© 2013 direct one communications, inc. all rights reserved. 1 nonadherence to immunosuppressive...

© 2013 Direct One Communications, Inc. All rights reserved. 1

Nonadherence to Immunosuppressive Medication: New Insights

Kasi R. McCune, MD

University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

A REPORT FROM THE 2013 AMERICAN TRANSPLANT CONGRESS


Medication Nonadherence

Nonadherence to immunosuppressive medication is a major, preventable cause of late graft loss in all types of solid organ transplants.

The prevalence may be as high as 23% across all solid organ transplant groups.1

From 15% to 60% of late acute graft rejections are associated with nonadherence, as are 5%–36% of all graft losses in solid organ transplant patients.2–6


Definitions and Measures

Nonadherence may be defined as “deviation from the prescribed medication regimen sufficient to adversely influence the regimen’s intended effect.”7

Direct measures: observations of medication intake and biologic assays of drug levels or drug metabolites in the blood or urine.

Indirect measures: patient self-reporting, collateral reports from family members or clinicians, pill counts, prescription fills, and electronic monitoring.8

When compared with electronic monitoring, no tool to study medical nonadherence demonstrates both high sensitivity and high specificity.9


Adherence Scales

The Immunosuppressant Therapy Adherence Scale (ITAS)

» A 5-item questionnaire exploring how often patients are noncompliant with prescribed immunosuppressive medications, validated in 200510,11

The Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS)

» Examines dosing habits over 4 weeks12

» Patients record information on several factors, such as adherence in taking the medicine, dosing on schedule, having drug holidays, and reducing doses.12


Misunderstanding and Nonadherence

Serper et al13 examined medical nonadherence among 192 liver and kidney transplant recipients in the context of medical misunderstanding.

Patients were interviewed to assess demographics, health literacy, cognitive function, social support, medication adherence, and ability to fill a pill tray.

Adherence was determined via self-reporting and measurement of serum tacrolimus levels.

Identified risk factors of nonadherence were poor scoring on the health literacy test, older age, greater complexity of the medical regimen, and a time span < 2 years since transplant.


Risk Factors for Nonadherence

Sanders-Pinheiro et al14 conducted a cross-sectional study of nonadherence among 100 kidney transplant recipients using the self-administered BAASIS tool, collateral reports from the treating physicians, and immunosuppressive medication serum levels.

In addition, they collected demographic data to fulfill the five World Health Organization’s dimensions for nonadherence: socioeconomic, therapy-related, patient-related, condition-related, and healthcare team–related.15


Risk Factors for Nonadherence

More than half (51%) of the kidney transplant recipients Sanders-Pinheiro et al14 studied did not adhere to their immunosuppressive medication.

Among the nonadherent patients, 89% had received an organ from a living donor, 65% were male, and 72% were white.

Risk factors for medication nonadherence included:

» Living > 100 km from a transplant center

» Having a high family income

» Having access to private insurance


Behaviors and Nonadherence

Weng et al16 interviewed 18 patients identified as being nonadherent according to their ITAS scores.

They probed medication-taking behaviors, tools used to remind them to take medication, descriptions of missed doses, and advice for transplant patients.

Risk factors for nonadherence included variations in patients’ routines and severe emotional and psychological issues.

Less-adherent patients were more passive in their response to missed doses, whereas more-adherent patients used missed doses to learn from their mistakes.


Nonadherence and Graft Failure

Gaynor et al17 prospectively followed a cohort of 628 kidney transplant recipients. Graft failure due to nonadherence represented

48.1% of death-censored graft failures 24 months post transplant.

Transplant recipients < 35 years of age and nonwhite transplant recipients had an increased risk of graft loss due to nonadherence.

Among nonwhite transplant recipients < 35 years old, 52% of graft losses resulted from nonadherence.

Among white transplant recipients > 50 years old, 0% of grafts were lost due to nonadherence.


Nonadherence and Graft Failure

Fischbach et al18 defined nonadherence as not using immunosuppressants for 7 days and/or missing more than three clinical appointments over 1 year.

Nearly a third (32.2%) of the renal transplant recipients they studied lost their grafts because of nonadherence, the most common cause of graft loss.

The only characteristic significantly associated with nonadherence was age < 50 years at transplant.

Nonadherence was independent of gender, race, or whether grafts came from cadavers or live donors or whether patients underwent single- or dual-organ transplants.


Summary

Nonadherence was found in 24%–51% of patients across five studies.17–21

Two studies found that younger age was a risk factor.

One study concluded that older age was a risk factor for nonadherence.

Another study proposed that limited health literacy was a risk factor.

