Medication Adherence in Chronic Disease: Issues in Posttransplant Immunosuppression

Medication Adherence in Chronic Disease: Issues in Posttransplant Immunosuppression R. Hansen, R. Seifeldin, and L. Noe ABSTRACT Poor medication adherence is a widespread problem that undermines the potential benefits of medical treatment. Typical adherence rates among chronic disease patients are approximately 50%, and these low adherence rates have a substantial economic impact, estimated at $100 to $300 billion annually. Nonadherence to immunosuppressants among transplant recipients is surprisingly frequent, and the consequences are serious. Among adult renal transplant patients, the median rate of nonadherence is approximately 22% and is associated with acute rejection episodes and approximately 36% of all graft losses. In the United States, nonadherence results in an estimated 903 episodes of acute rejection and 1319 renal transplants failures annually, costing approximately $15 million and $100 million, respectively. Drug regimen complexity is known to impact adherence. Research demonstrates an inverse relationship between dosing frequency and medication adherence in various chronic diseases, with once-daily dosing resulting in the highest adherence rates. Reducing the dosing frequency may positively impact both clinical and patient-reported outcomes, as well as health care costs. However, the increased costs of less frequently administered drugs must be outweighed by the net savings achieved through improved adherence rates and better health outcomes. If trends among patients with chronic diseases apply, once-daily dosing regimens may improve adherence rates by approximately 6% to 14% among renal transplant patients and could substantially reduce the number of acute rejection episodes and graft failures, although the exact economic impact is difficult to estimate. Further research into adherence issues in transplant patients and the potential clinical and economic benefits of once-daily dosing of immunosuppressants is warranted.

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ATIENTS WHO AGREE to take self-administered medications implicitly agree to follow the advice of health care providers and in doing so bear a great responsibility for their own care. Medication adherence generally refers to the degree to which patients take medications as prescribed or, in other words, the extent to which patients’ medication-taking behavior coincides with medical or health advice.1,2 Although the terms “compliance” and “adherence” are synonyms, “adherence” is generally preferred by many health care providers because it is nonjudgmental and implies a therapeutic agreement or collaboration between the patient and provider, rather than a passive following of orders.2 Poor medication adherence is a widespread problem that undermines the potential benefits of medical treatment.3 Rates of adherence vary from 0% among patients who take none of their prescribed medication to ⬎100% among patients who take more than the recommended amount, with typical adherence rates being

approximately 50%.1 Adherence rates tend to be higher among patients being treated for acute conditions not requiring long-term therapy and are frustratingly low among patients with chronic conditions, with adherence rates dropping considerably after six months of therapy.4 – 6 Medication adherence also has a substantial economic impact on the health care system. For example, among patients with chronic diseases, higher rates of adherence are associated with significantly lower hospitalization rates and lower disease-related medical costs.7 In fact, an estimated From the Ovation Research Group (R.H., L.N.), Health Economics, San Francisco, California; and Astellas Pharma US Inc. (R.S.), Health Economics and Outcomes Reasearch, Deerfield, Illinois Address reprint requests to Dr Robert Hansen, PharmD, MS, Ovation Research Group, Health Economics, 188 Embarcadero, Suite 200, San Francisco, CA 94105. E-mail: [email protected]

© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.02.074

Transplantation Proceedings, 39, 1287–1300 (2007)

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HANSEN, SEIFELDIN, AND NOE

Table 1. Possible Causes and Major Predictors of Poor Medication Adherence Possible Causes14

Patient factors Lack of knowledge about the illness, the treatment regimen, and the consequences of nonadherence Lack of motivation and/or inconvenience Lack of self-esteem Beliefs and attitudes concerning the effectiveness of treatment Lack of positive patient-physician relationship Treatment factors Complexity of treatment regimen and extended duration of treatment Comfort or discomfort associated with treatment Impact on patients’ lifestyle Treatment of asymptomatic disease Inadequate follow-up or discharge planning Side effects of medications Cost of medication, copayment, or both Lifestyle factors Environmental limitations, eg, poor housing Resource limitations, eg, lack of transportation Occupational limitations Substance abuse issues Missed appointments Psychosocial factors Presence of psychological problems, eg, depression, anxiety Patient’s perceptions, beliefs, and attitudes about benefit of treatment Presence of cognitive impairment

Major Predictors2

x

x x

x x x x

x x

potential effectiveness of the treatment regimen, and (5) a lack of a positive patient-physician relationship.14 In addition to these patient-related barriers, other factors contribute to nonadherence, such as issues related to the treatment regimens themselves (eg, the complexity, cost, and duration of the treatment15), lifestyle of patients, sociodemographic factors (whether patients can afford their medications), and psychosocial factors (eg, psychiatric problems), which interfere with a patient’s ability to adhere to health care recommendations. Research into the determinants of adherence, however, indicate that, in general, age, sex, race, intelligence, and education have little impact on adherence rates.15 Physicians also contribute to patients’ poor rates of adherence by not addressing these barriers, by prescribing complex regimens when simpler ones are available, by not adequately explaining the benefits and risks of medications, by not considering the patient’s lifestyle or the cost of medications, and by tolerating poor patient-physician relationships.2 Finally, health care systems can negatively impact adherence rates by creating systematic barriers to adherence that include limiting access to health care, using restrictive formularies, and allowing prohibitively expensive medications, high-cost copayments, or both.2 Recognizing and removing as many barriers to adherence as possible will significantly enhance a patient’s ability to follow a medication regimen and maintain consistent medication-taking behavior over time, which, ultimately, should improve health outcomes.

x x

33% to 69% of all medication-related hospital admissions in the United States are related to poor adherence, resulting in costs of $100 billion annually.8 –11 Overall, poor adherence to recommended medication regimens may cost the US health care system as much as $300 billion annually.12 REASONS FOR NONADHERENCE

There are several possible causes of medication nonadherence and several major predictors of poor medication adherence (Table 1). Research has been generally focused on the barriers that patients experience when taking their medications. When asked, typical reasons given by patients for not taking medications as prescribed include forgetfulness (30%), other competing priorities (16%), an active decision to skip doses (11%), lack of information (9%), and emotional factors (7%); an additional 27% of patients do not provide a reason for their nonadherence to the medication regimens prescribed to them.13 Patients contribute to nonadherence through (1) a lack of knowledge about the treatment regimens, (2) a lack of motivation and/or inconvenience to the patient, (3) lack of self-esteem, (4) beliefs and attitudes concerning the

MEASURING ADHERENCE

Methods for measuring medication adherence in patients with chronic disease are numerous but generally fall into two categories: direct methods and indirect methods of measurement (Table 2).2,3,16 Direct monitoring methods include directly observing medication self-administration, assays of drug (or metabolite) concentrations in blood or urine, and the measurement of biologic markers in the blood. While direct methods can be accurate and objective, they can be expensive to perform routinely. In addition, the accuracy of these methods is dependent upon the extent of patients’ nonadherence just prior to the blood or urine samples being taken. The phenomenon called “white-coat adherence” occurs when patients skip numerous doses of a drug and then give a false impression of adherence by taking a few doses before the blood or urine samples are taken in order to present with moderate blood or urine levels of the drug. Despite these issues, however, therapeutic drug monitoring is a useful means of assessing adherence for many drugs. Indirect methods of monitoring medication adherence include patient interviews, caregiver interviews, patient questionnaires or self-report, pill counts, prescription refill rates, the use of electronic monitoring devices, and the measurement of health outcomes. Many of these methods involve simple, objective measures that are generally easy to

