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CLINICAL

Medication Noncompliance in Patients


With Chronic Disease: Issues in Dialysis and
Renal Transplantation
Mahmoud Loghman-Adham, MD

For many chronic conditions, poor patient compliance with


prescribed medications and other aspects of medical treatment
can adversely affect the treatment outcome. Compliance with
long-term treatment for chronic asymptomatic conditions such
as hypertension is on the order of 50%. Although drugs with a
longer therapeutic half-life may ease the burden of repeated
daily dosing, the efficacy of any self-administered medication
depends to a large extent on patient compliance. This article
addresses the compliance issues in patients undergoing renal
replacement therapy and in those with a successful renal transplant. A focused discussion of compliance in dialysis and renal
transplant patients is followed by a general review of the literature on patient compliance. Many factors associated with
poor compliance in this patient population are identified via a
review of the recent literature. The difficulties in monitoring
medication compliance and the methods used are discussed.
Among factors associated with poor compliance, the following
have been identified in several studies: frequent dosing,
patients perception of treatment benefits, poor patient-physician communication, lack of motivation, poor socioeconomic
background, lack of family and social support, and younger
age. Many strategies have been suggested to improve medication compliance, most without scientific validation. Strategies
to improve compliance in dialysis and transplant patients are
similar to those described for other chronic conditions and
include simplifying the treatment regimen, establishing a partnership with the patient, and increasing awareness through
education and feedback.
(Am J Manag Care 2003;9:155-171)

ecent advances in molecular biology and


genetics have accelerated the rate at which
new and more effective drugs are introduced
to treat conditions that were once considered
untreatable. The study of human behavior in
relation to taking medications or following medical advice has not kept pace with scientific
breakthroughs. Although it is possible to precisely

VOL. 9, NO. 2

target a cancer cell or replace a missing hormone,


little can be done to ensure that medications are
taken as prescribed. The same is true for dietary and
lifestyle changes. As medicines become more effective, access to healthcare and patient noncompliance will become the leading causes of treatment
failure. Compliance issues must receive more attention and become the subject of innovative studies in
the hopes of reducing or eliminating a major impediment to achieving a healthier population.
Compliance is described as patient behavior in
response to requirements or exigencies of the
healthcare provider. Haynes et al1,2 define patient
compliance as the extent to which a persons
behavior, in terms of taking medications, following
diets, or executing lifestyle changes, coincides with
medical or health advice. Although the term compliance is now well accepted in the medical literature, it implies obedience to physician orders and
reflects a paternalistic attitude. Adherence may
be a better term, but it remains judgmental.
Concordance, introduced in 1997 by the Royal
Pharmaceutical Society of Great Britain, is intended
to remove the implications of patient obedience or
submissiveness to physicians orders.3 Despite its
eloquence, this term has not been widely adopted.
Throughout this review, I use the more familiar
terms, compliance and adherence.
Total noncompliance may be the result of poor
communication between the physician and the

From Hoffmann-La Roche, Inc. Nutley, NJ. At the time of writing, the author was with the Pediatric Research Institute, Saint Louis
University School of Medicine, St Louis, Mo.
The author has indicated no financial support for this manuscript.
Address correspondence to: Mahmoud Loghman-Adham,
MD, 26 Huntington Rd, Basking Ridge, NJ 07920. E-mail:
mloghman@att.net.

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patient or lack of trust or conviction on the part of
the patient.4 It leads to complete treatment failure,
with only urgent and sporadic treatments during
medical emergencies.5 Partial compliance is a more
common and more insidious problem and is the subject of this review. The criteria used to measure
treatment noncompliance are often arbitrary and
are not always linked to defined clinical outcomes.
The consumption of at least 80% of prescribed doses
has been used as an acceptable level of compliance
in chronic conditions such as HIV.6 Owing to lack of
uniform definitions, widely divergent results have
been obtained in different studies. The diversity of
criteria used to define noncompliance prevents systematic assessment of the impact of specific interventions aimed at improving compliance.7 The focus
of this review is on compliance issues in patients
with chronic renal failure who are receiving dialysis
and in those who have received a kidney transplant.

CONSEQUENCES OF POOR COMPLIANCE


Poor compliance has been reported as the most
common cause of failure to respond to medications and poor treatment outcomes.8,9 In clinical
trials, undetected partial noncompliance can
negate a therapeutic difference between treatments, leading to false conclusions about the
efficacy of a potentially useful drug.10-12 Poor compliance often leads to additional and often unnecessary tests, dosage adjustments, changes in the
treatment plan, emergency department visits, or
hospitalization, 13 which ultimately results in
increased cost of medical care.

MAGNITUDE OF THE PROBLEM:


ECONOMIC IMPLICATIONS
According to the US Renal Data Systems, 340,261
patients were receiving treatment for end-stage
renal disease (ESRD) and 88 091 new patients started ESRD treatment in 1999.14 In 1999, total
Medicare and non-Medicare expenditures for ESRD
were $17.9 billion.14 Based on these data, in 1999,
the average number of hospital days for ESRD
patients was 214 per 100 patient-years.15 Assuming
that a quarter of the hospitalizations are a direct
consequence of noncompliance with treatment
plans and an average hospitalization cost of $1300
per patient per day,16 $237 million are spent each
year for hospital care of ESRD patients owing to non-

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compliance. The economic implications of noncompliance in renal transplant patients are even more
compelling. Data compiled by the United Network
for Organ Sharing show that 12 381, 12 575, and
13 490 kidney transplants were performed in the
United States in 1998, 1999, and 2000, respectively.17,18 In adult renal transplant patients, more than
a quarter of graft losses beyond the second posttransplantation year are due to noncompliance.19
Assuming that a third of the patients who lose a kidney transplant will undergo retransplantation and an
average cost of $60 000 per transplant,20 it will cost
$573 million to offer second transplants to the 9558
noncompliant patients who will be added to the
50 123 patients currently awaiting a kidney transplant.17 This is a conservative estimate based on
transplantations performed during 3 consecutive
years. If one considers the total number of patients
with a functioning kidney transplant, the cost could
be doubled. This calculation also does not account
for costs associated with the treatment of rejection
episodes, which often require a renal biopsy and initial hospitalization.
The total cost associated with treatment of complications resulting from poor compliance in dialysis
and transplant patients exceeds $950 million. Thus,
efforts should be directed at reducing noncompliance in ESRD patients.

