Randomised clinical trial: First-line infliximab biosimilar is cost-effective compared to conventional treatment in paediatric Crohn's disease.

BACKGROUND: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. AIM: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. METHODS: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. RESULTS: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036). CONCLUSIONS: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. TRIAL REGISTRATION NUMBER: NCT02517684.

Cost-effectiveness of rituximab versus azathioprine for maintenance treatment in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Rituximab was proven superior to azathioprine for maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The high cost of rituximab might, however, limit its routine use. This study determined the cost-effectiveness of intravenous rituximab (5 x 500 mg until month 18), versus oral azathioprine (2 mg/kg per day, gradually decreased between month 12 and 22), for maintenance treatment of patients with granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited vasculitis, aged 18-75. METHODS: We performed a single-trial based economic evaluation. MAINRITSAN was a 28-month multicentre, prospective, randomised, controlled open-label trial. We estimated the cost of healthcare resources and quality of life using prospectively collected data. Healthcare costs were estimated from the perspective of the French Social Health Insurance's perspective, using 2016 tariffs for reimbursement. Utilities were derived from Short Form 36 scores. We estimated total average cost, incremental cost per incremental relapse averted and per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed to assess uncertainty over relapses, severe adverse events, discount rate, utility weights, time horizon and the cost of rituximab. Costs drivers were tested using a generalised linear model. RESULTS: Total average costs were €13,387 (€11,605-€15,646) and €10,217 (€7,567-12,949) in the rituximab and azathioprine groups respectively. The incremental cost-effectiveness ratio (ICER) was €12,824 per relapse averted and the incremental cost-utility ratio (ICUR) €37,782 per QALY gained. Besides the unit cost of rituximab, the major cost drivers were relapses and severe adverse events. CONCLUSIONS: Maintenance treatment by rituximab could be cost-effective for preventing relapses in patients with AAV.

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES: Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS: Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS: Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS: The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS: TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013544. FUNDING: The National Institute for Health Research HTA programme.

Preemptive Renal Transplantation-The Best Treatment Option for Terminal Chronic Renal Failure.

Renal transplantation is the best therapeutic option for end-stage chronic renal disease. Assuming that it is more advisable if performed early, we aimed to show the clinical, social, and economic advantages in 70% of our patients who were dialyzed only for a short period. For this purpose, we retrospectively collected data over 28 years in 142 kidney transplants performed in patients with <6 weeks on dialysis. 66% of our patients were 30-60 years old; 98% of the patients had living donors. At transplantation, 64% of our patients had no public support; however, 64% of them returned to work and got health insurance 2 months later. Full rehabilitation was achieved in all cases, including integration to the family, return to full-time work, school and university, sports, and reproduction. Immunosuppression consisted of 3 drugs, including steroids, cyclosporine, and azathioprine or mycophenolate. The cost in the 1st year, including patient and donor evaluation, surgery, immunosuppression, and follow-up, was $13,300 USD versus $22,320 for hemodialysis. We conclude that preemptive renal transplantation with <6 weeks on dialysis is the best therapeutic option for end-stage renal failure, especially in developing countries such as Bolivia, where until last year, full public support for renal replacement therapy was unavailable.

Is there still a room for azathioprine monotherapy in inflammatory bowel disease?

Azathioprine is an efficient maintenance treatment of IBD, able to maintain a complete clinical and anatomical remission in about one third of patients. However there are concerns regarding its long term tolerance, particularly myelosuppression and malignancy. Azathioprine is not required in about one third of Crohn's Disease patients and more than half of Ulcerative Colitis patients who will experience a mild disease course. In patients with more severe disease, although anti-TNF agents are more powerful and act more rapidly, there is a subset of patients with moderate-to-severe IBD without important anatomical damage who may achieve a prolonged steroid-free clinical and anatomical remission on azathioprine monotherapy. It is thus advised to initiate azathioprine monotherapy in these intermediate cases, and to continue azathioprine if anatomical remission is achieved.

Economic impact of combination therapy with infliximab plus azathioprine for drug-refractory Crohn's disease: a cost-effectiveness analysis.