Greater complexity of drug regimens and having transplant surgery 2 years or less before being interviewed were risk factors.


MORE Study

The MORE Study was a 4-year, prospective study conducted at 40 US sites.22

» It compared adherence among kidney transplant recipients using enteric-coated mycophenolate sodium (EC-MPS) versus mycophenolate mofetil (MMF).

» Nonadherence was defined as an ITAS score < 11.

49.7% of patients were nonadherent at some point.

» Patients taking EC-MPS were more likely to score better on the ITAS and to maintain their prescribed dose of medication at 1 year.

» Age, gender, and delayed graft function were not risk factors for nonadherence, although being black was.


Studies of Once-daily Tacrolimus

Cantarovich et al23 included 1,190 patients in a multicenter longitudinal study of extended-release, once-daily tacrolimus over 6 months.

7% were given once-daily tacrolimus immediately after surgery; the rest were switched from twice-daily to once-daily tacrolimus during follow-up (mean, 4.8 years).

Once-daily tacrolimus increased adherence by 20%.

» Only 10.5% of patients required a dose change.

» Four patients (3 kidney transplant recipients and 1 liver transplant recipient, or < 1% of the study population) experienced an acute rejection episode.



The TAESR trial24 was a prospective, randomized, controlled study that compared adherence to once-daily vs twice-daily tacrolimus after alemtuzumab induction and rapid steroid withdrawal at 7 days.

Among 50 renal transplant recipients, rejection-free graft survival at 1 year was the same across both treatment groups.

No significant differences were found in mean graft function, tacrolimus levels, tacrolimus trough levels, or subclinical graft rejection, as assessed by biopsy at 3 months and 1 year



Harada et al25 retrospectively looked at 121 kidney-transplant recipients, half of whom used twice-daily tacrolimus and the other half, once-daily tacrolimus plus MMF, basiliximab, and corticosteroids.

Seven patients dropped out of the once-daily tacrolimus group because of a “presumably adverse event.”

At 1 year, the number of acute graft rejections, opportunistic infections, and cases of biopsy-proven calcineurin nephrotoxicity were the same in both treatment arms.



Oh et al26 performed a multicenter, randomized clinical investigation of 60 kidney transplant recipients.

One month postoperatively, patients used twice-daily tacrolimus or switched to the daily extended-release formulation and were followed for 6 months.

At 5 months, biopsy-confirmed rejection was 0% among the group given once-daily tacrolimus and 10.7% among patients given twice-daily tacrolimus.

There were no differences in patient survival (100%), glomerular filtration rate, or safety and satisfaction profiles between the two treatment arms.



In a 1-year study, Andrés et al27 investigated the efficacy and safety of extended-release tacrolimus among 153 renal transplant recipients given grafts from various types of donors.

Patients began using extended-release tacrolimus immediately after transplant.

» There was no difference in tacrolimus levels.

At 1 year, graft survival was 91%, and patient survival was 95%.

» Acute rejection was low in all groups but was highest in the group given grafts from standard-criteria donors, which had the most hyperimmunized subjects.27


Summary

All but one study found that tacrolimus dosing and serum levels were similar when patients taking tacrolimus once daily were compared with those using twice-daily dosing.

One study with 1,190 patients reported a 20% improvement in adherence among users of the once-daily formulation.

Reducing dosing from twice daily to once daily by switching to an extended-release formulation drug can be safe and effective if serum tacrolimus trough levels are reviewed regularly.


References1. Dew M, Dimartini AF, De Vito Dabbs A, et al. Rates and risk factors for nonadherence to the

medical regimen after adult solid organ transplantation. Transplantation. 2007;83:858–873.

2. Dobbels F, Lut B, De Geest S, et al; Transplant 360 Task Force. The psychometric properties and practicability of self-report instruments to identify medication non-adherence in adult transplant patients to date: a systematic review. Transplantation. 2010;90:205–219.

3. Butler JA, Peveler RC, Roderick P, et al. Measuring compliance with drug regimens after renal transplantation: comparison of self-report and clinician rating with electronic monitoring. Transplantation. 2004;77:786.

4. Denhaerynck K, Dobbels F, Cleemput I, et al. Prevalence, consequences, and determinants of nonadherence in adult renal transplant patients: a literature review. Transplant Int. 2005;18:1121–1133.

5. Desmyttere A, Dobbels F, Cleemput I, De Geest S. Noncompliance with immunosuppressive regimen in organ transplantation: is it worth worrying about? Acta Gastroenterol Belg. 2005;68:347–352.

6. De Geest S, Dobbels F, Fluri C, et al. Adherence to the therapeutic regimen in heart, lung, and heart-lung transplant recipients. J Cardiovasc Nurs. 2005;20(5 suppl):S88–S98.