COMPLIANCE ISSUES IN PATIENTS


RECEIVING CHRONIC DIALYSIS
General

Dialysis is a lifesaving procedure, but at best it


replaces only about 10% of normal renal function.
As a result of incomplete replacement of kidney
function, patients undergoing chronic dialysis continue to have many health problems, including salt
and water retention, phosphate retention, secondary hyperparathyroidism, hypertension, chronic
anemia, hyperlipidemia, and heart disease. More
than a third of dialysis patients are diabetic, which
leads to additional complications, such as diabetic
retinopathy. To address all these medical problems,
most patients require fluid restriction, multiple
dietary restrictions, phosphate binders, vitamin D
preparations, antihypertensive medications, hypoglycemic agents, erythropoietin (EPO), iron supplements, and a variety of other medications. The
average dialysis patient takes 6 to 10 medicines a
day.21,22 Phosphate binders are particularly trouble-

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Medication, Chronic Disease, and Renal Issues


some because they taste bad and must be taken in
large quantities with each meal. In addition, both
hemodialysis and peritoneal dialysis patients must
spend a significant amount of time undergoing a
life-saving dialytic treatment either at a center or at
home. These complex therapeutic regimens place a
significant burden on the patient and create a
dependence on healthcare providers for many
aspects of treatment.
Definition, Incidence

Noncompliance is common in patients undergoing chronic hemodialysis.21,23,24 Depending on the


definition used, as many as 86% of dialysis patients
may be considered noncompliant with 1 or more
aspects of their treatment,25-28 but the median is
closer to 50%. Furthermore, different patients can be
noncompliant with different aspects of their treatment, which comprises not only adherence to medications but also adherence to dietary and fluid
restrictions.27 In addition to adherence to prescribed
medications and regular attendance at hemodialysis
sessions, most researchers define noncompliance in
the dialysis patient as an interdialytic weight gain
(IWG) >1.5 kg, a serum phosphorus level >6 mg/dL,
and a predialysis serum potassium level >5.5 mEq/L.
Changes in serum potassium or phosphorus concentrations are the result of factors such as dietary
intake, dialysis adequacy, sampling technique,
hemolysis (for potassium), and compliance with
phosphate binders.
Prediction of Noncompliance

Factors associated with noncompliance in dialysis


patients are similar to those for other chronic conditions. Although there is fairly good correlation
among biological measures of compliance (serum
potassium, serum phosphorus, and IWG), there is
generally no relationship between biological and
clinical measures of compliance.29 In this regard, a
compliance rating scale developed by Mai et al29 did
not correlate with selected biological measures of
compliance. There is also no correlation between
dietary compliance and compliance with fluids and
mediations,30,31 which precludes identification of
patients who are likely to be noncompliant with a
particular aspect of treatment. Of particular concern
is whether noncompliance during dialysis treatment
is a reliable predictor of noncompliance after kidney
transplantation. When evaluating patient populations as a whole, a positive correlation is found
between medication noncompliance before and
after kidney transplantation.32 Whether this conclu-

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sion can be extended to individual patients cannot


be supported by available information and requires
further study.
Demographic Factors, Patient Profiles

In adult hemodialysis patients, factors that


can influence compliance with diet, medication,
and fluid intake include age, race, sex, marital
status, socioeconomic status, and educational
level.23,25,31,33,34 In a study of medication compliance
in 135 hemodialysis patients, Curtin et al21 found
only race or ethnicity to be associated with noncompliance with antihypertensives and phosphate
binders, with particularly low compliance rates for
blacks. In patients undergoing peritoneal dialysis,
compliance is not influenced by age, race, or sex.35,36
Some researchers25 have advocated use of demographic profiles (eg, age, race, and socioeconomic status) to identify subgroups of dialysis patients likely to
be noncompliant with 1 or more aspects of treatment.
In a large multicenter study25 of 1230 hemodialysis
patients, only 2 demographic factorsyoung age
(P < .003) and being a widow (P < .03)correlated
with medication noncompliance, as assessed by
measurements of serum phosphorus concentration.
However, there were positive correlations between
age (P = .001), male sex (P < .005), or black race
(P < .036) and noncompliance with fluid restriction,
as assessed by IWG.25 Another study27 also showed
higher rates of noncompliance in men.
Few studies of treatment compliance have been
conducted in children receiving dialysis. In a study33
of children and adolescents, low adherence with
dialysis treatment (assessed by self-report, IWG,
blood pressure, and serum potassium and blood
urea levels) correlated with poor adjustment to dialysis (P < .05), anxiety and depression (P < .001),
adolescence (P < .001), low socioeconomic status (P
< .05), and poor family structure (P < .01). These
findings are similar to those reported in studies of
adult dialysis patients.
Relationship of Noncompliance to Outcome

Several studies23,24,37 have shown that noncompliance with hemodialysis treatment, as assessed by
the number of missed dialysis sessions, IWG (>5.7%
of body weight), and hyperphosphatemia (serum
phosphorus >7.5 mg/dL), is associated with
increased mortality. According to a recent study38 of
hemodialysis patients, the mortality risk increases
when the serum phosphorus level chronically
exceeds 6.5 mg/dL. The reasons for these observations are not clear but may be related to increased

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soft tissue and vascular calcification due to
increased calcium x phosphorus product.38 Based on
these findings, it was recently recommended that
serum phosphorus levels be maintained below 5.5
mg/dL.39 Using this value to define compliance, more
than 60% of dialysis patients would be considered
noncompliant with phosphate binders, dietary phosphorus restrictions, or both.27,39
Anemia in ESRD is associated with increased
morbidity and mortality.40,41 Therefore, maintaining
hemoglobin or hematocrit levels within a specified
range has been recommended and practiced by all
dialysis centers.42 Erythropoietin is an important
medication in the treatment of anemia in ESRD
patients. In hemodialysis patients, dialysis nurses
and technicians are responsible for administering
intravenous EPO, and noncompliance is not an
issue. Subcutaneous EPO has been advocated in predialysis and peritoneal dialysis patients.40 In most
instances, patients are instructed to administer their
own doses. Nicoletta et al43 studied compliance
(defined as receiving >90% of prescribed doses) with
subcutaneous EPO injections in 55 peritoneal dialysis patients; 55% of the patients were noncompliant
with EPO treatment. In addition, noncompliant
patients had lower hematocrits vs compliant
patients (31.5% vs 34%; P < .003).
Geographical Variations

