Transcript Slide 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
© 2013 Direct One Communications, Inc. All rights reserved.
1
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
© 2013 Direct One Communications, Inc. All rights reserved.
2
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
© 2013 Direct One Communications, Inc. All rights reserved.
3
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
© 2013 Direct One Communications, Inc. All rights reserved.
4
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.
© 2013 Direct One Communications, Inc. All rights reserved.
5
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
© 2013 Direct One Communications, Inc. All rights reserved.
6
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
© 2013 Direct One Communications, Inc. All rights reserved.
7
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.
© 2013 Direct One Communications, Inc. All rights reserved.
8
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.
© 2013 Direct One Communications, Inc. All rights reserved.
9
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.
© 2013 Direct One Communications, Inc. All rights reserved.
10
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.
© 2013 Direct One Communications, Inc. All rights reserved.
11
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.
© 2013 Direct One Communications, Inc. All rights reserved.
12
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.
© 2013 Direct One Communications, Inc. All rights reserved.
13
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
© 2013 Direct One Communications, Inc. All rights reserved.
14
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.
© 2013 Direct One Communications, Inc. All rights reserved.
15
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.
© 2013 Direct One Communications, Inc. All rights reserved.
16
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
© 2013 Direct One Communications, Inc. All rights reserved.
17
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.
© 2013 Direct One Communications, Inc. All rights reserved.
18
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.
19
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.
© 2013 Direct One Communications, Inc. All rights reserved.
20
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.
© 2013 Direct One Communications, Inc. All rights reserved.
21