Medication Adherence
James Neuberger DM, FRCP
Honorary Consultant Physician
Queen Elizabeth Hospital, Birmingham, UK
Search for more papers by this authorJames Ferguson MD, FRCPE
Consultant Hepatologist
Queen Elizabeth Hospital and Hon Reader in Medicine, University of Birmingham, Birmingham, UK
Search for more papers by this authorPhilip N. Newsome PhD, FRCPE
Professor of Experimental Hepatology and Director of the Centre for Liver and Gastrointestinal Research Consultant Transplant Hepatologist
University of Birmingham
Queen Elizabeth Hospital, Birmingham, UK
Search for more papers by this authorMichael Ronan Lucey MD, FRCPI
Professor of Medicine and Chief
Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Search for more papers by this authorSummary
The term “adherence” describes the degree to which a patient can follow a prescribed medication and treatment plan agreed by the patient and the medical provider. An essential component of adherence is the patient's willingness to participate and cooperate in their medical care. Medication adherence is one of the most important aspects of post-transplantation management. Methodology utilized for the measurement of adherence varies widely between studies, thus making the determination of overall prevalence of non-adherence within a population challenging. This chapter explores the methods for adherence measurement. Medication non-adherence is arguably one of the most important modifiable risk factors for poor graft function, rejection, and graft loss, and it is costly to both the individual and the healthcare system. Interventions that have demonstrated success in improving rates of adherence are numerous, and include electronic applications, educational interventions, and interventions that aim to change behavior through patient-driven initiatives.
Further reading
- Aceto P, Perilli V, Lai C, Ciocchetti P, Vitale F, Sollazzi L. Postoperative cognitive dysfunction after liver transplantation. Gen Hosp Psychiatr. 2015; 37: 109–115.
- Acri T, TenHave TR, Chapman JC, Bogner HR, Gross R. Lack of association between retrospectively collected pharmacy refill data and electronic drug monitoring of antiretroviral adherence. AIDS Behav. 2010; 14: 748–754.
- Ahmed I, Ahmad NS, Ali S, Ali S, George A, Saleem Danish H, et al. Medication adherence apps: review and content analysis. JMIR Mhealth Uhealth. 2018; 6: e62.
- Aikens JE, Rosland AM, Piette JD. Improvements in illness self-management and psychological distress associated with telemonitoring support for adults with diabetes. Prim Care Diabetes. 2015; 9: 127–134.
- Annunziato RA, Baisley MC, Arrato N, Barton C, Henderling F, Arnon R, et al. Strangers headed to a strange land? A pilot study of using a transition coordinator to improve transfer from pediatric to adult services. J Pediatr. 2013; 163: 1628–1633.
- Asavakarn S, Sirivatanauksorn Y, Promraj R, Ruenrom A, Limsrichamrern S, Kositamongkol P, et al. Systematic pharmaceutical educational approach to enhance drug adherence in liver transplant recipients. Transplant Proc. 2016; 48: 1202–1207.
- Beckebaum S, Iacob S, Sweid D, Sotiropoulos GC, Saner F, Kaiser G, 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.
- Benjamin RM. Medication adherence: helping patients take their medicines as directed. Public Health Rep. 2012; 127: 2–3.
- Blowey DL, Hebert D, Arbus GS, Pool R, Korus M, Koren G. Compliance with cyclosporine in adolescent renal transplant recipients. Pediatr Nephrol. 1997; 11: 547–551.
- Bucuvalas JC, Ryckman FC, Arya G, Andrew B, Lesko A, Cole CR, et al. A novel approach to managing variation: outpatient therapeutic monitoring of calcineurin inhibitor blood levels in liver transplant recipients. J Pediatr. 2005; 146: 744–750.
- Bunzel B, Laederach-Hofmann K. Solid organ transplantation: are there predictors for posttransplant noncompliance? A literature overview. Transplantation. 2000; 70: 711–716.
- Burra P, Germani G, Gnoato F, Lazzaro S, Russo FP, Cillo U, et al. Adherence in liver transplant recipients. Liver Transpl. 2011; 17: 760–770.
- Busuttil RW, Duffy JP. Long-term functional recovery and quality of life. In RW Busutill, G Klintmann, eds., Transplantation of the liver, 3rd edn (pp. 1389–1394). St. Louis, MO: Saunders.