MEDICATION ADHERENCE IN CHRONIC DISEASE

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Table 2. Methods of Measuring Adherence2,3 Test

Direct methods Directly observed therapy

Advantages

Disadvantages

●

Most accurate

●

Patients can “cheek” pills and then discard them Impractical for routine use

Measurement of level of drug or metabolite in blood or urine

Objective

Measurement of biologic marker

Objective

●

Requires expensive quantitative assays and collection of samples

Simple, inexpensive

●

Susceptible to error with increased time between visits Results easily distorted by patients Data easily manipulated by patient Does not confirm patients actually took prescribed medications Requires a closed pharmacy system Factors other than adherence can effect response Expensive Requires return visits and data download Assumes patient actually takes medication Marker may be absent for other reason (eg, increased metabolism, poor absorption, lack of response) Easily manipulated by patient Susceptible to distortion

● ● ●

Indirect methods Patient questionnaires, patient self-reports

● ●

Pill counts Prescription refill rates

Objective, quantifiable, and easy to perform Objective, easy to obtain data

Assessment of patient’s clinical response

Simple, generally easy to perform

●

Electronic medication monitors

Precise, quantifiable results, easily tracked

●

● ●

● ●

Measuring physiological markers (eg, blood pressure, heart rate, etc)

Easy to perform

●

Patient diaries Caregiver questionnaire

Help to correct for poor recall Simple, objective

●

administer, yet each has its disadvantages. For example, interviewing methods depend on the patient’s or the caregiver’s cognitive abilities, the honesty of replies, and the interviewer’s correct interpretation of responses.3 Prescription refill records also can be problematic for assessing adherence, because they provide no information on the timing of dosing or the quantity of doses taken at any one time. Finally, electronic monitoring devices, which record when prescription bottles are opened, can be expensive, impractical to use routinely, and do not record whether the patient actually took the correct dose at the time the bottle was opened. Still, electronic monitoring is generally recommended as the best measure of adherence for research studies.17,18 Compared with electronic monitoring, the best measure of adherence, especially for the detection of missed doses and erratic timing of medication administration, is the self-report at confidential interview.19 While this method may elicit important information about the underlying nature of the patient’s nonadherence, it may not be feasible in the clinical setting because of the potentially significant staff time and expense that it requires.

mon themes among interventions aimed at patient education include3,15: ●

●

providing increased education to patients about chronic diseases, the benefits of treatment, and the serious complications associated with nonadherence (including oral and written material and programmed learning) involving patients in their own care (eg, including selfmonitoring of blood pressure, seizures, or respiratory function)

Behavioral strategies are methods by which multidisciplinary health care providers adjust the therapy to the individual patient’s needs in order to improve adherence rates. These methods include3,15: ●

●

INTERVENTIONS FOR IMPROVING ADHERENCE

A variety of different interventions to improve medication adherence, alone and in combination, have been researched. In general, these interventions encompass two broad self-management strategies: (1) patient education strategies and (2) behavior modification strategies.20 Com-

●

Variations in metabolism “White-coat adherence” Expensive

●

increasing communication and counseling (including investigating patient preferences, providing compliance therapy, automated telephone communication, computerassisted patient monitoring and counseling, manual telephone follow-up, and family intervention) improving convenience of care (including providing work-site care, simplifying medication regimens, and reducing the number and frequency of medications) providing reminders (including teaching patients to relate the taking of medications to daily activities, providing special reminder packaging, dispensing unit dose medication, using medication charts, and appointment and prescription refill reminders)

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providing positive reinforcement for improved adherence and treatment response (including motivating patients to adhere to lifestyle changes required by therapy, reducing the frequency of visits for adherent patients, and providing partial payment for medical monitoring equipment)

While each of these methods has been evaluated for its impact on adherence, it is unlikely that they are equally effective in improving adherence rates. In a comprehensive review of the literature, for example, McDonald and colleagues systematically reviewed published, randomized controlled trials of interventions to assist patients’ adherence to prescribed medications in various chronic diseases.15 Of these interventions, 49% were associated with statistically significant increases in medication adherence, while only 17% reported improvements in treatment outcomes that were statistically significant. Nearly all of the interventions that proved to be effective for long-term care were complex. Effective strategies included combinations of more convenient care, patient education, counseling, reminders, selfmonitoring, reinforcement, family therapy, and other forms of additional supervision or attention. However, even the most effective interventions had only modest effects on adherence rates. Furthermore, improvements in adherence rates or clinical outcomes were neither associated with the number of interventions studied in a particular trial nor with the type of intervention that was used (ie, whether the type of intervention was categorized as including behavioral, cognitive, or social components). Nevertheless, many interventions did lead to improved adherence rates and clinical outcomes. The authors concluded that more innovative approaches are needed to assist patients in adhering to the medication regimens prescribed to them. MEDICATION ADHERENCE IN CHRONIC DISEASE Current Adherence Rates In Chronic Diseases

Although the methods for measuring adherence to prescribed medication regimens have varied widely by study, a consistent finding of the research conducted thus far is that adherence rates are low. Overall, medication adherence rates are approximately 50%.1 Published adherence rates for several different chronic diseases are outlined in Table 3. In chronic conditions that often cause no symptoms, like hypertension or hyperlipidemia, patients may lose sight over time of the benefit of treatment; as a result, their adherence may decrease over time. This may explain why up to 50% of patients taking antihypertensive medications discontinue treatment within 1 year and why only 25% of patients on statin therapy maintain good compliance after 5 years of therapy.1,20 In the treatment of HIV/AIDS, it is imperative that adherence to highly active antiretroviral therapy (HAART) be nearly perfect in order to reduce viral loads and avoid the emergence of drug-resistant strains.21 Adherence rates of ⱖ95% to HAART are recommended to maintain viral suppression and prevent resistance.22,23 Achieving such high rates of adherence to what are very complex and

HANSEN, SEIFELDIN, AND NOE Table 3. Adherence Rates in Chronic Diseases

Chronic Disease

Mean Adherence Rate (%)

Range (%)

Respiratory disease

20 57

All Asthma COPD Psychiatry

54 55 51

All Depression Schizophrenia Type 2 diabetes

78 48 53 73

75–83 32–60 24–90 66–85

Epilepsy

60

40–88

HIV/AIDS

73

33–95

Hypertension Hyperlipidemia Congestive heart failure Posttransplant immunosuppression

73 69 66

39–93 23–96 42–90

78 80 84

74–82 NR NR

Renal transplant Heart transplant Liver transplant

Source

37–92 37–92 50–52 20 27 26 57 20 57 20 57 24 64 65 20 66 67 19 40 41 42

NR, not reported.

expensive medication regimens is clearly very difficult, with only 33% of patients taking their medications as prescribed.24 Another group of patients who have unique adherence issues are patients with mental illness. In general, patients who have psychiatric illness have a difficult time adhering to the medications prescribed to them.25 For example, compared to patients with physical disorders who demonstrated a mean rate of medication adherence of 76% (range, 40% to 90%) in a clinical trial, patients with psychoses demonstrated a mean rate of adherence of 58% (range, 24% to 90%).26 In a systematic review of the literature, the rates of irregular medication use among schizophrenic patients were reported to be in the range of 31% to 62%, and dropout rates from clinical trials—a proxy for nonadherence—were 56.5% to 72% for haloperidol, 34.3% to 50% for olanzapine, 25% to 43% for clozapine, and 15.2% to 22.7% for risperidone.27 In general, study completion rates were higher in studies assessing newer drug treatments. Medication adherence is a significant issue among patients with depression. In a large sample of patients with depression, 32% to 42% of patients had not filled their prescription for antidepressant medications 6 to 8 weeks after starting treatment.28 Among primary care patients who were prescribed tricyclic antidepressants, approxi-

