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Adherence to the medical regimen in transplantation


Non-adherence in transplantation is associated with increased incidence of rejection and an incumbent effect on morbidity and mortality. Pharmacist consultations are more likely to add benefit for patients taking two or more concomitant medications

Anna Carollo PharmD PhD MS
Adriana Adamo PharmD
Piera Polidori PharmD MS
Clinical Pharmacy Department, ISMETT, Palermo, Italy
The World Health Organization (WHO) defines adherence as the degree to which the person’s behaviour corresponds with the agreed recommendations from a healthcare provider. Compliance is defined as the degree to which a patient correctly follows medical advice. Although related, ‘compliance’ suggests that the patient passively follows the physician’s orders, while ‘adherence’ acknowledges that the patient is part of the decision-making process, making this the preferred term.(1)
Non-adherence to medication is widely recognised as a major public health concern and contributes to patient morbidity, mortality and healthcare costs.(2,3)
Adherence to the medical regimen, both before and after organ transplantation, is of obvious importance for maximising the patient’s health and well-being. The increasingly sophisticated medical therapies and technologies available to prolong life - including organ replacement and organ supplementation - still require an active investment on the patient’s part in order to obtain the best outcomes. Transplant candidates and recipients are asked to engage in a large variety of behaviours, including medication taking, monitoring vital signs, attending clinical appointments and following exercise and diet plans. Non-adherence has the potential to place these patients’ health at risk. Despite recognition of the importance of patient adherence, there remains, as yet, little consensus on how to ensure that adherence history and current status are adequately evaluated. There is also little consensus on what specific roles adherence history should play in the transplant candidate selection process and in the post-transplant follow-up care programme.(4)
The patient-centered medical home model of healthcare delivery allows the pharmacist to be part of a physician- or nurse practitioner-led healthcare team.
While medication dispensing is the best-known function of the pharmacist, they - through counselling, medication therapy management, disease-state management, and other means - can play a pivotal role in patient care. There are opportunities in every type of pharmacy practice to improve patients’ adherence and therapeutic outcomes, and pharmacists must embrace and act on these. 
Many factors dictate a patient’s medication adherence, and each patient is unique. The pharmacist must approach each patient individually to determine the level of adherence and what barriers may exist that are preventing the patient from taking his or her medication appropriately.(5) 
Moreover, while the amount of empirical information on post-transplant adherence, in particular, is growing, many studies are methodologically weak. There have also been relatively few attempts to synthesise these studies’ findings and plan logical future work. Consequently, some adherence outcomes have been examined in numerous studies, while others that may be critical for patient well-being have been rarely, if at all, considered.(4)
Pre-transplant adherence 
Historically, transplant programmes and transplant specialists have generally agreed that data regarding a patient’s history and current status are relevant and must be collected to form a complete picture of the patient’s psychosocial strengths and liabilities before a transplant. These data includes patients’ compliance with medications and all others active treatment strategies for their physical illness, plus any required monitoring of health, dietary and fluid restrictions, prescribed exercise, and attendance at medical appointments. In addition, quantity and frequency of current and heaviest lifetime use of alcohol, nicotine and other substances, as well as symptoms of misuse and/or dependence, and treatment/rehabilitation history need to be considered. 
Generally, assessment of adherence history is completed in the context of the larger psychosocial evaluation that typically takes places at the time that patients are initially evaluated as potential candidates for transplant. This broader evaluation will, in most cases, include assessments of psychiatric history, mental status, social history and current quality of life.6 In fact, information about many of these elements is necessary in order to determine the accuracy and completeness of patients’ adherence histories and current status. For example, evidence of impaired cognitive functioning or current uncontrolled psychiatric illness at the time of the assessment will affect the patient’s ability to provide accurate, complete information on medical and behavioural adherence history.
Information about patients’ past and current psychosocial status and adherence history may be collected from multiple sources during the candidacy evaluation process. These sources include not only the patients’ self-report but also interviews with family members, reports obtained from other past and current treatment providers and additional laboratory tests. This information is also important for determining the accuracy and/or completeness of patients’ reports.(7) 
Measuring adherence
There is no recognised gold-standard method to measure adherence. There are direct and indirect ways to measure adherence and a combination of these may be needed to accurately quantify adherence in actual practice.