In one study,44 missed dialysis treatments were


virtually nonexistent in Japan and Sweden, whereas
2.3% of dialysis treatments were missed by patients in
the United States. Although many factors may contribute to these differences, the authors suggested
that emphasis on patient independence in the United
States may have led to physicians being unable to
influence poor decision-making by patients.44,45
Dialysis Modality

Compared with hemodialysis patients, compliance is lower in patients undergoing home peritoneal dialysis. In one study,35 a third of the patients
undergoing continuous ambulatory or continuous
cycling peritoneal dialysis were noncompliant, as
assessed by a supplies inventory of their homes. In
peritoneal dialysis patients, the incidence of peritonitis and the number of days hospitalized were
higher in noncompliant patients vs compliant
patients. The recent development of an electronic
memory card for cycler machines46 should provide
feedback on compliance with dialysis prescription
and help institute corrective measures to improve
compliance with dialysis prescription.

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COMPLIANCE ISSUES IN PATIENTS


WITH A KIDNEY TRANSPLANT
General

Although no longer dependent on dialysis to survive, renal transplant patients continue to have a
multitude of medical problems and require numerous medications, including prednisone, immunosuppressive drugs, antihypertensives, prophylactic
antibiotics, and antiviral agents. Because of the
importance of immunosuppressive medications in
the prevention of acute transplant rejections, most
studies of medication compliance in transplant
patients have addressed this class of medications.
The availability of methods for testing drug levels for
many immunosuppressive agents also provides an
objective measure of noncompliance. Most studies of
medication compliance in kidney transplant recipients have been conducted by questionnaire or have
relied on pill counts. Because patients generally
underestimate medication noncompliance by this
method,47,48 the incidence of noncompliance in renal
transplant recipients is likely much higher than generally appreciated.
Definition, Incidence

In renal transplant patients, noncompliance with


immunosuppressive drugs ranges from 2% to
26%.49-53 A survey of 56 US transplantation centers
found a noncompliance incidence of 22.4% in 1402
respondents.54 Noncompliance is the second most
common cause of late graft failure in renal transplantation,19,49,50,55 accounting for more than a quarter of graft losses 2 years after surgery.19,56,57 In
transplantation, stringent criteria are used to define
noncompliance. In support of such strict definitions
are studies that show increased incidence of acute
rejections even after minor medication noncompliance.54 Noncompliant patients are more likely than
compliant patients to lose their graft or to die.58,59
Much less information is available about compliance
issues in children and adolescents after successful
renal transplantation.55,60-63 The incidence of noncompliance with medications is close to 22%,60
which is identical to that reported for adults.
Although medication noncompliance is negligible
in the initial months after kidney transplantation,
late noncompliance remains a major problem, with
potentially severe consequences. A direct relationship is seen between the length of time since kidney
transplantation and the incidence of noncompliance.64-66 Late acute rejections are much higher in
noncompliant vs compliant transplant patients.50,56

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Medication, Chronic Disease, and Renal Issues


As reported for a variety of other conditions, medication noncompliance in kidney transplant
patients increases with the number of medications
prescribed.53
Demographics, Age, Race, Income

ance rate was only 5% at 5 months posttransplantation, it increased to 52% by the twelfth posttransplantation month. This study confirms the finding of
other studies that medication compliance wanes
with increased duration of treatment. It also suggests
that access to medications is not a major determinant of compliance. However, the number of
patients enrolled in this study was small (n = 18),
and the study may have been skewed toward noncompliant patients. Access to a clinic or hospital
does not seem to affect compliance because no relationship was found between distance traveled to the
dialysis unit and compliance in a pediatric kidney
transplant population.60

Most studies52,56 show higher noncompliance rates


in female transplant recipients, 2 studies found the
opposite,53,60 and another study54 did not find any
relationship between sex and compliance. Visible
adverse effects of corticosteroids and cyclosporine,
such as facial swelling and hirsutism, are more problematic in female patients, particularly in adolescents, and may predispose to noncompliance.
Studies of the effect of age on compliance in renal
transplant patients reached similar conclusions.
Geographical Variations
A study52 conducted in the Netherlands showed
Older patients are more compliant than younger
compliance with immunosuppressive medications
patients, with compliance rates being particularly
approaching 100%. The reasons for such high comlow in adolescents.49,54,67-69 DeGeest et al51 showed
that social network has an influence on medication
pliance are not clear. Differences between European
compliance in renal transplant patients, with more
and American patient demographics and in the
noncompliance observed in single vs married indihealthcare delivery system are unlikely to be major
viduals.51 Some studies show higher compliance
factors in better compliance in this population.
rates in professionals vs unskilled workers,70,71 and
Another study51 of 150 transplant patients conductothers show no difference in compliance based on
ed in Belgium, which has similar population demoeducation level and socioeconomic status.64
In one study,72 low income level was associated with reduced renal allograft survival;
Figure. Factors That May Influence Patient Medication
however, it did not affect medication compliCompliance
49,55,58,60,67,73
ance. In several studies
of medication compliance in organ transplant
Health beliefs,
motivation
recipients, compliance rates were lower in
Depression
Dosage frequency
blacks or Hispanics but generally correlated
more with socioeconomic status than with
Forgetfulness
Side effects
race.
Medication
taking cues

Knowledge of Treatment

In a study63 of 19 adolescent renal transplant recipients, poor medication knowledge


was associated with noncompliance with
cyclosporine treatment. In another study,51
improved knowledge about medications did
not lead to better compliance. Yet another
study74 showed that better knowledge of the
disease is associated with better compliance.
More studies are needed to better define the
role of patient education in improving compliance.
Availability and Access to Treatment
75

In a study conducted by Chisholm et al,


patients were provided free immunosuppressive medications. Although the noncompli-

VOL. 9, NO. 2

Visual reminders,
pill boxes

Drug-level
monitoring

Patient
Compliance

Age, sex

Feedback
Cost, payment,
insurance
Socioeconomic
situation

Transportation
Education
level

Race,
ethnicity

The physician (nephrologist) can influence and modify a number of factors,


for example, by reducing the dosage frequency, selecting drugs with fewer
adverse effects, providing feedback and encouragement along with incentives
during office visits, and helping the patient develop medication-taking cues to
reduce forgetfulness.