MEDICATION ADHERENCE IN CHRONIC DISEASE

mately 40% had discontinued treatment within 3 months of initiating therapy.29 Likewise, in a study of psychiatric patients receiving prophylactic lithium for unipolar or bipolar illness, approximately 43% of patients had discontinued their medication within a 6-month timeframe.30 Finally, among patients who stay on antidepressant treatment, reported rates of adherence are approximately 65% (range, 58% to 90%).26 Compared to older medications, however, newer antidepressant drugs and antipsychotic agents have fewer side effects and as a result their use is associated with lower rates of discontinuation and higher rates of adherence.2 Clinical and Economic Consequences of Nonadherence in Chronic Disease

Nonadherence to medications used to treat chronic diseases has the potential to negatively impact the clinical outcomes of treatment and to substantially increase health care costs. To better understand the clinical and economic consequence of nonadherence, Sokol and colleagues conducted a large retrospective claims analysis of a sample of over 137,000 patients enrolled in a medical and prescription benefits plan.7 The aim of the study was to assess the impact of medication adherence on health care utilization and cost for four chronic conditions that are major contributors to drug spending, including diabetes, hypertension, hypercholesterolemia, and congestive heart failure (CHF). In the study, adherence was defined as the percentage of days during which patients had a supply of one or more maintenance medications for the illness being assessed. Patients were then categorized into one of five categories based on their level of adherence (1% to 19%, 20% to 39%, 40% to 59%, 69% to 79%, 80% to 100%). Results of the analysis showed that for diabetes and hypercholesterolemia, high levels of medication adherence were associated with lower disease-related costs. When compared with the highest level of adherence, these differences were statistically significant for most adherence levels (P ⬍ .05). For these two conditions, higher medication costs were offset by reductions in disease-related health care costs, leading to an overall reduction in total health care costs. For diabetic patients, a 20% increase in drug use due to improved adherence was associated with a cost of $177. The associated disease-related medical cost reduction was $1251, which resulted in a net savings of $1074 per patient or a 7.1:1 return on investment (ROI). The results for patients with diabetes showed that disease-related costs were inversely proportional to medication adherence. This finding is generally consistent with other studies that have reported decreased medical care or total health care costs resulting from improved medication adherence among diabetic patients.31–33 For hypercholesterolemia, health care costs were lowest for patients with 80% to 100% adherence, although there was more variability than for diabetes. The ROI for a 20% increase in drug utilization for hypercholesterolemia patients was 5.1:1, and for hypertension patients it was 4.0:1.

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However, while medical costs for hypertension tended to be lowest at the highest level of adherence, the differences were generally not significant. Differences in medical costs, drug costs, or total costs for CHF were not significant. For all four conditions, patients who demonstrated adherence levels of 80% to 100% were significantly less likely to be hospitalized compared to patients with lower rates of adherence. These differences were statistically significant for most of the adherence levels tested (P ⬍ .05). Thus, for some chronic conditions at least, increased adherence to drug therapy can provide improved clinical outcomes and a net economic benefit. In a separate study, data from an ongoing longitudinal survey of community-dwelling older Americans were used to determine the association between cost-related poor medication adherence and health outcomes.34 The specific chronic conditions evaluated included hypertension (48%), arthritis (27%), cardiovascular disease (20%), diabetes (13%), psychiatric disorders (6%), and lung disease (excluding asthma) (6%). Adherence was assessed by selfreport when patients were asked whether they had taken less medication than was prescribed because of cost. Of the 8704 patients who were using medications for any reason, 7% reported cost-related poor adherence. These patients were significantly more likely than other patients to perceive their overall health as poor, to have been hospitalized in the past 2 years, and to report that their health worsened over the past 2 years, a worsening of hypertension, having uncontrolled hypertension, a worsening of heart disease, and higher depressive symptoms.

MEDICATION ADHERENCE IN POSTTRANSPLANT IMMUNOSUPPRESSION

Health care providers may recognize the barriers to medication adherence in patients with chronic disease, and they may even understand why a patient with an asymptomatic chronic disease, such as hypertension, may not feel compelled to take all of their medications exactly as prescribed. Yet, in the case of patients who are the recipients of solid organ transplants, the survival of which depends on the patient’s adhering to the immunosuppressant regimen, it is incomprehensible to health care providers— or anyone for that matter—that transplant patients would risk losing the organ transplant by being nonadherent to the immunosuppressant medications that they are prescribed. Medication nonadherence among organ transplant recipients is not unusual, however, and has three primary features: (1) it is often covert or hidden from the transplant team; (2) it is aimed against the recommended immunosuppressive regimen; and (3) it has a measurable effect on the outcome for the patient or the graft.35 Because of its frequency and the serious consequences that can result, nonadherence among transplant recipients is a unique problem that warrants further examination.

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HANSEN, SEIFELDIN, AND NOE Table 4. Classification of Nonadherence After Transplantation2,35

Timing

Early

Frequency

Origin

Occasional 1/6 near perfect adherence ● 1/6 nearly all doses, but with timing irregularities ● 1/6 miss an occasional dose Intermittent ● 1/6 take drug holidays 3– 4 times yearly Persistent ● 1/6 take drug holidays monthly or more often Complete ● 1/6 take few or no doses

Diagnostic Certainty

Accidental

Definite

Invulnerable

Probable

Decisive

Possible

●

Late Continuous

Classification of Nonadherence in Transplant Patients

Nonadherence among transplant patients can be classified using four basic characteristics: the timing of the nonadherence behavior, the frequency of nonadherence, its origin, and the certainty with which it can be diagnosed (Table 4).35 The timing of patients’ nonadherence can be early, late, or continuous. Early adherence with immunosuppressants is usually a function of the routine of inpatient posttransplant care. As a result, most patients are compliant with their immunosuppressant medications at this stage, unless education or pharmacy monitoring fails or language barriers compromise patients’ ability to adhere to therapy. Once a patient is discharged from the hospital, however, significant nonadherence can be seen as early as the first month after release. For example, in a 6-month study measuring adherence to azathioprine therapy using electronic prescription bottle monitors, Nevins et al reported that while 56% of the renal transplant patients skipped no doses of azathioprine in the first month after discharge, approximately 19% of patients missed 4 or more days of azathioprine.36 These proportions remained consistent throughout the study period, so that during the sixth month of the study, 57% of patients missed no doses of azathioprine and 18% missed four or more doses. As with other chronic diseases, there is some evidence to suggest that the rates of nonadherence to immunosuppressant therapy increase over time. For example, using pharmacy refill records, Chisholm and colleagues followed adherence rates among a small sample of renal transplant patients (n ⫽ 18) who received free immunosuppressant therapy with either cyclosporine or tacrolimus for 12 months after transplantation.37 In this study, adherent patients were defined as those who had at least 80% of the prescribed number of doses filled by pharmacy. At 5 months posttransplant, approximately 95% of patient remained adherent during each of the months after transplant. At 7 months after transplant, 75% of patients remained compliant each month, and by 12 months after transplant only 48% of the patients continued to be compliant each month since transplant. Among the patients followed in the study, the mean time to the first nonadherent month was 9.8 months (95% confidence interval [CI], 8.6 to 11.0). According to Chapman, the frequency of patients’ non-

