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Background: Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation., Method: A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance., Results: In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost-utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk., Conclusions: CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Objectives: To evaluate cost-effective pharmacological treatment in adult kidney transplant recipients from the perspective of the Colombian health system., Methods: A decision tree model for the induction phase and a Markov model for the maintenance phase were built. A review of the clinical literature was conducted to extract probabilities, and the life-years were used as the outcome. Costs were calculated using the administrative databases. The evaluating treatment schemes are organized by groups of evidence with direct comparisons., Results: In the induction phase, anti-thymocyte immunoglobulin+ methylprednisolone is dominant, more effective, and less expensive, compared with basiliximab+methylprednisolone. In the maintenance phase, azathioprine (AZA) is dominant in contrast to mycophenolate mofetil (MFM) both with cyclosporine (CIC)+ corticosteroids (CE); CIC is dominant relative to sirolimus (SIR) and tacrolimus (TAC) (both with MFM+CE or AZA+CE), and TAC is dominant compared with SIR (in addition with MFM+CE or mycophenolate sodium [MFS]+CE); MFM is dominant in relation to MFS and everolimus, and SIR is more effective MFM but it does not exceed the threshold (in sum with TAC+CE); MFS and MFM are dominant relative to everolimus, and SIR is more effective than MFM, but it does not exceed the threshold (in addiction with CIC+CE); MFM is dominant in relation to TAC (in sum with SIR+CE), and CIC+AZA+CE is dominant in relation to TAC+MFM+CE., Conclusions: The base-case results for all evidence groups are consistent with the different sensitivity analyses., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Outpatient burn surgery is increasingly used in acute burn care. Reports of its safety and efficacy are limited. This study aims to evaluate the safety and cost reduction associated with outpatient burn surgery and to describe our center's experience. This was a single-center, retrospective cohort study of consecutive patients who underwent outpatient burn surgery requiring split-thickness skin graft or dermal regenerative template from January 2010 to December 2018. Patient demographics, comorbidities, burn etiologies, operative data, and postoperative care were reviewed. The primary outcome is complications involving major graft loss requiring reoperation. One hundred and sixty-five patients and 173 procedures met the inclusion criteria. The average age was 44 years and 60.6% (100/165) were male. Annual outpatient procedure volume increased 48% from 23 to 34 cases over the 9-year period. The median (interquartile range) grafted percentage total body surface area was 1.0 (1.0)%. Rate of major graft loss requiring reoperation was 5.2% (9/172) and the most common site was the lower extremity (8/9, 88.9%). Age, sex, comorbidities, total body surface area, and procedure types were not significantly associated with postoperative complication rates. The outpatient burn surgery model was estimated to save CA$8170 per patient from inpatient costs. Demonstration of the safety and cost savings associated with outpatient acute burn surgery is compelling for further utilization. Our experience found the adoption of improved dressing care, appropriate patient selection, increased patient education, adequate pain control, and regimented outpatient multidisciplinary care to be fundamental for effective outpatient surgical burn care., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The study had two main aims. First, we assessed the cost-effectiveness of transplanting deceased donor kidneys of differing quality levels based on the Kidney Donor Profile Index (KDPI). Second, we assessed the cost-effectiveness of remaining on the waiting list until a high-quality kidney becomes available compared to transplanting a lower-quality kidney., Methods: A decision analytic model to estimate cost-effectiveness was developed using a Markov process. Separate models were developed for 4 separate KDPI bands, with higher values indicating lower quality. Models were simulated in 1-year cycles for a 20-year time horizon, with transitions through distinct health states relevant to the kidney recipient from the healthcare payer's perspective. Weibull regression was used to calculate the time-dependent transition probabilities in the base analysis. The impact uncertainty arising in model parameters was included by probabilistic sensitivity analysis using the Monte Carlo simulation method. Willingness to pay was considered as Australian $28 000., Results: Transplanting a kidney of any quality is cost-effective compared to remaining on a waitlist. Transplanting a lower KDPI kidney is cost-effective compared to a higher KDPI kidney. Transplanting lower KDPI kidneys to younger patients and higher KDPI kidneys to older patients is also cost-effective. Depending on dialysis in hopes of receiving a lower KDPI kidney is not a cost-effective strategy for any age group., Conclusion: Efforts should be made by the health systems to reduce the discard rates of low-quality kidneys with the view of increasing the transplant rates., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Except for benefits in survival and quality of life, renal transplantation is considered a method that is cheaper compared to alternative modalities of renal replacement therapy; it is thought that, after the first post-transplant year, costs of care decrease and then remain relatively low. However, over time, health problems accumulate in transplant recipients, which may be connected to increased costs of care. In this study, we attempted to verify whether costs of care actually remain low until the graft loss., Material and Methods: This study included 20 renal transplant recipients with grafts functioning at least 5 years post transplant who were managed in our transplant center and who lost their transplants in 2017 or 2018. Costs of post-renal transplant care in consecutive years post transplant were retrospectively assessed in these cases. Direct costs of inpatient as well as outpatient care, from the perspective of a transplant center, were considered., Results: This study included 8 (40%) men and 12 (60%) women. A significant increase in costs of care was observed in the final period of graft function at least in the year of graft loss. It was observed both in those who lost the transplant because of the graft failure and in those who died with a functioning graft. However, despite this increase, mean costs of post-transplant care in the last 6 years of graft function remained lower compared to hemodialysis., Conclusions: Despite the increase in costs of post-renal transplant care observed in the final period of graft function, treatment with renal transplantation remains cheaper compared with hemodialysis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Pediatric patients are at higher risk of nonadherence to immunosuppressive medication after kidney transplant and the resulting adverse outcomes. Factors associated with nonadherence vary, which follow an epidemiological framework and according to health system patterns. The Brazilian public health system covers all costs of kidney transplant, including immunosuppressive medications. We aimed to assess the prevalence and correlates of nonadherence to immunosuppressive medications in a pediatric kidney transplant population who received free access to immunosuppressive medications within the health care system., Materials and Methods: In this single-center crosssectional study, we studied a convenience sample of 156 outpatients (< 18 years old) who were a minimum of 4 weeks posttransplant. Implementation nonadherence to immunosuppressive medications was measured by the 4 questions of the Basel Assessment of Adherence to Immunosuppressive Medications Scale. Multilevel correlates to non - adherence (patient, micro, and macro levels) were assessed., Results: In our patient population, 61% were males, mean age was 13.6 ± 3.1 years, 77% were adolescents, and 84% received organs from deceased donors. We found that 33% were nonadherent to immuno - suppressive medications, mainly in timing (25%) and taking (10.9%) dimensions. Being an adolescent (odds ratio: 2.66; CI, 1.02-6.96), religion other than Catholic or Protestant (odds ratio: 4.33; CI, 1.13-16.67), and family income higher than 4 reference wages (odds ratio: 3.50; CI, 1.14-10.75) were factors associated with nonadherence., Conclusions: In our patient population of mostly adolescents, one-third displayed nonadherence to immunosuppressants. Unexpectedly, a higher economic profile, potentially representing better previous access to health care, was independently associated with nonadherence. This result highlights the need for identifying specific correlates to non - adherence before designing interventions.

