Medication adherence: Pharmacist perspective

Reviews

Medication adherence: Pharmacist perspective

Joseph Bubalo, Roger K. Clark Jr., Susie S. Jiing, Nathan B Johnson, Katherine A. Miller, Colleen J. Clemens-Shipman, and Amanda L. Sweet

Received December 20, 2008, and in revised form May 19, 2009. Accepted for publication July 17, 2009.

Abstract Objective: To provide pharmacists with a current, comprehensive review of medication adherence challenges and solutions. Data sources: A computerized search of the PubMed and Medline databases (through July 2008) identified English language review articles on medication adherence using the MeSH terms patient compliance or adherence and medication, drug regimen, or treatment. Study selection: By the authors. Data extraction: The results were filtered to include those published in pharmacy journals, and 117 publications were selected based on the content of their abstracts. The final version of this review article used 55 of the 117 publications. An additional 15 publications that provided examples of specific adherence issues were included. A vignette from the authors’ experience was used as a case study. Data synthesis: This article introduces the challenge of patient medication adherence, discusses the various methods by which to monitor medication adherence, describes various treatment- and condition-related barriers to adherence, and discusses the effectiveness of numerous adherence intervention strategies. Conclusion: Nonadherence to a medication regimen may have multiple underlying causes, some of which may be easier to address than others. Open discussion between the pharmacist and patient regarding barriers to adequate medication adherence, followed by a multifaceted, personalized intervention to address these barriers, plays a key role in encouraging patients to adhere to the recommendations of the health care team. Keywords: Medication adherence, persistence (medication), pharmacists. J Am Pharm Assoc. 2010;50:394–406. doi: 10.1331/JAPhA.2010.08180

Joseph Bubalo, PharmD, BCPS, BCOP, is Clinical Operations Manager, OHSU Pharmacy Services, Oregon Health and Science University, Portland. Roger K. Clark Jr., PharmD, BCPS, was a postgraduate year 1 pharmacy practice resident, OHSU Pharmacy Services, Oregon Health and Science University, Portland, at the time this study was conducted; he is currently a clinical pharmacist, OHSU Pharmacy Services, Oregon Health and Science University, Portland. Susie S. Jiing, PharmD, was a postgraduate year 1 pharmacy practice resident, OHSU Pharmacy Services, Oregon Health and Science University, at the time this study was conducted; she is currently a postgraduate year 2 oncology specialty resident, University of Washington Medical Center, Seattle. Nathan B Johnson, PharmD, was a postgraduate year 1 pharmacy practice resident, OHSU Pharmacy Services, Oregon Health and Science University, at the time this study was conducted; he is currently a clinical pharmacist, OHSU Pharmacy Services, Oregon Health and Science University, Portland. Katherine A. Miller, PharmD, was a postgraduate year 1 pharmacy practice resident, OHSU Pharmacy Services, Oregon Health and Science University, Portland, at the time this study was conducted; she is currently a postgraduate year 2 health system pharmacy administration specialty resident, OHSU Pharmacy Services, Oregon Health and Science University, Portland. Colleen J. Clemens-Shipman, PharmD, MPH, BCPS, was a postgraduate year 1 pharmacy practice resident, OHSU Pharmacy Services, Oregon Health and Science University, Portland, at the time this study was conducted; she is currently a clinical pharmacist, OHSU Pharmacy Services, Oregon Health and Science University, Portland. Amanda L. Sweet, PharmD, BCPS, was a postgraduate year 1 pharmacy practice resident, OHSU Pharmacy Services, Oregon Health and Science University, Portland, at the time this study was conducted; she is currently a clinical pharmacist, Froedtert Hospital, Milwaukee, WI, and OHSU Pharmacy Services, Oregon Health and Science University, Portland. Correspondence: Joseph Bubalo PharmD, BCPS, BCOP, OHSU Pharmacy Services, CR 9-4, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Fax 503-494-8100. E-mail: bubaloj@ ohsu.edu Disclosure: Dr. Bubalo is on the speaker’s board for Pfizer for adherence in oncology patients. The authors declare no conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria. Acknowledgment: To Rebecca Goldstein, PhD, for writing and editorial assistance. Funding: Funding for editorial assistance provided by Amgen, Inc.

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edical interventions are successful only if patients follow them as recommended. In this respect, adherence (previously referred to as compliance) is defined as the degree or extent to which patients follow agreed upon recommendations from health care providers,1 whereas persistence is defined either as the length of time a recommended regimen is continued2 or as the act of continuing the regimen for the prescribed duration.3 Adherence to a regimen encompasses not only correct dosing but also correct timing and frequency.3 Studies reveal that even patients who correctly adhere to the number of doses may not adhere as well to dose timing recommendations, which can affect the therapeutic concentration of a drug considerably.4 Whether nonadherence is unintentional (e.g., forgetting a dose or misunderstanding the correct dosing procedure) or intentional (e.g., taking a drug “holiday” for several days),5 pharmacists can be instrumental in enhancing patient adherence and persistence. Across a range of patient populations and disease settings, health care professionals have examined rates of medication adherence and influencing factors. These studies

At a Glance

Synopsis: Medication adherence is a complex issue that has a considerable impact on the effectiveness and financial burden of the health care system. A review of the literature was conducted to provide pharmacists with a current, comprehensive review of medication adherence challenges and solutions. Via collaboration with other health professionals, pharmacists play an important role in monitoring adherence and identifying potential barriers. The health care team can implement interventions, preplanned patient education, and a multifaceted approach to overcoming barriers to adherence. Many barriers can be addressed simply, whereas others will be more difficult to overcome. Pharmacists who prioritize open communication with patients and combine efforts with other health care providers will have greater success in encouraging patients to adhere to the recommendations of the health care team. Analysis: A variety of behavioral, educational, and technical tools are available to help pharmacists identify, encourage, and improve medication adherence. The causes underlying nonadherence vary from patient to patient; therefore, a multifaceted, individually tailored intervention is recommended for boosting adherence. Notably, many interventions shown to be effective at improving adherence in randomized controlled trials were quite complex and costly and may not be realistic to implement in community pharmacy. The intervention strategies section of the current work provides methods that may be more feasible in everyday practice.

