BTS 2013 Report – Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomised controlled trial using electronic monitoring

by Maria Dalby reporting on the presentation by Fabienne Dobbels, Leuven Hospital, Belgium.  The Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograf to Advagraf (ADMIRAD) study is the first fully powered adherence intervention study in kidney transplantation patients that has used a rigorous methodology with electronic monitoring of treatment adherence(1). The primary analysis of ADMIRAD showed that conversion from twice-daily to once-daily tacrolimus resulted in a 10% improvement in adherence, both in terms of taking the drug and dosing regularity. Professor Fabienne Dobbels from Belgium is one of the co-authors on ADMIRAD and presented the results on behalf of the study team.


Although graft survival following kidney transplantation has overall improved dramatically in recent years, the main improvement has occurred in the immediate post-transplant phase – long-term post-transplant graft survival has remained largely the same over the last ten years (2). Improving this situation is an area of intense research, with a range of measures preventing graft loss being studied. One prominent strategy is to address adherence to immunosuppressive therapy (3). A review of recent adherence-enhancing intervention studies in adult transplant recipients revealed that of a total of only ten studies found, the majority suffered from methodological shortcomings and no consistent positive outcome could be discerned (4); however, studies in other chronic conditions have demonstrated clearly that reducing the number of daily doses can significantly improve treatment adherence (5), and switching from twice-daily to once-daily administration may increase adherence by as much as 44% (6). The objective of the ADMIRAD study was to establish whether this is the case also amongst kidney transplant recipients.


Following a run-in period to determine baseline adherence, a total of 219 patients were randomised 2:1 to tacrolimus administered once daily or twice daily, with electronic monitoring of adherence (using the Helping Hand™ electronic adherence monitor for blister packs) for a study period of six months. The primary outcome measure was adherence to treatment, defined as persistence (the length of time the patient remained on the treatment) and level of implementation (the day-by-day proportion of patients taking their medication correctly and consistently).


The persistence data showed that there was a trend for patients in the once-daily arm to remain on their treatment for longer overall, although this difference did not reach statistical significance (81.5% vs. 71.9%; p=0.0824). Amongst those patients who remained on their treatment, 88.2% in the once-daily arm and 78.8% in the twice-daily arm took the prescribed number of daily doses (p=0.0009). Patients in the twice-daily arm missed on average 11.7% of doses in the morning vs. 14.2% of doses in the evening (p=0.0035), and there was also considerable variation throughout the week with more evening doses being missed on Tuesdays and Saturdays compared with the rest of the week. Patients in the once-daily arm required a higher number of dose adjustments (1.7 vs. 1.0; p=0.009) and plasma concentration checks (3.8 vs. 3.4; p=0.09) after conversion from twice-daily treatment, but this difference was only significant during the first two weeks post-conversion. No rejection episodes occurred during the study period and there was no difference in the adverse event rate.


Professor Dobbels concluded that although once-daily administration of tacrolimus significantly improves regimen implementation when switching from a twice-daily regimen, there is room for additional interventions to further improve adherence throughout the kidney transplant recipient population. To this end, Professor Dobbels and the team at the Leuven centre have launched the Transplant360 initiative, sponsored by Astellas Pharma, with the aim of developing educational tools and resources to support transplant recipients in staying healthy after transplantation. Some of the tools available for healthcare professionals include booklets and DVDs, a pocket intervention guide, questionnaires to assess adherence, and access to a free online training course on motivational interviewing. The Transplant360 task force includes healthcare professionals and representatives from patient organisations from across Europe.


1.  Kuypers DR, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013;95(2):333-40. Epub 2012/12/25.

2  Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2011;11(3):450-62. Epub 2010/10/27.

3.  Nankivell BJ, Kuypers DR. Diagnosis and prevention of chronic kidney allograft loss. Lancet. 2011;378(9800):1428-37. Epub 2011/10/18.

4.  De Bleser L, Matteson M, Dobbels F, Russell C, De Geest S. Interventions to improve medication-adherence after transplantation: a systematic review. Transplant international : official journal of the European Society for Organ Transplantation. 2009;22(8):780-97. Epub 2009/04/24.

5.  Kripalani S, Yao X, Haynes RB. Interventions to enhance medication adherence in chronic medical conditions: a systematic review. Archives of internal medicine. 2007;167(6):540-50. Epub 2007/03/29.

6.  Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. The American journal of managed care. 2009;15(6):e22-33. Epub 2009/06/12.