G. Muduma

Evaluating the cost-effectiveness of laparoscopic adjustable gastric banding versus standard medical management in obese patients with type 2 diabetes in the UK.

To evaluate the cost‐effectiveness of laparoscopic adjustable gastric banding (LAGB) versus standard medical management (SMM) in obese patients with type 2 diabetes from a UK healthcare payer perspective.

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

Background and Aims 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. Methods 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. Results 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. Conclusions 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.

Cost utility analysis of immunosuppressive regimens in adult renal transplant recipients in England and Wales.

Background End-stage renal disease is the irreversible final stage of chronic kidney disease and is fatal when not managed by either transplantation or dialysis. Transplantation is generally preferred over dialysis. However, to prevent graft rejection or loss, lifelong immunosuppression is required. Tacrolimus is currently the cornerstone of post-transplantation immunosuppression. The study aim was to carry out an economic evaluation of immunosuppression, including more recent agents such as a once-daily prolonged-release formulation of tacrolimus (Advagraf™) and belatacept, relative to a twice-daily immediate-release formulation of tacrolimus (Prograf™). Methods A model was constructed comprising six states: onset of biopsy-confirmed acute rejection, functioning graft with or without a biopsy-confirmed acute rejection, non-functioning graft (dialysis), re-transplantation, and death. Data on clinical effectiveness were derived from a systematic literature review and the model captured the effects of patient adherence to immunosuppressant therapy on graft survival using relative risk of graft survival and published data on adherence in patients using Advagraf and Prograf. In the base case, the time horizon was 25 years and one-way and probabilistic sensitivity analyses were conducted. Results The analysis demonstrated that Prograf was cost-effective when compared with cyclosporin and belatacept and was more effective than sirolimus, but would not be considered cost-effective against sirolimus. The modeled improvement in the adherence profile of patients using Advagraf relative to Prograf resulted in both improved clinical outcomes and reduced costs. Conclusion Prograf was more clinically effective than cyclosporin, belatacept, and sirolimus, supporting its current positioning as the mainstay of immunosuppressive therapy in renal transplant recipients. Based on improved patient adherence with Advagraf, the model projected that Advagraf would be both more effective and less costly than Prograf. Replacing Prograf with Advagraf as the standard of care for post-transplant immunosuppression could likely result in both cost savings and improved clinical outcomes.

Patient survey to identify reasons for non-adherence and elicitation of quality of life concepts associated with immunosuppressant therapy in kidney transplant recipients

Background Renal transplantation (RT) is considered the treatment of choice for end-stage renal disease compared to dialysis, offering better health-related quality of life (HRQoL) and higher survival rates. However, immunosuppressants are essential for the long-term survival of kidney grafts and patients’ non-adherence to their medication leads to poor outcomes. Immunosuppressants can also significantly alter patients’ HRQoL because of their side effects and the complex chronic medication regimen they represent. Purpose To elicit key concepts related to adherence to immunosuppressant therapy (IT) and reasons for non-adherence in terms of patient reported outcomes, side effects, and the impact of the medication on HRQoL in RT population, including patient preference of once daily over twice-daily immunosuppressive regimen. Results were used to develop an IT-specific conceptual framework and provide suggestions for improving patients’ adherence to IT. Materials and methods Interviews were conducted with three clinical experts to determine key concepts related to RT and immunosuppressants. Thirty-seven participants in four focus groups were asked to cite important concepts related to adherence and impact of IT on HRQoL and to rate them. Qualitative analysis was conducted to code participants’ responses. Results Non-adherence among participants where admitted was unintentional. The reason for this included forgetfulness, interference with lifestyle, being asleep at the time the medication should be taken, change in routine, and impact of side effects. Overall, participants reported that the evening dose was more problematic to remember and that the exclusion of this dose could make them more adherent. Participants also reported that IT impacted on their HRQoL in a number of ways including: placing restrictions on their lifestyle, causing anxiety, or impairing their ability to work. Conclusion This study provides qualitative evidence about the barriers to IT adherence and the components of HRQoL that are important from the perspective of RT patients. The developed conceptual framework of IT-HRQoL in RT transplants, including social, psychological, and work life domains, can be used to inform the development of a new IT-specific measure of HRQoL in RT patients for use in head-to-head clinical trials or observational studies. Despite limitations associated with the number and the age range of patients recruited, this study suggests that a change in the regimen from twice-daily to once daily among other measures could improve their adherence to IT and their HRQoL by placing less restrictions on their lifestyles.