Background: Socio-economic deprivation (SED) is emerging as a risk factor for acute graft rejection (AR) and reduced survival of heart transplant (HT) recipients. The study aim was to evaluate any association between SED status of HT recipients and the development of early AR and long-term survival in New Zealand., Methods: This was a retrospective cohort study. Over a 30-year period, 329 HT recipients were identified from the Australian and New Zealand Heart Transplant Registry. All patients were divided into two groups according to the 2013 New Zealand Deprivation Index (NZDep2013) Score. Heart transplant recipients with NZDep2013 scores of 1,030 and above that corresponded to the eighth, ninth and tenth NZDep2013 deciles were allocated to the higher SED group and those with NZDep2013 scores below 1,030 to the lower SED group., Results: The incidence of early AR in the higher SED group was 1.158/person-years and in the lower SED group 1.156/person-years. The crude incidence rate ratio was 1.0 (95% CI: 0.71-1.44; p = 0.9997). The prevalence of early AR in the higher SED group was 1.13/person-years and 1.15/person-years in the lower SED group. The crude prevalence rate ratio was 0.98/person-year (95% CI: 0.68-1.41/person-years; p = 0.468). In the higher SED group, mortality was 5.6/100 person-years (95% CI: 4.3-7.4/100 person-years) and 5.2/100 person-years (95% CI: 4.3-6.3/100 person-years) in the lower SED group. The adjusted mortality rate ratio estimate was 1.2 (95% CI: 0.8-1.7; p = 0.426). The higher and lower SED groups had similar survival (p = 0.196)., Conclusion: Socio-economic disparity in New Zealand HT recipients has no negative impact on the development of AR or survival., (Copyright © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Introduction: Filgrastim, a granulocyte colony-stimulating factor, is commonly used in autologous hematopoietic stem cell transplants (HSCTs) to assist with peripheral blood progenitor cell (PBPC) collection and to support stem cell engraftment. In the United States, tbo-filgrastim is approved under its own Biologic License Application and is limited to a single indication excluding the HSCT population., Methods: Approximately one year after a system-wide formulary change to tbo-filgrastim for all on- and off-label indications, our institution conducted an IRB-approved retrospective comparison of tbo-filgrastim to filgrastim in the autologous HSCT setting. The study included 71 patients who received an autologous HSCT from 1 January 2013 to 31 December 2016 with a documented administration of tbo-filgrastim or filgrastim., Results: There were no statistically significant differences noted on CD34 + counts during stem cell mobilization, neutrophil engraftment, infection rates during the engraftment phase, nor duration of hospitalization during the engraftment phase. More patients in the tbo-filgrastim group received plerixafor per protocol resulting in more patients meeting their PBPC collection goal in one day with fewer collection days overall, a result potentially confounded by institutional protocol changes. Utilizing tbo-filgrastim offered an average cost savings per patient of $2664.26 ($1907.33 for PBPC mobilization and $756.93 for stem cell engraftment) when comparing dollars spent on granulocyte colony-stimulating factor products only., Conclusion: Tbo-filgrastim demonstrates comparable efficacy with a cost savings benefit compared to filgrastim for autologous PBPC mobilization and stem cell engraftment.

ABO-incompatible kidney transplantation (ABO-ILKT) has been reported to have a higher rate of early complications and higher medical costs than ABO-compatible kidney transplantation (ABO-CLKT). We aimed to compare the clinical outcomes, complications, and medical costs between ABO-ILKTs and ABO-CLKTs at 2 years post-transplantation. We included 65 ABO-ILKTs and 94 ABO-CLKTs in this retrospective analysis. The patient survival, graft survival, rejection incidence, and graft function were similar between ABO-CLKT and ABO-ILKT. The hospitalization costs for ABO-CLKT and ABO-ILKT were 26 544 ± 4168 USD and 34 906 ± 18 732 USD, respectively (P = 0.0001). Total 2-year medical costs were 77 117 ± 15 609 USD and 85 325 ± 33 997 USD for ABO-CLKT and ABO-ILKT, respectively, indicating that the medical costs of ABO-ILKT recipients were non-significantly higher than those of ABO-CLKT recipients at 2 years post-transplantation (P = 0.0866). ABO-ILKT and ABO-CLKT recipients showed similar infectious adverse events and complications. In conclusion, medical cost at 2 years post-transplantation, including transplant hospitalization cost, and the frequency of early complications were not significantly higher in the ABO-ILKT group than in the ABO-CLKT group. ABO-ILKT is an acceptable treatment for patients with ESRD and is comparable to ABO-CLKT not only in terms of outcomes but also in terms of medical cost., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Protocol biopsies are defined as sampling of allograft tissue at predetermined times regardless of function. This procedure can be justified due to the lack of non-invasive methods to reliably diagnose rejection (acute or subclinical). Changes in creatinine are not seen with subclinical rejection or early acute rejection and do not always correlate with efficacy of treatment. Parents and providers are still hesitant to pursue protocol biopsy due to the potential complications and lack of definitive evidence of a benefit from doing this procedure. Importantly, the rate of transplant renal biopsy complications requiring additional intervention is low. It is unclear if detection and treatment of subclinical rejection detected on protocol biopsy will lead to improved graft survival. Our goal is to review the literature on this topic and share some of the experience in our center. Definition, indications, and complications of diagnostic transplant renal biopsies are not included in this review.