- Campagna F, Biancardi A, Cillo U, Gatta A, Amodio P. Neurocognitive-neurological complications of liver transplantation: a review. Metab Brain Dis. 2010; 25: 115–124.
- Charlton M, Levitsky J, Aqel B, O'Grady J, Hemibach J, Rinella M, Fet al. International Liver Transplantation Society consensus statement on immunosuppression in liver transplant recipients. Transplantation. 2018; 102: 727–743.
- Choudhary NS, Saigal S, Bansal RK, Saraf N, Gautam D, Soin AS. Acute and chronic rejection after liver transplantation: what a clinician needs to know. J Clin Exp Hepatol. 2017; 7: 358–366.
- Christina S, Annunziato RA, Schiano TD, Anand R, Vaidya S, Chuang K, et al. Medication level variability index predicts rejection, possibly due to nonadherence, in adult liver transplant recipients. Liver Transpl. 2014; 20: 1168–1177.
- Coilly A, Calmus Y, Chermak F, Dumortier J, Duvoux C, Guillaud O, et al. Once-daily prolonged release tacrolimus in liver transplantation: experts' literature review and recommendations. Liver Transpl. 2015; 21: 1312–1321.
- Collins BH, Pirsch JD, Becker YT, Hanaway MJ, Van der Werf WJ, D'Alessandro AM, et al. Long-term results of liver transplantation in older patients 60 years of age and older. Transplantation. 2000; 70: 780–783.
- Considine A, Tredger JM, Heneghan M, Agarwal K, Samyn M, Heaton ND, et al. Performance of modified-release tacrolimus after conversion in liver transplant patients indicates potentially favorable outcomes in selected cohorts. Liver Transpl. 2015; 21: 29–37.
- Cramer J, Vachon L, Desforges C, Sussman NM. Dose frequency and dose interval compliance with multiple antiepileptic medications during a controlled clinical trial. Epilepsia. 1995; 36: 1111–1117.
- De Bleser L, Matteson M, Dobbels F, Russell C, De Geest S. Interventions to improve medication-adherence after transplantation: a systematic review. Transpl Int. 2009; 22: 780–797.
- De Geest S, Abraham I, Moons P, Vandeputte M, Van Cleemput J, Evers G, et al. Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients. J Heart Lung Transpl. 1998; 17: 854–863.
- Denhaerynck K, Dobbels F, Cleemput I, Desmyttere A, Schafer-Keller P, Schaub S, et al. Prevalence, consequences, and determinants of nonadherence in adult renal transplant patients: a literature review. Transpl Int. 2005; 18: 1121–1133.
- Dew MA, Kormos RL, Roth LH, Murali S, DiMartini A, Griffith BP. Early post-transplant medical compliance and mental health predict physical morbidity and mortality one to three years after heart transplantation. J Heart Lung Transpl. 1999; 18: 549–562.
- Dobbels F, De Bleser L, Berben L, Kristanto P, Dupont L, Nevens F, et al. Efficacy of a medication adherence enhancing intervention in transplantation: the MAESTRO-Tx trial. J Heart Lung Transpl. 2017; 36: 499–508.
- Dobbels F, Vanhaecke J, Dupont L, Nevens F, Verleden G, Pirenne J, et al. Pretransplant predictors of posttransplant adherence and clinical outcome: an evidence base for pretransplant psychosocial screening. Transplantation. 2009; 87: 1497–1504.
- Doshi JA, Zhu J, Lee BY, Kimmel SE, Volpp KG. Impact of a prescription copayment increase on lipid-lowering medication adherence in veterans. Circulation. 2009; 119: 390–397.
- Drent G, De Geest S, Dobbels F, Kleibeuker JH, Haagsma EB. Symptom experience, nonadherence and quality of life in adult liver transplant recipients. Neth J Med. 2009; 67: 161–168.
- Drent G, Haagsma EB, Geest SD, van den Berg AP, Ten Vergert EM, van den Bosch HJ, et al. Prevalence of prednisolone (non)compliance in adult liver transplant recipients. Transpl Int. 2005; 18: 960–966.
