Non‐adherence to immunosuppressive medication in renal transplant recipients within the scope of the integrative model of behavioral prediction: a cross‐sectional study

Schmid‐Mohler G, Pechula Thut M, Wüthrich RP, Denhaerynck K, De Geest S. Non‐adherence to immunosuppressive medication in renal transplant recipients within the scope of the integrative model of behavioral prediction: a cross‐sectional study.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01056.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Non‐adherence to immunosuppressive medication is strongly associated with poor outcomes. Identifying the factors influencing it is a first step in developing adherence interventions. This study’s objective was to investigate the prevalence of self‐reported and collaterally‐reported non‐adherence to immunosuppressives, and, based on the Integrative Model of Behavioral Prediction, to explore the association between non‐adherence, intention to adhere, attitudes, norms and self‐efficacy. Methods: This cross‐sectional study included a convenience sample of 114 renal transplant recipients in follow‐up care, one to five yr post‐transplant. Non‐adherence was measured by self‐reports and collateral reports. Factors of the Integrative Model of Behavioral Prediction were assessed using a self‐report questionnaire. Results: Self‐reports showed non‐adherence of 23.7%; collateral reports showed 3.8%; and a combination of the two showed 26.4%. Logistic regression analysis showed that the attitude “Not all immunosuppressive drugs are necessary to prevent rejection” was less frequent in patients with higher intentions to adhere, with an odds ratio (OR) of 0.05 (95% CI 0.01–0.50). The barrier of “Forgetfulness/Interruption of daily routine” was associated with non‐adherence, with an OR of 3.74 (95% CI 1.55–9.03). Conclusions: Forgetfulness is the most powerful barrier against adherence. Intention to adhere plays a minor role in non‐adherence in renal transplant recipients.     

Factors related to immunosuppressant medication adherence in renal transplant recipients

Chisholm‐Burns M, Pinsky B, Parker G, Johnson P, Arcona S, Buzinec P, Chakravarti P, Good M, Cooper M. Factors related to immunosuppressant medication adherence in renal transplant recipients. Abstract: Non‐adherence to immunosuppressant medications (ISM) is a significant issue for transplant recipients. This study examines factors influencing ISM adherence in renal transplant recipients (RTRs). Patient‐reported data were collected through a cross‐sectional survey including use of ISMs, adherence behaviors, perceived adherence barriers, beliefs and attitudes toward ISMs, and patient life satisfaction. Logistic regression was conducted to examine how RTRs’ beliefs about use of ISMs, life satisfaction, and ISM adherence barriers were related to adherence. A total of 512 adult commercial insurance enrollees following renal transplantation were included in the analysis. One hundred and seventy‐seven RTRs were non‐adherent (34.5%); the most frequently cited reason was forgetfulness. RTRs aged 18–29 yr were more likely to be non‐adherent than recipients 46–64 yr old (p ≤ 0.001). Non‐adherent RTRs had greater adherence barriers than adherent RTRs (p < 0.001). Adherent RTRs believed their ISMs were more necessary than non‐adherent RTRs (p < 0.001), while non‐adherent RTRs had greater concerns about taking ISMs (p = 0.009) and believed they had less control over their lives than adherent RTRs (p < 0.001). Non‐adherent RTRs had lower life satisfaction (p < 0.001). Non‐adherence is significantly associated with patients’ beliefs about ISMs, perceived barriers, and lower life satisfaction. Strategies to increase ISM adherence are discussed.     

Evaluation of a hand-held, computer-based intervention to promote early self-care behaviors after lung transplant

Abstract: Background: Lung transplant recipients are expected to perform self‐care behaviors to maximize transplant‐related health outcomes. Despite high non‐adherence rates in performing these self‐care behaviors, and the dire clinical consequences of such non‐adherence, interventions are lacking. Pocket Personal Assistant for Tracking Health (Pocket PATH) is a hand‐held device developed for patients to record health data, review data trends, and report condition changes to the transplant team. Methods: A pilot trial was conducted to compare self‐care agency, self‐care behaviors, and health‐related quality of life (HRQOL) between recipients randomized to use Pocket PATH (n = 15) vs. standard care (n = 15) for the first two months following hospital discharge after lung transplantation. Results: Baseline characteristics were equivalent across groups. Patients in the Pocket PATH group showed significantly higher ratings of self‐care agency, performed self‐care behaviors at significantly higher rates, and reported significantly better HRQOL than standard care controls. Conclusion: Pocket PATH is more efficacious than standard care in promoting early self‐care agency, self‐care behaviors, and HRQOL in lung recipients. A large‐scale randomized controlled trial is needed to test the impact of Pocket PATH on long‐term self‐care behaviors.     