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confirm a common perception among health care providers: nonadherence to medication increases patient morbidity and mortality and increases overall health care costs.6,7 When pharmacists are made aware of known or suspected poor adherence indicators, they can identify potential adherence issues and intervene more often. After a discussion of specific challenges to medication adherence and the various intervention strategies that may lead to improvement, a case study of L.P., a 53-year-old white male prescribed medication for multiple chronic conditions, is provided (Table 1).

Objective The current work seeks to provide pharmacists with a current, comprehensive review of medication adherence challenges and solutions.

Methods A computerized literature search of the PubMed and Medline databases (through July 2008) was conducted to identify important developments and review articles containing the MeSH terms patient compliance or adherence and medication, drug regimen, or treatment. This preliminary search was then filtered for articles published in pharmacy and medical journals. From the search results, 117 publications were selected based on whether their abstracts suggested that they pertained to studies that evaluated or reviewed patient adherence to medication, adherence issues in specific diseases, or methods for monitoring adherence. The final version of this review article used 55 of the 117 identified publications, as these 55 contained information that was deemed pertinent to a discussion of adherence from a pharmacist’s perspective. An additional 15 publications were included that provided examples of specific adherence issues.

Monitoring medication adherence The process of identifying useful and predictable patterns of adherence presents a unique set of challenges.8 Viewed as a whole, studies on adherence rates are characterized by lack of uniformity in the definitions of adherence and persistence and inconsistency regarding the measurements used to describe these terms.9 Moreover, well-controlled trials have not identified a single adherence-monitoring method that is superior.5 The most common and inexpensive methods for assessing adherence and persistence rely on patient self-reporting. For obvious reasons, data gathered from patient interviews have historically overestimated adherence rates, especially if the questions are close-ended (e.g., “Do you take your medication as directed?”) rather than open-ended (e.g., “How do you take your medication?”) invitations to discuss the treatment.5 In large-scale adherence studies, interviews may not be feasible for routine patient monitoring, and these studies more often rely on pill counts and automated pharmacy refill databases to gather data. These methods also tend to overestimate adherence; although these methods can track www.japha.org

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Table 1. History and medication regimens for the example patient described herein (L.P.) Medical history Stage 2 hypertension diagnosed 10 years ago Dyslipidemia diagnosed 9 years ago HIV diagnosed 8 years ago, treated for 4 years Genotype I84V: resistance to all protease inhibitorsa Genotype D67N: resistance to zidovudine, thymidine analogs Social history Smoker, 30–pack year history Drinks occasionally Limited insurance coverage: drug discount cards Low literacy: fruit farm worker Family history Father: MI, died at 68 years of age Mother: Living, history of major depressive disorder Drug allergies Penicillin: hives Medications Enalapril 10 mg by mouth twice daily Hydrochlorothiazide 25 mg by mouth daily Simvastatin 40 mg daily at bedtime Kaletra (100 mg ritonavir/400 mg lopinavir) orally twice a day Combivir 1 tablet (lamivudine 150 mg/zidovudine 300 mg) orally twice a day Fish oil capsules 1,000 mg orally three times a day Abbreviations used: HIV, human immunodeficiency virus; MI, myocardial infarction. a It may take a number of mutations to confer absolute resistance by HIV to any particular medication.

when patients receive the medication, they cannot ensure that it is taken correctly (or at all).10 For instance, patients may simulate adherence by emptying their pill bottles just before a visit to their health care provider—a practice referred to as “pill dumping.”5 Barcode scanners provide similar but more detailed data, but they add an extra step to which patients must adhere (i.e., patients must take the medication and scan a barcode).5 Direct, more objective methods, such as measuring serum or urine levels of the medication or its metabolite(s), may provide greater accuracy but can be time consuming and prohibitively expensive. Medication event monitoring systems are an indirect alternative that show promise. (A review of these devices, including images and relative cost, is available in the literature.5) Such systems use a pill bottle cap with a computer chip that electronically tracks the number and frequency at which the bottle is opened. Similar devices exist for metereddose inhalers (only Doser [Meditrack] is currently available to patients). Although such systems are expensive to implement, they yield data that are precise and easily quantified and potentially are the most accurate way to monitor adherence.11 Hence, they are emerging as the gold standard for examining how patients self-dose.4,12,13 Health care teams constantly face the challenge of deter396 • JAPhA • 50 : 3 • M ay / J u n 2010

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mining which patients to monitor for medication adherence because as many as one-half of all patients do not take their medication as prescribed.14 No single underlying cause can explain why a patient does not adhere to proper treatment,5 and an individual patient’s nonadherence may be influenced by a number of factors. Many of these factors are within the control of the health care providers, and those that are not can still be recognized and addressed successfully by effective communication among the pharmacist, patient, and other health care providers.5,15–17

Treatment-related challenges to adherence Research suggests that the nature of the treatment regimen can affect adherence profoundly. When implementing a treatment regimen or plan, pharmacists should be aware of these risk factors and how they may affect medication adherence. Adverse effects Patients are less likely to adhere to treatment regimens with a high occurrence of adverse events,5 especially if the patient does not perceive the benefit to their overall health to be greater than the adverse effects experienced. Recognizing the impact of adverse effects, even those deemed tolerable by the treatment team, is important. For example, adverse effects had a substantial influence over whether breast cancer patients adhered to tamoxifen therapy, even though the adverse effects associated with tamoxifen pale in comparison to the threat of recurrent breast cancer. Patients who had initial severe adverse effects (hazard ratio [HR] per adverse effect = 1.2 [95% CI 0.97–1.5]) or developed them (HR per new adverse effect = 1.3 [1.0–1.6]) were more likely to discontinue the treatment regimen.18 Contrary to the perceptions of many patients, however, poor or incorrect adherence can exacerbate adverse effects or cause new ones, such as withdrawal symptoms from mood-stabilizing medications.5 Poor adherence to tricyclic antidepressants and selective serotonin reuptake inhibitors can cause gastrointestinal or somatic distress, sleep disturbances, mood fluctuations, and movement disorders.19 These symptoms may be mistaken for physical illness or relapse into depression and often lead to unnecessary and costly tests and treatment.20 Lack of effect in the absence of correct adherence Many drugs function within a narrow therapeutic range, so even partial adherence may render the therapy ineffective or exacerbate the underlying condition. Poor adherence to warfarin, for example, can lead to poor anticoagulation control because proper levels of anticoagulation may be difficult to maintain. In a recent study of 136 patients taking warfarin, participants who had extra pill bottle openings on more than 10% of days had a statistically significant increase (14%; P < 0.001) in the odds of supratherapeutic anticoagulation (adjusted odds ratio 1.73 [95% CI 1.09–2.74]).21 A cycle of poor adherence may cause the patient to begin to believe that the underlying condition is worsening despite treatment.5 Journal of the American Pharmacists Association