- Dumortier J, Duvoux C, Dubel L, Bazin F, Houssel-Debry P. A multicenter, prospective, observational study of conversion from twice-daily immediate-release to once-daily prolonged-release tacrolimus in liver transplant recipients in France: the COBALT study. Ann Transpl. 2019; 24: 506–516.
- Durand F. How to improve long-term outcome after liver transplantation? Liver Int. 2018; 38(Suppl 1): 134–138.
- Evans LD, Stock EM, Zeber JE, Morissette SB, MacCarthy AA, Sako EY, et al. Posttransplantation outcomes in veterans with serious mental illness. Transplantation. 2015; 99: e57–e65.
- Faeder S, Moschenross D, Rosenberger E, Dew MA, DiMartini A. Psychiatric aspects of organ transplantation and donation. Curr Opin Psychiatr. 2015; 28: 357–364.
- Fine RN, Becker Y, De Geest S, Eisen H, Ettenger R, Evans R, et al. Nonadherence consensus conference summary report. Am J Transpl. 2009; 9: 35–41.
- Foster BJ, Pai ALH, Zelikovsky N, Amaral S, Bell L, Dharnidharka VR, et al. A randomized trial of a multicomponent intervention to promote medication adherence: the Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT). Am J Kidney Dis. 2018; 72: 30–41.
- Garnock-Jones KP. Tacrolimus prolonged release (Envarsus®): a review of its use in kidney and liver transplant recipients. Drugs. 2015; 75: 309–320.
- Greenstein S, Siegal B. Compliance and noncompliance in patients with a functioning renal transplant: a multicenter study. Transplantation. 1998; 66: 1718–1726.
- Hansen R, Seifeldin R, Noe L. Medication adherence in chronic disease: issues in posttransplant immunosuppression. Transplant Proc. 2007; 39: 1287–1300.
-
Haque L, Palumbo CS, Batisti J. PRO: older adults should be offered liver transplantation. Clin Liver Dis. 2019; 14: 66–69.
10.1002/cld.821 Google Scholar
- Jeffery RA, Navarro T, Wilczynski NL, Iserman EC, Keepanasseril A, Sivaramalingam B, et al. Adherence measurement and patient recruitment methods are poor in intervention trials to improve patient adherence. J Clin Epidemiol. 2014; 67: 1076–1082.
- Kerkar N, Annunziato RA, Foley L, Schmeidler J, Rumbo C, Emre S, et al. Prospective analysis of nonadherence in autoimmune hepatitis: a common problem. J Pediatr Gastroenterol Nutr. 2006; 43: 629–634.
- Keswani RN, Ahmed A, Keeffe EB. Older age and liver transplantation: a review. Liver Transpl. 2004; 10: 957–967.
- Khorassani F, Tellier S, Tsapepas D. Pharmacists’ role in improving medication adherence in transplant recipients with comorbid psychiatric disorders. J Pharm Pract. 2019; 32: 568–578.
- Kim SH, Lee SD, Kim YK, Park SJ. Conversion of twice-daily to once-daily tacrolimus is safe in stable adult living donor liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2015; 14: 374–379.
- Klein A, Otto G, Kramer I. Impact of a pharmaceutical care program on liver transplant patients' compliance with immunosuppressive medication: a prospective, randomized, controlled trial using electronic monitoring. Transplantation. 2009; 87: 839–847.
- Kruse W, Weber E. Dynamics of drug regimen compliance—its assessment by microprocessor-based monitoring. Eur J Clin Pharmacol. 1990; 38: 561–565.
- Kumar JB, Bosworth HB, Sleath B, Woolson S, Olsen M, Danus S, et al. Quantifying glaucoma medication adherence: the relationship between self-report, electronic monitoring, and pharmacy refill. J Ocul Pharmacol Ther. 2016; 32: 346–354.
- Kuo SZ, Haftek M, Lai JC. Factors associated with medication non-adherence in patients with end-stage liver disease. Dig Dis Sci. 2017; 62: 543–549.
- Lenahan JL, McCarthy DM, Davis TC, Curtis LM, Serper M, Wolf MS. A drug by any other name: patients' ability to identify medication regimens and its association with adherence and health outcomes. J Health Commun. 2013; 18(Suppl 1): 31–39.