Medication understanding,non‐adherence,and clinical outcomes among adult kidney transplant recipients

We sought to evaluate the prevalence of medication understanding and non‐adherence of entire drug regimens among kidney transplantation (KT) recipients and to examine associations of these exposures with clinical outcomes. Structured, in‐person interviews were conducted with 99 adult KT recipients between 2011 and 2012 at two transplant centers in Chicago, IL; and Atlanta, GA. Nearly, one‐quarter (24%) of participants had limited literacy as measured by the Rapid Estimate of Adult Literacy in Medicine test; patients took a mean of 10 (SD=4) medications and 32% had a medication change within the last month. On average, patients knew what 91% of their medications were for (self‐report) and demonstrated proper dosing (via observed demonstration) for 83% of medications. Overall, 35% were non‐adherent based on either self‐report or tacrolimus level. In multivariable analyses, fewer months since transplant and limited literacy were associated with non‐adherence (all P<.05). Patients with minority race, a higher number of medications, and mild cognitive impairment had significantly lower treatment knowledge scores. Non‐white race and lower income were associated with higher rates of hospitalization within a year following the interview. The identification of factors that predispose KT recipients to medication misunderstanding, non‐adherence, and hospitalization could help target appropriate self‐care interventions.     

Improving Outcomes of Renal Transplant Recipients With Behavioral Adherence Contracts: A Randomized Controlled Trial

The objective of this randomized controlled trial was to assess the effects of a 1‐year behavioral contract intervention on immunosuppressant therapy (IST) adherence and healthcare utilizations and costs among adult renal transplant recipients (RTRs). The sample included adult RTRs who were at least 1 year posttransplant, taking tacrolimus or cyclosporine and served by a specialty pharmacy. Pharmacy refill records were used to measure adherence and monthly questionnaires were used to measure healthcare utilizations. Direct medical costs were estimated using the 2009 Medicare Expenditure Panel Survey. Adherence was analyzed using the GLM procedure and the MIXED procedure of SAS. Rate ratios and 95% confidence intervals were estimated to quantify the rate of utilizing healthcare services relative to treatment assignment. One hundred fifty RTRs were enrolled in the study. Intervention group RTRs (n = 76) had higher adherence than control group RTRs (n = 74) over the study period (p < 0.01). And 76.1% of the intervention group compared with 42.7% of the control group was not hospitalized during the 1‐year study period (RR = 1.785; 95% CI: 1.314, 2.425), resulting in cost savings. Thus, evidence supports using behavioral contracts as an effective adherence intervention that may improve healthcare outcomes and lower costs.     

Association between day of the week and medication adherence among adolescent and young adult kidney transplant recipients

Disruption of usual routines may hinder adherence, increasing the risk of rejection. We aimed to compare weekend versus weekday medication adherence among adolescent and young adult kidney transplant recipients, hypothesizing poorer adherence on weekends. We examined data from the Teen Adherence in Kidney transplant Effectiveness of Intervention Trial (TAKE‐IT). We assessed the 3‐month run‐in period (no intervention) and the 12‐month intervention interval, considering a potential interaction between weekend/weekday and treatment group. Adherence was monitored using electronic pillboxes in participants 11‐24 years followed in eight transplant centers in Canada and the United States. We used logistic regression with generalized estimating equations to estimate the association between weekends/weekdays and each of perfect taking (100% of prescribed doses taken) and timing (100% of prescribed doses taken on time) adherence. Taking (OR = 0.72 [95% CI 0.65‐0.79]) and timing (OR = 0.66 [95% CI 0.59‐0.74]) adherence were poorer on weekends than weekdays in the run‐in (136 participants) and the intervention interval (taking OR = 0.74 [0.67‐0.81] and timing OR = 0.71 [95% CI 0.65‐0.77]). There was no interaction by treatment group (64 intervention and 74 control participants). Weekends represent a disruption of regular routines, posing a threat to adherence. Patients and families should be encouraged to develop strategies to maintain adherence when routines are disrupted. TAKE‐IT registration number: Clinicaltrials.gov registration: NCT01356277 (May 17, 2011).     