BACKGROUND: Combination therapy with infliximab (IFX) and azathioprine (AZA) is significantly more effective for treatment of active Crohn's disease (CD) than IFX monotherapy. However, AZA is associated with an increased risk of lymphoma in patients with inflammatory bowel disease. AIM: To evaluate the cost-effectiveness of combination therapy with IFX plus AZA for drug-refractory CD. METHODS: A decision analysis model is constructed to compare, over a time horizon of 1year, the cost-effectiveness of combination therapy with IFX plus AZA and that of IFX monotherapy for CD patients refractory to conventional non-anti-TNF-α therapy. The treatment efficacy, adverse effects, quality-of-life scores, and treatment costs are derived from published data. One-way and probabilistic sensitivity analyses are performed to estimate the uncertainty in the results. RESULTS: The incremental cost-effectiveness ratio (ICER) of combination therapy with IFX plus AZA is 24,917 GBP/QALY when compared with IFX monotherapy. The sensitivity analyses reveal that the utility score of nonresponding active disease has the strongest influence on the cost-effectiveness, with ICERs ranging from 17,147 to 45,564 GBP/QALY. Assuming that policy makers are willing to pay 30,000 GBP/QALY, the probability that combination therapy with IFX plus AZA is cost-effective is 0.750. CONCLUSIONS: Combination therapy with IFX plus AZA appears to be a cost-effective treatment for drug-refractory CD when compared with IFX monotherapy. Furthermore, the additional lymphoma risk of combination therapy has little significance on its cost-effectiveness.

Cost-effectiveness analysis of top-down versus step-up strategies in patients with newly diagnosed active luminal Crohn's disease.

BACKGROUND: Top-down (TD) strategy with frontline infliximab proved to be more effective than the traditional step-up (SU) approach in newly diagnosed luminal moderate-to-severe CD patients. However, the considerable cost of infliximab calls its universal use as frontline treatment into question. The aim of this study is to evaluate the cost-effectiveness of the TD approach using a Markov decision model. METHODS: Four states were modelled, namely step 1, step 2, step 3 and death. The first three steps were in TD infliximab induction plus azathioprine, infliximab rechallenge plus azathioprine and steroids plus azathioprine, and in SU steroid induction, azathioprine plus steroid rechallenge and infliximab plus azathioprine. Each health state lasted 1 month. The time horizon of the model was 5 years. Transition probabilities and quality of life were estimated from a randomised trial. First- and second-order sensitivity analyses were done to test the robustness of the results. RESULTS: At baseline analysis, TD improved quality-adjusted life expectancy from 3.76 to 3.90 quality-adjusted life years (QALYs), that is, 0.14 QALYs, while allowing a saving of euro 773, proving dominant when compared to SU. TD was cost-saving in 66% of the Monte Carlo simulations and cost

Methotrexate: underused and ignored?

For more than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid-dependent active Crohn's disease. However, international data on medication utilization suggest that this drug is rarely used in clinical practice for an indication of Crohn's disease. This review investigates the potential reasons for the underuse of methotrexate in patients with inflammatory bowel diseases.

Comparative cost-effectiveness of strategies to prevent postoperative clinical recurrence of Crohn's disease.

