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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
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.
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.
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
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.
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.
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
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
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.
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 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.