Modifiable risk factors for non-adherence to immunosuppressants in renal transplant recipients: a cross-sectional study

Janet A. Butler1, Robert C. Peveler1, Paul Roderick2, Peter W. F. Smith3, Robert Horne4 and Juan C. Mason5

1 Mental Health Group, Community Clinical Sciences Research Division, University of Southampton, Royal South Hants Hospital, Southampton, 2 Health Care Research Unit, Community Clinical Sciences Research Division, University of Southampton, Southampton General Hospital, Southampton, 3 Southampton Statistical Sciences Research Institute, University of Southampton, Southampton, 4 Centre for Health Care Research, University of Brighton, Brighton and 5 Wessex Renal Unit, Queen Alexandra Hospital, Cosham, Portsmouth, UK

Correspondence and offprint requests to: Dr Janet A. Butler, Mental Health Group, Royal South Hants Hospital, Southampton SO14 0YG, UK. Email: jab7{at}soton.ac.uk



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Non-adherence to immunosuppressants is a major cause of renal transplant failure. Interventions to improve adherence need to target modifiable risk factors.

Methods. Adherence was measured using the ‘gold standard’ measure of electronic monitoring in 58 adult renal transplant recipients from a UK transplant unit. Subjects were identified from a stratified random sample of 153 recipients recruited to a larger cross-sectional study comparing different measures of adherence. Inclusion criteria included age over 18 years and a functioning renal transplant, transplanted 6–63 months previously. Exclusion criteria included residence outside the region served by the unit and inability to give informed consent. Health beliefs, depression and functional status were measured using standardized questionnaires (Beliefs about Medicines Questionnaire, Illness Perception Questionnaire, Revised Clinical Interview Schedule and SF-36) and semi-structured interview. Transplant and demographic details were collected from the notes.

Results. Seven [12%, 95% confidence interval (CI) 4–20%] subjects missed at least 20% of days medication and 15 (26%, 15–37%) missed at least 10% of days. Lower belief in the need for medication and having a transplant from a live donor were the major factors associated with non-adherence. Depression was common, although not strongly associated with non-adherence.

Conclusions. Beliefs about medication are a promising target for interventions designed to improve adherence. The lower adherence in recipients of transplants from live donors needs confirming but may be clinically important in light of the drive to increase live donation.

Keywords: health beliefs; non-adherence; renal transplant



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Not taking medication as prescribed (non-adherence) is a major challenge for modern medicine [1]. The consequences of non-adherence are particularly evident in relation to immunosuppressant medication following organ transplantation where, in renal transplant recipients, non-adherence appears to be a significant cause of late acute rejection episodes and transplant loss [2]. This has led to calls for interventions to reduce non-adherence and hence prolong graft survival, thereby maximizing the effectiveness of the scarce supply of donor organs [3].

Modifiable factors associated with adherence are targets for interventions to improve adherence. In renal transplant recipients to date, most studies have largely been confined to identifying factors that cannot be modified after transplantation. Health beliefs form the basis for current recommendations relating to research and clinical practice targeted towards improving adherence. A few existing studies have investigated the influence of beliefs about medication and the transplant on adherence in renal transplant recipients [3–7]. However, their findings are conflicting. Generalizable conclusions are difficult to draw since the studies have used different, non-standardized instruments to measure a variety of different beliefs.

In patients with a range of chronic physical illnesses, a meta-analysis indicates that depression increases the relative risk of non-adherence by 1.74 [8]. Conflicting results have been found regarding the association between depression and adherence following renal transplantation, and no studies in this population have used diagnostic instruments to identify depression [3,9,10].

Patients' illness and medication-related beliefs or emotions are potentially modifiable and are the final common pathway of factors determining adherence according to theoretical models of health behaviour [11]. An existing form of therapy, cognitive–behaviour therapy (CBT), has been shown to be effective in changing behaviour and improving mood in a variety of psychological disorders. CBT relies heavily on collaboratively exploring and testing patients' beliefs to produce belief change that is theoretically thought to underlie the resulting behaviour change. Thus if beliefs and emotions are related to adherence, CBT could form a basis for developing interventions to improve adherence.

