© 2013 direct one communications, inc. all rights reserved. 1 improving medication adherence and...

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

Improving Medication Adherence and Outcomes in Transplant Recipients

Martin I. Montenovo, MD

University of Washington Medical Center, Seattle, Washington

A REPORT FROM THE 2013 AMERICAN TRANSPLANT CONGRESS


Defining Adherence

Adherence is “The extent to which a person’s behavior—taking medication, following a diet, and/or executing lifestyle changes—corresponds with the agreed recommendations from a healthcare provider.”1

Among transplant recipients, nonadherence to immunosuppressive medication is a major risk factor for rejection and allograft loss. » More prevalent than previously assumed,

» Difficult to measure accurately,

» Linked to worse outcomes,

» And difficult to change from a behavioral perspective.2


The Scope of the Problem

In a meta-analysis, Dew et al3 found medication nonadherence across all types of solid organ transplants to be 22.6 cases/100 patient-years.

An estimated 50% (range, 20%–73%) of late acute allograft rejections and 15% (range, 3%–35%) of graft loss are linked to medication nonadherence.4,5

Pinsky et al6 identified an increase of $12,840 (US) in individual 3-year medical costs for patients who exhibit persistently low compliance.

Cleemput et al7 reported that renal transplantation is more cost-effective than is hemodialysis, even if patients are nonadherent post transplant.


Impact of Nonadherence

Nonadherence to an immunosuppressive drug regimen may be defined as deviation from the prescribed medication plan sufficient to adversely influence the regimen’s intended effect.

» Post-transplant nonadherence is common, ranging from 5% to > 45% of patients in different studies.8

» Nonadherence rates increase dramatically > 6 months post transplantation.

» Accurately quantifying nonadherence can be difficult because of inconsistent methodology.

» Nonadherence adverse effects on transplant outcomes include rejection episodes, graft loss, and consequent resumption of dialysis.



Butler et al8 performed a meta-analysis of 36 cross-sectional and cohort studies and case series.» The odds of graft failure increased sevenfold in

nonadherent subjects when compared with adherent subjects (P < 0.001).

» Standardized methods to assess medication adherence in clinical populations must be developed.

» Future studies should identify the level of adherence that increases the risk of graft failure.

Nonadherence is common and greatly impacts transplant survival.» Institution of effective interventions to improve

adherence may provide significant improvements in graft survival.



Vlaminck et al9 monitored adherence among 146 adult kidney transplant recipients. Nonadherent patients (22.6% of the total) demonstrated progressive worsening of renal function over time, even in the absence of acute rejection; more likely had markers of antibody activation at biopsy than did adherent patients with renal dysfunction; and had substantially more interstitial fibrosis and tubular atrophy than did medically compliant patients.



Sellarés et al10 followed 315 kidney transplant recipients who were biopsied 6 days to 32 years after surgery; 60 kidneys progressed to renal failure during the follow-up period (median, 31.4 months).

Glomerulonephritis or antibody-mediated rejection (ABMR) accounted for most cases of renal failure.

Among patients with rejection losses, 17 of 36 (47%) were independently identified by their physicians as being nonadherent.

Medication nonadherence was identified in 32% of patients who progressed to renal failure and 3% of those who survived.


Role of Antibody-mediated Rejection

Antibody-mediated rejection (ABMR), in whole or in part, was responsible for 64% of cases of renal failure among 315 kidney transplant patients. Nearly half (47%) of these episodes were due to medication nonadherence.10


Electronic Medication Monitoring

Electronic medication monitoring is the gold standard for measuring adherence to oral medication.

It involves a microdevice in the cap that records each time a medication bottle is opened.

Primarily a research tool, its limitations include the lack of:

» Certainty that the medication or correct dose was ingested

» Availability of these devices in community pharmacies

» Means and personnel to monitor and record data in clinical practice and analyze the information over time


Self-reporting and Other Measures Patients may not be willing to disclose medication nonadherence, even

in nonthreatening circumstances

Prescription refill rates correlate with adherence; however, they may be difficult to monitor in clinical practice and reveal nothing about the timing of ingestion or daily usage.

Drug-level monitoring, when used as a surrogate for compliance, may be a potentially useful metric for measuring adherence but is subject to “white coat” bias when patients increase adherence before their blood or urine is sampled.


Nonadherence Behavioral Patterns

Behavioral patterns of medication nonadherence should be evaluated to:

Reduce nonadherence in the future

Help physicians understand patients’ clinical outcomes

Develop evidence-based screening tools for patients most likely at risk of nonadherence

Design interventions to help prevent nonadherence in the patient population


Identifying Nonadherent Patients

Greenstein and Siegal11 identified three groups of noncompliers with different origins and needs of intervention: » Accidental noncompliers (47%)

» Invulnerable noncompliers who had a belief of invincibility (28%)

» Decisive noncompliers (25%)

Other common reasons for noncompliance include:

» Oversleeping

» Experiencing work-related barriers and forgetfulness

» Forgetting to refill medications

» Traveling without medication


Effects of Reducing the Dosing Frequency

Beckebaum and others12 examined efficacy, safety, and immunosuppressant adherence in 125 stable liver transplant patients switched from twice-daily tacrolimus to once-daily tacrolimus.

» Decreasing the dosing frequency reduced nonadherence rate from 66.4% at study entry to 30.9% post conversion (P < 0.0001).