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graphics, showed 22.3% noncompliance with
immunosuppressive medications. There were more
acute rejections and lower 5-year graft survival in
noncompliant vs compliant patients.51
Psychological Factors, Depression

Depression and lack of perceived benefit from


treatment are major factors in medication noncompliance in renal transplant recipients.54,68,69 Stress
and depression may lead to avoidance coping strategies and may result in poor compliance with medications.69 Patient attitudes and beliefs correlate well
with noncompliance and can be used to predict
future noncompliance.76 For example, noncompliance is higher among patients who believe that the
locus of control rests with powerful others.5,68
A positive correlation is found between medication noncompliance before and after successful kidney transplantation.32,44,50 Identification of subsets of
patients more likely to be noncompliant, along with
careful psychosocial evaluation and implementation
of methods to improve compliance, should be an
important goal of any organ transplantation program. Many programs, particularly those dealing
with organs in short supply (liver, heart, and lung)
would not offer an organ to those with a history of
noncompliance owing to chronic substance abuse,
psychiatric disorders, or chronic depression.77 In
kidney transplantation, fewer exclusionary criteria
are imposed because living-related donor transplants are available. The Figure depicts some of the
factors that may influence medication compliance.

METHODS TO MONITOR
MEDICATION COMPLIANCE
Traditional Methods

Direct monitoring methods include assays of drug


concentrations in biological fluids, use of markers
incorporated into pills, and direct observation of pill
taking; indirect methods include patient self-reports
through interviews or by questionnaire, compliance
ratings by nurses, pill counts, and use of microelectronic devices.78 The validity of 3 measures of complianceblood chemistries, ratings by health
professionals, and patient self-reportswas low to
marginal in a study by Cummings et al.79
With the introduction of microelectronic monitoring devices, it has become evident that counts of
returned tablets and patient diaries overestimate
medication consumption.21,47,48,80-84 Furthermore, pill
counts provide no information regarding patterns of

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noncompliance.80 Dumping the unused pills or


emptying inhaler canisters before the scheduled
clinic visit can give the false impression that the
doses were used as prescribed.84,85 Measurement of
drug concentrations may provide limited insight into
compliance but is relatively expensive and often
misleading.86 The information obtained pertains to
the most recent doses rather than to the entire period between measurements.85,86 Often, there is no
precise relationship between pharmacological halflife and therapeutic effectiveness.87 Improved compliance immediately before a clinic visit can mask
potential ongoing noncompliance.5,83 Despite these
shortcomings, transplantation nephrologists rely
heavily on immunosuppressive drug levels to maintain adequate immunosuppression.
Microelectronic Monitoring Systems

These systems use microelectronic recording


devices (microchips) incorporated into drug container caps88-90 or inhalers91,92 that record the date
and time when the cap is opened or the aerosol is
dispensed. Information on the use of microelectronic medication monitoring in dialysis or transplant
patients is limited.21,63 Although superior to traditional methods such as pill counts or patient diaries,
relying on information provided by these devices
requires many assumptions. It is assumed that opening the cap is followed by removal and ingestion of
the pills; however, the patient may open the cap and
either take no medication or take too much.
Informing the patient that a medication is monitored
may improve compliance owing to heightened
awareness.
When used properly and with the previously mentioned limitations in mind, microelectronic monitoring devices such as Medication Events Monitoring
System caps (Aprex Corp, Fremont, CA) or the
MDI Chronolog inhaler (Medtrac Technologies,
Lakewood, CO) allow a better understanding of
dose-taking behavior. The data collected can help
patients develop schedules that meet their individual lifestyles.5,63,78 However, these devices are expensive, and their routine use cannot be recommended.
Monitoring 1 or 2 medications, chosen as sentinel
drugs, is usually sufficient and reduces the cost associated with the purchase of multiple microelectronic caps.
A recent advance in home peritoneal dialysis has
been the introduction of automated peritoneal dialysis systems (HomeChoice Pro, Baxter Healthcare
Corporation, Deerfield, Ill). These machines are
equipped with microelectronics that allow patient

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Medication, Chronic Disease, and Renal Issues


data to be stored and transmitted to the dialysis
center via modem. The devices can also be remotely programmed by the staff. The data stored can
form the basis of discussion of compliance issues.
To date, no studies of patient compliance are available using feedback from the automated peritoneal
dialysis system.

DETERMINANTS OR PREDICTORS
OF NONCOMPLIANCE

medication had a profound influence on persistence


with the treatment over time. Compared with other
antihypertensive agents, angiotensin-converting
enzyme inhibitors resulted in the highest rate of
compliance at 6 months (89% vs 80% for diuretics;
P < .001).104 Because hypertension is common in
dialysis and kidney transplant patients, these findings are relevant to these populations.
Disease-Related Factors

The severity of disease or the gravity of outcome


does not lead to better treatment compliance, as

Patient Factors

Most patient noncompliance factors are common to all patients


with chronic conditions, including
dialysis and kidney transplant
patients (Table 1). Forgetfulness,
adverse effects, and irregular
lifestyle were factors cited by
patients responding to a questionnaire. 19 Patient satisfaction
with the treatment plan and a
strong relationship between the
patient and health providers are
associated with improved compliance.23,100
Clinical or subclinical depression is a significant risk factor for
noncompliance in patients with
chronic conditions, as suggested by
a recent meta-analysis of the literature.101 The effect of depression on
compliance was more pronounced
in patients with ESRD than with
other chronic conditions.101
Other important issues are
acceptance of the disease and the
treatment prescribed, which may
be one reason younger patients and
patients recently diagnosed as having a chronic illness are less compliant. In a large study of patients
treated for hypertension, Caro et
al103 found that patients with newly
diagnosed hypertension were less
likely to persist with the prescribed antihypertensive treatment
than those with established hypertension (78% vs 97% at the end of 1
year; P < .001). In a related
study,104 the same authors found
that the choice of antihypertensive