Lifelong immunosuppression (IS) after liver transplantation is associated with severe adverse effects and increased recipients' morbidity and mortality. Clinical operational tolerance has been reported in up to 40% in very well-selected recipients. Longterm survival and cost savings within the Italian national health system in operational tolerant recipients is reported. Seventy-five liver recipients were enrolled for IS withdrawal at our institution during the period from April 1998 to December 2015. The study population comprised 32 (42.7%) tolerant patients; 41 (54.7%) nontolerant patients needing uptake of IS after clinical or biopsy-proven rejection; and 2 (2.7%) immediate nontolerant patients who developed early rejection after the first drug reduction. The primary endpoint of the study was to assess the longterm patients and graft outcome; the secondary endpoint was the assessment of cost savings in the context of IS withdrawal. The follow-up was 95.0 months (interquartile range, 22.5-108.5 months). IS withdrawal did not result in patient nor graft loss and resulted in a major cost savings reaching about €630,000. In conclusion, longterm IS withdrawal represents a remarkable cost savings in the health care of liver recipients without exposing them to graft loss., (© 2018 by the American Association for the Study of Liver Diseases.)

The use of once-daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once-daily tacrolimus (LCPT, Envarsus) and once-daily tacrolimus extended-release formulation (ER-Tac, Advagraf) compared with twice-daily immediate-release tacrolimus (IR-Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus-based immunosuppression within 2 clinical trials were included in a single-center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration-dose (C/D) ratio over 12 months. Intrapatient variability in trough levels and C/D ratios after 3 months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR-Tac, and 36 with ER-Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195-8.892€) for LCPT, 9.813€ (IQR 7.630-16.832€) for IR-Tac, and 9.838€ (IQR 7.503- 13.541€) for ER-Tac (Kruskal-Wallis test, P = .003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients., Materials and Methods: This observational study inclu-ded 44 liver transplant patients (median age of 59 y; 63.6% men; median delay after transplant of 72.5 mo). Conversion was based on a 1:0.70 proportion., Results: Mean dose of tacrolimus was 2.65 ± 1.24 mg/day before conversion and 2.09 ± 1.68 mg/day after conversion (P < .05), with ratio of 1:0.79. Mean serum tacrolimus trough level increased after conversion (4.92 ± 1.65 vs 5.60 ± 2.89 ng/mL; P < .05), with ratio of 1:1.14. Six months after conversion, mean dose of tacrolimus was 1.65 ± 0.93 mg/day (ratio of 1:0.62) and mean serum tacrolimus trough level was 4.82 ± 1.85 ng/mL, similar to the initial level before conversion. At the end of follow-up, 2 patients had returned to once-daily prolonged-release tacrolimus because of adverse effects (allergy, digestive trouble), which resolved thereafter. The mean cost of tacrolimus therapy was 5.54 ± 2.29 Euros/patient/day before conversion and 4.11 ± 2.32 Euros/patient/day after conversion (P < .05)., Conclusions: Conversion from prolonged-release to extended-release tacrolimus in stable liver transplant patients is safe and cost-effective; however, initially, dose adaptations and careful monitoring are required.

The Model for End-Stage Liver Disease (MELD) score predicts higher transplant healthcare utilization and costs; however, the independent contribution of functional status towards costs is understudied. The study objective was to evaluate the association between functional status, as measured by Karnofsky Performance Status (KPS), and liver transplant (LT) costs in the first posttransplant year. In a cohort of 598 LT recipients from July 1, 2009 to November 30, 2014, multivariable models assessed associations between KPS and outcomes. LT recipients needing full assistance (KPS 10%-40%) vs being independent (KPS 80%-100%) were more likely to be discharged to a rehabilitation facility after LT (22% vs 3%) and be rehospitalized within the first posttransplant year (78% vs 57%), all P < .001. In adjusted generalized linear models, in addition to MELD (P < .001), factors independently associated with higher 1-year post-LT transplant costs were older age, poor functional status (KPS 10%-40%), living donor LT, pre-LT hemodialysis, and the donor risk index (all P < .001). One-year survival for patients in the top cost decile was 83% vs 93% for the rest of the cohort (log rank P < .001). Functional status is an important determinant of posttransplant resource utilization; therefore, standardized measurements of functional status should be considered to optimize candidate selection and outcomes., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: Perioperative complications impose both a clinical and financial burden on patients and the healthcare system. This study sought to identify the frequency and economic impact of complications following orthotopic liver transplantation (OLT)., Methods: The Premier Perspective ® Hospital Database was queried for patients undergoing OLT between 2008 and 2015. Complications were identified by ICD-9 code and grouped by complication type. Complication frequency as well as impact on clinical and economic outcomes was calculated. Complication frequency and effect on cost were combined to determine the annual impact of each complication type on perioperative OLT cost., Results: Among 2747 OLT patients, the most common groups of complications following OLT were pulmonary, bleeding, and infectious. The complications with the greatest average effect on treatment-related costs were infectious, neurologic, deep vein thrombosis/pulmonary embolus, and hepatic arterial thrombosis. Infectious, pulmonary, and bleeding complications had the greatest annual effect on perioperative OLT cost., Conclusions: Efforts focused on preventing coagulopathic bleeding, improving post-operative pulmonary toilet, and minimizing sources of infection can help improve the cost-effectiveness of OLT. Additionally, the combination of these cost data and systematized protocols can help insurers construct bundled payments for OLT that more accurately reflect the cost of perioperative transplant care., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support England's National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base., Methods: A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post-transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of £20 000 and £30 000 per quality-adjusted life year were used., Results: Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of £100 000 per quality-adjusted life year were used., Conclusions: A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate-release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources., (© Crown copyright 2017.)

Background: Induction therapy in deceased donor kidney transplantation is costly, with wide discrepancy in utilization and a limited evidence base, particularly regarding cost-effectiveness., Methods: We linked the United States Renal Data System data set to Medicare claims to estimate cumulative costs, graft survival, and incremental cost-effectiveness ratio (ICER - cost per additional year of graft survival) within 3 years of transplantation in 19 450 deceased donor kidney transplantation recipients with Medicare as primary payer from 2000 to 2008. We divided the study cohort into high-risk (age > 60 years, panel-reactive antibody > 20%, African American race, Kidney Donor Profile Index > 50%, cold ischemia time > 24 hours) and low-risk (not having any risk factors, comprising approximately 15% of the cohort). After the elimination of dominated options, we estimated expected ICER among induction categories: no-induction, alemtuzumab, rabbit antithymocyte globulin (r-ATG), and interleukin-2 receptor-antagonist., Results: No-induction was the least effective and most costly option in both risk groups. Depletional antibodies (r-ATG and alemtuzumab) were more cost-effective across all willingness-to-pay thresholds in the low-risk group. For the high-risk group and its subcategories, the ICER was very sensitive to the graft survival; overall both depletional antibodies were more cost-effective, mainly for higher willingness to pay threshold (US $100 000 and US $150 000). Rabbit ATG appears to achieve excellent cost-effectiveness acceptability curves (80% of the recipients) in both risk groups at US $50 000 threshold (except age > 60 years). In addition, only r-ATG was associated with graft survival benefit over no-induction category (hazard ratio, 0.91; 95% confidence interval, 0.84-0.99) in a multivariable Cox regression analysis., Conclusions: Antibody-based induction appears to offer substantial advantages in both cost and outcome compared with no-induction. Overall, depletional induction (preferably r-ATG) appears to offer the greatest benefits.

