Medication adherence following a solid organ transplant
Organ transplantation is the removal of an organ from one individual and placement within another individual. Solid organ transplantation refers to transplantation of the heart, lungs, kidney, pancreas or liver, and successful transplantation involves collaboration across surgical, medical, legal, political and bioethical disciplines. Adequate suppression of the immune system is required for short and long-term survival of the organ transplant, thus immunosuppressive therapy forms the central part of clinical management of an organ transplant recipient. Immunosuppressant strategies and pharmacological agents are similar across all solid organ transplants, most commonly involving oral administration of a calcineurin inhibitor and an antimetabolite, with or without corticosteroids1, in order to sustain a graft free from rejection, and to minimise the potential for graft loss and/or mortality following transplantation. A meta-analysis of 147 organ donor cohorts has yielded a non-adherence rate of 23% to immunosuppressant therapy, however this masks the significant heterogeneity in non-adherence rates (0%-68%), which in part may be due to methodological variability. The importance of adhering to immunosuppressive therapy cannot be overemphasised, with non-adherence contributing to approximately 20% of late acute rejection episodes and 16%-36% of graft losses2.
Epidemiology and costs of solid organ transplantation in Ireland: Organ transplant types
The Office of Organ Donation Transplant Ireland (ODTI) is the national office responsible for service planning, statistics and coordination of organ procurement services in Ireland. In 2015, there were 266 organ transplants – 153 kidney (120 deceased and 33 living donors), 61 liver, 36 lung, 16 heart, 0 pancreas. Demand continues to exceed supply, with 648 patients waiting for an organ transplant at the end of 2015. The mean waiting time for transplantation varies significantly depending on transplant type, from 2.9 months (liver) to 35 months (kidney) 3. The indication for organ transplantation varies by type of solid organ transplant. Kidney transplantation is the most common form of transplantation worldwide, and accounts for 58% of all transplants in Ireland. The need for kidney transplantation arises from the transition from Chronic Kidney Disease (CKD) to End Stage Renal Disease (ESRD). Data from the National Kidney Disease Surveillance Programme in Ireland reported an 11.8% prevalence of CKD. Those who progress to ESRD require renal replacement therapy (RRT) for survival via dialysis therapy, which involves filtration of toxins from the blood over a four-hour period three times per week (haemodialysis), or 3-4 times over a 24 hour period (peritoneal dialysis). At the end of 2015, there were 2,015 people in Ireland on renal dialysis, equating to over 6,000 dialysis treatments delivered per week. In Ireland 52% of all patients with ESRD are treated with a functioning renal transplant in their lifetime and renal transplantation remains the most cost-effective treatment for ESRD3. Pancreatic transplants are usually carried out in conjunction with a kidney transplant for some diabetic patients with ESRD. Other transplants are less common, but have their own unique indications. A liver transplant is required in the case of chronic liver failure, most commonly caused by alcoholic liver disease or hepatitis. Acute liver failure can also require a liver transplant in some cases, particularly following poisoning or drug overdose. Liver cancer may be an additional indication for a liver transplant4. End stage lung disease arising from conditions such as cystic fibrosis, emphysema, pulmonary fibrosis and lung cancer is the common indication for a lung transplant, the most common indication being Chronic Obstructive Pulmonary Disease (COPD) 5. A heart transplant is offered to patients with severe heart failure who are medically suitable.
Costs of transplantation and non-adherence
The cost benefits of optimised post-transplant medication adherence are substantial when considering the healthcare cost savings through long-term successful transplantation. The average haemodialysis patient has an annual cost of approximately €60,000 per patient. With a once-off cost of €74,000 to perform a kidney transplant, followed by €10,000 per annum for transplant patient care, each individual transplant results in savings to the health service of €770,000 over the lifetime of the graft (approximately 15 years)3. Living kidney donation in particular has been a big success in increasing the numbers of kidney transplants. It is imperative that adherence to immunosuppressant therapy is optimised to ensure that patients don’t return to dialysis. A pancreatic transplant usually co-occurs with a kidney transplant, and there is currently reconfiguration of pancreatic transplant services in Ireland, meaning cost data for a pancreatic transplant are currently unavailable. Irish data are similarly unavailable for the cost of liver transplantation but, importantly, a person with liver failure cannot be sustained mechanically as with kidney, heart or lung failure, therefore a transplant is the only available treatment option. This reliance on liver transplantation means that adherence to immunosuppressive therapy is critical to post-transplant recovery for liver transplant patients, and is key to reducing post-transplant mortality. Ireland has the highest mortality rate from respiratory diseases in the EU, with such diseases having a total healthcare cost of €437 million5. A lung transplant has a once-off cost of €112,3543, with subsequent costs for immunosuppressant medications having similar costs to other transplants. The most common reason for requiring a heart transplant is the presence of heart failure. There are approximately 90,000 people living with heart failure in Ireland, with an associated cost of €660 million6. Given that 7% of all hospital in-patient stays are heart failure related, the one-off cost of a heart transplant (€195,039)3 offers considerable healthcare cost savings if acute organ rejection is avoided through adherence to immunosuppressive therapy. Reasons for non-adherence are multifactorial and can be attributed to both healthcare and patient factors. Healthcare factors include the prescription of complex drug regimens, poor communication of drug-related information and limited access to care7. Patient factors can be attributed to ‘intentional’ or ‘non-intentional’ adherence. Intentional non-adherence involves conscious decision-making to alter or abstain from the prescribed regimen, whilst non-intentional non-adherence arises from forgetting, or misunderstanding medication instructions. Given the complexity of barriers to adherence, strategies to improve adherence must be capable of addressing the multi-dimensionality of medication adherence.
The need for Cochrane Review evidence
Given the reported high non-adherence rates, coupled with the critical importance of adherence to the immunosuppressant regimen to maximise and maintain successful transplantation, medication adherence is a key factor in successful long-term outcome after an organ transplant. Clear evidence is required to identify effective interventions that improve adherence following a solid organ transplant. Previous research has attempted to summarise literature relating to adherence post transplantation, however this work has a number of shortcomings8, 9. For example, a systematic review in 2009 identified five randomised controlled trials (RCT) that examined interventions to improve adherence to immunosuppressive therapy. However, this review only focused on heart, liver and kidney transplants, had shortcomings in the defined search strategy, such as exclusion of MeSH (Medical Subject Headings) headings, and did not include the full range of intervention types used in improving adherence, such as electronic monitoring or pharmacy-led interventions. There is also a lack of consensus on the definition of non-adherence to immunosuppressant therapy9, with no standard measurement of non-adherence identified from previous reviews. It has been shown that hospitalisation rates doubled when patients had an adherence rate of 80% compared with 90% posttransplantation2, highlighting the need for consistency in measurement of non-adherence. Furthermore, the small number of RCTs identified in early reviews suggests that there is limited research aimed at developing strategies to improve adherence for transplant recipients. This proposed Cochrane Review will provide the highest form of evidence for improving adherence post transplantation, and will include studies up to 2016.