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Table 1. Factors That Influence Medication Compliance*


Determinant

Outcome/Comments

Drug pharmacokinetics

Increased dosage frequency leads to decreased


compliance93,94

Ease of administration;
adverse reactions

Lower compliance with increased complexity of


regimen and with adverse reactions95

Duration of treatment

Compliance wanes with longer treatment93

Number of drugs prescribed

Increased number of drugs leads to reduced


compliance

Race; socioeconomic status

Lower compliance in Hispanics and blacks may be


related to socioeconomic status49,67,73

Age

Higher compliance in older patients49,67; poor


compliance in adolescents

Education level

Low education level may lead to decreased compliance70,71; poor correlation with knowledge of
disease and treatment96,97

Family support

Higher compliance in married patients or when


family support is available51

Motivation and psychosocial


factors

Increased compliance with higher motivation98,99;


decreased compliance in patients with anxiety
and depression100

Severity of disease

No direct relationship between severity and


compliance50,101,102

Presence and absence of


symptoms

Lower compliance in chronic asymptomatic


conditions

Availability of drug-level
monitoring

Compliance is not ensured by random monitoring


of drug levels; therapeutic drug levels can be
reached by taking medication correctly several
days before assay11,106

*Reproduced in part from Murphy and Coster.9 Superscripted numbers refer to articles
listed in the reference section of the present article.

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attested by relatively high noncompliance rates with
oral chemotherapy in cancer patients78,102 and HIVinfected patients.6 Relatively high noncompliance
rates are also observed with immunosuppressive
medications in solid organ transplant recipients.50,105
The Time Factor

In patients with chronic disease, compliance rates


tend to decrease over time.21,106 Compliance
improves immediately before a scheduled clinic
visit, perhaps owing to heightened awareness,107
remains high for several days after the visit,100 and
then wanes within a month.93,108 Increased frequency of office visits, therefore, may improve medication compliance.93 Enhanced compliance immediately
before and following each clinic visit has been
dubbed white coat compliance.11,93 This phenomenon can lead to false assumptions about medication
compliance when one relies solely on drug levels in
blood or urine.11 For drugs with a short half-life, levels can be near target values during the visit with no
relationship to levels maintained between visits.5,11
Treatment Complexity

The number of medications prescribed and the


frequency of doses can influence patient compliance.109 The latter seems to be a more important
determinant of compliance than the former.94
Several studies47,110-112 have found an inverse relationship between the number of doses prescribed
and compliance, with compliance declining as
dosage frequency increases. In a study111 of diabetic
patients taking oral hypoglycemic agents, compliance rates were 74.8% for once-a-day doses and
38% for thrice daily doses. More than one third of
patients taking once-a-day doses used more doses
than prescribed.111 Therefore, reducing the frequency to a single daily dose may have the unintended consequence of increasing the risk of
overconsumption.111
Health Provider Issues

The constant demand on physicians for more rapid


patient turnover has significantly reduced the time
spent with each patient. Therefore, the use of nurses
and paraprofessionals to assist with patient education
and follow-up has been advocated. Although this
approach is generally thought to be successful, few
studies are available to support this recommendation.
Studies113 of hypertensive subjects suggest that use of
such individuals does not substantially alter medication compliance or lower treatment dropout. Since
the impact of nurses may be greater than that of non-

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nurse helpers, more studies are needed to assess the


efficacy of educational programs by nurse educators.
In patients undergoing hemodialysis, ample opportunities are available for communication among staff,
the nephrologist, and the patient. Whether increased
time spent discussing treatment issues improves compliance in this population has not been studied.
During the first few months after kidney transplantation, frequent visits with the transplant team allow for
discussion of compliance issues and patient education. Good communication between the surgical and
nephrology teams is necessary to avoid conflicting
treatment recommendations to patients.
Behavioral Models

Hoover34 reviewed several behavioral models used


in attempts to predict medication noncompliance in
the context of patients receiving dialysis. The health
belief model, originally proposed by Becker et al,114
states that the individuals action is influenced by
his/her perception of the illness, its severity, and
its consequences, as well as the potential benefits
of the action weighed against physical, psychological, and financial costs of initiating the recommended action.1,34,114 The overall importance of
components of this model on patient behavior has
been summarized.115 There have been few recent
studies on the use of this model in predicting noncompliance in hemodialysis patients.116,117 Wiebe
and Christensen117 examined the relationship of
health beliefs and personality on patient adherence
with diet and fluid restriction in 70 hemodialysis
patients. Although interaction of health belief and
conscientiousness predicted differences in serum
phosphorus levels, it failed to explain changes in
IWG.117 More studies are needed to further dissect
these complex interactions.
The locus of control model is based on the precept that patients perceive behavioral reinforcement
on a continuum ranging from predominantly internal to predominantly external.118 (Those with an
internal locus of control would perceive rewards and
punishments occurring as a consequence of their
own behavior).34 Several studies118-121 have documented that hemodialysis patients with internal
locus of control tend to better adjust to treatment
and are in general more compliant. Two other studies,113,122 however, did not find a significant correlation between compliance and locus of control, as
determined by a standardized scale. These contradictory results suggest complex interrelationships
between psychological factors and compliance in the
dialysis population.123

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Medication, Chronic Disease, and Renal Issues


Table 2. Studies of Medication Noncompliance in Hemodialysis Patients
Study

Patients,
No.