Evaluation of tools for annual capture of adherence to immunosuppressive medications after renal transplantation – a single‐centre open prospective trial

Annual assessment of adherence would strengthen long‐term outcome assessments from registry data. The objective of this study was to evaluate tools suitable for annual routine capture of adherence data in renal transplant recipients. A single‐centre open prospective trial included 295 renal transplant recipients on tacrolimus. Two‐thirds of the patients were included 4 weeks post‐transplant, randomized 1:1 to intensive or single‐point adherence assessment in the early phase and 1‐year post‐transplant. One‐third were included 1‐year post‐transplant during a cross‐sectional investigation. Adherence was assessed using multiple methods: The “Basel Assessment of Adherence to Immunosuppressive Medication Scale” (BAASIS^©) questionnaire was used to assess self‐reported adherence. The treating clinician scored patient′s adherence and tacrolimus trough‐concentration variability was calculated. In the analyses, the data from the different tools were dichotomized (adherent/nonadherent). The BAASIS^© overall response rate was over 80%. Intensive BAASIS^© assessment early after transplantation increased the chance of capturing a nonadherence event, but did not influence the 1‐year adherence prevalence. The adherence tools generally captured different populations. Combining the tools, the nonadherence prevalence at 1 year was 38%. The different tools identified to a large degree different patients as nonadherent. Combining these tools is feasible for annual capture of adherence status.     

Significance of patient self‐monitoring for long‐term outcomes after lung transplantation

Kugler C, Gottlieb J, Dierich M, Haverich A, Strueber M, Welte T, Simon A. Significance of patient self‐monitoring for long‐term outcomes after lung transplantation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01197.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Lung transplant (LTx) recipients’ adherence to regular self‐monitoring of lung function (SMLF) is important in maintaining health. This study investigated patients’ behavior based on electronic monitoring (EM) and compared these findings with self‐reported data. Methods: This single‐center study included 269 patients following LTx. Patients reported on adherence regarding SMLF, and data were compared to electronically stored measurements for the last three months prior to self‐reporting. Results: Non‐adherence was 59.4% based on EM for a total of 22 052 measurements performed. Main reported reasons for non‐adherence were forgetfulness (22%), lack of time (19%), and good self‐perception of health status (19%). Determinants for non‐adherence were patients constraining beliefs (p ≤ 0.0001), low perceived support from the transplant center (p ≤ 0.008), a history of infections (p ≤ 0.014) and rejections (p ≤ 0.043), and bronchiolitis obliterans (p ≤ 0.006). Multiple logistic regression revealed low‐perceived support from the transplant center (OR 3.22; 95% CI 1.32–7.83; p < 0.01), and lack of support from patient organizations (OR 2.19; 95% CI 1.02–4.72; p < 0.04) as independent predictors for non‐adherence. Conclusions: LTx recipients had some difficulties maintaining SMLF on a daily basis. Non‐adherence regarding lung function monitoring may provide a clinically relevant estimate of suspect cases for critical events impacting outcomes after LTx.     

Long‐Term Follow‐up of a Randomized Controlled Trial Evaluating a Mobile Health Intervention for Self‐Management in Lung Transplant Recipients