» Prevalence of nonadherence at baseline was significantly higher among patients converted > 2 years after liver transplant and those 60 years of age and younger.

» Converting to once-daily tacrolimus proved to be safe and enhanced immunosuppressant adherence.


Managing Adverse Effects

Toledo and colleagues13 studied 31 liver transplant patients treated with mycophenolate mofetil who had gastrointestinal (GI) disturbances post transplant and were converted to equimolar enteric-coated mycophenolate sodium.

» The overall GI Symptom Rating Scale score improved significantly from baseline to 1 month and 3 months, with significant reductions in all patient subgroups except the GI reflux subgroup.

» All patient subgroups except the social functioning and medical treatment subgroups showed significant improvements in overall GI Quality-of-Life Index between 1 month and 3 months.13


Managing Adverse Effects

Improvement in gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in 31 liver transplant recipients. GSRS = GI Symptom Rating Scale. * P = 0.0012; ** P = 0.1484; *** P = 0.0003; **** P = 0.0071; ***** P = 0.004.13


Access to Immunosuppressants

Woodward et al14 investigated whether Medicare’s extension of maintenance immunosuppressants from 1 to 3 years following surgery would improve graft survival among low-income renal transplant recipients.

No differences in graft survival at 1 year were found between low-income and high-income patients.

When immunosuppressants were covered by Medicare for only 1 year, graft survival at 3 years was 4.5% lower among low-income patients.

When Medicare provided 3 years of drug coverage (1994–1997), graft survival at 3 years was the same between low- and high-income patients.


The Effect of Age

Greenstein and Siegal11 discovered that 22.4% of 1,402 respondents using immunosuppressants were noncompliant.

Factors most predictive of noncompliance were:

» Age

» Occupation

» Time since transplant

» Three medication-related beliefs


Effect of Patient Age on Adherence

Pinsky and colleagues6 analyzed Medicare claims for immunosuppressants among 15,525 renal transplant recipients with at least 1 year of graft function to evaluate long-term adherence as a function of age.

Adolescents and young adults, 19–24 years of age, were more likely to be persistently nonadherent than were patients 25–44 years of age.

At the other end of the age spectrum, patients who were 65 years of age and older were more likely to be nonadherent than younger adults, possibly due to poorer verbal memory skills and cognitive impairments affecting medication compliance.


Improving Medication Adherence Delaying renal transplantation until patients

demonstrate adherence to a dialysis regimen.

Educating patients about the importance of taking immunosuppressive agents as directed, possibly using repetitive teaching and a team approach

Simplifying the dosing regimen (fewer drugs, less-frequent dosing by switching to extended-release immunosuppressant formulations)

Switching to biologic immunosuppressants such as belatacept for chronic maintenance therapy via monthly intravenous infusions15


Improving Medication Adherence Using social media (eg, Facebook, Twitter) and

cutting-edge technology (eg, smartphone and tablet apps and pocket-sized personal computers) to educate and keep in touch with transplant recipients.

Sending regularly scheduled text-message reminders to transplant recipients or their caregivers can result in significant improvements in medication adherence.16

Having social workers help patients access benefits they are entitled to also can enhance adherence to immunosuppressive drug regimens by making the drugs more affordable.


References1. Sabaté E. Adherence to long-term therapies—evidence for action. World Health Organization Report.

Geneva, Switzerland: World Health Organization; 2003.

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

3. Dew MA, DiMartini AF, De Vito DA, et al. Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation. Transplantation. 2007;83:858–873.

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

5. Dobbels F, Damme-Lombaert R, Vanhaecke J, et al. Growing pains: non-adherence with the immunosuppressive regimen in adolescent transplant recipients. Pediatr Transplant. 2005;9:381–390.

6. Pinsky BW, Takemoto SK, Lentine KL, et al. Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression. Am J Transplant. 2009;9:2597–2606.

7. Cleemput I, Kesteloot K, Vanrenterghem Y, et al. The economic implications of non-adherence after renal transplantation. Pharmacoeconomics. 2004;22:1217–1234.

8. Butler JA, Roderick P, Mullee M, et al. Frequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review. Transplantation. 2004;77:769–776.

9. Vlaminck H, Maes B, Evers G, et al. Prospective study on late consequences of subclinical noncompliance with immunosuppressive therapy in renal transplant patients. Am J Transplant. 2004;4:1509–1513.

10. Sellarés J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012;12:388–399.

11. Greenstein S, Siegal B. Compliance and noncompliance in patients with a functioning renal transplant: a multicenter study. Transplantation. 1998;66:1718–1726.


References12. Beckebaum S, Iacob S, Sweid D, et al. Efficacy, safety, and immunosuppressant adherence

in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation. Transpl Int. 2011;24:666–675.

13. Toledo AH, Hendrix L, Buchholz V, et al. Improvement of gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients. Clin Transplant. 2012;26:156–163.

14. Woodward RS, Schnitzler MA, Lowell JA, et al. Effect of extended coverage of immunosuppressive medications by Medicare on the survival of cadaveric renal transplants. Am J Transplant. 2001;1:69–73.

15. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant. 2010;10:535–546.

16. Miloh T, Annunziato R, Arnon R, et al. Improved adherence and outcomes for pediatric liver transplant recipients by using text messaging. Pediatrics. 2009;124:844–850.

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