 – 43 Results from these systematic reviews that included populations with and without cognitive impairment may be used to design adherence interventions within specific older adult populations. Components of successful interventions in these reviews included regularly scheduled follow-up, dose administration aids, pharmacist review of medications, self-monitoring symptoms, written medication instructions, and multifaceted tailored interventions. Interestingly, Conn et al39 showed that neither med-

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ication nor disease-state education had a significant impact on medication adherence in the studies included in their review. Translating results from these systematic reviews, as well as those reported using our search criteria, would suggest that an adherence intervention in cognitively impaired older adults would require multiple capabilities such as frequent human interactions, the ability to assess for and address barriers to adherence that may be experienced by older adults with cognitive impairment, medication regimen review from a pharmacist at regular intervals, and written medication instructions and dosing aids as necessary. This review highlights gaps in the existing knowledge of methods to improve medication adherence in cognitively impaired older adults; however, these results are subject to limitations. First, articles identified in this review were recognized through multiple sources; however, unpublished interventions improving medication adherence practices in cognitively impaired older adults or observational studies identifying barriers to adherence may exist that were not included in this review. Second, studies that were excluded from the analysis due to a lack of assessment of cognitive function may have masked potentially promising or effective interventions or identification of barriers by not reporting results in subgroups with cognitive impairment. Third, review of titles and abstracts and data extraction was conducted by 1 author (N.L.C.), suggesting the possibility of selection bias. Finally, we limited this review to articles with at least an abstract published in the English language. Interventions targeting this population or studies describing barriers to adherence that were not available in English may have been unknowingly excluded. Given the sparse data identifying medication adherence interventions within the growing population with cognitive impairment, well studied and widely accepted practice standards need to be verified and disseminated. Ongoing clinical trial work was identified in the form of published or publicly available protocols. Ireland et al77 in Canada are studying a nurse case management model to improve medication adherence in ambulatory older adults after their first stroke. The intervention included medication management to optimize pharmacotherapy of stroke risk factors (conducted by an internist), medication and lifestyle education, memory cuing devices if not already used, and at least monthly telephone follow-up by the nurse case manager. Although preliminary results were not stratified by cognitive function, pilot data suggest improvement in blood pressure con-

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trol, medication adherence, and transitional care services. A second study examined a home-based medication management program aimed at improving adherence, health outcomes, use of health-care services, and health-care costs among older adults with cognitive impairment (Marek et al NCT01321853: Home Care Medication Management Program for the Frail Elderly, unpublished at the time the manuscript was accepted). In this study, investigators employed a nurse care coordinator with 1 of 2 medication dispensing aids. Future studies should build on this work in providing a comprehensive evaluation of benefits and harms of such adherence interventions in older adults with cognitive impairment and attempt to maximize outcomes with consideration to implementation costs. Although several barriers for medication nonadherence have been identified, few barriers have been addressed in a population at high risk for incorrectly managing medications. Although the population of older adults with cognitive impairment is intuitively at risk for failing to remember medication directions and adherence tasks, other barriers to medication nonadherence should not be left unaddressed. Therefore, future interventions should improve on previous work by enhancing the capabilities of medication adherence interventions to improve not only medication adherence, but also relevant clinical outcomes. Results of this review will assist in designing future interventions to improve medication adherence in older adults with cognitive impairment, which may positively influence long-term outcomes of disease state management, cognitive function, quality of life, and resource utilization.

ACKNOWLEDGMENTS This work was supported by grant R01 HS019818-01 from the Agency for Healthcare Research and Quality. The authors thank Lisa Marchino for her assistance in the acquisition of published articles as well as in manuscript preparation. Drs. Campbell and Murray and Ms. Skopelja assisted in establishing the protocol for the systematic review. The execution of the search criteria was performed by Dr. Campbell and Ms. Skopelja, with the review of titles and abstracts and data extraction completed by Dr. Campbell. Each author contributed to the interpretation and discussion sections.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

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Address correspondence to: Noll L. Campbell, PharmD, Department of Pharmacy Practice, Purdue University College of Pharmacy, Regenstrief Building, RG 6, 1050 Wishard Boulevard, Indianapolis, Indiana 46202-2872. E-mail: [email protected]

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