BACKGROUND: A number of treatments have been shown to reduce the risk of postoperative recurrence of Crohn's disease (CD). The optimal strategy is unknown. The aim was to evaluate the comparative cost-effectiveness of postoperative strategies to prevent clinical recurrence of CD. METHODS: Three prophylactic strategies were compared to "no prophylaxis"; mesalamine, azathioprine (AZA) / 6-mercaptopurine (6-MP), and infliximab. The probability of clinical recurrence, endoscopic recurrence, and therapy discontinuation due to adverse drug reactions (ADRs) were extracted from randomized controlled trials (RCTs). Quality-of-life scores and treatment costs were derived from published data. The primary model evaluated quality-adjusted life years (QALYs) and cost-effectiveness at 1 year after surgery. Sensitivity analysis assessed the impact of a range of recurrence rates on cost-effectiveness. An exploratory analysis evaluated cost-effectiveness outcomes 5 years after surgery. RESULTS: A strategy of "no prophylaxis" was the least expensive one at 1 and 5 years after surgery. Compared to this approach, AZA/6-MP had the most favorable incremental cost-effectiveness ratio (ICER) ($299,188/QALY gained), and yielded the highest net health benefits of the medication strategies at 1 year. Sensitivity analysis determined that the ICER of AZA/6-MP was preferable to mesalamine up to a recurrence rate of 52%, but mesalamine dominated at higher rates. In the 5-year exploratory analysis, mesalamine had the most favorable ICER over 5 years ($244,177/QALY gained). CONCLUSIONS: Compared to no prophylactic treatment, AZA/6-MP has the most favorable ICER in the prevention of clinical recurrence of postoperative CD up to 1 year. At 5 years, mesalamine had the most favorable ICER in this model.

Strategies for the prevention of postoperative recurrence in Crohn's disease: results of a decision analysis.

OBJECTIVES: Nearly 70% of patients with Crohn's disease (CD) undergo surgical resection, with one-quarter subsequently developing clinical recurrence within 12 months. Several options exist for the prevention of postoperative recurrence in CD, but the comparative cost effectiveness of these competing strategies has not been previously analyzed. METHODS: We developed a decision analytic model comprising five strategies--No Treatment, azathioprine (AZA), antibiotics (ABX), upfront infliximab (IFX), and tailored IFX that consisted of no upfront therapy with initiation of IFX in patients with severe endoscopic recurrence at 6 months. The base-case 1-year clinical recurrence rate was 24% with reduction in recurrence by 41%, 77%, and 99% for AZA, ABX, and IFX, respectively. A 1-year time horizon was used and sensitivity analyses were performed. RESULTS: At the base-case analysis, the ABX (0.82 quality-adjusted life years (QALYs)) and AZA (0.81 QALYs) arms were more effective and less expensive than the No Treatment strategy (0.80 QALYs). The most effective strategy was upfront IFX (0.83 QALYs); however, this was also the most expensive and resulted in a high incremental cost-effectiveness ratio (ICER) ($777,732/QALY) compared with no treatment. The tailored IFX arm was less effective than upfront use but had a more acceptable ICER. On increasing the recurrence rate to 78% (high-risk patients), upfront IFX resulted in 0.07 QALYs (ICER $130,580/QALY) gained compared with No Treatment, whereas ABX, AZA, and tailored IFX arms dominated No Treatment. CONCLUSION: Antibiotics are the most cost-effective option for preventing postoperative recurrence, but they have been associated with high rates of intolerance precluding widespread use. Upfront IFX is the most efficacious strategy but is not cost effective even in high-risk patients. Reserving IFX use for high-risk patients with early endoscopic recurrence is more cost effective than upfront use in all patients.

Cost-effectiveness analysis of adjunct VSL#3 therapy versus standard medical therapy in pediatric ulcerative colitis.