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Multiple daily doses Treatment schedules that call for two or more daily doses are associated with lower adherence than those with once-daily dosing,22,23 presumably because more opportunities exist for missing a dose or taking it at the wrong time. In a systematic review of 76 studies, the associations between dose regimens and medication adherence were calculated. Mean (±SD) dose-taking adherence for all dosing regimens was 71% ± 17% (range 34– 97%). Adherence was the greatest for one dose (79% ± 14%) and declined as the number of doses increased: two doses (69% ± 15%), three doses (65% ± 16%), and four doses (51% ± 20%) (P < 0.001 among dose schedules).22,24

windows or high variability among patients (e.g., cyclosporine30), making routine office visits for blood level monitoring a necessity. These visits create another task to which patients must adhere in order to assess therapeutic effectiveness. In addition to drug interactions and dosing considerations, medications often need to be administered under special conditions. For example, patients must take alendronate at least 30 minutes before the first food consumption of the day with only water and must avoid lying down and consuming food until after at least the requisite half-hour waiting time.31 These administration instructions can exacerbate the low adherence rates associated with this osteoporosis therapy.32

Multiple concurrent treatments When health care providers prescribe multiple medications, they consider the effectiveness and safety issues that may arise from concurrent regimens, such as the potential for drug–drug interactions. Thus, drug choices and recommended dosing instructions are based on an integrated understanding of patient needs. Patients may not always have this perspective, and depending on their understanding of the goals for each of their therapies, they may choose which therapy they will adhere to based on what they believe is a priority in their care at any one point in time. This issue, combined with the increased dosing and administration burden associated with multiple medication regimens, creates a linear relationship between the number of long-term comorbidities and the rate of failure to refill at least one prescription; a higher number of prescriptions translates to a greater likelihood that at least one will not be filled or refilled.25 Despite the presumption that patients with multiple chronic conditions or drug regimens may be prone to nonadherence, evidence suggests that they may be more adherent,26 although this trend may not be true among the elderly14,27 or when new prescriptions are added to an existing regimen.18 For example, among breast cancer patients who were prescribed a 5-year course of tamoxifen, those with more prescriptions at baseline were more likely to complete treatment. In contrast, patients who at a later time were prescribed another prescription along with their tamoxifen regimen were more likely to discontinue tamoxifen therapy.18

Condition-related challenges to adherence

Specialized dosing and/or administration requirements In addition to their prescription drugs, patients often take one or more over-the-counter medication or herbal remedy, which have the potential to interact with prescribed medication. Moreover, lifestyle practices (such as smoking) or common foods can alter the effectiveness or safety profile of certain drugs. Grapefruit juice can potentially affect drug metabolism via the cytochrome P450 enzyme system.28 The ability to maintain a patient’s goal international normalized ratio while on warfarin therapy can be adversely affected by consuming foods rich in vitamin K, such as leafy green vegetables. The activity of certain oral antibiotics, such as fluoroquinolones, may be blunted by taking them with dairy or calcium-fortified drinks29 because of decreased absorption. Additionally, some medications have narrow therapeutic Journal of the American Pharmacists Association

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Characteristics of the underlying conditions can influence the likelihood of patients adhering to therapy.5 Asymptomatic conditions Even if patients understand that their medication is necessary, they are less likely to adhere to or persist with treatment if they do not experience a perceivable benefit from the medication. For similar reasons, patients may be less likely to adhere to a preventive regimen. Patients with osteoporosis or human immunodeficiency virus (HIV) who are asymptomatic or currently in virologic suppression may have low adherence rates.23 Similarly, adherence to medications to prevent or treat cardiac disease such as hypertension have shown poor adherence behavior. For example, in one study of 3,240 patients who were written a first-time prescription for an antihypertensive medication, only 2,685 (83%) generated a corresponding claim within 30 days.33 Further, patient adherence to these medications decreased over time. Another study of 4,052 individuals aged 65 years or older investigated adherence to antihypertensive and lipid-lowering therapy. The results showed that 40.5%, 32.7%, and 32.9% of patients were adherent to both therapies after 3, 6, and 12 months, respectively.34 Another study examined adherence in children with moderate asthma and the use of daily preventive medications (e.g., inhaled corticosteroids), looking at time points before and after the National Institutes of Health published guidelines citing the benefits of preventive asthma therapy. Although the guidelines had been in effect for 7 years and all of the children received Medicaid coverage, adherence to preventive asthma therapy was low. Only 11.2% of children were dispensed enough medication to treat them half the time (as measured by refills after an initial prescription). Encouragingly, however, this figure was almost double the 6.1% adherence rate measured before publication of the guidelines, highlighting the importance of widespread educational intervention.35 Chronic conditions requiring multiple concurrent medications The rapid initiation of multiple concurrent medications may affect patient adherence to prescribed instructions.24 Congestive heart failure24 and HIV36 are examples of conditions for which patients are commonly given as many as five new medications upon diagnosis. www.japha.org