Direct methods include directly observing treatment, or measuring the concentration of the drug or metabolite or a biological marker (for example, tacrolimus levels) added to the drug in blood or urine. However, these methods tend to be costly and burdensome. Indirect methods include questionnaires, pill counts, prescription refill rates, measurement of physiological markers, filling out a medication diary and electronic medication monitoring.(8,9) These methods are thought to be less onerous, but subject to distortion by the patient, which may result in an overestimation of adherence.
The prescription refill rate is a commonly used measure of adherence in a pharmacy system using software database, but does not reflect actual medication intake. Electronic medication monitors track patterns of medication intake by recording times when the medication bottle is opened, but neither does this method document actual ingestion of the pill or the taking of the correct dose.(1,9) Commonly used measures of medication adherence for immunosuppressants include questionnaires and prescription refill rates, and, as directly, measurement of concentration of the drug (for example, tacrolimus level).
Causes of non-adherence
Causes of non-adherence are complex and can be broadly classified into three categories: patient related, caregiver related and health system related.(10) 
Patient related 
Patient-related factors leading to non-adherence include low health literacy, lack of understanding of the disease being treated, attitudes concerning the effectiveness of the treatment, anxiety about the complexity of the regimen to be followed,(11) negative previous experience with pharmacological therapies, presence of psychological problems, and/or cognitive impairment. Forgetfulness plays a role, but underlying reasons often contribute to forgetfulness, including lack of prioritisation of the importance of medication intake. 
The motivation of the patient to adhere to prescribed treatments is influenced by an understanding of their perceived benefits.(12) 
Caregiver related
Complex drug regimens prescribed by physicians, lack of adequate explanation about the disease, lack of education about the benefits and potential adverse events of medications by the clinical pharmacist, and multiple physicians with inconsistent messages, all contribute to medication non-adherence.
Health system related
The economics of the healthcare market place severely limits the time a physician can spend with an individual patient. This can interfere with adequate patient education.
The phenomenon of adherence to prescribed treatments is a phenomenon that affects all age groups; however, the presence of a cognitive and functional impairment in the elderly increases the risk of poor adherence.(13) The biggest obstacles for adherence to the pharmacological treatments in transplant patients, as described in the literature, range from lack of information, inability to manage independently or a very complex regimen, to the patient's difficulty in finding the right motivation and the lack of necessary support to change certain behaviours, or the availability of medical aids enabling the patient to deal with them better.
Co-morbidities and the consequent need to follow complex therapeutic regimes further undermine adherence to treatments are also noted. Starting from these obstacles, clinical pharmacists and other caregivers can provide particularly significant interventions that aim to change habits and lifestyles. The WHO is well aware that it is necessary to provide patients with valid support because they then learn how to manage the disease independently.
Interventions to improve adherence
To improve adherence to treatment is crucial, and physicians, clinical pharmacist and social carer interventions strengthen the motivation of the patient by increasing his/her perception of the importance of adherence and strengthening his/her confidence in an ability to learn how to manage the disease independently. Any educational intervention must respond to the following questions: how should you interview the patient? How can you learn from factors and interventions already made? How should they be identified and priorities chosen, between the interventions available and appropriate ones? In what way should the progress of the patient be followed and evaluated? This strategy can be created using techniques of ‘roleplay’ or other educational strategies, through which all caregivers can cause their behaviour to favour certain tools, accede to treatments and work with them on a day-to-day basis. Clinical pharmacist education, while helpful, is usually not enough to persuade the patient to comply with the physician’s drug orders. Information must be presented by the clinical pharmacist in a clear, easy-to-understand language, and the patient must understand not only the benefits of adherence, but also the repercussions of non-adherence.