BACKGROUND: Inflammatory bowel diseases (IBDs) are costly chronic gastrointestinal diseases, with pediatric IBD representing increased costs per patient compared to adult disease. Health care expenditures for ulcerative colitis (UC) are >$2 billion annually. It is not clear whether the addition of VSL#3 to standard medical therapy in UC induction and maintenance of remission is a cost-effective strategy. PATIENTS AND METHODS: We performed a systematic review of the literature and created a Markov model simulating a cohort of 10-year-old patients with severe UC, studying them until 100 years of age or death. We compared 2 strategies: standard medical therapy versus medical therapy + VSL#3. For both strategies, we assumed that patients progressed through escalating therapies--mesalamine, azathioprine, and infliximab--before receiving a colectomy + ileal pouch anal anastamosis (IPAA) if the 3 medical therapy options were exhausted. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), defined as the difference of costs between strategies for each quality-adjusted life-year (QALY) gained. One-way sensitivity analyses were performed on variables to determine the key variables affecting cost-effectiveness. RESULTS: Standard medical care accrued a lifetime cost of $203,317 per patient, compared to $212,582 per patient for medical therapy + VSL#3. Lifetime QALYs gained was comparable for standard medical therapy and medical therapy + VSL#3 at 24.93 versus 25.05, respectively. Using the definition of ICER <50,000/QALY as a cost-effective intervention, medical therapy + VSL#3 produced an ICER of $79,910 per QALY gained, making this strategy cost-ineffective. Sensitivity analyses showed that 4 key parameters could affect the cost-effectiveness of the 2 strategies: cost of colectomy + IPAA, maintenance cost after surgery, probability of developing pouchitis after surgery, and the quality of life after a colectomy + IPAA. High surgical and postsurgical costs, a high probability of developing pouchitis, and a low quality of life after a colectomy + IPAA could make adjunct VSL#3 use a cost-effective strategy. CONCLUSIONS: Given present data, adjunct VSL#3 use for pediatric UC induction and maintenance of remission is not cost-effective, although several key parameters could make this strategy cost-effective. The quality of life after an IPAA is the single most important variable predicting whether this procedure benefits patients over escalating standard medical therapy.

Effectiveness and cost of replacing a calcineurin inhibitor with sirolimus to slow the course of chronic kidney disease in renal allografts.

Renal grafts suffer a progressive decrease in glomerular filtration rate (GFR) because of several factors including calcineurin inhibitor (CNI) nephrotoxicity. Switching CNIs to sirolimus may improve this adverse prognosis. We performed a prospective, open-label clinical trial among 18 kidney transplant patients with more than 12 months of evolution (range, 385-1826 days), showing progressive GFR decreases and biopsies with interstitial fibrosis and tubular atrophy (IFTA). Immunosuppressive treatment included cyclosporine, ketoconazole, and steroids associated with azathioprine or mycophenolate mofetil. After signing an Institutional Review Board-approved written consent, cyclosporine was switched to sirolimus seeking to achieve a trough blood sirolimus concentration of 6-15 ng/mL. Wilcoxon and Student's t-tests were used to compare the values in the annual periods before and after the switch. GFR was estimated by the Modification of Diet in Renal Disease formula. There were no acute rejection episodes. Estimated GFR on the day of the switch was 38.0 +/- 12.1 mL/min. After CNI switch, the slope of the estimated GFR significantly improved from -6.5 +/- 9.2 to 8.1 +/- 14.0 mL/min/year (P < .01). The estimated GFR 1 year after the switch was 47.2 +/- 16.9 mL/min (P = .003 vs baseline). Total expenditures increased. The ratio of post-switch versus baseline total expenditures was 1.93 (95% confidence interval, 1.54-2.31) and the ratio of sirolimus to CNI cost was 2.16 (95% confidence interval, 1.53-2.78). Switching from CNI to sirolimus for kidney transplants with decreasing GFR and a biopsy with IFTA changes, suggesting progressive graft nephropathy, almost doubled total expenses. It is necessary to conduct trials using clinical end points to definitively validate this therapeutic intervention.

Thiopurine S- methyltransferase [corrected] testing in idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis.

Azathioprine in combination with N-acetylcysteine (NAC) and steroids is a standard therapy for idiopathic pulmonary fibrosis (IPF). Its use, however, is limited by its side effects, principally leukopenia. A genotypic assay, thiopurine S-methyltransferase (TPMT), has been developed that can potentially identify those at risk for developing leukopenia with azathioprine, and thereby limit its toxicity. In those with abnormal TPMT activity, azathioprine can be started at lower dose or an alternate regimen selected. Determine the cost-effectiveness of a treatment strategy using TPMT testing before initiation of azathioprine, NAC, and steroids in IPF by performing a computer-based simulation. We developed a decision analytic model comparing three strategies: azathioprine, NAC and steroids with and without prior TPMT testing, and conservative therapy, consisting of only supportive measures. Prevalence of abnormal TPMT alleles and complication rates of therapy were taken from the literature. We assumed a 12.5% incidence of abnormal TPMT alleles, 4% overall incidence of leukopenia while taking azathioprine, and that azathioprine, NAC, and steroids in combination reduced IPF disease progression by 14% during 12 months. TPMT testing before azathioprine, NAC, and steroids was the most effective and most costly strategy. The marginal cost-effectiveness of the TPMT testing strategy was $49,156 per quality adjusted life year (QALY) gained versus conservative treatment. Compared with azathioprine, NAC and steroids without prior testing, the TPMT testing strategy cost only $29,662 per QALY gained. In sensitivity analyses, when the prevalence of abnormal TPMT alleles was higher than our base case, TPMT was "cost-effective." At prevalence rates lower than our base case, it was not. TPMT testing before initiating therapy with azathioprine, NAC, and steroids is a cost-effective treatment strategy for IPF.