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Conditions characterized by physical decline Pharmacists must be mindful of potential physical limitations that may interfere with adherence, including those that may not be initially identifiable. Declining eyesight may limit patients’ ability to read and interpret labels and dosing instructions, while decreased hearing may prevent adequate counseling and transmission of important medical information. Conditions associated with manual weakness or peripheral neuropathy may affect how well patients can remove tamper-proof seals, open medication bottles, operate inhalers, or administer ophthalmic or otic preparations.5,37 Generalized physical weakness or ambulatory difficulties may also hinder patients in filling prescriptions or attending medical visits. Moreover, having a disability correlates with cost-related barriers to adherence.25 These factors may account for the observed lower adherence rates in patients with glaucoma, chronic obstructive pulmonary disease, or breast cancer.5,37 Patients with psychiatric conditions Nonadherence in patients with psychiatric conditions is a result of accompanying cognitive issues such as deficits in conceptualization and memory,38 as well as a lingering stigma regarding psychiatric therapy in general15 and a tendency for patients to believe that these conditions do not have a medical basis.14 In one study, among a subgroup of Medicare beneficiaries who self-reported a range of chronic conditions, those with a psychiatric condition were most likely to let a prescription go unfilled.25 Likewise, patients with schizophrenia are more likely to experience comorbidities associated with concurrent conditions. Patients with diabetes and schizophrenia were 25% less likely to adhere to oral hypoglycemic therapy than those who did not have schizophrenia.39 Notably, long-term conditions can be accompanied by declining cognitive function and concurrent psychiatric issues, like depression, which may further hinder adherence in these patients. In one study, even after adjusting for confounding factors, adherence to angiotensin-converting enzyme inhibitors and recommended lifestyle modification was lower in patients with cardiovascular disease who were also taking an antidepressant.40 Also of note, patients with cardiovascular and psychiatric disease who do not adhere to prescribed medication have significantly higher rates of hospitalization.15,25 Examples of challenging disease states Specific conditions are sometimes characterized by their own pattern of low adherence based on one or more of the above factors. Often these diseases are long-term conditions for which patients who do not exhibit obvious symptoms must continue therapy indefinitely to maintain their health (Table 2). A large survey of more than 14,000 Medicare patients revealed high failure-to-fill rates for prescriptions to treat chronic conditions such as psychiatric disorders (8.0%), arthritis (5.2%), cardiovascular disease (5.2%), or pulmonary disease (6.6%); notably, some of these conditions may not be associated with symptoms that are apparent to the patient.25

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Patient characteristics that challenge adherence Particular groups of patients may be more prone to nonadherence because of their need for extra physical or educational intervention or their perception of their overall health.16 A patient may fall into one or more of these categories, each of which influences the patient’s adherence to medication and how the pharmacist should approach the intervention. Elderly patients Although few patients adhere perfectly to medication recommendations, in most studies, elderly patients are less likely than younger patients to take medications correctly.5,24 One study suggested that nonadherence may be the underlying cause for as many as 26% of hospitalizations for patients older than 75 years.27 Multiple age-related chronic conditions can burden older adults with a complex medication schedule that may require up to five to eight drugs daily.14,41 Elderly patients are also at a greater risk for adverse drug reactions and drug–drug interactions because of decreased renal and hepatic function. Adherence in this population is also more likely to be hindered by cognitive challenges (e.g., decreased memory or coping skills), physical challenges (e.g., impaired hearing and/or vision), or generation-specific perceived barriers to taking medication.5,14,24 Additionally, economic limitations are a commonly cited reason for nonadherence among this population, which often has a fixed income or relies on Medicare for medication coverage.5,25 Young patients Adolescents face many specific and unique adherence challenges. Adolescence is a time for developing identity, and some young people may deny their illness as a part of their evolving sense of self.42 Because of limited life experiences, some youth feel invincible and do not fully comprehend the negative consequences of not taking their medications. Other young adults may try to assert their independence by choosing not to follow directions, which may result in failure to take medications correctly, attend doctor appointments, or follow dietary restrictions. Teens that are experiencing emotional, social, or family problems may struggle to adhere to medications. In a recent study of 153 youths (aged 8–16 years) with type 1 diabetes, lower parental knowledge and a greater parental-perceived burden of diabetes care correlated with lower disease control.43 Children with attention deficit hyperactivity disorder demonstrated poor adherence to methylphenidate if they experienced maternal psychological distress, indifferent parenting, maternal overprotection/control, poor family support, decreased interaction with parents, or increased problems at home.44 Homeless patients Tracking, contacting, and following up on homeless patients is particularly difficult because they lack a permanent physical address or phone contact information. Additionally, these patients are commonly burdened with other barriers to treatment adherence, such as low health literacy (see below), lack of prescription insurance coverage, financial instability, and sometimes Journal of the American Pharmacists Association

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Table 2. Adherence challenges associated with specific disease states.

Disease state Diabetes CVD Hypertension

Can be asymptomatic

Challenges to adherence Associated with multiple medications or challenging Chronic condition dosing

ü ü ü

Emphysema HIV Osteoporosis Asthma

ü ü ü

COPD Psychiatric disorders

ü

ü ü ü ü ü ü ü ü ü

May be associated with declining cognition or elderly patients

ü ü ü

ü ü ü ü ü ü

ü ü ü ü ü

ü ü

Abbreviations used: COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; HIV, human immunodeficiency virus.

impaired cognitive abilities. Homelessness was shown to be associated with poorer adherence among patients with diabetes receiving care from a Department of Veterans Affairs (VA) facility.39 Functional health literacy Functional health literacy is the extent to which a patient can read, understand, and act on health information,45 and it plays a role in how well a patient adheres to a prescribed regimen. The American Medical Association is seeking to make health care providers aware that approximately one-quarter of the adult population “has limited literacy and difficulty reading and understanding oral and written health care information.”46 In U.S. studies, as many as 48% of English-speaking patients45 and more than one-half of Spanish-speaking Medicare enrollees24 demonstrated subpar health literacy. Moreover, low health literacy was more common among the elderly, even after adjusting for confounding factors like vision, level of education, demographics, and cognition.5,24 Despite ongoing efforts to increase health literacy awareness, health care providers routinely tend to overestimate the health literacy of their patients. Additionally, health care providers have limited time to communicate with individual patients. In many cases, a disparity exists between what patients are expected to understand and what they actually understand.46 Individual perceptions Patient beliefs can influence the degree to which they adhere to a prescribed regimen.16 Such beliefs can pertain directly to the regimen itself: more adherent patients may have a stronger perception that the regimen is effective and/or they may have more confidence in the judgment of their health care team.14 Perceptions about the condition can also influence adherence. If patients believe the cause of their condition has a medical basis or that they need the medication to control or treat their condition, adherence and persistence are more likely.14,16 Journal of the American Pharmacists Association

