Impact of Once- Versus Twice-Daily Tacrolimus Dosing on Medication Adherence in Stable Renal Transplant Recipients: A Canadian Single-Center Randomized Controlled Trial

Abstract

Background: Prevalence of immunosuppressant nonadherence in renal transplant recipients is high despite negative clinical outcomes associated with nonadherence. Simplification of dosing has been demonstrated to improve adherence in renal transplant recipients as measured through electronic monitoring and self-report.

Objective: The purpose of this study was to replicate and extend previous findings by measuring adherence with multiple methods in a Canadian sample.

Design: The study design was a randomized controlled medication dosing trial in adult renal transplant patients. The trial length was 4 months.

Setting: This study was conducted within the Solid Organ Transplant (SOT) Clinic at Vancouver General Hospital (VGH; Vancouver, Canada).

Patients: A total of 46 adult renal recipients (at least 1 year post-transplant) were recruited through the SOT clinic. With 8 withdrawals, 38 individuals completed all phases of the study.

Measurements: Medication adherence was measured for a period of 4 months using multiple methods, including electronic monitoring (MEMS [Medication Event Monitoring System]), pharmacy refill data (medication possession ratio [MPR]), and by self-report using the Adherence subscale of the Transplant Effects Questionnaire (TEQ).

Methods: Participants were randomized to twice-daily (n = 19) or once-daily tacrolimus dosing (n = 19) and followed over a 4-month period via monthly clinic study visits. Comparisons between the treatment groups were performed using the Mann-Whitney U and chi-square tests, for continuous and categorical variables, respectively.

Results: As outlined in Table 3, the once-daily dosing group showed significantly better MEMS Dose Adherence (P = .001), whereas MEMS Timing Adherence showed a tendency toward better adherence for this group, but was not significant (P = .052). MEMS Days Adherent (P = .418), MPR% (P = .123), and self-reported adherence (P = .284) did not differ between the once- and twice-daily dosing groups when measured as continuous variables. The MPR% was significantly better for the once-daily dosing group when measured dichotomously but not continuously (P = .044). Notably, most of those exposed to once-daily dosing (63.2%) preferred this to the twice-daily regimen.

Limitations: Limitations included small sample size and short follow-up period, precluding the examination of clinical outcome differences.

Conclusions: Results for dose adherence replicate the finding that dose simplification increases adherence to immunosuppressants as measured through electronic monitoring. Such an advantage for the once-daily dosing group was not seen across the 2 other electronic monitoring measurement variables (days and timing adherence). This study extends previous research by examining adherence in once versus twice-daily dosing via prescription refill data in a Canadian sample. Given the gravity of potential health outcomes associated with nonadherence, although results indicate inconsistencies in significance testing across measurement methods, the medium to large effect sizes seen in the data favoring better adherence with once-daily dosing provide an indication of the potential clinical significance of these findings.

Trial registration: This study was registered with ClinicalTrials.gov (NCT01334333) on April 11, 2011.

Keywords: Advagraf; Prograf; electronic monitoring; medication adherence; renal transplantation; tacrolimus.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.

Participant recruitment flowchart. Note. Regarding inclusion/exclusion criteria at intake, participants who indicated less than 3 of 4 preferences as “English” for speaking, reading, writing, and thinking on an acculturation questionnaire were considered ineligible due to language requirements for neurocognitive testing necessary for the larger study, of which these participants were a part; in addition, those reporting any of the abovementioned physical or mental health exclusions were ineligible. Not interested = participants who declined study participation due to lack of interest; Not scheduled = participants who expressed interest in the study, but who had scheduling conflicts and did not participate.