Medication-taking behaviour is complex. Thus, interventions to improve adherence are aimed at the middle 50% of individuals who may adhere if given support and encouragement. Strategies with some degree of success are multifaceted combinations of patient education, patient-physician communication enhancement, extended care through ancillary health care providers, simplification of drug regimens, and increased patient monitoring and follow-up, but these are labour intensive and expensive. More practical interventions are needed for use in routine clinical practice.(14) 

All healthcare professionals, as well as physicians and clinical pharmacists, often assume that a patient is, or should be, motivated to follow a therapeutic protocol correctly. However, recent studies in behavioural sciences revealed that this assumption is incorrect.(15,16) There is some information regarding the necessary training to caregivers that will achieve effective individualised interventions. Ockene et al(17) reported the effectiveness of brief interventions centred on the patient and also in several randomised clinical trials: the study WATCH (diet),(18,19) the Project Health (alcohol),(20) the Nurse-Delivery Diabetic Smoking Intervention Project,(21) and the Physician-Delivered Smoking Intervention Project (to stop smoking).(22) In particular, the latter showed a statistically significant improvement after an intervention lasting only five-to-nine minutes.
From these studies, it is clear that good adherence to treatment is achieved through a continuous and dynamic process. The population of patients can be subdivided depending on the level of willingness to follow medical instructions.(15,16) When a doctor's attempt to intervene shows no correlation with the patient's ability to receive the instruction, the result is either complex treatment or non compliance. In general, the patient transplanted follows a complex therapeutic scheme and the more complex the treatment, the less likely will be his ability to follow it correctly. The indicators of the complexity of the treatment include the frequency of self-care behaviours, namely, how many times a day the patient should perform certain actions. Motivation and behavioural skills are important determinants, and at the same time are independent from behavioural variations.(23,24) Information and motivation influence behaviour, especially through behavioural competencies; however, when the latter are simple and familiar to the patient, information and motivation can have a direct influence on behaviour. In this case, a patient may follow a prescription (simple and usual behaviour) based on the information received from the provider.
The relationship between information and motivation is weak. In practical terms, a very motivated patient might have little information, whereas another well-informed patient might have little motivation. However, in the IBM model, the presence of both information and motivation increases the likelihood of adherence to treatments. Transplant patients receiving good information before and after transplantation exhibit good adherence to treatment. For example, in patients with kidney transplant immunosuppressive therapies, membership ranges from 50 to 95% and the non-membership can even determine an organ rejection.(25) It has been found that, in these cases, the intervention of clinical pharmacists improves compliance, on average by more than 100% over 12 months.(26) 
Whatever the barriers to adherence, the only way to assess them is to talk to the patient. The pharmacist needs to be diligent about including the patient in the treatment experience. The more trust the patient has in the pharmacist, the more open he or she will be in disclosing any apprehensions or difficulties about taking his or her medication. Only then can the pharmacist play an integral role in improving a patient’s adherence.
Improved adherence to treatment also means increasing patient safety. Improved adherence to treatment will result in a significant reduction in overall health expenditure linked to less costly interventions (hospitalisation, new treatments, diagnostic tests, re-transplant). If you want to improve adherence to pharmacological treatments, in addition to biomedical intervention, it is absolutely necessary to build patient motivation, increasing their perception of the importance of compliance, and reinforcing confidence in relation to their ability to self-manage the disease. This approach offers the possibility of carrying out interventions on adherence to the increasingly sophisticated treatments.
The pharmacist can have a key role in the patient management of pharmacological therapy through: education, counselling and memory enhancement to improve enrollees’ understanding of their medications; monitoring of treatment and the identification of problems, in close collaboration with other service providers and with patients; improvement of medication adherence, including providing the patient advice on proper lifestyle (exercise, diet) and detection of adverse drug reactions and patterns of improper prescription medication use.(27) In fact, clinical pharmacist counselling improves patient outcomes and safety, results in stricter adherence to therapy and changes in patient behaviour, and contributes to faster convalescence.
The counselling programme provided by clinical pharmacists can increase drug adherence and raise awareness of correct immunosuppressive treatment management in transplant patients. This programme can reduce the risks associated with mis-management of therapy, and improve the transplant outcome.
Pharmacists can also organise a therapy plan, including the name of the drug, an image (if possible), the associated therapeutic condition, directions for administration, and time and day of administration (morning, afternoon, evening, or bedtime).(28) 
Key points
  • Adherence is the agreement to physician recommendations where the patient is part of the decision-making process.
  • The combination of several methods allows for accurate quantification adherence in actual practice.
  • The biggest barrier to adherence is the lack of information and patient education on the pharmacological therapy management and correct behaviour.
  • The clinical pharmacist must present not only the benefits of adherence but also the repercussions of non-adherence.