- Leven EA, Annunziato R, Helcer J, Lieber SR, Knight CS, Wlodarkiewicz C, et al. Medication adherence and rejection rates in older vs younger adult liver transplant recipients. Clin Transpl. 2017; 31(6): 10.1111/ctr.12981.
- Levitsky J, Goldberg D, Smith AR, Mansfield SA, Gillespie BW, Merion RM, et al. Acute rejection increases risk of graft failure and death in recent liver transplant recipients. Clin Gastroenterol Hepatol. 2017; 15: 584–593.e582.
- Lieber SR, Volk ML. Non-adherence and graft failure in adult liver transplant recipients. Dig Dis Sci. 2013; 58: 824–834.
- Lloyd JT, Maresh S, Powers CA, Shrank WH, Alley DE. How much does medication nonadherence cost the Medicare fee-for-service program? Med Care. 2019; 57: 218–224.
- Marvanova M, Roumie CL, Eden SK, Cawthon C, Schnipper JL, Kripalani S. Health literacy and medication understanding among hospitalized adults. J Hosp Med. 2011; 6: 488–493.
- Mehta SJ, Asch DA, Troxel AB, Lim R, Lewey J, Wang W, et al. Comparison of pharmacy claims and electronic pill bottles for measurement of medication adherence among myocardial infarction patients. Med Care. 2019; 57: e9–e14.
- Miloh T, Annunziato R, Arnon R, Warshaw J, Parkar S, Suchy FJ, et al. Improved adherence and outcomes for pediatric liver transplant recipients by using text messaging. Pediatrics. 2009; 124: e844–e850.
- Moayed MS, Khatiban M, Nassiri Toosi M, Khodaveisi M, Soltanian AR, Ebadi A. Barriers to adherence to medical care programs in liver transplant recipients: a qualitative study. Int J Organ Transpl Med. 2019; 10: 115–126.
- Morrissey PE, Flynn ML, Lin S. Medication noncompliance and its implications in transplant recipients. Drugs. 2007; 67: 1463–1481.
- Musgrave CR, Pilch NA, Taber DJ, Meadows HB, McGillicuddy JW, Chavin KD, et al. Improving transplant patient safety through pharmacist discharge medication reconciliation. Am J Transpl. 2013; 13: 796–801.
- NEHI. Thinking outside the pillbox: a system-wide approach to improving patient medication adherence for chronic disease. A NEHI Research Brief. Boston, MA: New England Healthcare Institute, 2009. https://www.nehi.net/writable/publication_files/file/pa_issue_brief_final.pdf (accessed July 31, 2020).
- Nerini E, Bruno F, Citterio F, Schena FP. Nonadherence to immunosuppressive therapy in kidney transplant recipients: can technology help? J Nephrol. 2016; 29: 627–636.
- Neuberger JM, Bechstein WO, Kuypers DR, Burra P, Citterio F, De Geest S, et al. Practical recommendations for long-term management of modifiable risks in kidney and liver transplant recipients: a guidance report and clinical checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) group. Transplantation. 2017; 101: S1–s56.
- O'Carroll RE, Couston M, Cossar J, Masterton G, Hayes PC. Psychological outcome and quality of life following liver transplantation: a prospective, national, single-center study. Liver Transpl. 2003; 9: 712–720.
- O'Carroll RE, McGregor LM, Swanson V, Masterton G, Hayes PC. Adherence to medication after liver transplantation in Scotland: a pilot study. Liver Transpl. 2006; 12: 1862–1868.
- Parekh J, Aacher NL, Roberts JP. Rejection after transplantation. In RW Busutill, G Klintmann, eds., Transplantation of the liver, 3rd edn (pp. 1212–1226). St. Louis, MO: Saunders.
- Partovi N, Chan W, Nimmo CR. Evaluation of a patient education program for solid organ transplant patients. Can J Hosp Pharm. 1995; 48: 72–78.
- Rice JP, Eickhoff J, Agni R, Ghufran A, Brahmbhatt R, Lucey MR. Abusive drinking after liver transplantation is associated with allograft loss and advanced allograft fibrosis. Liver Transpl. 2013; 19: 1377–1386.