Unlikely

adherence can be occasional, intermittent, persistent, or complete.35 This categorization roughly mirrors the six general patterns of medication adherence among patients with chronic illnesses outlined by Osterberg and Blaschke.2 In this case, patients with occasional nonadherence could include the one sixth of patients who have near perfect adherence, the one sixth who take nearly all dosing, but with timing irregularities, and the one sixth who miss an occasional single day’s dose. Patients with intermittent adherence could be seen as the one sixth who takes drug holidays three to four times a year. Patients with persistent nonadherence could be defined as the one sixth of patients who take drug holidays monthly or more often. Finally, patients with complete nonadherence take few or no doses of medication while giving the impression of good adherence. Nonadherence can also be classified by its origin; that is, by the patient-specific variables that affect the individual patient’s likelihood of nonadherence and that can be used to distinguish between nonadherent patients. Greenstein and Siegal surveyed 1402 renal transplant patients who were seen at multiple transplant centers in the United States using self-reporting questionnaires to examine correlates with nonadherence.38 The authors identified three distinct profiles of nonadherent patients: accidental noncompliers (accounting for 47% of nonadherent patients), which included those patients who sometimes simply forgot to take their medications; invulnerable noncompliers (28%), who believed that they did not need to take their medications regularly; and decisive noncompliers (25%), who brought their own independent decision-making habits to their medical regimens. The real value of understanding the source of the nonadherent behavior is that these profiles can be used by clinicians and educators to identify patients who are likely to become nonadherent and to individualize patient education programs to address the beliefs of patients. Finally, nonadherence can be classified according to its diagnostic certainty. Definite nonadherence only comes when the patient directly admits to the nonadherence to the prescribed regimen. The certainty of identifying a patient as nonadherent can also be probable, possible, or unlikely, depending on the means of establishing and/or evaluating

MEDICATION ADHERENCE IN CHRONIC DISEASE

the patient’s nonadherence. The most common methods of identifying nonadherence among transplant patients include therapeutic drug monitoring, pharmaceutical monitoring, and monitoring for allograft rejection. CURRENT ADHERENCE RATES Renal Transplant Recipients

Many studies have found that nonadherence to immunosuppressants in adult renal transplant patients is common, particularly after the first year of transplantation.19 The estimates of the frequency of nonadherence and the degree of impact on graft survival vary widely between studies. Results of individual studies vary depending on the characteristics of the sample of patients included and on how adherence was defined and measured in the study. Butler et al conducted a systematic review of the literature and identified 36 studies that reported the frequency and impact of nonadherence in adult renal transplant patients.19 Standardized definitions of nonadherence, which were used in only 10 of the 36 studies, related to the quantity and frequency of missed medication or delays in medication taking and were assessed by questionnaire, interview, pill counts, pharmacy refill records, therapeutic drug monitoring, and by electronic monitoring (in two studies only). In the studies identified, nonadherence was most commonly defined as missing, forgetting, or altering a dose at least once per month; this level of nonadherence corresponded to missing 3% of doses for a subject on daily dosing. In other studies nonadherence was defined using different thresholds, including missing three doses per month (10% of doses) to a high of six doses per month (20% of doses). Among the cross-sectional studies, which used similar definitions of nonadherence, the median rate of nonadherence was found to be 22.3% of subjects (interquartile range 17.75% to 25.9%). Heart/Liver Transplant Recipients

Even when graft loss can result in the loss of life, as is the case with heart or liver transplants, nonadherence to immunosuppressant medications occurs. Although the research into nonadherence among heart and liver transplant patients is not as extensive as is the research among renal transplant patients, studies have reported significant rates of nonadherence among these patients as well. Shapiro and colleagues, for example, found that about one third (34.4%) of long-term heart transplant patients were nonadherent in at least some areas of their care.39 Dew and colleagues evaluated adherence across eight domains in a cohort of heart transplant patients in the first year posttransplant and found persistent nonadherence to immunosuppressant medication in 20% of patients.40 Dobbels et al reported comparable levels of nonadherence with immunosuppressant medication (16.8%) among heart recipients who were more than 1 year posttransplantation.41 Adherence rates among adult liver transplant patients are even less frequently reported in the literature. However, a nonadher-

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ence rate of 16% has been reported among liver transplant recipients, which was based on therapeutic drug monitoring of immunosuppressant medications.42 IMPACT OF NONADHERENCE ON GRAFT SURVIVAL Renal Transplant Recipients

For nearly 20 years, medication nonadherence has been recognized as a leading cause of renal graft loss, perhaps even the third leading cause of graft failure.43 As a result of this attention, several studies have been conducted that attempted to assess the impact of nonadherence on the survival of renal transplants. Comparison across these studies is difficult because of the various ways adherence was defined, the different adherence measures that were used, and the small sample sizes included in these studies. As part of their systematic review of current compliance rates among renal transplant patients, Butler et al also performed a meta-analysis to estimate the size of the impact of nonadherence on graft failure.19 Analysis of the cohort studies demonstrated that a median (interquartile range) of 36.4% (13.8% to 65.2%) of graft losses are associated with prior nonadherence. A random effects analysis was used to account for the heterogeneity of the studies and showed that the odds of graft failure were increased sevenfold in nonadherent patients compared to adherent patients (random effects combined odds ratio ⫽ 7.1, 95% CI, 4.4% to 11.7%, P ⬍ .001). In a prospective study of the impact of early (first 6 months after transplant) adherence to azathioprine immunosuppression among renal transplant patients, researchers found that over a 4-year follow-up period, patients who had lower adherence rates during the first 6 months were associated in a dose-response fashion with acute graft rejection (P ⫽ .006) and graft loss (P ⫽ .02).36 Moreover, in patients with early declining compliance, defined as those who skipped at least 2 more days of medication during the second month posttransplant compared to their first month, the odds for experiencing later acute rejection was 13.9 times higher than for patients with steady adherence (95% CI, 2.9 to 68, P ⫽ .0011) and the adjusted odds of graft loss were 4.3 times higher (95% CI, 1.1 to 16, P ⫽ .0321). In an evaluation of renal transplants (n ⫽ 1027) carried out at a single site, Michelon et al reported on the 5-year survival of grafts and compared the survival rates among adherent and nonadherent patients.44 Among the patients evaluated, there were 448 graft losses (43.6%), of which 238 were due to rejection (77 acute and 161 chronic). Nonadherence was diagnosed when patients admitted to having discontinued the immunosuppressive medications prescribed to them. A total of 53 patients (5.2%) admitted to being nonadherent to their immunosuppressant medications. Among these nonadherent patients, 47 experienced graft loss (two within 6 months of transplantation) and the remaining six kept their transplants but with compromised renal function (serum creatinine ⬎3.0 mg/dL). A comparison of the graft survival in adherent and nonadherent patients over time is provided in Fig 1. Although no

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Fig 1. Graft survival among adherent and nonadherent renal 44 transplant recipients. (Reprinted with permission from Elsevier Inc.)

statistical analysis was performed on these data, the findings suggest that patients who are nonadherent to their medications have a much higher risk of graft loss compared to patients who are adherent. Even if nonadherent patients do not lose their renal transplants before they reinstate the medication regimen, it is likely that nonadherence contributes to a certain number of acute rejection episodes.45 For example, Morissey and colleagues reviewed the cases of all renal transplant patients seen at their hospital over a 7-year period whose allografts survived more than 30 days after transplantation.46 Of the 443 patients they reviewed, 87 patients (20%) experienced 107 episodes of acute rejection, including 47 (11%) in the first 6 months after transplantation and 40 (9%) after 6 months. In this study, acute rejection events that were ascribed to nonadherence with immunosuppressants (assessed by patient history at time of biopsy to confirm acute rejection) included 4 of the 47 events (9%) in the first 6 months and 21 of the 40 events (53%) after 6 months (P ⬍ .0001). Acute rejection events attributable to nonadherence occurred at a mean of 556 days compared to 242 days for other causes of acute rejection (P ⬍ .002).