Electronic monitoring of adherence enables recording of all pill bottle openings. With the assumption that bottle openings correspond to medication ingestion, this allows adherence to be measured in a continuous manner and for both missed doses and timing variations to be reported. These factors contribute to electronic monitoring being widely regarded as the best measure of adherence [12].

The current study is the first reporting investigation of non-adherence to immunosuppressants in adult renal transplant recipients using both electronic monitoring and theoretically based and standardized measures of associated, potentially modifiable risk factors. We hypothesized that beliefs about medication and depression would be strongly associated with adherence.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Recruitment
All patients from one regional transplant unit over the age of 18 years with a functioning renal transplant and transplanted 6–63 months prior to recruitment were eligible for a larger study comparing different measures of adherence [13]. Subjects residing outside the region served by the unit (22 subjects) and those unable to give informed consent (two subjects) were excluded. From the 153 subjects consenting to the larger study, stratified random sampling (using time since transplantation) was used to identify 60 subjects to receive electronic monitors for 6 weeks. Data were collected by postal questionnaire, notes review and interview. Ethical approval was granted by the local Multi-centre Research Ethics Committee.

Assessment of adherence
Electronic monitors comprised a lid and a 60 ml opaque plastic bottle filled with prednisolone. Adherence data were obtained after downloading of information from the manufacturer, Aardex. Although a study in heart transplant recipients indicates that missing >5% of days immunosuppression is associated with rejection episodes [14], the clinically significant level of non-adherence has not been determined following renal transplantation. A small survey of staff in the unit did not reveal a consensus of opinion, so existing literature was reviewed to find previously used definitions of non-adherence. Adherence is known to vary over time, and an intervention to improve adherence should not miss potentially non-adherent subjects. Thus this study used the review to identify a conservative, but commonly used, definition of missing at least 20% of days medication to determine non-adherent subjects. Since prednisolone was not prescribed more than once daily, this is equivalent to a definition of missing at least 20% of doses. A dichotomy of adherent vs non-adherent subjects was used since adherence was thought likely to have a highly skewed distribution with most subjects lying at the adherent end of the distribution. The details of measurement are reported in another paper [13]. This report concentrates on the factors associated with adherence.

Assessment of demographic and clinical factors
Socio-demographic, transplant-related and psychosocial variables were assessed (Table 1). Functional health status and social support were measured using the total scale scores of the Short Form 36 (SF-36) [15] and the Significant Others Scale, respectively [16].


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Table 1. Variables assessed for their relationship with non-adherence

 
Assessment of health beliefs
Illness and medication beliefs were measured using standardized self-report questionnaires including the Illness Perception Questionnaire (IPQ) [17] and the Beliefs about Medicines Questionnaire (BMQ) [18]. The IPQ has five scales (identity, cause, time-line, consequences and control/cure) measuring themes that people use to understand their illness. The BMQ has four scales organized into two sections measuring beliefs people have about medicines in general (harm and overuse scales) and about a specific medication (necessity and concerns scales). Subjects received two specific sections of the BMQ, one asking about their views of immunosuppressants in general and the other asking specifically about prednisolone. Two immunospressant-specific items were added to the concerns scale for this study. This is in accordance with the planned use of the questionnaire since concerns are thought to be more drug specific than beliefs about need (R. Horne, 2003, personal communication). Prior to analysis, the modified concerns scale was checked to ensure that the additional items did not impair internal reliability. Two scales were included from revised versions of the IPQ [19] and BMQ (R. Horne, 1999, personal communication) being developed at the time of the study: a benefit scale in the general section of the BMQ and an emotions scale in the IPQ. Items used in the study are available from the authors on request. The separate scales on each questionnaire, except the identity scale of the IPQ, were used as separate variables in the analysis.

Assessment of depression
The revised Clinical Interview Schedule (CIS-R) [20] is a standardized psychiatric interview used to obtain both a continuous measure of distress and psychiatric diagnoses according to ICD-10 criteria. The recommended total score of 12 or more was used to define a case of psychological distress. The only derived diagnosis in this study was depression since this was the diagnosis related to the study hypotheses.