Mobile health interventions may help transplant recipients follow their complex medical regimens. Pocket Personal Assistant for Tracking Health (Pocket PATH) is one such intervention tailored for lung transplant recipients. A randomized controlled trial showed Pocket PATH's superiority to usual care for promoting the self‐management behaviors of adherence, self‐monitoring and communication with clinicians during posttransplant year 1. Its long‐term impact was unknown. In this study, we examined associations between Pocket PATH exposure during year 1 and longer term clinical outcomes—mortality and bronchiolitis obliterans syndrome (BOS)—among 182 recipients who survived the original trial. Cox regression assessed whether (a) original group assignment and (b) performance of self‐management behaviors during year 1 predicted time to outcomes. Median follow‐up was 5.7 years after transplant (range 4.2–7.2 years). Pocket PATH exposure had no direct effect on outcomes (p‐values >0.05). Self‐monitoring was associated with reduced mortality risk (hazard ratio [HR] 0.45; 95% confidence interval [CI] 0.22–0.91; p = 0.027), and reporting abnormal health indicators to clinicians was associated with reduced risks of mortality (HR 0.15; 95% CI 0.04–0.65; p = 0.011) and BOS (HR 0.27; 95% CI 0.08–0.86; p = 0.026), regardless of intervention group assignment. Although Pocket PATH did not have a direct impact on long‐term outcomes, early improvements in self‐management facilitated by Pocket PATH may be associated with long‐term clinical benefit.     

Improving medication adherence and outcomes in adult kidney transplant patients using a personal systems approach: SystemCHANGE™ results of the MAGIC randomized clinical trial

This study determined if a SystemCHANGE? intervention was more efficacious than attention control in increasing immunosuppressive medication adherence and improving outcomes in adult kidney transplant recipients during a 6‐month intervention phase and subsequent 6‐month (no intervention) maintenance phase. The SystemCHANGE? intervention taught patients to use person‐level quality improvement strategies to link adherence to established daily routines, environmental cues, and supportive people. Eighty‐nine patients (average age 51.8 years, 58% male, 61% African American) completed the 6‐month intervention phase. Using an intent‐to‐treat analysis, at 6 months, medication adherence for SystemCHANGE? (median 0.91, IQR 0.76‐0.96) and attention control (median 0.67, IQR 0.52‐0.72) patients differed markedly (difference in medians 0.24, 95% CI 0.13‐0.30, P < .001). At the conclusion of the subsequent 6‐month maintenance phase, the gap between medication adherence for SystemCHANGE? (median 0.77, IQR 0.56‐0.94) and attention control (median 0.60, IQR 0.44‐0.73) patients remained large (difference in medians 0.17, 95% CI 0.06‐0.33, P = .004). SystemCHANGE? patients evidenced lower mean creatinine and BUN at 12 months and more infections at 6 and 12 months. This first fully powered RCT testing SystemCHANGE? to improve and maintain medication adherence in kidney transplant recipients demonstrated large, clinically meaningful improvements in medication adherence. Clinical Trial Registration: NCT02416479.     

Report from the American Society of Transplantation Psychosocial Community of Practice Adherence Task Force: Real‐world options for promoting adherence in adult recipients

Starting in 2015, the American Society of Transplantation Psychosocial Community of Practice, with representatives of the Transplant Pharmacy Community of Practice, convened a taskforce to develop a white paper that focused on clinically practical, evidenced‐based interventions that transplant centers could implement to increase adherence to medication and behavioral recommendations in adult solid organ transplant recipients. The group focused on what centers could do in their daily routines to implement best practices to increase adherence in adult transplant recipients. We developed a list of strategies using available resources, clinically feasible methods of screening and tracking adherence, and activities that ultimately empower patients to improve their own self‐management. We limited the target population to adults because they predominate the research, and because adherence issues differ in pediatric patients, given the necessary involvement of parents/guardians. We also examined broader multilevel areas for intervention including provider and transplant program practices. Ultimately, the task force aims to foster greater recognition, discussion, and solutions required for implementing practical interventions targeted at improving adherence.     

Evaluation of adherence and tolerability of prolonged‐release tacrolimus (Advagraf™) in kidney transplant patients in Germany: A multicenter,noninterventional study

