Download Slide 1 - The Immunology Report

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
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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
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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
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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
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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.
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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
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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
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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.
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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.
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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.
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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.
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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.
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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 twicedaily 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.
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Studies of Once-daily Tacrolimus

The TAESR trial24 was a prospective, randomized,
controlled study that compared adherence to oncedaily 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
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Studies of Once-daily Tacrolimus

Harada et al25 retrospectively looked at 121 kidneytransplant 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.
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Studies of Once-daily Tacrolimus

Oh et al26 performed a multicenter, randomized
clinical investigation of 60 kidney transplant
recipients.

One month postoperatively, patients used twicedaily tacrolimus or switched to the daily extendedrelease 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.
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Studies of Once-daily Tacrolimus

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
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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 oncedaily 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.
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References
1.
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.
© 2013 Direct One Communications, Inc. All rights reserved.
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References
11. 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.
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References
21. 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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