Age
Range

Duration of
Follow-up

Measured Parameter

Curtin et al21

135 HD

NA

Medications (self-report,
pill count, MEMS)

Leggat et al23

6251

>1 y

PO4, IWG, missed dialysis

NA

Beck Depression Inventory;


other scales

NA

Protein, potassium restriction,


fluids, medications

Kimmel et al24

Bame et al25

1230
(from 29
facilities)

Safdar et al27

50

19-69 y

1 mo

Potassium, IWG

Clearly et al28

51 HD
21 PD

51 and
45 y (mean)

4 mo

Korbin et al30

NA

NA

NA

Medication recall,
knowledge of antihypertensives, PO4 binders,
and calcitriol
Potassium, PO4, IWG

Mai et al29

48

NA

Morduchowicz et al31 50

NA

Bleyer et al44

415 in US,
6 mo
84 in Sweden,
194 in Japan

NA

Brownbridge and
Fielding33

60 (PD
and HD)

Pediatric

NA

Bernardini and
Piraino35

20 PD

4-8 wk

NA

Diaz-Buxo et al46

HD

Shaw-Stuart
and Stuart125

50 HD
31 cont

57.9 y
(mean)

1y

Christensen
and Smith126

72 (HD
+ PD)

46.39 y
(mean)

NA

Results Summary
Only race was associated with
noncompliance: blacks were less
compliant
8.5% missed 1 HD a month, 22%
with high PO4 (>7.5 mg/dL) and
10% with high IWG (>5.7%);
increased risk of death in noncompliant patients
Depression seen in 25% of patients;
younger patients less compliant with
dialytic treatment; HD patients
missed 13 PO4 binder doses and
6.7 calcitriol doses each month
~50% noncompliant with medications or fluids; 9% noncompliant
with protein; 2% noncompliant with
potassium
64% noncompliant with either diet
or fluid restrictions; predictors of
noncompliance included older age,
male sex, lower education, single
status, and depression
39% of HD patients and 57% of
PD patients could recall all their
medications

The fraction of prescribed time the


patient is dialyzed is a good
measure of compliance
IWG, potassium, PO4,
Compliance rating scale could not
a compliance rating scale
be validated with biological
measures of compliance
Potassium, PO4, IWG
Correlation between fluid intake and
medication compliance. Variables
affecting serum potassium and
PO4 were identified
Missed dialysis
28.1% of US patients missed
treatments in 6 mo; no patients
from Japan and Sweden missed
treatments during 3 mo
Questionnaire, interview
Low compliance correlated with
poor adjustment to diagnosis,
anxiety, duration of dialysis, low
socioeconomic status
HD supplies inventory;
4% noncompliant with prescribed
measured/predicted
exchanges; no correlation between
creatinine ratio
measured/predicted creatinine and
compliance
Dialysis parameters monitored Description of the method; no
using a memory card
patients actually enrolled
Serum PO4
The educational program (developed
by Abbott) did not result in improved
compliance compared with traditional
nutrition counseling
NEO Five-Factor Inventory;
Conscientiousness was significantly
potassium, PO4
correlated with adherence to medications but not with dietary adherence

MEMS indicates Medication Events Monitoring System; IWG, interdialytic weight gain; HD, hemodialysis; PD, peritoneal dialysis; NA, not
available; PO4 = phosphorus; and NEO, Neuroticism, Extraversion, and Openess Personality Inventory.

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CLINICAL
Table 3. Studies of Medication Noncompliance in Renal Transplant Patients
Study

Patients,
No.

Age
Range

Duration of
Follow-up

Measured Parameter

Results Summary

Hong et al56

514

NA

Graft survival

13% of graft losses due to


noncompliance

Schweizer et al58

538

3y

Medication
compliance

18% noncompliance in retrospective


study; 15% noncompliance in
prospective study; higher noncompliance in young, poor, blacks, and
Hispanics

Douglas et al59

126

3y

Correlation between
pretransplantation and
posttransplantation
compliance

Significant correlation between


pretransplantation noncompliance and
posttransplantation noncompliance
and graft loss

DeGeest et al51

150

18-69 y
(46.19
12.38 y)

NA

Self-report, interview

23% subclinical noncompliance;


noncompliance correlated with
marital status, perceived self-efficacy;
more acute rejections and lower graft
survival in noncompliers

Hilbrands et al52

127

17-65 y

1y

Monthly pill counts

Noncompliance correlated with acute


rejection; lower rates of noncompliance
than in other studies

Greenstein and
Siegal54

1402
56 US
transplant
centers

46.6 12.5 y NA

Questionnaire,
self-report

22.4% incidence of noncompliance


with medications; age, occupation,
time since transplantation, and
medication-related beliefs were best
predictors of compliance; 3 noncomplier profiles identified

Meyers et al60

77

Pediatric

NA

Missed meds or clinic visits


or admissions

22% noncompliant; positive correlation with lower social class; no correlation with parental marital status or
distance from hospital

Wolff et al62

85

7.4-19.3 y
(12.7 2.9)

4.4 y

Retrospective analysis;
interviews

Patients have valid reasons for noncompliance. Subjective reasons for


noncompliance should be identified

Blowey et al63

19

12.5-17.9 y

3 mo

Medication taking
(MEMS caps), cyclosporine
levels

21% of patients took < 80% of doses;


26% of patients missed 3 consecutive
doses (drug holiday); poor medication
knowledge was associated with noncompliance

Kiley et al53

105

42 11.4 y

NA

Medication and diet


compliance; graft loss

26% noncompliant; noncompliance


more common in males, black race,
depressed, unemployed, those with
external locus of control; graft loss
correlated with depression, perception
of lack of benefit

Kalil et al72

202

NA

Graft survival

Increased incidence of graft loss in


patients who were noncompliant with
clinic visits; no effect of family income
on graft loss

NA

Medication compliance

Patients <20 years old, blacks, and


Hispanics (low socioeconomic status)
were most noncompliant

NA

Mail survey

Noncompliance correlated with young


age and with internal locus of control
of health outcome; increased compliance when positive feeling about physician and with transplant experience
(continued)

Swanson et al67

Raiz et al68

164

357

50.3 y
(mean)

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Medication, Chronic Disease, and Renal Issues


Table 3. Studies of Medication Noncompliance in Renal Transplant Patients Continued)
Patients,
No.