Fig 2. Influence of acute rejection episodes on graft survival (censored for patient 46 death with allograft function). AR, acute rejection. (Reprinted with permission from Elsevier Inc.)

HANSEN, SEIFELDIN, AND NOE

In this study, nonadherence did not affect patient survival directly. However, nonadherence was associated with late acute rejection (P ⬍ .0002), and patient survival was lower in the group with acute rejection compared with patients without acute rejection. Twelve patients (14%) died in the group with acute rejection (n ⫽ 87) compared to 23 (6.5%) with no acute rejection (n ⫽ 356). In addition, the number of allografts lost, censored for death with function, was significantly higher after acute rejection (P ⬍ .0001); there were 21 grafts lost (25%) in the acute rejection group compared with 7 (2%) in patients without acute rejection (Fig 2). Current renal function was worse on average in the group experiencing acute rejection. Nadir creatinine levels within 30 days of transplantation were slightly higher (1.4 ⫾ 0.4 mg/dL vs 1.3 ⫾ 0.5 mg/dL, P ⫽ .037) in the rejection group. The mean creatinine continued to rise in this group and was significantly worse at last follow-up (2.1 ⫾ 1.0 mg/dL vs 1.5 ⫾ 0.5 mg/dL, P ⬍ .0001). The authors concluded that nonadherence is a risk factor for acute rejection and that acute rejection is a risk factor for allograft failure. Similar findings are seen in nonadherent patients more than 1 year beyond renal transplantation. Vlaminck and colleagues prospectively followed a convenience sample of 146 renal transplant patients from their hospital for a period of 5 years for late acute rejection, which was defined as acute rejection occurring more than 1 year posttransplant.47 Nonadherence was measured using self-reports and interviews; based on these measures, patients were categorized as nonadherent if they admitted to having skipped immunosuppressant medication on more than three occasions per month or taking drug holidays on a regular basis during the first 12 months after transplantation. The average time since transplantation was 4 years (range 1 to 18 years). Of the 146 patients followed in the study, 33 (22.6%) were identified as nonadherent to their immunosuppressant medications. No differences were found between adherent and nonadherent patients on several factors, including time since transplantation, serum creatinine at 1 year posttrans-

MEDICATION ADHERENCE IN CHRONIC DISEASE

Fig 3. Changes in serum creatinine for adherent versus non47 adherent renal transplant patients. Linear Mixed Models Statistics, P ⬍ .001. (Reprinted with permission from Blackwell Publishing.)

plantation, and the number of acute rejections within the first year posttransplantation. However, nonadherent patients had a significantly higher increase in serum creatinine over time compared to adherent patients (Mixed Models, F:8.84, P ⬍ .001; Fig 3). In addition, Kaplan-Meier survival analysis showed a decreased rejection-free time in nonadherent patients compared with adherent patients (log rank: 4.55; P ⫽ .03; Fig 4). According to the authors, nonadherence seemed to be the most important risk factor for late acute rejection, which is a known risk factor for chronic rejection and consequent graft loss. Heart/Liver Transplant Recipients

Like nonadherent renal transplant patients, nonadherent heart transplant patients tend to experience worse outcomes compared to adherent patients. For example, a convenience sample of 101 heart transplant patients who were at least 1 year posttransplantation were assessed for subclinical noncompliance over 3-month period using electronic monitoring devices.48 During the observation period, medication adherence was high, with a median medication adherence of 99.4%. When further evaluated, however, patients were found to be significantly different in terms of adherence (P ⬍ .0001); patients were categorized as excellent compliers (84% of patients), minor subclinical noncompliers (7%), and moderate subclinical noncompliers (9%). The rates of late acute rejection also were significantly different among these patients (1.19% incidence among excellent compliers, 14.28% among minor subclinical noncompliers, and 22.22% among moderate subclinical noncompliers, P ⫽ .01). The authors concluded that even minor deviations from medication regimens were associated with increased risk of late acute rejection episodes. These same patients were evaluated after a 5-year follow-up period to determine whether their adherence status during the 3-month observation period was predictive of late acute rejections, transplant coronary artery disease, retransplantation, or death.41 The researchers reported that more late acute rejections occurred among nonadherent heart transplant patients in the first year posttransplantation compared to adherent patients (17.6% vs 4.8%, P ⫽ .091) and

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that these patients also experienced a larger number of rejections per patient-year in the same time frame (0.47 vs 0.007, P ⫽ .026). In the 5 years after transplantation, the authors reported that nonadherent patients had significantly more transplant coronary artery disease (P ⫽ .025). In addition, nonadherent patients had a numerically greater risk of experiencing late acute rejection compared to adherent patients (11.8% vs 2.4%, respectively) and retransplantation (13.3% vs 2.5%, respectively), although these differences were not statistically significant. Mortality rates after 5 years were similar in both groups. The authors concluded that nonadherence is a continuous risk factor for negative clinical events after heart transplantation. Economic Impact of Nonadherence in Renal Transplant Recipients

In the United States, a total of 27,014 solid organs were transplanted in 2004, and renal transplants accounted for 15,671 (58%) of these (Table 5).49 Following renal transplants in frequency are liver (21%) and heart (7%) transplants. Short- and medium-term graft survival, and to a lesser extent long-term graft survival, following renal transplantation has improved considerably over the past few years as a result of new immunosuppressive drugs.50 Unadjusted 1-year graft survival after cadaveric renal transplantation was 89% in 2004 and for renal transplants from living donors, it was greater than 95%.49 In other words, 1319 renal transplants failed in the first year after transplantation in 2004. Assuming that 36.4% of these graft failures resulted from patients’ nonadherence to their immunosuppressant medications,19 an estimated 480 renal graft failures were attributable to nonadherence in 2004 alone. First-year charge estimates for a renal transplant (in 2005 US$) are approximately $210,000, which includes charges for organ procurement, hospital, physician fees, evaluation, follow-up care, and outpatient immunosuppressant therapy.51 Thus, for renal transplants alone, the annual cost of first-year graft failures resulting from nonadherence is approximately $100 million. This does not take into account, however, the cost of

Fig 4. Late acute rejection-free time in adherent versus nonad47 herent renal transplant patients. Kaplan-Meier survival analysis, P ⫽ .03. (Reprinted with permission from Blackwell Publishing.)