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Conversely, if patients believe medication is unnecessary, they are likely to demonstrate lower adherence. In one study, more than one-half (52%) of intentionally nonadherent elderly patients cited a belief that the therapy was unnecessary (for comparison, only 15% cited adverse effects).47 Also, research has revealed that patients with osteoporosis frequently perceive a low risk of an osteoporosis-related bone fracture, which contributes to the high nonadherence rate associated with this condition.32 Abstract beliefs can also influence adherence. For example, patients who are confident in their ability to self-administer medication or handle adverse effects will likely be more adherent, as will those who believe they have a high level of control over their own health.14 Additionally, patients who believe they have a quality relationship with their health care providers and place trust in their advice are more likely to adhere to their recommendations.14,25 Family/cultural issues An individual’s cultural background may influence his or her belief in modern medicine (i.e., pharmaceuticals) and thus may present challenges to adherence. In a cross-sectional study of 500 students in the United Kingdom, students with an Asian background were more likely to perceive medication as intrinsically harmful (especially drugs that were potentially addictive) than students of European origin.48 Older black adults with HIV were shown to experience more doubt regarding their physician’s competence regarding medication-prescribing behaviors.49 This distrust may be related to perceived ethnic disparities in quality of care.14

Intervention strategies Pharmacists have a variety of behavioral, educational, and technical tools at their disposal to identify, encourage, and improve adherence (Table 3).13,23,50–62 Because the causes underlying nonadherence vary from patient to patient, a multifaceted, indiwww.japha.org

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vidually tailored intervention is an effective approach to boosting adherence.63 For example, in a multiphase prospective study of 200 community-based patients aged 65 years or older taking at least four chronic medications for coronary disease, pharmacist intervention—through standardized medication education, regular personalized follow-up, and medications dispensed in blister packs—led to increases in not only medication adherence and persistence but also clinically meaningful reductions in blood pressure.24 A comprehensive review summarizing the results of randomized controlled trials (RCTs) of interventions to help patients follow prescriptions for medications was published recently.64 Notably, many of the adherence interventions shown to be effective in RCTs were quite complex and costly and may not be realistic to implement in community pharmacy. The strategies discussed below may be more feasible in everyday practice. Monitoring medication adherence Patients may be more likely to adhere to and persist with a prescribed therapy if they know that their health care team is monitoring their adherence. This so-called “white coat effect” stems from a patient’s conscious or unconscious desire to appear as a “good patient” or to avoid confrontation. Although automated pill boxes, dosing and refill reminders, and medical services incorporated into home-monitoring systems have been evaluated in adherence studies, none have demonstrated a substantial boost in adherence that is not confounded by frequent in-person medical monitoring. In these studies, regardless of which technological monitoring device was used, patient adherence was typically highest in the periods immediately before and after a medical visit.5 Technological interventions, however, are useful in that they alert caregivers to the need for targeted education regarding adherence, which may stave off unnecessary pharmacologic changes or interventions. In some patients, especially the elderly, the technology may interfere with established routines or present a technological learning curve that may undermine adherence efforts. Further, like low-technology pill counts and refill requests, these devices cannot ensure that patients actually take the medication, although they can distinguish between actual adherence and pill dumping (or the inhaler equivalent, canister dumping) just before a visit.5 Using behavioral cues Studies in various settings have reported a wide range of adherence (15–93%),8 and it can be challenging to determine at which end of the spectrum a patient will fall. Pharmacists can evaluate adherence and persistence by using principles of behavioral medicine, even in patients who are consciously not complying with a prescribed regimen. The stages-of-change model, first proposed by Garfield and Caro,65 predicted adherence in hypertensive patients.5 According to the model, patients fall into one of five categories: (1) precontemplation (patient does not want to consider adhering to the regimen), (2) contemplation (patient considers change), (3) preparation (patient begins making small changes) (4) action (patient makes active changes), and (5) maintenance (change 400 • JAPhA • 50 : 3 • M ay / J u n 2010

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becomes a long-term behavior modification). A patient’s stage of change may dictate which intervention may most effectively and durably improve adherence; for example, medication monitoring devices may only be appropriate for patients in the action or maintenance stages.5 Development and validation of the stagesof-change model (also known as the transtheoretical model) has been thoroughly reviewed.66–68 Although pharmacists have no control over some factors that influence patients’ personal beliefs, such as cultural background or past experience, conversations with patients may reveal beliefs that influence adherence. Open-ended discussion, education, and follow-up Regardless of the basis for nonadherence or how it is identified, a health care team that actively communicates among its members is more likely to have success in fostering adherence in its patients. Establishing a relationship with the patient that promotes trust, honesty, and free discussion can improve adherence to a recommended strategy.5,14,16 Pharmacists can also provide an open door by which patients may ask questions or address specific concerns in the future. Discussions with the patient provide a unique opportunity for pharmacists to dispel fears or misconceptions that may negatively influence adherence. Such discussions may highlight drug effectiveness compared with supportive care or home remedies and how the intervention addresses the cause of the condition.5 Appropriate self-management techniques or in-office follow-up should be discussed as well.14 Patient education can lead to an increased understanding of the consequences associated with poor adherence and may provide additional motivation to adhere to medication. Educating patients through open-ended discussions is an effective way to boost medication adherence because the resolutions are more likely to reflect patients’ personal needs, lifestyle, and desires. Education concerning any regimen-related issues will eliminate unknowns for patients and give them confidence, which may promote adherence.14 To prevent adverse events or drug interactions, health care providers should foster patient education about potential drug interactions and adverse events at the beginning of the regimen(s) to ensure that the patient is prepared for their potential onset. Such preparation may or may not include recommending palliative or self-management techniques to the patient. Initiating one-on-one follow-up with patients who are not adhering to treatment has been shown to boost overall adherence rates in several chronic disease states. The Longitudinal Adherence Treatment Evaluation, a telephone-based behavioral intervention program that was targeted toward patients with cardiovascular disease and diabetes, significantly improved adherence to therapy in patients who were behind on filling a prescription. The program consisted of direct telephone interaction between patients and care managers who were trained on the following topics: health behavior change techniques, motivational interviewing and active listening, and resources to overcome common adherence barriers. Patients in the intervention group reinitiated lapsed therapy more often (59.3% vs. 42.1%; P < 0.05) and were nonadherent for shorter lengths of time (59.5 ± 69.0 vs. 107.4 ± 109 days; P < 0.05) than patients in the Journal of the American Pharmacists Association