Study
Frazier et al69

241

Meyers74

56

Chisholm et al75

18

Siegal and
Greenstein66

397

Age
Range

Duration of
Follow-up

Measured Parameter

Results Summary

NA

Self report; mail survey

Noncompliance more common in


young, lower income, unmarried, and
retransplanted patients; stress was best
predictor of medication and follow-up
noncompliance

2.53-20.85 y

NA

Questionnaire

Medication noncompliance correlated


with missed clinic visits, inability to
name medications, lower knowledge
of disease

4.8 9.3 y

12 mo

Self-report; free medication

5% noncompliance at 5 mo, 52%


noncompliance at 12 mo; drug cost
alone is not a factor in compliance

NA

Mail survey; chart audits

18% noncompliance with immunosuppressive medications; noncompliance correlated with time elapsed
since transplantation, age, sex, and
ethnicity

MEMs indicates Medication Events Monitoring System; NA, not available.

Willey et al124 applied the stages-of-change model


to measure medication adherence in 2 cohorts of
patients with chronic diseases: 161 HIV-positive
patients and 731 hypertensive patients. They found
that this model can reliably predict medication-taking behavior (P < .03) and that interventions to
improve medication adherence should be tailored to
the patients readiness for change rather than being
applied uniformly in all patients.124 Major studies
of medication noncompliance in hemodialysis and
in transplant patients are summarized in Tables 2
and 3.

STRATEGIES TO IMPROVE
COMPLIANCE
The Patients Perspective

A key determinant of compliance is the adequacy


of patient-physician communication. Physicians
should make an effort to assess the patients beliefs
about the illness and the treatment plan through
open discussion.62 They should strive to establish a
partnership with the patient and to see the medication-taking behavior from the patients perspective.4,62,98,99 Improving communication between
healthcare providers and patients and simplifying

VOL. 9, NO. 2

the treatment regimen are at the core of strategies


proposed to improve compliance.15,16,99,127 Other
strategies include tailoring medications to the
patients schedule, improving patient satisfaction,
offering incentives, and soliciting the help of the
patients social support network.128
Simplification and Visual Reminders

Reducing the number and frequency of pills prescribed, developing individualized treatment
plans,129 helping patients identify cues or reminders
for each dose, and providing medication calendars
have variable degrees of success.5,130 When available, using forgiving drugs with a long half-life
should compensate for occasional lapses in medication dosage.85,131 Special medication boxes with
compartments and electronic alarms to remind
patients when their dose is due have been used in
elderly patients,132 but experience with such aids is
limited. Calendar blister packaging seems to
improve medication compliance, particularly in the
elderly and in those with a history of noncompliance.127 In a study133 of patients taking vitamin supplements, pill organizers and blister packs improved
compliance only in subjects who had demonstrated
low adherence with medications. Because of
increased production costs and storage require-

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CLINICAL
ments, blister packs have not been well accepted in
the United States, but they continue to be popular
in other countries. Medication reminder charts95
and mailed or telephone reminders have also been
suggested as strategies to improve compliance with
medications and clinic visits.9,134,135
Providing written instructions about prescribed
medications, inquiring about the manner in which
each medication is taken, requesting that patients
bring all prescribed medications to their clinic visit,
and providing feedback and reinforcement on the
optimum dosing interval are general strategies to
help improve compliance.10,129 Peck and King136 also
recommend fear-arousing health messages as a
means of improving compliance with prescriptions.
In a study of 116 hemodialysis patients, interventions consisting of behavioral contracting and weekly telephone contacts resulted in reductions in
serum potassium levels and IWG. However, the benefits were transient, and, by the third month, the
effects had disappeared and compliance returned to
preintervention levels.137 Long-term and ongoing
interventions, therefore, may be necessary to alter
compliance.
Patient Education

Although there is evidence that improved patient


education results in better outcome,138 the role of
education in improving treatment compliance has
not been proven. A meta-analysis of educational
programs in adult asthmatics confirmed that such
programs are associated with improved compliance.139 Similarly, an educational program for
patients undergoing hemodialysis resulted in
improved compliance.140 In contrast, an educational program for pediatric renal transplant patients
improved knowledge about drugs but did not have
a significant impact on medication compliance.55
An intensive educational program involving 50
adult hemodialysis patients failed to produce a significant change in serum phosphorus levels, a commonly used indicator of compliance in this patient
population.125 Another study141 involving 29
hemodialysis patients reached a similar conclusion. An education initiative by the National
Kidney Foundation is under way to educate large
numbers of pre-ESRD patients.142 Although the
choice of dialysis modality was influenced by this
program,142 it remains to be seen if compliance
with treatment will improve in program participants. Studies51,63,75 of the effect of education on
compliance in kidney transplant patients are
inconclusive. Therefore, based on the available evi-

166

dence, no recommendations can be made regarding


patient education to improve compliance in dialysis
and kidney transplant patients.
Just as it is important for physicians to learn
how to communicate well with patients, it is
possible that improved communication skills on
the part of patients may improve compliance.
Cegala et al143 studied compliance behavior of
patients who received training booklets to learn
information-seeking skills. Trained patients were
more compliant with follow-up appointments.143
Whether patient communication training would
also improve medication compliance has not been
studied.
Incentives

As in other areas of human psychology, positive


reinforcement in various forms to encourage or
improve compliance may be more beneficial than
chastising the patient for poor compliance. In a
study75 of renal transplant patients, provision of free
immunosuppressive medications resulted in shortterm improvement in compliance, but there was no
benefit beyond the first year after transplantation. In
adolescent girls followed at a prenatal clinic, the
offer of an incentive significantly improved compliance with postpartum appointments.96 Use of financial incentives to improve compliance has also
been advocated but remains controversial. In a
recent literature review,97 10 of 11 studies showed
improvements in patient compliance with use of
financial incentives. Using monetary incentives to
improve compliance has been condemned by some
as coercion and contrary to the mutual participation principle of decision making advocated by
some experts.144
Feedback Sessions

Feedback sessions based on information obtained


with microelectronic monitoring systems can
increase patient awareness regarding drug-taking
behavior, which in turn may increase medication
compliance.145 Studies5,146,147 in asthmatic patients
using Chronolog inhalers have shown a significant
improvement in compliance in those who received
feedback regarding their inhaled dosing intervals.
Similar results were obtained in hypertensive
patients who were provided feedback on dosing
intervals based on information obtained by the
Medication Events Monitoring System system.15
As electronic monitoring becomes incorporated
into more hemodialysis machines, opportunities
exist to use this information to study and

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Medication, Chronic Disease, and Renal Issues


improve patient compliance.148
In home peritoneal dialysis
patients, the use of automated
peritoneal dialysis machines
capable of storing and transmitting data should provide valuable information on patient
adherence to prescribed dialytic
treatment, fluid restriction, and
blood pressure control. The
information could be shared
with the patient and the treatment modified accordingly.
In general, a combination of
different strategies works better
than a single strategy.149,150 Some
useful strategies to improve medication compliance are listed in
Table 4.