Do patients consider postoperative maintenance therapy for Crohn's disease worthwhile?

BACKGROUND: Treatment decision making for postoperative Crohn's disease is complex because of the increasing number of maintenance therapies available with competing risk-benefit profiles. The main objective of this study was to determine the distribution of patients' preferences for selected postoperative maintenance therapies. METHODS: The study was a cross-sectional survey in which patients with Crohn's disease completed a standardized interview. Each participant completed 5 tasks that compared: (1) no medication and 5-ASA, (2) fish oil and 5-ASA, (3) metronidazole and 5-ASA, (4) budesonide and 5-ASA, and (5) azathioprine and 5-ASA. For each task, the minimum change in treatment effect size between the 2 treatments that the participant considered worthwhile was determined. RESULTS: The distribution of the participants' preference scores varied widely for each task. When fish oil, metronidazole, budesonide, and azathioprine were considered equally effective to 5-ASA, 92.9%, 28.8%, 38.4%, and 19% of the participants, respectively, preferred these medications relative to 5-ASA. These percentages increased to 98.4%, 54.8%, 61.9%, and 50.8%, respectively, when fish oil, metronidazole, budesonide, and azathioprine were considered to offer a 5% absolute risk reduction relative to 5-ASA. Regression analysis did not identify any clinical or demographic variables predictive of the participants' treatment preferences. CONCLUSIONS: The participants' preferences for postoperative maintenance therapies were widely distributed, and no clinical or demographic factors predicted these preferences. This emphasizes the need for effective communication between physician and patient in order to select the treatment options most consistent with a patient's informed preferences.

Economic evaluation of everolimus and mycophenolate mofetil versus azathioprine in de novo heart transplantation.

UNLABELLED: Both the proliferation signal inhibitor everolimus (1.5 mg/day) and mycophenolate mofetil (MMF) (3 g/day) have shown superior efficacy versus azathioprine in de novo heart transplantation. The cost-effectiveness of everolimus and MMF versus azathioprine was assessed to 6 months posttransplantation. METHODS: The evaluation was performed from the German health insurance payer perspective. The composite efficacy endpoint in the everolimus trial was death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR) grade>or=3A, rejection with hemodynamic compromise, and loss to follow-up. The composite endpoint in the MMF trial included only death, retransplantation, and BPAR with hemodynamic compromise. To mimic the everolimus endpoint, an estimated number of patients with BPAR>or=3A was added to the MMF trial results, using two mapping scenarios. RESULTS: The incremental 6-month cost versus azathioprine was euro2535 for everolimus and euro3007 for MMF. The absolute reduction in efficacy failure versus azathioprine was 10.4% for everolimus and 9.8% and 10.1% for MMF, respectively, using scenarios 1 and 2. The incremental cost per efficacy failure avoided (ie, the incremental cost versus azathioprine divided by the reduction in efficacy failure) was euro24,457 for everolimus, and euro30,628 and euro29,912 for MMF in scenarios 1 and 2. CONCLUSION: This analysis, based on findings from two clinical trials, suggested that everolimus was more cost-effective than MMF versus azathioprine in the first 6 months after heart transplantation. Data from a head-to-head trial are required to confirm these results.