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Table 3. Effectiveness of medication adherence intervention strategies by type Medication, disease state, or population Monitoring patient adherence Diabetes; hypertension Diabetes Elderly patients Diabetes; indigent patients Altering how prescribing information is presented Various Various Following up on individual patients CVD and diabetes Altering dosing to a less frequent schedule HIV Antidepressants Osteoporosis Hormonal contraception Hormonal contraception Providing financial aid and/or counseling Transplantation Heart disease

Intervention strategy

Method of measurement

Successa

Reference

Pill counts; refill requests MEMS CompuMed autodispensing pill box (vs. traditional pill box) Health Buddy interactive medical pager

Clinical evaluations Clinical evaluations Clinical evaluations

+/– + ++

54,55 56 57

Clinical evaluations

++

58

Pictorial and written in combination Presenting in number of times per day instead of hours

Patient recall surveys Questionnaire

+/– ++++

51 50

Targeted telephone follow-up after a late prescription refill

Pharmacy claims data

+++

13

Daily dosing (vs. twice-daily) Weekly dosing (vs. daily) Weekly dosing (vs. daily) Weekly patch (vs. daily oral) Monthly vaginal ring (vs. daily oral)

MEMS, pill counts, questionnaires MEMS Medication possession ratiob Self-report via diary Self-report via diary

+++ +++ ++++ ++++ +

23 59 60 61 62

Aid in securing financial resources Direct economic aid

Patient surveys Patient surveys; clinical evaluations

+++ ++++

52 53

Abbreviations used: CVD, cardiovascular disease; HIV, human immunodeficiency virus; MEMS, monitoring events medication system. a ++++, produced a significant difference in adherence (P < 0.001); +++, produced a significant difference in adherence (P < 0.05); ++, produced a significant difference in adherence but results are questionable; +, did not produce a significant adherence difference but yielded other patient benefits (indirect effect); +/–, did not reliably affect adherence and may have had detrimental effects. b Actual divided by expected filled prescriptions.

control group.13 Regular interaction with a health care provider may also benefit patients with psychiatric disorders. For example, veterans with diabetes and schizophrenia receiving ongoing VA care were more likely to adhere to oral hypoglycemic therapy than those with diabetes but not receiving ongoing VA care.60 Pharmaceutical mail order or delivery services associated with specific insurance companies or pharmacies may benefit some patients with disabilities; however, the lack of personal interaction can create a disconnect between the pharmacist and the patient that could exacerbate adherence issues. Pharmacists should therefore ensure that patients actually receive their mail order medications via a follow-up telephone call. This call also gives the pharmacist an opportunity to address any questions that the patient may have regarding the medication. Additionally, asking patients to bring medication bottles to their next clinic visit allows the pharmacist to ensure that the dosing and administration instructions were correctly printed and properly understood by the patient. With so many points of adherence to remember, considJournal of the American Pharmacists Association

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erable effort is needed by patients to correctly self-administer many treatments. Alternative formulations continue to emerge, giving pharmacists more opportunities to offer patients equivalent choices with less challenging adherence burdens. If no alternatives exist, however, pharmacists must do what they can to help patients cope with specialized dosing or administration requirements. Such measures include a thorough discussion with the patient regarding the requirements and why they exist (i.e., to maximize effectiveness or prevent adverse effects), verifying patient understanding, and following up with the patient. Clarifying instructions for patients with cognitive challenges or the elderly For patients with cognitive challenges or inadequate functional literacy, pharmacists can improve adherence to medication by using uncomplicated language to explain the expected benefits, dosing regimen, and potential adverse effects.24 An effective approach to minimizing dosing confusion is phrasing www.japha.org

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the instructions in terms of number of doses per day instead of hours between doses (e.g., “four times per day” instead of “every 6 hours”).50 Such verbal intervention is crucial because the documentation accompanying the medication may be written at a reading level that exceeds the eighth-grade reading level of the average U.S. adult.46 Patients with literacy issues, particularly those for whom English is a second language, may also benefit from packaging containing physical or pictorial clues to help them take their medication correctly. Such clues may include colored dots on the labels or colored pill boxes that differentiate between morning and evening dosing. Labels may also contain pictures that remind patients of specific dosing instructions (e.g., picture of a full glass alongside the instructions to take the medication with a full glass of water). Adherence in elderly patients may be improved by simple, helpful aids. For patients with poor eyesight, larger print on labels and instruction sheets, accompanied by a verbal reinforcement of dosing instructions from the pharmacist, can help patient adherence.24 Pharmacists can also recommend organizational methods like calendars, medication cards, compartmentalized pill boxes (manual or autodispensing), or electronic reminder systems5 to aid patients in their adherence to multiple treatments. When appropriate, pharmacists should recommend devices and services that help patients conduct tasks related to their treatment (e.g., automatic dispensers, community shuttle services to and from medical appointments). Formal screening tools Several screening tools allow pharmacists to evaluate patients’ ability to manage medications. Meyer and Schuna’s37 geriatric assessment, the Drug Regimen Unassisted Grading Scale tool,69 and the MedTake tool70 all assess patients’ ability to correctly identify the dose and type of medication, knowledge of proper dosing and administration instructions, and (for the first two tools) physical ability to take the medication. Clinical practices have simple health literacy screens at their disposal that can be administered in minutes. (A review of these screens and their potential benefits and drawbacks is available in the report of the Journal of the American Medical Association Committee on Health Literacy for the Council on Scientific Affairs.46) A quick evaluation may involve asking a patient to read a short passage, such as their dosing instructions.5 Potential literacy issues should be handled tactfully, as patients may be unaware of their literacy issues or ashamed or embarrassed to have them evaluated and documented in a chart.46 The effectiveness of these tools will depend on factors such as whether the patient is intentionally nonadherent and the amount of time required by the pharmacist. Unfortunately, comprehensive adherence evaluations for every patient may not be feasible because of time and reimbursement constraints.5 This makes ad hoc proactive planning for such evaluations and the ensuing patient educational process a critical aspect of patient care. 402 • JAPhA • 50 : 3 • M ay / J u n 2010