SUMMARY AND DISCUSSION

Table 4. Useful Strategies to Improve Medication Compliance*


Behavior to Impact or Enhance . . .

Method

Commitment

Empower patients by allowing them to


participate in their care12,98; offer positive
reinforcement and incentives141

Awareness of disease and


its treatment

Provide written materials or videos about the


disease and medications58; reinforce by verbal
interaction

Awareness of medication-taking
behavior

Provide feedback using data from microelectronic


devices78,90-92

Complexity of treatment

Simplify the treatment regimen (eg, reduce


dosage frequency)9; use sustained-release
medications with single daily dose when available124,138; supply medications in single units
or blister packaging5,124; use optimum dose of
one drug before introducing a new drug
(stepped-care approach); use combination
drugs (eg, diuretic-antihypertensive)

Forgetfulness

Take medications when brushing teeth, inserting


or removing contact lenses, or at breakfast,
lunch, or dinner138; use blister packaging if
available127; dispense medications in bottles with
microelectronic alarms9,128; use electronic
devices to alert the pharmacist or a relative when
a dose is missed; send pharmacy-generated refill
reminders for each medication9,102,109

Noncompliance with medications and other aspects of treatment is seen in almost half of the
patients treated for chronic conditions, such as those undergoing dialytic treatment or after
kidney transplantation. IdentifyInteraction with professionals,
Allow more time per visit to discuss treatment
ing patients more likely to be
communication
issues and answer questions; consider compliance issues from the patients perspective98; get
noncompliant with treatment
help
from nurses and pharmacists to answer
has been the subject of many
medication questions
studies. Various factors may
influence medication compliance, including young age, socio*Reproduced in part from Murphy and Coster.9 Superscripted numbers refer to articles listed
economic status and family
in the reference section of the present article.
support, complexity of the treatment regimen, and patient beliefs
and motivation. Improved communication, simplifiperspective and to mutual participation in the concation of treatment regimen, increased frequency of
duct of medical treatments has led to several new
visits, and use of microelectronic devices have been
studies. This area promises to reveal the complexirecommended as strategies to improve medication
ties of patient noncompliance. More attention
compliance. This review of the literature on patient
should focus on dissecting patient attitudes toward
compliance has revealed several areas where gaps in
disease and its treatment, patient education, and
knowledge exist and more research is needed (see
Recent
patient-physician
communication.151
148
the following sections).
studies have begun to address this issue in the
dialysis population. Similar assessment methods
Methodology
should be applied to the study of compliance in renal
Although excellent studies are available, many
transplant recipients.
studies have been poorly designed and contribute
little to the advancement of knowledge in the field.
Monitoring Devices
The shift from looking at the issue of compliance
Use of microelectronic devices has been hailed as
from the physicians perspective to the patients
a major advance in medication monitoring. They are

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167

CLINICAL
useful in clinical research. Not only do they help
determine whether medications are taken as prescribed, but they also provide information on medication-taking behavior, allowing physicians to
provide feedback to the patient. These devices
extend the paternalistic notion that patients are not
trustworthy and cannot be relied on to determine
what is in their own best interest. Additional studies
need to address the following: (1) Does use of these
devices actually improve patient compliance? (2)
Can their high cost be justified in terms of medical
expense savings? (3) Should patients be informed
when these devices are used? Compliance rates
are relatively low in patients undergoing home
peritoneal dialysis. The availability of automated
peritoneal dialysis machines with electronic memory cards and the possibility of remote monitoring
offer many research opportunities to identify problem areas in patient compliance with prescribed
dialysis treatments. Increased use of electronic
charts and telemedicine offer additional opportunities to study patient behavior and compliance.
Patient Profiling

The relationship between noncompliance with


one type of treatment and compliance with another
is not clear. Can one justify using demographic profiles or history of compliance with a previous treatment to classify patients as compliers and
noncompliers? Several studies have shown that noncompliance with one aspect of treatment does not
predict noncompliance with other aspects. Other
studies have identified psychiatric diseases and substance abuse as reliable indicators of future noncompliance.77 Certain personality traits may also predict
compliance.126 Patient profiling implies that noncompliance is an inherent characteristic of the patient
rather than equally shared by the healthcare
providers. The answers to these important questions
require carefully designed studies. The issue of
patient selection based on certain profiles may
linger until the problem of organ shortage is resolved.
Outcomes Research

Recent studies23,24,37 have shown that noncompliance with hemodialysis treatment is associated with
increased mortality. Missed or abbreviated dialysis
sessions can reduce dialysis adequacy, which may
be a reason for increased mortality,152 and hyperphosphatemia may be another reason.38 Owing to
the need for large numbers of pills and frequent dosing, it is unlikely that compliance with current phosphate binders could be significantly improved.

168

Research efforts should be directed at better


removal of phosphate by dialysis and the development of more effective and longer-acting phosphate
binders.
Another common problem in dialysis patients is
renal anemia secondary to EPO deficiency.40
Uncorrected anemia is this patient population is
associated with increased morbidity and mortality.40 Suggested areas of research include the development of needle-free injection devices and
longer-acting EPO derivatives requiring less frequent administration. Both are likely to result in
improved compliance. Studies should be planned to
assess compliance with these newer therapeutic
options.

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