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HANSEN, SEIFELDIN, AND NOE Table 5. Renal Transplants and Graft Survival in the United States in 2004

Organ Type

Kidney: deceased donor Kidney: living donor Total

No. of Transplants in the United State in 200449

Unadjusted 1-year Graft Survival49

9025 6646

89.0% 95.1%

1-Year Graft Failure, n (%)

Graft Losses Associated with Prior Nonadherence (%)

Graft Losses Associated with Prior Nonadherence (n)

Charge for Organ Transplant ($)51

993 (11.0%) 326 (4.90%)

36.4%19 36.4%19

361 119

210,000 210,000

treating an episode of acute rejection in the renal transplant patient, which was estimated to be $15,000 to $18,000 (in US$, year of costing not given).52 Assuming that 11% of renal transplant patients experience an episode of acute rejection in the first 6 months after transplantation (9% of which result from nonadherence) and another 9% after 6 months posttransplantation (53% of which result from nonadherence),46 out of the 15,671 renal transplants that occurred in 2004, there would be an estimated 903 episodes of acute rejection that are likely attributable to medication nonadherence. In total, these events would require approximately $13.5 to $16.3 million to treat to prevent graft failure. For heart and liver transplant patients, there is insufficient published data to estimate either the cost of treating rejection episodes or the cost of graft failures that can be attributed to nonadherence to immunosuppressants. While estimates of nonadherence rates in these patients are available, there are no published estimates of the percentage of rejection episodes or graft failures that result from nonadherence. As a result, the economic impact of nonadherence in these patients is unknown. IMPACT OF DOSING FREQUENCY ON ADHERENCE RATES

Both clinical experience and research suggest that adherence to medication regimens is poor, and this nonadherence comes at a high price, in terms of both clinical and

Charge for Graft Losses Associated with Nonadherence ($)

75,885,810 24,892,992 100,778,800

economic outcomes. Efforts or interventions to improvement medication adherence for chronic diseases are, for the most part, complex, labor-intensive, and not consistently effective.15 Drug regimen complexity, a modifiable factor affecting medication adherence, has long been thought to impact adherence. For example, the major factor found to be associated with poor adherence in type 2 diabetic patients is the dosing frequency of oral antihyperglycemic drugs.53 Because of the inverse relationship between dosing frequency and medication adherence, the highest adherence rates for oral antihyperglycemic drugs are seen with regimens that incorporate once-daily administration.54 –56 Does this relationship hold true for other chronic diseases as well? Two recent publications (a systematic review57 and a meta-analysis58) have directly linked a simplified dosing regimen (ie, reduced dose frequency) with improved medication adherence in other chronic diseases, in addition to reaffirming this relationship in diabetes. Claxton et al reviewed 76 studies in which adherence to medication regimens for a variety of medical disorders was measured with electronic monitoring devices; data from these studies were pooled to calculate mean adherence with once-daily, twice-daily, three-times-daily, and four-timesdaily dosing regimens.57 The data confirmed an inversely proportional relationship between the frequency of dosing and adherence (Fig 5). While the mean adherence rate was 71% ⫾ 17% for all regimens, it significantly declined as the number of daily doses increased (P ⬍ .001 among dose

Fig 5. Impact of dosing frequency on 2,57 medication adherence rates. Vertical lines represent 1 SD on either side of the mean rate of adherence (horizontal bars). 57 Data are from Claxton et al. (Reprinted with permission. Copyright ©2005 Massachusetts Medical Society. All rights reserved).

MEDICATION ADHERENCE IN CHRONIC DISEASE

schedules). Once-daily dosing was associated with a mean adherence rate of 79% ⫾ 14%, twice-daily dosing led to a mean adherence rate of 69% ⫾ 15%, three-times-daily dosing regimens had a mean adherence rates of 65% ⫾ 16%, and four-times-daily dosing was 51% ⫾ 20%. According to the analysis, adherence was significantly higher for once-daily versus three-times-daily regimens (P ⫽ .008), once-daily versus four-times-daily (P ⬍ .001), and twicedaily versus four-times-daily regimens (P ⫽ .001). Results of the analysis of the pooled data did not conclude that there were significant differences in adherence rates between once-daily and twice-daily regimens or between twice-daily and three-times-daily regimens. Using the Bonferroni correction, which is a statistical adjustment for multiple comparisons where the significance level is divided by the number of comparisons made, differences between once-daily and twice-daily regimens and between twicedaily and three-times daily regimens were significant at the P ⬍ .0083 level. The authors concluded that simpler, less frequent dosing regimens resulted in better compliance across a variety of therapeutic classes. Similar findings also were reported by Iskedjian et al who performed a meta-analysis of eight studies comparing the rates of adherence with once-daily dosing, twice-daily dosing, and multiple-daily dosing antihypertensive drug regimens.58 A total of 11,485 observations were included in the meta-analysis of studies where assessment of adherence rates was the primary objective (1830 for once-daily dosing, 4405 for twice-daily dosing, 4147 for greater than twicedaily dosing, and 9655 for multiple-daily dosing). The average adherence rate for once-daily dosing was significantly higher than for multiple-daily dosing (91.4% ⫾ 2.2% vs 83.2% ⫾ 3.5%, respectively; P ⬍ .001). The average rate for once-daily dosing was also significantly higher than for twice-daily dosing (92.7% ⫾ 4.7% vs 87.1% ⫾ 2.9%, respectively; P ⬍ .026). The difference in adherence rates between twice-daily dosing and greater than twice-daily dosing was not significant (90.8% ⫾ 4.7% vs 86.3% ⫾ 6.7%, respectively; P ⫽ .069). The authors concluded that oncedaily dosing regimens are associated with greater adherence to antihypertensive medications than regimens requiring more frequent administration. Not only does reducing the dosing frequency improve adherence rates among patients taking medications for chronic conditions, but it also may have an important impact on health outcomes and health care costs. Richter et al conducted a comprehensive search of the literature to identify peer-reviewed studies that reported on the impact of a change of dose frequency on chronic disease.59 In this review, the methods used for lowering the dosing frequency identified in the literature included (1) increasing the dose of an existing drug with longer dosing interval, (2) introducing reformulations or novel deliver methods for an existing drug, or (3) substituting the currently prescribed drug with a new one with a lower dose frequency. A total of 27 articles were identified that compared the efficacy of the same medications for various

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chronic diseases at different doses and dose frequencies. Of these studies, 17 (63%) reported either equivalent or better efficacy with less frequent dosing regimens compared to regimens with greater frequency, 8 (30%) reported worse efficacy, and in 2 (7%) studies the impact was unclear. An additional 11 studies compared the efficacy of different formulations/reformulations or novel delivery methods of the same agent at different dose frequencies. In all 11 studies, the efficacy of regimens requiring less frequent administration was equivalent or superior to regimens requiring more frequent administration. Finally, a total of 13 studies were identified that compared the efficacy of different medication regimens with varying (lower) dose frequencies. In all cases, the efficacy of the regimens requiring a lower dose frequency were equivalent or superior to the regimens requiring more frequent administration. Therapeutic areas where reduced dose frequencies were successful included osteoarthritis, diabetes mellitus, angina, depression, Parkinson’s disease, chronic obstructive pulmonary disease (COPD), and pain syndromes. By contrast, study results were mixed in asthma, hypertension, epilepsy, and HIV. In addition to increasing adherence rates, reducing the frequency of dosing also may have a positive impact on patients’ health-related quality of life. Richter et al reviewed the literature to identify studies that reported on the impact of dosing frequency on patients’ quality of life. In the seven studies identified, which included patients with angina, asthma, COPD, Parkinson’s disease, and seizure disorders, reducing the number of doses per day was associated with a maintenance of or improvement in patients’ health-related quality of life. No study reported a negative impact of a reduction in dosing frequency. In addition to these quality of life advantages of less frequent dosing regimens, patients also report preferring once-daily dosing regimens, as long as these regimens remain efficacious and provided adequate symptom control.59 Reducing the frequency of medication administration is also preferred by patients or caregivers whose schedules are negatively impacted by frequent daily dosing, patients who are stigmatized by taking medications in public, and those for whom less frequent dosing provides feelings of less dependent on medications.59 In order for overall costs of care to be reduced, the increased costs of the less frequently administered drugs (eg, extended-release or slow-release formulations) must be outweighed by the net savings achieved within the health care system due to improved adherence rates and better health outcomes. For example, the impact of an immediaterelease and a slow-release formulation of diltiazem for the treatment of hypertension were compared to evaluate the impact of these different formulations on total health care expenditures over a 1-year time frame.60 Although the slowrelease formulation was significantly more expensive than the immediate-release formulation, total health care expenditures significantly decreased over the 1-year period, primarily due to lower physician expenditures and reduced