  • Clinical pharmacist counseling improves patient outcomes and leads to a faster convalescence.
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  2. Cutrona SL et al. Targeting cardiovascular medication adherence interventions. J Am Pharm Assoc 2012;52(3):381-97.
  3. Calvert SB et al. Patient-focused intervention to improve long-term adherence to evidence-based medications: a randomized trial. Am Heart J 2012;163 (4):657-65.
  4. Dew MA et al. Adherence to the medical regimen in transplantation. Biopsychosoc Perspect Transplant 2001; 93-124
  5. Carter BL, Foppe van Mil JL. Comparative effectiveness research: evaluating pharmacist interventions and strategies to improve medication adherence. Am J Hypertens 2010;23:949-55.
  6. Olbrish M, Levenson J. Psychosocial assessment of organ transplant candidates. Current status of methodological and philosophical issues.Psychosomatics 1995;36(3):236-43.
  7. Crone CC, Wise TN. Psychiatric issues in transplantation, II: Preoperative issues. Crit Care Nurs 1999;19:51-63.
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  9. SIDS - Farmacie Comunali Riunite di Reggio Emilia. Dalla prescrizione all'assunzione dei farmaci: come può il farmacista promuovere l'aderenza del paziente alla terapia? 2012;
  10. Brown MT, Bussel JK. Medication adherence: WHO cares? Mayo Clin Proc 2011;86(4):304-14.
  11. Horne R. Patients’ beliefs about treatment: the hidden determinant of treatment outcome? J Psychosomatic Res 1999;47:491-5.
  12. Miller W, Rollnick S. Motivational Interviewing. New York, Guilford Press;1999.
  13. Pinzone HA et al. Prediction of asthma episodes in children using peak expiratory flow rates, medication compliance, and exercise data. Ann Allergy 1991;67:481-6.
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  15. Prochaska JO, Di Clemente CC. Stages of change in the modification of problem behaviors. Prog Behav Modification 1992;28:183-218.
  16. Prochaska JO, Redding C, Evers K. The Transtheoretical Model. ln: Glanz K LF, Rimer BK (eds). Health Behavior and Health Education: Theory, Research, and Practice. San Francisco, Jossey-Bass;1997.
  17. Ockene J. Strategies to increase adherence to treatment. ln: Burke LE, Ockene J (eds). Compliance in Health care and Research. Armonk, New York, Futura; 2001:43-55.
  18. Ockene IS et al. Effect of physician-delivered nutrition counseling training and an office-support program on saturated fat intake, weight and serum lipid measurements in a hyperlipidemic population: Worcester Area Trial for Counseling in Hyperlipidemia (WATCH). Arch Intern Med 1999;159:725-31.
  19. Ockene IS et al. Effect of training and a structured office practice on physician delivered nutrition counseling: the Worcester-Area Trial for Counseling in Hyperlipidemia (WATCH). Am J Prevent Med 1996;12:252-8.
  20. Ockene JK et al. Provider training for patient centered alcohol counseling in a primary care setting. Arch Intern Med 1997;157:2334-41.
  21. Canga N et al. Intervention study for smoking cessation in diabetic patients: a randomized controlled trial in both clinical and primary care settings. Diabet Care 2000;23:1455-60.
  22. Ockene JK et al. The Physician-Delivered Smoking Intervention Project: factors that determine how much the physician intervenes with smokers. J Gen Intern Med 1994;9:379-84.
  23. Fisher JD, Fisher WA. Changing AIOS-risk behavior. Psychological Bull 1992; 111:455-74.
  24. Fisher JD et al. Changing AIDS risk behavior: effects of an intervention emphasizing AIDS risk reduction information, motivation, and behavioral skills in a college student population. Health Psychol 1996;15:114-23.
  25. Greenstein S, Siegel B. Compliance and noncompliance in patients with a functioning renal transplant: a multicenter study. Transplantation 1998;66:1718-26.
  26. Chrisholm MA et al. Impact of clinical pharmacy services on renal transplant patients’ compliance with immunosuppressive medications. Clin Transplant 2001;15:330-6.
  27. Pellegrino AN et al. Medication therapy management services: Definitions and outcomes. Drugs 2009;69(4):393-406.
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