Background: Heart transplantation allocation is often restricted from patients with low socioeconomic status (SES) due to concern for worse outcomes. We hypothesised that comorbidities would have a greater impact on risk of severe rejection post-orthotopic heart transplant than would Medicaid insurance and Median Household Income (MHI)., Methods: A retrospective study of 171 patients who underwent orthotopic heart transplant between 7/1999-11/2013 at our facility were followed until 9/2014 for rejection hospitalisations or death. Survival and multivariable analyses with adjustment for age, race, and gender were performed to estimate the risk of severe cellular rejection, ≥2r (hazard ratio [HR], 95% confidence interval [CI])., Results: Eighteen per cent of patients had Medicaid, and 72% of patients had low or medium MHI. Severe rejection occurred in 23% of patients. In the univariable analysis, Medicaid and diabetes were associated with increased risk of rejection while age >60 years, Caucasian race, and male sex were associated with reduced risk [Medicaid 2.32(1.20,4.51), diabetes 2.49(1.09,5.69), age 0.41(0.20,0.84), Caucasian 0.44(0.21,0.93), male 0.49(0.26,0.92)]. Median Household Income had no correlation [MHI 0.79(0.51,1.23)]. In the multivariable adjusted model, Medicaid was not associated with rejection [1.65(0.79,3.41)]; diabetes was strongly associated with risk of severe rejection [3.9(1.59,9.39)], and age >60 years was associated with risk reduction [0.42(0.20,0.82)]., Conclusions: Medicaid insurance and MHI were not associated with increased risk of severe cellular rejection requiring hospitalisation post-orthotopic heart transplant in the adjusted model. Rather the presence of diabetes and age ≤60 years were associated with increased risk., (Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Islet transplantation is a minimally invasive β-cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4 years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1 nmol L -1 , and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4 years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347 297±60 588 NOK, or 35 424±6182 EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Conventionally, free transverse rectus abdominis myocutaneous (fTRAM) flap breast reconstruction has been associated with decreased donor site morbidity and improved flap inset. However, clinical success depends upon more sophisticated technical expertise and facilities. This study aims to characterize postoperative outcomes undergoing free versus pedicled TRAM (pTRAM) flap breast reconstruction., Methods: Nationwide inpatient sample database (2008-2011) was reviewed for cases of fTRAM (ICD-9-CM 85.73) and pTRAM (85.72) breast reconstruction. Inclusion criteria were females undergoing pTRAM or fTRAM breast reconstruction; males were excluded. We examined demographics, hospital setting, insurance information, patient income, and comorbidities. Clinical endpoints included postoperative complications, length-of-stay (LOS), and total charges (TC). Bivariate/multivariate analyses were performed to identify independent risk factors associated with increased complications and resource utilization., Results: Overall, 21,655 cases were captured. Seventy-percent were Caucasian, 95 % insured, and 72 % treated in an urban teaching hospital. There were 9 pTRAM and 6 fTRAM in-hospital mortalities. On bivariate analysis, the fTRAM cohort was more likely to be obese (OR 1.2), undergo revision (OR 5.9), require hemorrhage control (OR 5.7), suffer hematoma complications (OR 1.9), or wound infection (OR 1.8) (p < 0.003). The pTRAM cohort was more likely to suffer pneumonia (OR 1.6) and pulmonary embolism (OR 2.0) (p < 0.004). Reconstruction type did not affect risk of flap loss or seroma occurrence. TC were higher with fTRAM (p < 0.001). LOS was not affected by procedure type. On risk-adjusted multivariate analysis, fTRAM was an independent risk factor for increased LOS (OR 1.6), TC (OR 1.8), and postoperative complications (OR 1.3) (p < 0.001)., Conclusion: Free TRAM has an increased risk of postoperative complications and resource utilization versus pTRAM on the current largest risk-adjusted analysis. Further analyses are required to elucidate additional factors influencing outcomes following these procedures., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A3 online Instructions to Authors. www.springer.com/00266 .

Background: Injuries to arms and legs following severe trauma can result in the loss of large regions of tissue, disrupting healing and function and sometimes leading to amputation of the damaged limb. People experiencing amputations of the hand or arm could potentially benefit from composite tissue transplant, which is being performed in some countries. Currently, there are no composite tissue transplant programs in Canada., Methods: We conducted a systematic review of the literature, with no restriction on study design, examining the effectiveness and cost-effectiveness of hand and arm transplant. We assessed the overall quality of the clinical evidence with GRADE. We developed a Markov decision analytic model to determine the cost-effectiveness of transplant versus standard care for a healthy adult with a hand amputation. Incremental cost-effectiveness ratios (ICERs) were calculated using a 30-year time horizon. We also estimated the impact on provincial health care costs if these transplants were publicly funded in Ontario., Results: Compared to pre-transplant function, patients' post-transplant function was significantly better. For various reasons, 17% of transplanted limbs were amputated, 6.4% of patients died within the first year after the transplant, and 10.6% of patients experienced chronic rejections. GRADE quality of evidence for all outcomes was very low. In the cost-effectiveness analysis, single-hand transplant was dominated by standard care, with increased costs ($735,647 CAD vs. $61,429) and reduced quality-adjusted life-years (QALYs) (10.96 vs. 11.82). Double-hand transplant also had higher costs compared with standard care ($633,780), but it had an increased effectiveness of 0.17 QALYs, translating to an ICER of $3.8 million per QALY gained. In most sensitivity analyses, ICERs for bilateral hand transplant were greater than $1 million per QALY gained. A hand transplant program would lead to an estimated annual budget impact of $0.9 million to $1.2 million in the next 3 years, 2016 to 2018, to treat 3 adults per year., Conclusions: Composite tissue transplant of the hand or arm may improve a patient's ability to function, but because the overall quality of evidence is of very low quality, there is considerable uncertainty as to whether benefits outweigh harms. Compared with standard care, both single- and double-hand transplants are not cost-effective.