Budget impact of switching from an immediate-release to a prolonged-release formulation of tacrolimus in renal transplant recipients in the UK based on differences in adherence

Background and aims Advagraf is a once-daily prolonged-release formulation of tacrolimus with proven noninferiority to Prograf, a twice-daily immediate-release formulation of tacroli-mus, in biopsy-proven acute rejection, graft survival and patient survival in renal transplant recipients. Advagraf is associated with improved adherence compared with Prograf, which may ultimately improve long-term outcomes. The present study assessed the budget impact of switching patients from Prograf to Advagraf in the UK. Materials and methods A budget-impact model was constructed based on published data on acute rejection, graft failure, and mortality in the UK setting. Patients were assumed to convert from Prograf to Advagraf on a 1:1 milligram:milligram basis. In a study comparing the adherence rates between once-daily versus twice-daily formulations of tacrolimus, the proportion of patients taking the prescribed number of daily doses was 88.2% in Advagraf patients and 78.8% in Prograf patients. The model applied a relative risk of graft failure of 3.47 to nonadherent patients based on data from a 2004 meta-analysis (based on graft-failure rates of 1.3%–40.0% in adherent patients, compared with 6.1%–100% in nonadherent patients). Cost data were taken from the March 2013 British National Formulary and 2012–2013 National Health Service tariff information. The analysis was performed over a 5-year time horizon and future costs were not discounted, in line with International Society for Pharmacoeconomics and Outcomes Research guidelines. Results Over a 5-year time horizon, the mean cost per patient (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was £29,328 (standard deviation [SD] £2,844) for Advagraf versus £33,061 (SD £3,178) for Prograf. The total cost saving of £3,733 (SD £530) was driven primarily by reduced dialysis costs arising from the lower incidence of graft failure (21.6% with Prograf versus 18.3% with Advagraf) in the larger proportion of adherent patients in the Advagraf arm. In a hypothetical transplant centre of 100 kidney-transplant recipients, this would result in cost savings approaching £375,000 over 5 years. Conclusion Conversion of renal transplant recipients from Prograf to Advagraf was associated with lower pharmacy and dialysis costs, with the reduction in dialysis costs being driven by improved adherence to Advagraf regimen and the consequent improvement in graft survival.

A UK analysis of the cost of switching renal transplant patients from an immediate-release to a prolonged-release formulation of tacrolimus based on differences in trough concentration variability

Abstract Background and aims: Randomized controlled trials have shown that a once-daily prolonged-release (PR) tacrolimus formulation (PR tacrolimus; Advagraf), is non-inferior to a twice-daily immediate-release (IR) tacrolimus formulation (IR tacrolimus; Prograf) in terms of biopsy-proven acute rejection, graft failure and mortality in renal transplant recipients. However, relative to IR tacrolimus, PR tacrolimus exhibits reduced tacrolimus trough concentration variability, which has been associated with reduced graft failure. Based on these data, the present study evaluated the cost of switching UK renal transplant patients from IR tacrolimus to PR tacrolimus. Methods: UK-specific data on acute rejection, graft failure, and mortality were used to construct a budget impact model to assess the costs of switching from IR tacrolimus to PR tacrolimus on a 1:1 mg:mg basis. The model assumed that 3.1% of patients on PR tacrolimus had high tacrolimus trough concentration variability compared with 17.4% on IR tacrolimus, based on a study comparing PR tacrolimus and IR tacrolimus pharmacokinetics. A relative graft failure risk of 2.38 was applied to high variability patients based on data from a tacrolimus variability study in which 10/148 patients with low variability experienced graft failure, compared with 24/149 in the high variability group. Cost data were taken from the British National Formulary and 2012–2013 NHS tariff information. Results: The mean per-patient cost (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was GBP 26,941 (standard deviation [SD] = GBP 2765) with PR tacrolimus vs GBP 30,356 (SD = GBP 3085) for IR tacrolimus over a 5-year period, corresponding to a saving of GBP 3415 (SD = GBP 516) per patient or GBP 341,500 in a hypothetical 100-patient transplant center. Cost savings were driven primarily by lower dialysis costs resulting from the lower proportion of PR tacrolimus patients with high tacrolimus trough concentration variability (leading to lower graft failure risk). Limitations: The main limitation of the study was the use of heterogeneous data sources to capture the effect of within-patient variability on graft failure. The most important difference between the studies was the definition of the threshold between low and high within-patient variability. This was explored in sensitivity analyses in which the inter-arm difference in the inter-arm proportions of patients with high and low variability was abolished. Conclusions: Converting UK renal transplant recipients from IR tacrolimus to PR tacrolimus was associated with lower pharmacy and dialysis costs.