- Rodgers JE, Thudium EM, Beyhaghi H, Sueta CA, Alburikan KA, Kucharska-Newton AM, et al. Predictors of medication adherence in the elderly: the role of mental health. Med Care Res Rev. 2018; 75: 746–761.
- Rodriguez-Peralvarez M, Rico-Juri JM, Tsochatzis E, Burra P, De la Mata M, Lerut J. Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal. Transpl Int. 2016; 29: 961–973.
- Russell CL, Hathaway D, Remy LM, Aholt D, Clark D, Miller C, et al. Improving medication adherence and outcomes in adult kidney transplant patients using a personal systems approach: SystemCHANGE results of the MAGIC randomized clinical trial. Am J Transpl. 2020; 20(1): 125–136.
- Russell CL, Moore S, Hathaway D, Cheng AL, Chen G, Goggin K. MAGIC study: aims, design and methods using SystemCHANGE to improve immunosuppressive medication adherence in adult kidney transplant recipients. BMC Nephrol. 2016; 17: 84.
- Serper M, Patzer RE, Reese PP, Przytula K, Koval R, Ladner DP, et al. Medication misuse, nonadherence, and clinical outcomes among liver transplant recipients. Liver Transpl. 2015; 21: 22–28.
- Serper M, Reese PP, Patzer RR, Levitsky J, Wolf MS. The prevalence, risk factors, and outcomes of medication trade-offs in kidney and liver transplant recipients: a pilot study. Transpl Int. 2018; 31: 870–879.
- Serper M, Van Wagner L, Kang R, Hohmann S, Olthoff K. Burden of readmission following liver transplantation: results from US academic medical centers. Abstract B1213. Transplantation. 2014; 98: 832.
- Shemesh E, Annunziato RA, Shneider BL, Dugan CA, Warshaw J, Kerkar N, et al. Improving adherence to medications in pediatric liver transplant recipients. Pediatr Transpl. 2008; 12: 316–323.
- Shemesh E, Bucuvalas JC, Anand R, Mazariegos GV, Alonso EM, Venick RS, et al. The Medication Level Variability Index (MLVI) predicts poor liver transplant outcomes: a prospective multi-site study. Am J Transplant. 2017; 17: 2668–2678.
- Shemesh E, Fine RN. Is calculating the standard deviation of tacrolimus blood levels the new gold standard for evaluating non-adherence to medications in transplant recipients? Pediatr Transpl. 2010; 14: 940–943.
- Shemesh E, Lurie S, Stuber ML, Emre S, Patel Y, Vohra P, et al. A pilot study of posttraumatic stress and nonadherence in pediatric liver transplant recipients. Pediatrics. 2000; 105: E29.
- Shneider C, Dunphy C, Shemesh E, Annunziato RA. Assessment and treatment of nonadherence in transplant recipients. Gastroenterol Clin North Am. 2018; 47: 939–948.
- Sketris I, Waite N, Grobler K, West M, Gerus S. Factors affecting compliance with cyclosporine in adult renal transplant patients. Transplant Proc. 1994; 26: 2538–2541.
- Stuber ML, Shemesh E, Seacord D, Washington J 3rd, Hellemann G, McDiarmid S. Evaluating non-adherence to immunosuppressant medications in pediatric liver transplant recipients. Pediatr Transpl. 2008; 12: 284–288.
- Tran D, Vallee M, Collette S, Senecal L, Lafrance JP, Dandavino R, et al. Conversion from twice-daily to once-daily extended-release tacrolimus in renal transplant recipients: 2-year results and review of the literature. Exp Clin Transpl. 2014; 12: 323–327.
- Trunecka P, Boillot O, Seehofer D, Pinna AD, Fischer L, Ericzon BG, et al. Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transpl. 2010; 10: 2313–2323.
- Venkat VL, Nick TG, Wang Y, Bucuvalas JC. An objective measure to identify pediatric liver transplant recipients at risk for late allograft rejection related to non-adherence. Pediatr Transpl. 2008; 12: 67–72.
- Whittaker R. Issues in mHealth: findings from key informant interviews. J Med Internet Res. 2012; 14: e129.
- Yap AF, Thirumoorthy T, Kwan YH. Systematic review of the barriers affecting medication adherence in older adults. Geriatr Gerontol Int. 2016; 16: 1093–1101.