The infrequent use of ABO-incompatible (ABOi) kidney transplantation in the United States may reflect concern about the costs of necessary preconditioning and posttransplant care. Medicare data for 26 500 live donor kidney transplant recipients (2000 to March 2011), including 271 ABOi and 62 A2-incompatible (A2i) recipients, were analyzed to assess the impact of pretransplant, transplant episode and 3-year posttransplant costs. The marginal costs of ABOi and A2i versus ABO-compatible (ABOc) transplants were quantified by multivariate linear regression including adjustment for recipient, donor and transplant factors. Compared with ABOc transplantation, patient survival (93.2% vs. 88.15%, p = 0.0009) and death-censored graft survival (85.4% vs. 76.1%, p < 0.05) at 3 years were lower after ABOi transplant. The average overall cost of the transplant episode was significantly higher for ABOi ($65 080) compared with A2i ($36 752) and ABOc ($32 039) transplantation (p < 0.001), excluding organ acquisition. ABOi transplant was associated with high adjusted posttransplant spending (marginal costs compared to ABOc - year 1: $25 044; year 2: $10 496; year 3: $7307; p < 0.01). ABOi transplantation provides a clinically effective method to expand access to transplantation. Although more expensive, the modest increases in total spending are easily justified by avoiding long-term dialysis and its associated morbidity and cost., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

With the worldwide shortage of donor organs, use of ventricular assist device (VAD) therapy is rapidly increasing in both the bridge to transplant and destination therapy settings. However, the high cost of VADs and VAD care is a cause for concern for policy makers who have relied on the limited supply of donor hearts to naturally cap health expenditure on heart transplantation (HTx). We sought to compare costs of the first 12 months of care of VADs vs. HTx. Single center retrospective study utilizing real generated costs over a three yr span from 2010-2012. Only patients with 12 months of costing data were included. Costs of 28 HTx patients and 24 VAD patients were analyzed. Index admission costs were more than double in the VAD group compared to the HTx group and this was driven by the procurement costs and length of stay which increased almost all aspects of in hospital care costs. Subsequent costs were six times higher in the HTx group and this was driven largely by pharmaceuticals. VAD therapy remains a very expensive treatment option for end stage heart failure patients. Device prices need to reduce substantially to make this a more widely applicable and cost effective treatment option., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Tacrolimus and cyclosporine are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of cyclosporine and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane Controlled Trials Register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection, and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and quality-adjusted life years gained and incremental cost-effectiveness. Altogether, 6137 patients from 27 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of patient mortality, graft loss, acute rejection, and hypercholesterolemia. Nevertheless, tacrolimus increased the risk of new-onset diabetes. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events following renal transplant. Tacrolimus is an effective and safe immunosuppressive agent and it may be more cost-effective than cyclosporine for the primary prevention of graft rejection in renal transplant recipients. However, new-onset diabetes should be closely monitored during the medication period.

Background: In December 2014, a new national deceased donor kidney allocation policy was implemented, which allocates kidneys in the top 20% of the kidney donor profile index to candidates in the top 20% of expected survival. We examined the cost implications of this policy change., Methods: A Markov model was applied to estimate differences in total lifetime cost of care and quality-adjusted life years (QALY)., Results: Under the old allocation policy, average lifetime outcomes per listed patient discounted to 2012 US dollars were US $342,799 and 5.42 QALY, yielding US $63,775 per QALY gained. Under the new policy, average lifetime cost was reduced by US $2090 and lifetime QALYs increased by 0.03. Thus, the new policy improved on the old policy by producing more QALYs at lower cost. The present value of total lifetime cost savings from the policy change is estimated to be US $271 million in the first year and US $55 million in subsequent years. The higher transplant rates and allograft survival expected for candidates in the top 20% of expected survival would decrease costs by reducing time on dialysis. Most cost savings are expected to accrue to Medicare, and most increased access to transplant is expected in private payer populations., Conclusions: The new allocation policy was found to be dominant over the old policy because it increases QALYs at lower cost.

Background: Mycophenolate mofetil (MMF) is effective in decreasing rejection and graft loss in renal transplant patients. Enteric-coated mycophenolate sodium (EC-MPS) was designed to reduce MMF gastrointestinal (GI) effects. Dose manipulations in MMF/EC-MPS produce GI tolerability, increasing the risk of rejection. Significant differences in tolerance of MMF/EC-MPS may have economic influence in transplant efficacy outcomes. Herein, we performed a pharmacoeconomic evaluation of acute rejection incidence and interventions in GI-intolerant patients using MMF/EC-MPS., Methods: A cost-effectiveness analysis was performed through a decision tree model with a 1-year time horizon estimating costs and effectiveness of MMF and EC-MPS in renal transplant patients with GI intolerance. The costs and use of resources (US dollars; USD) were from payer perspective (Mexican Social Security). Primary health outcomes were mean cost of acute rejection and GI adverse events treatment. A probabilistic sensitivity analysis (PSA) was generated to test robustness of the model., Results: Calculated incidence of MMF GI intolerance was 44%, and calculated rejection incidence for MMF was 24.05%. Calculated incidence of EC-MPS GI intolerance was 29%, and calculated rejection incidence for EC-MPS was 20.1% Total cost of MMF with GI intolerance during 1-year period plus cost of treating one rejection sums $752,107.25 USD. Total cost of EC-MPS with GI intolerance plus cost of treating one rejection sums $638,018.97 USD., Conclusion: EC-MPS-based treatment is a cost-saving alternative vs MMF in GI-intolerant kidney transplant patients. PSA supports the decision to utilize EC-MPS based on cost-effectiveness analysis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: Antibody-mediated rejection (AbMR) is a leading cause of late graft loss in kidney transplant recipients, accounting for up to 60% of late graft failures. AbMR manifests as two distinct phenotypes: the first occurs in the immediate post-transplant period in sensitized patients; the second occurs in the late post-transplant period and has been associated with non-adherence to immunosuppression. The present review summarizes the current treatment options for AbMR, its clinical and economic burden, and approaches for reducing the risk of AbMR. While AbMR is typically refractory to treatment with corticosteroids, there are numerous other approaches focused on removal, inhibition or neutralization of donor-specific antibodies, or inhibition of complement-mediated allograft damage. AbMR treatment is generally expensive with one US study reporting costs of USD 49,000-155,000 per episode. However, leaving AbMR untreated puts patients at high risk of capillaritis, microangiopathy, necrosis and graft failure, which may ultimately result in much greater costs associated with a return to dialysis. Given the barriers to treatment, which include the high cost and the fact that pharmacologic treatments are currently used off-label, prevention of AbMR is important, with improvement in patient adherence to immunosuppression a key strategic approach that may be worthy of further evaluation., Funding: Astellas Pharma EMEA Limited.