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Pharmacologic or dosing adjustments For patients who have a tendency to forget doses or take them at the wrong time, a more forgiving alternative medication may improve the effectiveness of the regimen. Such medications would have similar treatment endpoints, but their pharmacokinetic and pharmacodynamic properties would have less clinical consequences in cases of nonadherence. This increased flexibility may also allow for greater variability in dose timing.5 Fewer daily doses theoretically means greater convenience for the patient (or at least fewer opportunities for nonadherence); thus, once-daily dosing tends to yield better adherence than multiple daily dosing.22 In one study, patients with HIV who were maintaining viral suppression using a complex antiretroviral schedule requiring two or more daily doses were switched to less complex once-daily regimens or extended-release formulations. In addition to the superior adherence (80.0% with the once-daily regimen vs. 75.8% with multiple daily doses), 91% of patients preferred the simpler regimen.23 When such options are available and appropriate, they have the potential to affect medication adherence considerably. Recently, the use of intermittent dosing schedules (dosing less frequently than once a day) has increased. One retrospective review suggested that patients are 8% to 12% more likely to adhere to a weekly dosing schedule than to a daily one.11 Most patients preferred less frequent dosing, but this preference may not correlate to substantial increases in adherence.11 One caveat to less frequent dosing is that if a patient omits a dose, it may pose a more serious threat regarding effectiveness or adverse effects.5 Nonpharmacologic interventions Although pharmacotherapy is the standard of treatment for most psychiatric conditions, parallel nonpharmacologic intervention (e.g., cognitive behavioral therapy, psychoeducation) has also been shown to improve adherence to psychotropic medication, in addition to addressing the condition itself. Encouraging these patients and the health care team to pursue nonpharmacologic methods in combination with medication management may improve adherence.15 Financial assistance and sensitivity Compared with prescribers, pharmacists may be more aware of the increasing patient costs tied to most medications; even insured patients can face considerable out-of-pocket expenses. In addition to being able to afford the medication, patients should also be able to afford the indirect costs associated with medication refills, such as copayments for health care visits and transportation to these visits and the pharmacy.25 A substantial portion of nonadherence to prescribed therapy stems from insufficient financial means, especially in uninsured, elderly, indigent, or homeless patients.39,53 Contrary to common perception, however, financial issues also influence adherence in middle-income patients with prescription drug insurance coverage.5 Medicare recipients most frequently cite drug costs (55.5%) and inadequate insurance coverage (20.2%) as reasons for not filling a prescription.25 Financial barriers to adherence present a touchy subject for many patients and caregivers, Journal of the American Pharmacists Association

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but open-ended questions regarding how or whether a patient is able to pay for medication may unearth a potential for nonadherence and begin the process of connecting the patient with help for this issue.5 Pharmacists can discuss with patients the overall financial merits of investing in themselves by adhering to therapy. For example, taking medication correctly may lead to better overall health,24 which will in turn minimize the financial impact of missed work caused by illness, as well as manifestations of symptoms associated with advanced or poorly controlled disease. Often, however, patients will not have the means to make such an investment, and pharmacists should be mindful of the barriers to adherence that could result from expensive therapies, especially from changing a patient’s treatment to a more expensive drug. Pharmacists can discuss equally effective lower-cost generic equivalents to brand-name drugs with the health care team.25 Such substitutions will help ease the out-of-pocket expenses associated with medications.5 Alternatively, a single expensive drug may be more cost effective if it replaces two or more existing medications. Although free or subsidized medication programs substantially improve adherence,53 patients may also benefit from counselors or social workers who help them secure means to pay for medication.52 Pharmacists should have knowledge of programs sponsored by their state or local area, as well as programs or discount drug cards offered by pharmaceutical companies for specific diseases.5 One source for such information is www. needymeds.com. Medicare recipients will benefit from up-to-date information concerning Medicare Part D prescription drug benefits that are intended to ease the high cost of prescription drugs (www. medicare.gov/pdphome.asp). Of note, data from the Medicare study25 cited above predated the implementation of this program in 2006.