Statistical analysis
Logistic regression analysis was used to identify major factors associated with adherence. The large number of variables measured increased the risk of type 1 errors. Therefore, the first stage of model selection involved initial screening using Mann–Whitney or {chi}2 tests to identify variables that were likely to have the largest impact on adherence. Exact tests of significance were used. A forward stepwise procedure was used to select variables from those that were significant on initial screening (taken as P ≤ 0.1 significance). The selected model included the major factors associated with missing at least 20% of days medication. A sensitivity analysis using missing at least 10% of days medication to define non-adherence was performed.

Using a two-sided 5% t-test, a sample of 60 subjects, with 15% in one group (nine non-adherent subjects) and 85% in another group (51 adherent subjects), was calculated to allow identification of a standardized difference of 0.90 between scores on each scale of the BMQ with 80% power.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Characteristics of the sample
There were no differences in socio-demographic factors between those who consented to the larger study (153 subjects) and those who refused (19 subjects) or between those given electronic monitors (60 subjects) and those who were not (73 subjects). The only difference in transplant-related factors was that subjects receiving electronic monitors were less likely to have received pre-emptive transplantation ({chi}2 = 5.46, df = 1, P = 0.02). One subject died during the monitoring period and his monitor was not recovered. Data from a second monitor were not used since, at the end of the monitoring period, the subject reported decanting medication once a week. The characteristics of the sample of 58 with data from electronic monitoring are shown in Table 2.


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Table 2. Characteristics of the sample (n = 58)

 
Prevalence of non-adherence
Seven [12%, 95% confidence interval (CI) 4–20%] of the 58 subjects with data available from electronic monitors missed at least 20% of days medication and 15 (26%, 32–58%) missed at least 10% of days. However, half the subjects did not miss any medication [median percentage of days where medication was missed 0%, interquartile range (IQR) 0–12%, range 0–45%]. The time of taking medication was very variable, with the median SD of inter-dose intervals being 5 h (IQR 2–9).

Relationship of individual variables with adherence
The variables associated with non-adherence (missing medication on 20% of days or more) and used in logistic regression analysis are shown in Table 3. The main modifiable variables associated with adherence were beliefs related to medication and negative emotional impact of the transplant. Gender, time since transplantation, experience of previous rejection episodes and the number of symptoms reported on the IPQ were not significantly associated with adherence.


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Table 3. Variables related to non-adherencea and entered into a logistic regression model

 
As a group, subjects held a relatively strong belief in the need for immunosuppressants or prednisolone, as indicated by 97 and 91%, respectively, scoring in the upper half of the necessity scale on the BMQ. However, within the sample's variation in perceived need, lower belief was strongly associated with non-adherence (Table 3). The average strength of the belief in the need for prednisolone was lower than that for immunosuppressants as a group (Z = –8.0, P<0.001). The two necessity scale scores were only moderately correlated with each other, indicating that subjects had different beliefs about the need for prednisolone compared with immunosuppressants as a group. Surprisingly, concerns about medication and the number of reported side effects were not significantly associated with adherence.

Unlike negative emotions linked to the transplant (IPQ emotions scale), depression itself was not strongly associated with adherence. However, depressive illness was common, with 13 subjects (22%) fulfilling diagnostic criteria for a moderate or severe depressive episode. None of these subjects were prescribed antidepressant medication.

Logistic regression analysis
Variables showing co-linearity (ideal practical support, type of first transplant) or with few subjects (pre-emptive transplantation) were excluded from multivariate analysis of factors related to non-adherence (Table 3). The main factors associated with non-adherence were having a transplant from a live donor [odds ratio (OR) 31.6, 95% CI 1.2–827.1] and having low belief in the need both for immunosuppressants as a group (OR for a one unit decrease on the necessity scale 2.0, 95% CI 1.1–3.7) and for prednisolone specifically (OR for a one unit decrease on the necessity scale 1.8, 95% CI 1.1– 2.9). Sensitivity analysis showed that the results did not differ significantly when a level of missing at least 10% of days medication was used to define non-adherence.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This is the first study to report the association between standardized assessment of potentially modifiable factors and adherence assessed using electronic monitoring in an adult renal transplant population >6 months post-transplantation. The results show that non-adherence has a strong association with perceived need for immunosuppressants and receiving a transplant from a live donor. Depression was common but not strongly associated with non-adherence.