The use of public insurance is associated with diminished survival in patients with cystic fibrosis (CF) following lung transplantation. No data exist on benefits of gaining private health insurance for post-transplant care among such patients previously using public insurance. The United Network for Organ Sharing database was used to identify first-time lung transplant recipients participating in Medicare or Medicaid, diagnosed with CF, and transplanted between 2005 and 2015. Survival outcomes were compared between recipients gaining private insurance after transplantation and those maintaining public coverage throughout follow-up. Since implementation of the lung allocation score, 575 adults with CF received lung transplantation funded by Medicare or Medicaid and contributed data on insurance status post-transplant. There were 128 (22%) patients who gained private insurance. Multivariable analysis of time-varying insurance status found no survival benefit of gaining private insurance (HR = 0.822; 95% CI = 0.525, 1.286; p = 0.390). Further analysis demonstrated that resuming public insurance coverage was detrimental, relative to gaining and keeping private insurance (HR = 2.315; 95% CI = 1.020, 5.258; p = 0.045). Survival disadvantages of lung transplant recipients with CF who have public health insurance were not ameliorated by a switch to private coverage for post-transplant care., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pelvic lymphoceles/lymph fistulas are commonly observed after kidney allotransplantation, especially when the kidney is placed in a retroperitoneal position. While the majority are <5 cm in diameter and resolve without intervention, some may continue to enlarge, and cause local or systemic symptoms or graft dysfunction. Among 1662 recipients of both living and deceased donor kidney transplants between January 2003 and July 2014, we found 46 (2.7%) patients with symptomatic lymphoceles requiring intervention. We studied the clinical outcomes and charges for three treatment modalities including open surgical drainage (22), laparoscopic surgical drainage (11), and percutaneous fibrin glue injections into the drained lymphocele cavity (13). The patient demographics and clinical characteristics were comparable for each treatment group, although maintenance immunosuppressive drugs differed by era. We found fibrin glue injections resulted in significantly lower (p = 0.04) rates of recurrence (1; 7.7%) than either laparoscopic (6; 54%) or open surgical drainage (6; 27.3%). In addition, fibrin glue injections generated significantly (p < 0.001) lower median ($4559) charges compared to either laparoscopic ($26,330) or open surgical drainage ($23,758). Fibrin glue treatment has the advantage of being an outpatient procedure, performed with the patient under local anesthesia, and does not incur the expense of an operative procedure or hospital admission associated with laparoscopic or open surgery., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Generic immunosuppressive drugs are available in Europe, Canada, and the United States. Between countries, there are large differences in the market penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration criteria for generic immunosuppressive drugs are often criticized. However, it is unlikely that the criteria for registration of narrow therapeutic index drugs are going to change, and bioequivalence studies, performed in healthy volunteers, will remain the backbone of the registration process. It would be good if the registration authorities would demand that all generic variants of an innovator drug have the same pill appearance to reduce errors and promote drug adherence.To allow for safe substitution, a number of criteria need to be fulfilled. Generic substitution should not be taken out of the hands of the treating physicians. Generic substitution can only be done safely if initiated by the prescriber, and in well-informed and prepared patients. Payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance treatment with innovator drug. Instead, together with transplant societies, they should design guidelines on how to implement generic immunosuppressive drugs into clinical practice. Substitutions must be followed by control visits to check if the patient is taking the medication correctly and if drug exposure remains stable. Inadvertent, uncontrolled substitutions from 1 generic to another, initiated outside the scope of the prescriber, must be avoided as they are unsafe. Repetitive subsequent generic substitutions result in minimal additional cost savings and have an inherent risk of medication errors.

Background: The Affordable Care Act initiated innumerable cost-containment measures, including promoting generic conversion from brand medications and directing the Food and Drug Administration to decrease requirements for generic approvals. Despite this mandate, few data existed on generic conversion of immunosuppressant medications with narrow therapeutic troughs., Methods: A retrospective analysis of our initial experience with generic tacrolimus (n = 39) was performed using a control cohort from our renal transplant database. A rejection and cost analysis was performed using a consecutive 2-year prior cohort (n = 159) as a control to determine the effect of generic conversion on tacrolimus a narrow therapeutic index immunosuppressant medication., Results: During the first year after transplantation, the generic group had a greater drug variability (20% ± change in trough levels) that required more dosage adjustments (5.42 vs 3.59 drug dosage changes; P = .038) to obtain a stable dose, required increased number of intravenous magnesium infusions (4.95 vs 1.68 infusions; P = .001), and incurred a greater incidence of rejection (23.1% vs 10.2%; P = .024). A yearly institutional cost was evaluated against a negotiated $18,000/yearly central pharmacy cost savings compared with a $652,862 institutional cost to treat unanticipated rejections., Conclusion: Programmatic conversion from brand to generic tacrolimus resulted in increased drug variability, a greater incidence of magnesium wasting, and more episodes of rejection, leading to increases in institutional costs of care. This government-driven attempt at cost containment may be applicable to noncritical medications such as antibiotics and antihypertensives, but this policy should be reconsidered for narrow therapeutic index medications, such as tacrolimus and other immunosuppressant medications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Standards of immunosuppression in renal transplantation have changed dynamically in recent years. We here provide a refined advanced pharmacoeconomic model which uses state-of-the-art methods including a mixed treatment comparison (MTC) analysis. The aim was to assess the cost-effectiveness of current immunosuppressive therapy regimens (TR): "sirolimus + early withdrawal of cyclosporine + steroids" (TR1), "sirolimus-early transition" (TR2), "everolimus-early transition" (TR3) and "tacrolimus low dose + mycophenolate mofetil (MMF) + steroids" (TR4)., Methods: An up-to-date Markov model with current source data was employed to assess the cost-effectiveness of modern immunosuppressive regimens over 12-month and 10-year time periods. Transition probabilities for the occurrence of events for the first year were based on an MTC analysis. The robustness of the model was tested in extensive sensitivity analyses., Results: Within the 12-month time period TR2 yields the highest life years (0.987 LY), generating costs of 17,500 . In terms of years with functioning graft (FG), TR4 yields the best efficacy over the 12-month model duration (0.970 years with FG). For the 10-year time period, TR2 yields the lowest costs (107,246 ) and dominates both TR3 and TR1, as it is simultaneously more effective. Within the 10-year model duration, TR4 reaches slightly higher effects compared with TR2 (6.493 vs. 6.474 LY) resulting in an incremental cost-effectiveness ratio of 387,684 per LY gained., Conclusions: The early transition to sirolimus provides long-term efficiency results comparable with a tacrolimus-based regimen, which represents a common treatment standard after kidney transplantation. Both are superior to other investigated immunosuppressive regimens.