Case study: adherence challenges and solutions Our example patient, L.P., has multiple barriers to medication adherence that are products of his complex medication regimen, multiple chronic conditions, and relatively low health literacy. He has stage 2 hypertension, dyslipidemia, and HIV, which was diagnosed 8 years ago. He has been undergoing antiretroviral therapy (ART) for 4 years, but his recent decrease in CD4 count, accompanied by an increase in viral load, indicates that his current ART is failing. Moreover, L.P.’s hypertension and cholesterol levels have worsened since his last visit. His Framingham score gives him a 30% risk of having a cardiac event in the next 10 years, and his systolic blood pressure ranges from 160 to 167 mm Hg. L.P., a fruit farm worker with an eighth-grade education, has trouble remembering the indications for many of his medications and admits that he frequently forgets to take his medications. Therefore, failure of his current antiretroviral, antihypertensive, and lipid-lowering therapies could be a result of inadequate adherence to medication. L.P. was interviewed for potential problems with taking his Journal of the American Pharmacists Association

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medications as prescribed, and this discussion revealed that his two primary barriers to medication adherence included difficulty understanding the indications of each medication and difficulty remembering when to take them. In the following sections, L.P.’s case will be discussed using the information and intervention tactics presented in the current report. L.P.’s case will illustrate how pharmacists can have a considerable impact on a patient’s overall health by promoting medication adherence. Changes in medication L.P. cited “too many pills too many times a day” as a major barrier to being adherent to his medication strategies. For example, he admitted that he took his ART only about 75% of the time. Therefore, while changing his medications to better meet his treatment goals, reducing the number of pills that L.P. had to take per day was a specific focus. L.P.’s HIV genotype revealed I84V and D67N mutations that conveyed resistance to protease inhibitors and to the zidovudine portion of his lamivudine/zidovudine (Combivir—GlaxoSmithKline) therapy, respectively. His genotype necessitated a change from his current ART of lopinavir/ritonavir (Kaletra—Abbott Laboratories) and lamivudine/zidovudine but also limited the number of effective alternatives. Efavirenz/emtricitabine/tenofovir (Atripla—Bristol-Myers Squibb) was the recommended alternative ART regimen because it is effective against his current strain of HIV and can be administered as a single daily dose. L.P.’s cholesterol levels had also worsened, and and the protease inhibitor component of his current HIV regimen may have been contributing to his increased lipid levels. Changing his HIV medication to efavirenz/emtricitabine/tenofovir should help decrease his lipid levels. Because efavirenz is known to decrease blood levels of statins, his simvastatin dose was increased to 80 mg every evening to mitigate concentration adjustments resulting from the switch. In addition, his fish oil supplement was discontinued because it was not helping to lower his cholesterol level. This further reduced his pill burden, which may boost his adherence to his other therapies. To make further improvements on the number of pills L.P. was taking, his current antihypertensive regimen (consisting of a pill burden of three: enalapril twice daily and hydrochlorothiazide [HCTZ] once daily) was changed to lisinopril 20 mg/HCTZ 12.5 mg, which allowed L.P. to take a single combination tablet once daily in the morning. These changes addressed L.P.’s failing ART, dyslipidemia, and hypertension while collectively reducing his overall pill burden. Medication reminders L.P.’s difficulty remembering the indications for his medications and when to take them are likely related to his low health literacy. L.P. agreed to use a regularly updated medication card containing simple descriptions of when, how, and why to take each medication. To address comprehension, the medication card was written at a fifth-grade level and a corresponding example pill was taped on the card next to each medication name. As another visual reminder, L.P. agreed to use a weekly pill reminder box. This approach should help him develop a routine of organizing his medications. L.P. was monitored and assisted when organizing his pill box until he demonstrated comfort doing it himself. www.japha.org

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Financial considerations L.P. has limited insurance and income, increasing concern that changes to his medication may place additional cost-related barriers to adherence. For example, L.P. had difficulty remembering evening doses and his dyslipidemia may have been exacerbated by inadequate adherence to his evening simvastatin regimen. As a result, L.P. may have benefited from a switch to atorvastatin or rosuvastatin because the longer half-lives of these agents allow for a once-daily morning dose. However, both of these medications had an increased cost compared with simvastatin. Therefore, L.P. remained on simvastatin, with the caveat that atorvastatin or rosuvastatin could be revisited at a later time if his dyslipidemia failed to improve. Changing L.P.’s ART to efavirenz/emtricitabine/tenofovir also addresses his dyslipidemia without increasing his out-ofpocket medication expenses. Although this medication is more expensive than either of his current antiretroviral agents, the single pill replaces both his lamivudine/zidovudine and lopinavir/ ritonavir regimens and the overall cost of his ART will remain approximately the same. L.P.’s case is an example in which careful planning by the pharmacist and the patient helps address adherence to a complicated regimen, while still maintaining effectiveness. These issues can be accomplished without increasing outof-pocket medication expenses for a patient with limited income and insurance coverage.

systematically implement interventions, preplanned patient education, and a multifaceted approach to overcoming these barriers to adherence. Many such barriers can be addressed simply, whereas others will be more difficult to overcome. In the long run, however, pharmacists who prioritize open communication with patients and combine efforts with other health care providers will have greater success in encouraging patients to adhere to the recommendations of the health care team.

Scheduled follow-up and a plan for the future Accordingly, discussions with L.P. included a follow-up visit 4 days later to provide him with the completed medication card and to oversee organization of his pill box for the first week. L.P. also agreed to return to the clinic for future medication changes related to dosing, indication, frequency, and route of administration. Since the plan was developed collaboratively, L.P. agreed to the interventions and scheduled follow-up visits. This process allows L.P. to be actively engaged in his health care management, and he is more likely to follow through. As an added measure, the health care providers at these future visits can ensure that the adherence measures are properly implemented and that L.P.’s new medications have sufficiently improved his current state of health.

7. Dimatteo MR. Variations in patients’ adherence to medical recommendations: a quantitative review of 50 years of research. Med Care. 2004;42:200–9.

Conclusion Adherence to medication is a complicated issue that has a considerable impact on the effectiveness and financial burden of the health care system. Although this article provides pharmacists with multiple indicators of poor adherence to a medication regimen, the list is not considered complete. Even the indicators that have been identified require rigorous verification. As exemplified by patients like L.P., the best approach is an open discussion about the issues that are barriers to adequate medication adherence, followed by a multitier intervention that addresses these issues in ways that consider the patient’s medical history, personal habits, health literacy, and financial limitations. Pharmacists, in collaboration with other health care professionals, play an important role in monitoring adherence and identifying potential barriers. The team can then proactively and 404 • JAPhA • 50 : 3 • M ay / J u n 2010

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Schooling Hammerhead Sharks • Galápagos Islands • September 20, 2009 • Kim E. Haney, PharmD, MBA

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