Clinical and economic impact of immunosuppressive therapy in the treatment and management of adult renal and liver transplantation

World wide the number of people living with renal or liver transplants is growing due to the increase in prevalence of end stage renal disease and end stage liver disease which neccesitate transplantation. Life long immunosuppression is needed for transplant recipients to prevent graft rejection and or death. Whilst the immunosuppression can significantly improve patient and graft survival it comes at a cost to the healthcare services. It is therefore, important that the immunosuppression used in clinical practice is supported by both clinical and cost effectiveness evidence. The aim of this thesis is to evaluate the clinical and economic impact of immunosuppression therapy in the treatment and management of adult renal and liver transplant recipients based on author's published research. Healthcare systems across the world are now placing greater importance on optimising their finite resources in demonstrating clinical and cost effectiveness of treatments. A number of health authorities such as the United Kingdom(UK), National Institute of Health and Care Excellence (NICE) have implemented methodologies guiding resource allocation decisions through formal health technology assessment (HTA). Clinical and economic evidence generation and synthesis reflecting current clinical practice can help to inform HTA decisions which impacts patients access to medicines. This thesis presents and critically appraise eight peer reviewed publications to demonstrate the clinical and economic impact of immunosuppression therapy in adult renal and liver transplant recipients. Each publication updated and or contributed to new knowledge in the field. The thesis highlights how the eight publications formed a cohesive body of evidence which can be used by policy makers to inform the development and or updating of clinical and reimbursemsent guidelines which ultimately impact product adoption and patient accesss to immunosuppressive medicines. The clinical effectiveness of immunosuppression was explored through systematic literature reviews, meta-analysis and indirect treatment comparison to establish the efficacy and safety of the different interventions used in post renal and liver transplant. The outputs from the clinical effectiveness together with relevant data from other sources was used to develop economic models to assess the cost effectiveness of immunosuppression. An assessment of the budget impact of immunosuppression in post renal transplant was also examined. Based on this research prolonged release tacrolimus was shown to be clinically and economically more effective than immediate release tacrolimus the current standard of care. The thesis concluded that tacrolimus remains the cornerstone of renal and liver post transplant immunosuppression while also highlighting the strengths and limitations of the current research and making recommendations for future studies

Systematic Review and Meta-Analysis of Tacrolimus versus Ciclosporin as Primary Immunosuppression After Liver Transplant

<div><p>Background and Aims</p><p>Several meta-analyses comparing ciclosporin with tacrolimus have been conducted since the 1994 publication of the tacrolimus registration trials, but most captured data from randomized controlled trials (RCTs) predating recent improvements in waiting list prioritization, induction protocols and concomitant medications. The present study comprised a systematic review and meta-analysis of ciclosporin and tacrolimus in liver transplant recipients using studies published since January 2000.</p><p>Methods</p><p>Searches of PubMed, the Cochrane Library and EMBASE identified RCTs of tacrolimus and ciclosporin as the immunosuppressant in adult primary liver transplant recipients, published between January 2000 and August 6, 2014. A random effects meta-analysis was conducted to evaluate the relative risk of death, graft loss, acute rejection (AR), new-onset diabetes after transplantation (NODAT) and hypertension with tacrolimus relative to ciclosporin at 12 months.</p><p>Results</p><p>The literature search identified 11 RCTs comparing ciclosporin with tacrolimus. Relative to ciclosporin, tacrolimus was associated with significantly improved outcomes in terms of patient mortality (risk ratio [RR] with ciclosporin of 1.26; 95% confidence interval [95%CI] 1.01–1.58). Tacrolimus was superior to ciclosporin in terms of hypertension (RR with ciclosporin 1.26; 95%CI 1.07–1.47), but inferior in terms of NODAT (RR with ciclosporin 0.60; 95%CI 0.47–0.77). There were no significant differences between ciclosporin and tacrolimus in terms of graft loss or AR.</p><p>Conclusions</p><p>Meta-analysis of RCTs published since 2000 showed tacrolimus to be superior to ciclosporin in terms of patient mortality and hypertension, while ciclosporin was superior in terms of NODAT. No significant differences were identified in terms of graft loss or AR. These findings provide further evidence supporting the use of tacrolimus as the cornerstone of immunosuppressive therapy in liver transplant recipients.</p></div

Literature review flow diagram.

<p>Literature review flow diagram.</p

Incidence of new-onset diabetes after transplantation in liver transplant recipients on ciclosporin- or tacrolimus-based immunosuppressive regimens.

<p>Incidence of new-onset diabetes after transplantation in liver transplant recipients on ciclosporin- or tacrolimus-based immunosuppressive regimens.</p

Incidence of hypertension in liver transplant recipients on ciclosporin- or tacrolimus-based immunosuppressive regimens.

<p>Incidence of hypertension in liver transplant recipients on ciclosporin- or tacrolimus-based immunosuppressive regimens.</p

Included studies reporting endpoints of interest.

<p>Included studies reporting endpoints of interest.</p

Patient mortality in liver transplant recipients on ciclosporin- or tacrolimus-based immunosuppressive regimens.

<p>Patient mortality in liver transplant recipients on ciclosporin- or tacrolimus-based immunosuppressive regimens.</p

Key sensitivity analyses around the primary analyses.

<p>Key sensitivity analyses around the primary analyses.</p