Kidney transplantation is the best treatment option in comparison to dialysis, although patients are obliged to receive life-long medical treatment with immunosuppressive drugs (ISDs) for prevention of the graft rejection. Such immunosuppressive treatment may be costly and associated with multiple adverse effects. Since costs are viewed as one of the major constraints for the increasing number of transplantation, the use of generic ISDs may decrease the overall cost of transplantation and raise the possibility for its further development. An ideal ISD should have the security margin between toxic and therapeutic dose, and prevent development of acute or chronic rejection of the transplanted kidney. This is particularly important for drugs with a "narrow therapeutical index" (NTI), where small differences in dose or concentration lead to dose and concentration-dependent, serious therapeutic failures and/or adverse drug reactions. The NTI generic drug is approved if within 90%-112% of the area under the curve of the original product the pharmacokinetics fulfills the strict criteria of pharmaceutical equivalence and bioequivalence. Every generic has to be proven to be bioequivalent to the innovator product, and not to other generic products because of the possible generic "drift". Thus, the generic ISDs may be economically attractive, but theoretically, they may pose a risk to transplant patients. Such risks may be reduced if a long-term clinical studies showing cost-effectiveness of generic ISDs in de novo and prevalent transplant patients for every new generic ISD are performed. In conclusion, the increased number of solid organ transplantation goes in line with the increased health care expenditure for ISDs. The generic immunosuppressants could be a possible solution if safely substituted for innovator products or other generic drug of choice. The substantial cost reduction needs to be redirected into organ donation initiatives so that more patients can benefit from the further increase in transplantation.

Although biliary complications (BCs) have a significant impact on the outcome of liver transplantation (LT), variation in BC rates among transplant centers has not been previously analyzed. BC rate, LT outcome and spending were assessed using linked Scientific Registry of Transplant Recipients and Medicare claims (n = 16,286 LTs). Transplant centers were assigned to BC quartiles based upon risk-adjusted observed to expected (O:E) ratio of BC separately for donation after brain death (DBD) and donation after cardiac death (DCD) donors. The median incidence of BC was 300% greater in the highest versus lowest DBD quartiles (19.0% vs. 5.9%) and varied 250% between DCD quartiles (20.3%-8.4%). Donor and recipient characteristics suggest that high BC centers actually used lower donor risk index organs, fewer split livers and fewer imports (p < 0.001 for all). Transplant at a center in the highest O:E quartile was associated with increased posttransplant mortality (adjusted hazard ratio [aHR] 2.53, p = 0.007) in DCD transplant and increased graft loss (aHR 1.21, p = 0.02) in DBD transplant. Medicare spending was $22,895 (p < 0.0001) higher at centers in highest versus lowest BC quartile. In summary, BC rates vary widely among transplant centers and higher rates are a marker for an increased risk of death, graft failure and health-care spending., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Induction therapy in renal transplantation reduces the incidence of acute rejection (AR) in expanded criteria donation (ECD) and donation after cardiac death (DCD). We compared the efficacy of Thymoglobulin (Sanofi-Aventis, Spain), ATG Fresenius (ATG-Fresenius, Spain), and Simulect (Novartis Farm, Spain) in a calcineurin-free protocol in ECD and DCD renal transplantation by evaluating patient survival, graft survival, and AR at 1 year and overall costs., Methods: An observational retrospective study was performed using our database of 289 consecutive cadaveric ECD renal transplant recipients (n = 178) and DCD recipients (n = 111) from April 1999 to December 2011. Induction therapy consisted of Simulect, Thymoglobulin, and ATG Fresenius. Calcineurin-inhibitor (CNI)-free maintenance therapy consisted of mycophenolate mofetil or sodium and steroids., Results: There were no differences in the patients' demographic characteristics or patient and graft survival. One-year AR rates were equivalent (ECD: 10%, 19.1%, 17.7% versus DCD: 14.3%, 7.1%, 16.7%). Leukopenia and thrombopenia were significantly more frequent in the ECD group treated with polyclonal induction. The average total cost of transplantation was higher in the ECD group but there were no significant differences in the average total cost between ECD and DCD: 39,970.31 ± 7,732€ versus 35,058.34 ± 6,801€ (P = NS)., Conclusion: Our study shows the same efficacy with polyclonal and monoclonal antibody induction and a CNI-free treatment regimen in ECD and DCD renal transplantation with no differences in overall costs at 1 year after transplantation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

Background: Kidney transplant improves quality of life and survival compared with dialysis. Despite advances in immunosuppressant regimens and the prevention and treatment of acute rejection, graft survival rates have not improved significantly in the past decade. Although the clinical effectiveness of these regimens has been studied, the impact of changes over time on cost has not., Methods: Costs of kidney transplant were compared between 2 periods demarcated by a programmatic change from cyclosporine (early) to tacrolimus (late) and from nonroutine induction (early) to routine induction (late) therapy in adult patients receiving a first kidney-only transplant in Calgary, Alberta, Canada, in an 8-year period., Results: Complete costs for 3 years after transplant was available for 344 patients, including 161 adult recipients in the early period (April 1, 1998-December 31, 2001) and 183 adult recipients in the late period (January 1, 2002-March 31, 2006). The mean total 3-year cost of transplant for recipients was Can$100 034 in the early period and Can$144 712 in the late period largely attributed to increases in the cost of immunosuppressants (P< .001)., Conclusions: Given that the cost of transplant has increased significantly over time, the cost-effectiveness of these and other immunosuppressive regimens should be evaluated carefully.

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.

Objective: Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects., Methods: To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once-daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1-0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx., Results: RAPA ≥0.5 mg/Kg, FK506 ≥0.5 mg/Kg, and MMF ≥120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection., Conclusion: IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection.

Background: Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients., Methods/design: Recipients>1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate>30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibody-positive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but <10% in biomarker-led care. The secondary outcomes include the rate of transplant dysfunction, incidence of infection, cancer and diabetes mellitus, an analysis of adherence with medication and a health economic analysis of the combined screening and treatment protocol. Blood samples will be collected and stored every 4 months and will form the basis of separately funded studies to identify new biomarkers associated with the outcomes., Discussion: We have evidence that the biomarker-led care regime will be effective at preventing graft dysfunction and expect this to feed through to graft survival. This trial will confirm the benefit of routine screening and lead to a greater understanding of how to keep kidney transplants working longer., Trial Registration: Current Controlled Trials ISRCTN46157828.