7. Fine RN, Becker Y, De Geest S, et al. Nonadherence consensus conference summary report. Am J Transplant. 2009;9:35–41.

8. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487–497.

9. Schafer-Keller P, Steiger J, Bock A, Denhaerynck K. Diagnostic accuracy of measurement methods to assess non-adherence to immunosuppressive drugs in kidney transplant recipients. Am J Transplant. 2009;8:616–626.

10. Chisholm MA, Lance CE, Williamson GM, Mulloy LL. Development and validation of the immunosuppressant therapy adherence instrument (ITAS). Patient Educ Couns. 2005;59:13–20.


References11. Chisholm MA, Lance CE, Williamson GM, Mulloy LL. Development and validation of an

immunosuppressant therapy adherence barrier instrument. Nephrol Dial Transplant. 2005;20:181–188.

12. Cleemput I, Dobbels F. Measuring patient-reported outcomes in solid organ transplant recipients: an overview of instruments developed to date. Pharmacoeconomics. 2007;25:269–286.

13. Serper M, Patzer R, Przytula K, et al. Determinants of medication misunderstanding and non-adherence among kidney and liver transplant recipients [abstract]. Am J Transplant. 2013;13(suppl 5):259.

14. Sanders-Pinheiro H, Marsicano E, Fernandes N, et al. Risk factors to non-adherence in kidney transplantation patients applying triangulation methodology in a universal access medication health system [abstract]. Am J Transplant. 2013;13(suppl 5):273–274.

15. World Health Organization. Overview: Medication Adherence—Where Are We Today? Geneva, Switzerland: World Health Organization; 2006:1–16.

16. Weng F, Clark E, Chandwani K, et al. Medication non-adherence after kidney transplantation: a qualitative study using depth interviews of adherent and non-adherent patients [abstract]. Am J Transplant. 2013;13(suppl 5):274.

17. Gaynor J, Ciancio G, Guerra G, et al. Noncompliance as a major cause of late graft failure in kidney transplantation [abstract]. Am J Transplant. 2013;13(suppl 5):419.

18. Fischbach B, Gonzalez S, Chandrakantan A, et al. Medical nonadherence as a cause of renal allograft failure: a ten year single center retrospective analysis [abstract]. Am J Transplant. 2013;13(suppl 5):423.

19. Prendergast MB, Gaston RS. Optimizing medication adherence: an ongoing opportunity to improve outcomes after kidney transplantation. Clin J Am Soc Nephrol. 2010;5;1305–1311.

20. Germani G, Lazzaro S, Gnoato F, et al. Nonadherent behaviors after solid organ transplantation. Transplant Proc. 2011;43:318–323.


References21. Hardinger KL, Hutcherson T, Preston D, Munillo D. Influence of pill burden and drug cost on

renal function after transplantation. Pharmacotherapy. 2012;32:427–432.

22. Tsapepas D, Langone L, Chan A, et al. Adherence with immunosuppressive therapy: results to 4 years after kidney transplantation in the Mycophenolic Acid Observational Renal Transplant (MORE) study [abstract]. Am J Transplant. 2013;13(suppl 5):338.

23. Cantarovich D, Cointault O, Loupy A, et al. Advagraf immunosuppression initiation in kidney and liver transplant recipients: 3 month-interim analysis of a French multicenter observational study [abstract]. Am J Transplant. 2013;13(suppl 5):261.

24. McLean A, Chan K, Galliford J, et al. 1-Year outcomes of a prospective, open label, randomized, controlled trial of standard vs extended-release tacrolimus as maintenance monotherapy in kidney transplantation after alemtuzumab induction with rapid steroid withdrawal (TAESR trial) [abstract]. Am J Transplant. 2013;13(suppl 5):358.

25. Harada H, Fukuzawa N, Hotta K, et al. Once-daily extended-release formulation of tacrolimus does not require double dose of twice-daily formulation of tacrolimus in kidney transplantation [abstract]. Am J Transplant. 2013;13(suppl 5):315.

26. Oh C, Huh J, Lee J, et al. Multicenter randomized clinical investigation for the safety and efficacy of Advagraf (extended-release tacrolimus) vs Prograf (twice-daily tacrolimus) in de novo Korean adult kidney recipients [abstract]. Am J Transplant. 2013;13(suppl 5):317.

27. Andrés A, Gonzalez E, Polanco N, et al. Extended-release tacrolimus therapy is effective and safe in de novo kidney transplant recipients from living and expanded, standard, or after cardiac death deceased donors [abstract]. Am J Transplant. 2013;13(suppl 5):428.

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