This study assessed adherence to prolonged‐release tacrolimus (PR‐T)‐based immunosuppression during routine maintenance of renal transplant recipients in Germany. Patients had received PR‐T for ≥1 month at inclusion. Data were collected during four visits (V): baseline (V1), 6 (V2), 12 (V3), and 18 (V4) months. Composite primary endpoint: nonadherence at V4, defined as self‐reported nonadherence on the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS^©), investigator‐rated nonadherence, and/or V4 tacrolimus trough level outside a predefined range. Secondary endpoints: individual BAASIS items, incidence of rejection, kidney function, and safety. Overall, 153 adult kidney recipients (mean [standard deviation] time post‐transplant 5.8 [4.6] years) were included. Nonadherence was high at V4 (67.7% [95% confidence interval 58.9%, 75.6%]). Medication‐taking adherence was 86.9% and 91.3% at V1 and V4, respectively; adherence to timing of medication intake was 58.2% and 58.3%, with little evidence of missed doses/drug holidays. Investigators rated adherence “good” in 85.6% of patients (V4). Two (1.3%) patients had acute rejection episodes. Kidney function remained stable (mean creatinine clearance, V1: 62.1 mL/min; V4: 65.3 mL/min). Investigators rated effectiveness of PR‐T as “very good”/“good” in 91.5% of patients. Most patients (94.7%) found PR‐T dosing more convenient than immediate‐release tacrolimus. PR‐T was well tolerated with high medication persistence.     

The Synergistic Effect of Class II HLA Epitope‐Mismatch and Nonadherence on Acute Rejection and Graft Survival

Predicting long‐term outcomes in renal transplant recipients is essential to optimize medical therapy and determine the frequency of posttransplant histologic and serologic monitoring. Nonadherence and human leukocyte antigen (HLA) mismatch are risk factors that have been associated with poor long‐term outcomes and may help individualize care. In the present study, class II HLA mismatches were determined at the HLA epitope level in 195 renal transplant recipients in whom medication adherence was prospectively measured using electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high (≥10 HLA‐DR, ≥17 HLA‐DQ) or low epitope‐mismatch load. We found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss. Nonadherent recipients with HLA‐DR epitope mismatch ≥10 had increased graft loss (35% vs. 8%, p < 0.01) compared to adherent recipients with low epitope mismatch. At the HLA‐DQ locus nonadherent recipients with HLA‐DQ epitope mismatch ≥17 had increased graft loss (33% vs. 10%, p < 0.01) compared to adherent recipients with low epitope mismatch. Subclinical nonadherence early posttransplant combined with HLA class II epitope mismatch may help identify recipients that could benefit from increased clinical, histologic, and serologic monitoring.     

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

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.     

Measuring compliance with drug regimens after renal transplantation: comparison of self-report and clinician rating with electronic monitoring

Nonadherence to immunosuppressants in renal transplant recipients is a major factor affecting graft survival, but it is difficult to detect accurately in clinical practice. Adherence was measured in 153 adult renal transplant recipients using self-report questionnaires and interview, clinician rating, and cyclosporine levels. The sensitivity and specificity of these measures were determined by comparison with electronic monitoring in a randomly selected subsample of 58 subjects. Measures of adherence in current clinical use do not perform well when tested against electronic monitoring. Self-report at a confidential interview was the best measure of adherence for the detection of both missed doses and erratic timing of medication. However, the use of a confidential interview is not directly applicable to a clinical setting. Further research on how best to facilitate disclosure in clinical settings may be the best way to develop adherence measures for use in routine practice.     

Telemedically Supported Case Management of Living‐Donor Renal Transplant Recipients to Optimize Routine Evidence‐Based Aftercare: A Single‐Center Randomized Controlled Trial

Improving mid‐term and long‐term outcomes after solid organ transplantation is imperative, and requires both state‐of‐the‐art transplant surgery and optimization of routine, evidence‐based aftercare. This randomized, controlled trial assessed the effectiveness of standard aftercare versus telemedically supported case management, an innovative aftercare model, in 46 living‐donor renal transplant recipients during the first posttransplant year. The model includes three components: (i) chronic care case management initiated after discharge, (ii) case management initiated in emerging acute care situations, and (iii) a telemedically equipped team comprising a transplant nurse case manager and two senior transplant physicians (nephrologist, surgeon). Analyses revealed a reduction of unplanned inpatient acute care, with considerable cost reductions, in the intervention group. The prevalence of nonadherence over the 1‐year study period was 17.4% in the intervention group versus 56.5% in the standard aftercare group (p = 0.013). Only the intervention group achieved their pre‐agreed levels of adherence, disease‐specific quality of life, and return to employment. This comparative effectiveness study provides the basis for multicenter study testing of telemedically supported case management with the aim of optimizing posttransplant aftercare. The trial was registered with the German Clinical Trials Register ( www.DRKS.de ), DKRS00007634.