Kidney transplantation is the preferred treatment for patients with ESRD. It improves the quality of life in recipients, increases patient survival, and is also substantially less costly than maintenance dialysis. Long-term transplant success requires immunosuppressant drug therapy for the life of the allograft. Under current law, Medicare coverage for most recipients (except for those recipients over 65 years of age or with nonkidney-related disabilities) lasts only 3 years, leaving many recipients unable to afford these medications. Lack of drug therapy often leads to allograft rejection, resulting in premature graft failure, return to dialysis, or death. This article reviews the current policy for Medicare immunosuppressive drug coverage and analyzes the potential impact of pending legislative proposals H.R. 2969 and S. 1454 and the Patient Protection and Affordable Care Act.

Hematopoietic cell transplantation (HCT) remains the sole available curative option for patients with β-thalassemia major. Expanded and improved supportive therapies for thalassemia now routinely extend the life span of affected individuals well into adulthood. Consequently, in regions of the world where this care is readily available, HCT has been pursued infrequently, in part owing to concerns about an expected lack of balance between risks and benefits. More recently, however, recognition of significant health problems in older patients with thalassemia, along with recognition of increased risks of graft-versus-host disease (GVHD), graft rejection, and impaired organ function leading to inferior HCT outcomes in this particular group, seem to be turning the wheels and tipping the balance again in the direction of consideration for earlier HCTs. In contrast, in countries where thalassemia is most prevalent (>100,000 new children born each year in Middle East and southeast Asia), lack of supportive care standards together with often insufficient access to dedicated health care facilities, results in the majority of these children not reaching adulthood, further supporting the need for expanded access to HCT for these patients. The cost of HCT is equivalent to that of a few years of noncurative supportive care, such that HCT in low-risk young children with a compatible sibling is justified not only medically and ethically but also financially. International cooperation can play a major role in increasing access to safe and affordable HCT in countries where there is a considerable shortage of transplantation centers. In this article, we review the current status of bone marrow transplantation for thalassemia major, with particular emphasis on a global prospective., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The new law implemented in August 2007 changed the criteria to select renal transplantation (RT) candidates in Portugal, favoring hyperimmunized subjects and those on the waiting list for a longer time, making human leukocyte antigen (HLA) compatibilities less important. The authors compared patients who received a deceased donor kidney between 2005 and 2010. Patients were divided in group A who underwent transplantation before August 2007 (n = 132) and group B (n = 125) after that date. We considered a value of P < .05. Overall mean age at RT was 46.6 ± 13.9 years with 58.8% men, 88% on hemodialysis (HD), with a mean dialysis time of 82.8 ± 119 months. Also, 10.5% of patients underwent a previous transplantation. The mean follow-up was 35 ± 17.1 months. Group B showed significant adverse differences, including dialysis time (50.9 vs. 117 months), length of hospitalization (14.4 vs. 23.2 days), need for HD (1 vs. 3.4 days), HLA match (3.3 vs. 1.4 compatibilities), previous sensitization (4.4% vs. 21.7%), acute rejection episodes in the 1st year (23% vs. 37%), greater use of immunosuppressive drugs, higher costs of induction therapy (2790 vs 4360ϵ), and greater costs of drugs during first hospitalization (3456 vs. 7144ϵ). Among the 16 subjects who lost their grafts, 7 were in group A (3 in the first year) and 9 in group B all in the first year. There was a 5.1% decrease in graft survival at 12 months (P = .07). Univariate analysis showed an association of acute rejection episodes with HLA mismatches, hyperimmunized patients, absence of immediate graft function, hospitalization time, longer HD need, and higher creatinine level at months 1, 2, 3, and 6. Multivariate analysis revealed acute rejection episodes to be associated with a lower number of HLA compatibilities (odds ratio = 0.65; 95% confidence interval, [0.46-0.9]). Application of the law has led to a greater number of acute rejection episodes in the first year and increased costs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

HLA antibody screening is conducted routinely prior to kidney transplantation, but the comparative prognostic value and cost-effectiveness of different methods are unclear. Pre-transplant sera of 141 patients transplanted between 1998 and 2000 were screened by ELISA and Luminex assays, and antibody specificities of reactive sera determined using bead array techniques. ELISA screening detected donor-specific antibodies (DSA) in 19 patients, who had a higher incidence of impaired graft function (60% vs. 20%, p = 0.04) and antibody-mediated rejection (AMR) within 90 d after transplantation (AMR, 35% vs. 5%, p = 0.02). Luminex screening detected eight additional patients with DSA, among those one with AMR. Six of eight patients with Luminex-only-DSA reported no prior immunizing events. Death-censored graft survival was shorter only in patients with DSA and AMR (median, 1.7 yr instead of between 9.5 and 11.0 yr for patients without DSA or patients with DSA but no AMR, p < 0.001). Material costs per detected clinically relevant DSA were about 57% higher for Luminex screening, but this increase could be avoided by modifying the cut-off recommended by the manufacturer. Conclusively, specification of antibodies only in sera reactive in screening tests was cost-effective to prevent shortened graft survival. Preformed DSA were only harmful if AMR was diagnosed within 90 d after transplantation., (© 2012 John Wiley & Sons A/S.)

We wanted to evaluate factors associated with high costs after allogeneic haematopoietic SCT (HSCT). We collected all in-patient and outpatient costs during the first year after HSCT over 5 years, from 2003 to 2007. Mean 1-year costs per patient were \[euro]141,493 (95% confidence interval (95% CI)=125,019-157,967). Patients treated with non-myeloablative conditioning (NMC) had reduced costs, but patients treated with reduced-intensity or myeloablative conditioning had similar 1-year costs. Multivariate analysis showed that increased 1-year costs were seen in post-transplant complications: rejection (relative hazard (RH) 1.24, P<0.001), acute GVHD of grades III-IV (1.31, P<0.001) and invasive fungal infection (1.15, P=0.02). In addition, increased costs were associated with re-transplantation (1.21, P=0.001), mesenchymal stem-cell therapy (1.26, P<0.001), unrelated donor transplants (1.20, P=0.002) and the need for G-CSF treatment due to poor engraftment (1.12, P=0.047). In patients without any of these risk factors, mean 1-year costs were \[euro]84,773 (95% CI=71,145-98,400) (n=51). With three risk factors, the cost increased to \[euro]249,775 (95% CI=166,824-332,727) (n=14). To conclude, major complications increased the costs of HSCT. Unrelated donor transplants were more expensive than HLA-identical sibling transplants. Costs were reduced in patients treated with NMC.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.