Indirect treatment comparison of belatacept versus tacrolimus from a systematic review of immunosuppressive therapies for kidney transplant patients

Abstract Objective: End-stage renal disease is the final and irreversible stage in chronic kidney disease, leading to patient mortality, unless managed by dialysis or transplantation (the treatment of choice). This study aimed to compare a currently recommended immunosuppressive treatment, tacrolimus, against a newer treatment, belatacept, using indirect treatment comparison (ITC) techniques since no head-to-head randomized controlled trials (RCTs) comparing tacrolimus against belatacept currently exist. Methods: ITC was employed to calculate estimates for the relative risks and mean difference of tacrolimus against belatacept. The choice of the Bucher ITC model was driven by the available data and the simple indirect treatment comparison involving three treatments was considered appropriate. Results: The results of the indirect analysis showed no significant differences between belatacept and tacrolimus treatments for mortality and graft loss. The acute rejection rate was significantly lower with tacrolimus (Prograf* and Advagraf*) compared with belatacept (0.22 [0.13, 0.39] to 0.44 [0.20, 0.99]). Conclusions: The results of this systematic review and meta-analysis suggests that tacrolimus is significantly superior to belatacept in terms of acute rejection outcomes but comparable for graft and patient survival. Further research should include a properly designed clinical trial comparing tacrolimus against belatacept directly. Limitations: These include variations in terms of clinical and design differences among the trials, weaknesses in the Bucher method and the lack of long-term clinical trial data with tacrolimus to compare with the recent long-term (7 years) belatacept trial data.

Evaluating the economic implications of non-adherence and antibody-mediated rejection in renal transplant recipients: the role of once-daily tacrolimus in the UK

Abstract Background and aims: While short-term kidney graft survival has gradually improved over time, improvements in long-term graft survival have been more modest. One key clinical factor limiting improved longer-term outcomes is antibody-mediated rejection (AbMR), the incidence of which appears to be higher in patients who are non-adherent to immunosuppressants. Recent data show that adherence can be improved by reducing pill burden. The aim of the present study was to model the incidence and economic consequences of graft loss and AbMR in patients taking once- vs twice-daily tacrolimus in the UK. Methods: A combined decision tree and Markov model was developed to estimate the incidence of graft failure, AbMR and mortality in renal transplant recipients taking once- vs twice-daily tacrolimus. Underlying rates of graft failure and mortality were derived from UK-specific sources. Proportions of patients adherent to once- vs twice-daily tacrolimus were taken from a recent randomized clinical trial and relative risks of graft failure and AbMR were taken from a prospective, multi-center analysis of 315 patients. Cost data were taken from the British National Formulary and National Health Service reference costs and reported in 2014 pounds sterling. Results: Modeling results showed that improved adherence would be associated with reduced incidence of AbMR and graft failure in renal transplant recipients. Based on improvements in adherence resulting from switching from twice-daily to once-daily tacrolimus, the modeling analysis projected cost savings of GBP 4862 per patient over 5 years with Advagraf relative to Prograf, on absolute costs of GBP 40,974 and GBP 45,836, respectively. Conclusions: Using Advagraf in place of Prograf in renal transplant recipients was predicted to be associated with lower pharmacy, dialysis and AbMR treatment costs, with the reduction in AbMR and dialysis costs being driven by improved adherence to the Advagraf regimen and consequent reductions in graft failure and onset of AbMR.