The association of perceived need for medication and adherence is consistent with previous studies in a variety of other medical conditions using the BMQ [11]. However, in contrast to the studies using other populations, concerns about medication were not strongly associated with adherence. This is surprising in view of the recognized side effects of immunosuppressants. It may be explained by fear of transplant rejection, as indicated by a strong belief in the need for the medication, being significantly more salient that troublesome side effects. However, the finding needs replicating in future studies of transplant recipients. If replicated, the reasons for concerns about immunosuppressants compared with concerns about other medications being less important determinants of adherence need exploring. The difference between reported need for prednisolone specifically vs immunosuppressants as a whole shows that patients may hold different beliefs about different drugs even if they are used for a similar purpose. Our study was not designed to identify factors contributing to beliefs, but previous studies in renal transplant recipients indicate that prior medical management [6] and beliefs related to the transplant [7] may contribute to perceived need for immunosuppressants. Such associations could not be detected with the generic questionnaire used in our study.

Emotional impact of the transplant (IPQ emotions scale [19], functional limitations scale of the SF-36 [15]) was related to adherence on initial screening. Logistic regression analysis indicated that the relationship to adherence can be accounted for by transplant-related factors. However, since transplant-related factors cannot be altered after transplantation, interventions addressing the emotional impact of a transplant may also improve adherence.

The main limitations of our study relate to the relatively small sample size and large number of variables studied, resulting in a risk of both type 1 and type 2 errors. The cross-sectional design means that the direction of association between measured variables and adherence cannot be established. Monitoring adherence over a longer period may have shown that factors related to adherence change over time. Although subjects did not appear to know that their adherence was being monitored, using a different pill bottle could have altered their behaviour such that the results do not fully reflect natural patterns of non-adherence. It is impossible to monitor adherence without potentially affecting the behaviour, but a post-study interview may have given subjects the opportunity to report such changes.

Clinical importance
The association of lower perceived need for immunosuppression with non-adherence makes non-adherence more understandable from the patient's perspective. Previous research has suggested that prior medical management contributes to beliefs about treatment. Thus adherence may be improved if medical teams help patients correct their unhelpful beliefs about medication by altering information given to transplant recipients, exploring beliefs in all patients and discussing distorted beliefs. This may require specialist skills such as techniques from CBT. Although concerns about immunosuppressants did not appear related to adherence in this study, side effects and other concerns are likely to impact on patients' quality of life and relate to the strength of desire to take the medication. Thus patients' concerns about their medication should also be explored in clinical settings.

Although not related to adherence, depression was common. Depression has been associated with reduced quality of life and increased morbidity. Thus clinicians should be alert to the presence of depression post-transplantation. Therapeutic interventions and antidepressant medication to improve the emotional state of transplant recipients are important independently of affecting adherence.

The finding that recipients of transplants from a live donor are more likely to be non-adherent is particularly important in the light of current attempts to increase the number of live donors. If replicated, our results suggest that survival of these transplants may be enhanced further in comparison with cadaveric grafts if adherence can be improved. Although the association of live and pre-emptive transplantation with non-adherence needs to be replicated and the reasons for the association require further explanation, current results suggest that clinicians should be particularly sure to discuss the need for immunosuppression in patients with a transplant from a live donor and to discuss the differences in outcomes between dialysis and transplantation with patients who have not experienced dialysis.

Future research
Our study raises several important questions to address in future research. Since beliefs about medication are potentially modifiable and are associated with adherence, they offer a target for interventions to improve adherence. Such interventions are likely to require identification of the determinants of necessity beliefs, their relationship to concerns about the medication, the degree of change in beliefs needed to produce a clinically significant outcome and the duration of such a change. Information is needed on how many missed immunosuppressants increase the risk of graft loss and how erratic timing relates to this risk. The apparent increase in risk of non-adherence in recipients of a transplant from a live donor and, possibly, those who have never received dialysis is tentative due to the lack of precision in the estimated OR resulting from the small sample size; it requires addressing in future larger studies. Given the frequency of depression, its association with adherence needs further investigation in view of the conflicting findings in the literature to date.



   Acknowledgments
 
Research funding was from the Medical Research Council as part of a Clinical Research Training fellowship for J.A.B.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 9. 3.04
Accepted in revised form: 31. 8.04





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