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hospital and laboratory costs. Another study showed that once-daily flutamide was as efficacious at flutamide three times daily in patients with prostate cancer and resulted in a 30% cost savings.61 Simplifying medication regimens have also been shown to reduce overall costs in severe asthma patients and in patients with Parkinson’s disease.59 DISCUSSION

Research across several chronic diseases demonstrates that nonadherence to prescribed medications is a common and significant problem. Not only does it prevent patients from fully realizing the benefits of medical therapy, it constitutes a significant economic burden to the health care system. For health care providers, an important first step in addressing the issue is to identify the barriers to adherence. Once these barriers are identified, they should be evaluated and prioritized to see which can be modified. For example, a patient’s lack of knowledge about a medication and its possible side effects is a common barrier to adherence and one that can be overcome with patient education.1 Patients’ understanding of the disease and the importance of adhering to the prescribed therapy also can be improved through the use of interdisciplinary teams that provide counseling and education to patients as well as the medical team.62 In this way, multiple barriers to adherence can be addressed simultaneously. A recurring theme among studies evaluating medication adherence and interventions to improve adherence rates is the need for simpler and more convenient drug dosing regimens. Not all regimens can be simplified, but in many cases they can be. Simpler drug regimens consistently result in greater adherence rates than more complex regimens; in most cases, they provide equal, or superior, efficacy; they can result in an improved health-related quality of life, and they are preferred by patients.57–59 Ideally, medications for chronic diseases would be dosed using a once-daily regimen. This seems to be the optimal regimen for type 2 diabetes patients, who appear to be especially sensitive to dosing frequency, because when once-daily medications are prescribed to these patients, adherence rates are maximized. Even among transplant patients, for whom there may be a higher expectation of adherence, nonadherence is a significant issue, because of the risks and consequences of losing a transplant. A rough estimation of the economic impact of graft loss among renal transplant recipients demonstrates that approximately $100 million is attributable to nonadherence annually. Once the cost of treating acute rejection episodes among these patients is included, the true economic cost of noncompliance may approach $116 million annually. Moreover, the financial impact of nonadherence among other organ transplant recipients has yet to be factored in, because of a lack of data needed to estimate the full impact of nonadherence in these patients. Currently, there is very little information in the literature

HANSEN, SEIFELDIN, AND NOE

related to adherence issues in heart and liver transplant patients. Estimates of current adherence rates and how these impact organ function, acute rejection episodes, and graft survival are needed to more fully understand the extent to which this is a problem among these patients. More importantly, research into interventions for improving adherence rates in these patients is necessary, since it is all but missing in the literature. Expanding the research focus to include heart and liver transplant patients would provide a more fully developed understanding of the issues and barriers they face and would allow health care providers and researchers to develop strategies to affect change in these patients. There likely are unique barriers to adherence that are encountered by transplant patients, but like patients with chronic disease, drug regimen complexity and dosing frequency are well-recognized barriers to adherence among transplant patients.63 If trends in other disease states hold true, providing once-daily dosing options to transplant patients could improve compliance rates by approximately 6% to 14%.57,58 This intervention alone could substantially reduce the number of acute rejection episodes, the number of allograft failures, and the economic impact of these events, although the exact extent of its impact is difficult to estimate from the available literature. Further research into adherence issues in transplant patients, and in particular, the potential benefits of once-daily dosing of immunosuppressant medications are warranted. REFERENCES 1. Haynes RB, Yao X, Degani A, et al: Interventions to enhance medication adherence. Cochrane Database Syst Rev 4:CD000011, 2005 2. Osterberg L, Blaschke T: Adherence to medication. N Engl J Med 353:487, 2005 3. Balkrishnan R: The importance of medication adherence in improving chronic-disease related outcomes: what we know and what we need to further know. Med Care 43:517, 2005 4. Cramer J, Rosenheck R, Kirk G, et al: Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes. Value Health 6:566, 2003 5. Haynes RB, McDonald HP, Garg AX: Helping patients follow prescribed treatment: clinical applications. JAMA 288:2880, 2002 6. Jackevicius CA, Mamdani M, Tu JV: Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 288:462, 2002 7. Sokol MC, McGuigan KA, Verbrugge RR, et al: Impact of medication adherence on hospitalization risk and healthcare cost. Med Care 43:521, 2005 8. Berg JS, Dischler J, Wagner DJ, et al: Medication compliance: a healthcare problem. Ann Pharmacother 27(9 suppl):S1, 1993 9. Levy G, Zamacona MK, Jusko WJ: Developing compliance instructions for drug labeling. Clin Pharmacol Ther 68:586, 2000 10. McDonnell PJ, Jacobs MR: Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother 36: 1331, 2002 11. Senst BL, Achusim LE, Genest RP, et al: Practical approach to determining costs and frequency of adverse drug events in a health care network. Am J Health Syst Pharm 58:1126, 2001

MEDICATION ADHERENCE IN CHRONIC DISEASE 12. Bender BG, Rand C: Medication non-adherence and asthma treatment cost. Curr Opin Allergy Clin Immunol 4:191, 2004 13. Cramer J: Identifying and improving compliance patterns. In Cramer J, Spilker B (eds): Patient Compliance in Medical Practice and Clinical Trials. New York: Raven Press; 387, 1991 14. Rosner F: Patient noncompliance: causes and solutions. Mt Sinai J Med Mar 73:553, 2006 15. McDonald HP, Garg AX, Haynes RB: Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA 288:2868, 2002 16. Loghman-Adham M: Medication noncompliance in patients with chronic disease: issues in dialysis and renal transplantation. Am J Manag Care 9:155, 2003 17. De Geest S, Vanhaecke J: Methodological issues in transplant compliance research. Transplant Proc 31:81S, 1999 18. Spilker B: Methods of assessing and improving compliance in clinical trials. In Cramer JA, Spilker B (eds): Patient Compliance in Medical Practice and Clinical Trials. New York: Raven Press; 37, 1991 19. Butler JA, Peveler RC, Roderick P, et al: Measuring compliance with drug regimens after renal transplantation: comparison of self-report and clinician rating with electronic monitoring. Transplantation 77:786, 2004 20. World Health Organization: Adherence to long-term therapies: evidence for action. Available at: http://www.int/ chronic_conditions/en/adherence_report.pdf.2003. Accessed August 10, 2006 21. Garcia de Olalla P, Knobel H, Carmona A, et al: Impact of adherence and highly active antiretroviral therapy on survival in HIV-infected patients. J Acquir Immune Defic Syndr 30:105, 2002 22. Chesney M: Adherence to HAART regimens. AIDS Patient Care STDS 17:169, 2003 23. Ickovics JR, Cameron A, Zackin R, et al: Consequences and determinants of adherence to antiretroviral medication: results from Adult AIDS Clinical Trials Group protocol 370. Antivir Ther 7:185, 2002 24. Bedell SE, Jabbour S, Goldberg R, et al: Discrepancies in the use of medications: their extent and predictors in an outpatient practice. Arch Intern Med 160:2129, 2000 25. Nose M, Barbui C, Gray R, et al: Clinical interventions for treatment non-adherence in psychosis: meta-analysis. Br J Psychiatry 183:197, 2003 26. Cramer JA, Rosenheck R: Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 49:196, 1998 27. Thieda P, Beard S, Richter A, et al: An economic review of compliance with medication therapy in the treatment of schizophrenia. Psychiatr Serv 54:508, 2003 28. Lin EH, Katon WJ, Simon GE, et al: Low-intensity treatment of depression in primary care: is it problematic? Gen Hosp Psychiatry 22:78, 2000 29. Peveler R, George C, Kinmonth AL, et al: Effect of antidepressant drug counselling and information leaflets on adherence to drug treatment in primary care: randomised controlled trial. BMJ 319:612, 1999 30. Schumann C, Lenz G, Berghofer A, et al: Non-adherence with long-term prophylaxis: a 6-year naturalistic follow-up study of affectively ill patients. Psychiatry Res 89:247, 1999 31. Balkrishnan R, Rajagopalan R, Camacho FT, et al: Predictors of medication adherence and associated health care costs in an older population with type 2 diabetes mellitus: a longitudinal cohort study. Clin Ther 25:2958, 2003 32. Balkrishnan R, Rajagopalan R, Shenolikar RA, et al: Healthcare costs and prescription adherence with introduction of thiazolidinedione therapy in Medicaid type 2 diabetic patients: a retrospective data analysis. Curr Med Res Opin 20:1633, 2004 33. Hepke KL, Martus MT, Share DA: Costs and utilization associated with pharmaceutical adherence in a diabetic population. Am J Manag Care 10:144, 2004