Laparoscopic adjustable gastric banding vs standard medical management in obese patients with type 2 diabetes: a budget impact analysis in the UK

Abstract Objective: To evaluate the financial consequences of using laparoscopic adjustable gastric banding (LAGB) in place of standard medical management (SMM) in obese patients with type 2 diabetes from a UK healthcare payer perspective. Design and methods: A budget impact model was constructed to evaluate the budgetary implications of LAGB in obese patients with type 2 diabetes in the UK. For patients undergoing LAGB, the model captured pre-, peri-, and post-operative costs including consultations with physicians, psychologists, nurses, and dieticians, the cost of surgery, and costs associated with post-surgical complications. The model also captured costs associated with medication for diabetes, asthma, hypertension, and hyperlipidemia, costs of diabetes complications, sleep apnea, and asthma, and costs of diagnostic tests. The SMM arm also captured costs associated with very low calorie diet products. Costs were modeled in a simulated UK cohort of 100 obese patients with newly-diagnosed diabetes. Future costs were discounted at 3.5% per annum and all costs were reported in 2010 pounds sterling. Results: Over the 5-year time horizon, the cohort of 100 patients who underwent LAGB incurred costs £91,287 lower than an equivalent cohort receiving SMM (£818,668 and £909,955, respectively). Costs of surgery and post-surgical complications (£254,000 and £40,981, respectively) were more than offset by savings arising from reduced diabetes, asthma, and sleep apnea medication costs, reduced incidence of diabetes complications, and fewer healthcare professional contacts. Sensitivity analysis (SA) showed that the model was most sensitive to assumptions around diabetes medication use, although none of the SA findings showed LAGB to be more costly than SMM. Limitations: In order to capture the diverse resource use and medical care costs arising in obese patients with type 2 diabetes, the analysis made use of a range of heterogeneous data sources. While the vast majority of data were applicable to obese patients with recently-diagnosed diabetes in the UK setting, some surrogate data (e.g. from different geographies) were used in cases where data in the target population were unavailable. Additionally, given the largely uncharacterized long-term risk profile in patients with remission of type 2 diabetes, remission was captured using a transparent and highly conservative approach. Conclusions: Based on the findings of the present analysis, the high initial costs of performing LAGB are offset within 5 years after surgery when compared with SMM in a population of obese patients with type 2 diabetes. The high up-front costs associated with surgery should not therefore be a barrier to its reimbursement in this patient group.

A budget impact analysis of parenteral iron treatments for iron deficiency anemia in the UK: reduced resource utilization with iron isomaltoside 1000

Background and aims The reported prevalence of iron deficiency anemia (IDA) varies widely but estimates suggest that 3% of men and 8% of women have IDA in the UK. Parenteral iron is indicated for patients intolerant or unresponsive to oral iron or requiring rapid iron replenishment. This study evaluated differences in the cost of treating these patients with iron isomaltoside (Monofer®, IIM) relative to other intravenous iron formulations. Methods A budget impact model was developed to evaluate the cost of using IIM relative to ferric carboxymaltose (Ferinject®, FCM), low molecular weight iron dextran (Cosmofer®, LMWID), and iron sucrose (Venofer®, IS) in patients with IDA. To establish iron need, iron deficits were modeled using a simplified dosing table. The base case analysis was conducted over 1 year in patients with IDA with mean bodyweight of 82.4 kg (SD 22.5 kg) and hemoglobin levels of 9.99 g/dL (SD 1.03 g/dL) based on an analysis of patient characteristics in IDA trials. Costs were modeled using UK health care resource groups. Results Using IIM required 1.3 infusions to correct the mean iron deficit, compared with 1.3, 1.8, and 7.7 with LMWID, FCM, and IS, respectively. Patients using IIM required multiple infusions in 35% of cases, compared with 35%, 77%, and 100% of patients with LMWID, FCM, and IS, respectively. Total costs were estimated to be GBP 451 per patient with IIM or LMWID, relative to GBP 594 with FCM (a GBP 143 or 24% saving with IIM) or GBP 2,600 with IS (a GBP 2,149 or 83% saving with IIM). Conclusion Using IIM or LMWID in place of FCM or IS resulted in a marked reduction in the number of infusions required to correct iron deficits in patients with IDA. The reduction in infusions was accompanied by substantial reductions in cost relative to FCM and IS over 1 year.