A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn's disease treated with azathioprine or 6-mercaptopurine.

BACKGROUND: Azathioprine (AZA) is effective for the maintenance of a steroid free remission in Crohn's disease (CD). Thiopurine methyltransferase (TPMT) is important for the metabolism of AZA and influences the production of active AZA metabolites. AZA dose selection based on pharmacogenetic testing of TPMT and metabolite monitoring (MM) may offer a safety and efficacy advantage over traditional dosing strategies. We performed a decision analysis to estimate the potential costs and effectiveness of TPMT screening and MM as disease management strategies for CD. METHODS: Strategies applying TPMT and/or MM to influence treatment decisions were compared to community care (CC). The impact on toxicity minimization and improved time to initial and sustained response was evaluated. A 1-yr model was developed from the third-party payer perspective for mild to moderately chronically active, steroid-treated CD patients. Effectiveness and toxicity defined by time to response CD activity index (CDAI <150, +/- steroids) or time to sustained response (CDAI <150, off steroids x 8 wk) and reduction in leukopenic events, respectively. One- and two-way sensitivity analyses were conducted to determine the effect of varying individual estimates from those used in the base-case analysis. RESULTS: MM, TPMT, and TPMT + MM strategies as compared to CC achieved an earlier time to initial response (18.66, 18.96, and 19.10 vs. 22.41 wk, respectively) and sustained response (39.83, 42.91, and 39.8 vs. 45.36 wk, respectively). The least costly strategy at 1 yr was TPMT ($3,861) and the most costly strategy was CC ($7,142). Each alternative strategy was shown to dominate CC (i.e., less costs and faster time to response or sustained response). The cost-effectiveness rankings were robust to sensitivity analyses on key variables. CONCLUSION: The addition of alternative strategies to CC may improve AZA outcomes and reduce the total cost of care for steroid treated chronically active CD patients, with TPMT being more beneficial for initial response to treatment and MM being more beneficial for sustained response to treatment.

Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease.

BACKGROUND: Azathioprine is a useful agent in the management of inflammatory bowel disease. Its use is limited by its side-effect profile. Marrow toxicity occurs in approximately 3.2% of patients and is known to be associated with diminished thiopurine methyltransferase enzyme activity resulting from genetic polymorphisms. AIM: To evaluate the cost-effectiveness of screening for thiopurine methyltransferase gene polymorphisms prior to initiation of azathioprine therapy. METHODS: Analysis of the literature was undertaken to calculate the expected frequency of leucopenia and its relationship with thiopurine methyltransferase polymorphisms in a model of theoretical inflammatory bowel disease patients. Decision analysis was then applied to assess the cost of a pre-treatment genotyping strategy, taking account of direct costs and cost per life-year saved. RESULTS: In 1000 inflammatory bowel disease patients treated with azathioprine, 32 will develop myelosuppression and one will die because of this. Of those who develop myelosuppression during azathioprine therapy, 32% are attributable to lower thiopurine methyltransferase activity. Pre-treatment genotyping costs pound 347 per life-year saved for a 30 year old and pound 817 per life-year saved for a 60 year old. This compares favourably with other health care technologies. CONCLUSION: The use of pre-treatment screening for thiopurine methyltransferase polymorphisms in inflammatory bowel disease patients commencing azathioprine therapy represents good value for money.

A retrospective assessment of safety, efficacy, and pharmacoeconomics of generic azathioprine in heart-transplant recipients.

Although a generic formulation of azathioprine (AZA) has been available since 1996, safety, efficacy and pharmacoeconomic implications following conversion from Imuran (AZA) to generic AZA in heart-transplant patients remains to be determined. A retrospective, safety and efficacy assessment, in addition to a cost comparison, was performed in 30 heart-transplant patients who had been switched from Imuran to generic AZA. In heart-transplant patients converted from Imuran to generic AZA, no compromise in safety and efficacy, as measured by white blood cell (WBC) count, infections, rejections, malignancies, and hospitalizations was observed. Generic substitution of Imuran results in an annual cost savings of $318 per patient.