1299 34. Mojtabai R, Olfson M: Medication costs, adherence, and health outcomes among Medicare beneficiaries. Health Aff (Millwood) 22:220, 2003 35. Chapman JR: Compliance: the patient, the doctor, and the medication? Transplantation 77:782, 2004 36. Nevins TE, Kruse L, Skeans MA, et al: The natural history of azathioprine compliance after renal transplantation. Kidney Int 60:1565, 2001 37. Chisholm MA, Vollenweider LJ, Mulloy LL, et al: Renal transplant patient compliance with free immunosuppressive medications. Transplantation 70:1240, 2000 38. Greenstein S, Siegal B: Evaluation of a multivariate model predicting noncompliance with medication regimens among renal transplant patients. Transplantation 69:2226, 2000 39. Shapiro PA, Williams D, Gelman I, et al: Compliance complications in cardiac patients. Am J Psychiatry 154:1627, 1997 40. Dew MA, Roth LH, Thompson ME, et al: Medical compliance and its predictors in the first year after heart transplantation. J Heart Lung Transplant 15:631, 1996 41. Dobbels F, De Geest S, van Cleemput J, et al: Effect of late medication non-compliance on outcome after heart transplantation: a 5-year follow-up. J Heart Lung Transplant 23:1245, 2004 42. Berlakovich GA, Langer F, Freundorfer E, et al: General compliance after liver transplantation for alcoholic cirrhosis. Transpl Int 13:129, 2000 43. Didlake RH, Dreyfus K, Kerman RH, et al: Patient noncompliance: a major cause of late graft failure in cyclosporine-treated renal transplants. Transplant Proc 20(3 suppl 3):63, 1988 44. Michelon TF, Piovesan F, Pozza R, et al: Noncompliance as a cause of renal graft loss. Transplant Proc Nov 34:2768, 2002 45. Hilbrands LB, Hoitsma AJ, Koene RA: Medication compliance after renal transplantation. Transplantation 60:914, 1995 46. Morrissey PE, Reinert S, Yango A, et al: Factors contributing to acute rejection in renal transplantation: the role of noncompliance. Transplant Proc 37:2044, 2005 47. Vlaminck H, Maes B, Evers G, et al: Prospective study on late consequences of subclinical non-compliance with immunosuppressive therapy in renal transplant patients. Am J Transplant 4:1509, 2004 48. De Geest S, Abraham I, Moons P, et al: Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients. J Heart Lung Transplant 17:854, 1998 49. 2005 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994 –2003: Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI 50. Hariharan S: Long-term kidney transplant survival. Am J Kidney Dis 38(6 suppl 6):S44, 2001 51. Milliman Research Report: 2005 US Organ and Tissue Transplant: Cost Estimates and Discussion. Available at http:// www.milliman.com/pubs/healthcare/content/research_report/USOrgan-Tissue-Transplant-2005-RR.pdf. Accessed August 14, 2006 52. Young M, Plosker GL: Mycophenolate mofetil: a pharmacoeconomic review of its use in solid organ transplantation. Pharmacoeconomics 20:675, 2002 53. Guillausseau PJ: Impact of compliance with oral antihyperglycemic agents on health outcomes in type 2 diabetes mellitus: a focus on frequency of administration. Treat Endocrinol 4:167, 2005 54. Eisen SA, Miller DK, Woodward RS, et al: The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 150:1881, 1990 55. Guillausseau PJ: Influence of oral antidiabetic drugs compliance on metabolic control in type 2 diabetes. A survey in general practice. Diabetes Metab 29:79, 2003

1300 56. Lau DT, Nau DP: Oral antihyperglycemic medication nonadherence and subsequent hospitalization among individuals with type 2 diabetes. Diabetes Care 27:2149, 2004 57. Claxton AJ, Cramer J, Pierce C: A systematic review of the associations between dose regimens and medication compliance. Clin Ther 23:1296, 2001 58. Iskedjian M, Einarson TR, MacKeigan LD, et al: Relationship between daily dose frequency and adherence to antihypertensive pharmacotherapy: evidence from a meta-analysis. Clin Ther 24:302, 2002 59. Richter A, Anton SE, Koch P, et al: The impact of reducing dose frequency on health outcomes. Clin Ther 25:2307, 2003 (discussion 2306) 60. Skaer TL, Sclar DA, Robison LM, et al: Effect of pharmaceutical formulation for diltiazem on health care expenditures for hypertension. Clin Ther 15:905, 1993 61. Thrasher JB, Deeths J, Bennett C, et al: Comparative study of the clinical efficacy of two dosing regimens of flutamide. Mol Urol 4:259, 2000 (discussion 265)

HANSEN, SEIFELDIN, AND NOE 62. Chisholm MA, Mulloy LL, Jagadeesan M, et al: Impact of clinical pharmacy services on renal transplant patients’ compliance with immunosuppressive medications. Clin Transplant 15:330, 2001 63. Chisholm MA: Identification of medication-adherence barriers and strategies to increase adherence in recipients of renal transplants. Manag Care Interface 17:44, 2004 64. Sethi AK: Adherence and HIV drug resistance. HIV Clin Trials 5:112, 2004 65. Legorreta A, Yu A, Chernicoff H, et al: Adherence to combined Lamivudine ⫹ Zidovudine versus individual components: a community-based retrospective medicaid claims analysis. AIDS Care 17:938, 2005 66. Schedlbauer A, Schroeder K, Peters TJ, et al: Interventions to improve adherence to lipid lowering medication. Cochrane Database Syst Rev 4:CD004371, 2004 67. Hope CJ, Wu J, Tu W, et al: Association of medication adherence, knowledge, and skills with emergency department visits by adults 50 years or older with congestive heart failure. Am J Health Syst Pharm 61:2043, 2004