Key considerations for modelling the long-term costs and benefits of treatments for ANCA-associated vasculitis.

OBJECTIVES: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of severe and chronic autoimmune diseases. Patients undergo two treatment phases: inducing remission and maintaining remission to prevent organ damage. Immunosuppressants, including glucocorticoids (GCs) are used as first-line treatment, but long-term GC use is associated with toxic effects. Novel treatments reduce or replace the need for long-term GC, and therefore can reduce GC-related toxicity. The evolving treatment landscape has presented new challenges for health technology assessment (HTA) of new treatments in AAV and long-term modelling of costs and outcomes in this disease. METHODS: Using the appraisal of avacopan in England (NICE) as a case study, this paper aims to identify the key challenges involved in the economic evaluation of new treatments for AAV, with a particular focus on the long-term modelling of the treatment costs and benefits for the purpose of HTA. The outcome of this study is a set of recommendations for modelling the cost-effectiveness of new treatments for AAV from the HTA perspective. RESULTS: The discussion focuses on the appropriate model structure, approach to modelling end-stage renal disease (ESRD) as a key determinant of costeffectiveness, capturing the impact of GC-related adverse events, and estimation of short and long-term costs of AAV. CONCLUSIONS: Economic evaluation of new treatments for AAV needs to capture all relevant downstream effects. ESRD is a key driver of cost-effectiveness but is associated with major uncertainty. Future observational studies need to offer sufficient detail to allow for differentiation in event rates across treatment options.

A cost-effectiveness analysis of patiromer in the UK: evaluation of hyperkalaemia treatment and lifelong RAASi maintenance in chronic kidney disease patients with and without heart failure.

BACKGROUND: Chronic kidney disease (CKD) patients with and without heart failure (HF) often present with hyperkalaemia (HK) leading to increased risk of hospitalisations, cardiovascular related events and cardiovascular-related mortality. Renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, the mainstay treatment in CKD management, provides significant cardiovascular and renal protection. Nevertheless, its use in the clinic is often suboptimal and treatment is frequently discontinued due to its association with HK. We evaluated the cost-effectiveness of patiromer, a treatment known to reduce potassium levels and increase cardiorenal protection in patients receiving RAASi, in the UK healthcare setting. METHODS: A Markov cohort model was generated to assess the pharmacoeconomic impact of patiromer treatment in regulating HK in patients with advanced CKD with and without HF. The model was generated to predict the natural history of both CKD and HF and quantify the costs and clinical benefits associated with the use of patiromer for HK management from a healthcare payer's perspective in the UK. RESULTS: Economic evaluation of patiromer use compared to standard of care (SoC) resulted in increased discounted life years (8.93 versus 8.67) and increased discounted quality-adjusted life years (QALYs) (6.36 versus 6.16). Furthermore, patiromer use resulted in incremental discounted cost of £2,973 per patient and an incremental cost-effectiveness ratio (ICER) of £14,816 per QALY gained. On average, patients remained on patiromer therapy for 7.7 months, and treatment associated with a decrease in overall clinical event incidence and delayed CKD progression. Compared to SoC, patiromer use resulted in 218 fewer HK events per 1,000 patients, when evaluating potassium levels at the 5.5-6 mmol/l; 165 fewer RAASi discontinuation episodes; and 64 fewer RAASi down-titration episodes. In the UK, patiromer treatment was predicted to have a 94.5% and 100% chance of cost-effectiveness at willingness-to-pay thresholds (WTP) of £20,000/QALY and £30,000/QALY, respectively. CONCLUSION: This study highlights the value of both HK normalisation and RAASi maintenance in CKD patients with and without HF. Results support the guidelines which recommend HK treatment, e.g., patiromer, as a strategy to enable the continuation of RAASi therapy and improve clinical outcomes in CKD patients with and without HF.

Evaluation of the Cost-Effectiveness of Iron Formulations for the Treatment of Iron Deficiency Anaemia in Patients with Inflammatory Bowel Disease in the UK.

INTRODUCTION: In patients with inflammatory bowel disease (IBD), iron deficiency anaemia (IDA) can impair quality of life and increase healthcare costs. Treatment options for IDA-associated IBD include oral iron and intravenous iron formulations (such as ferric carboxymaltose [FCM], ferric derisomaltose [FD, previously known as iron isomaltoside 1000], and iron sucrose [IS]). The present analysis compared the cost-effectiveness of FCM versus FD, IS, and oral iron sulfate in terms of additional cost per additional responder in the UK setting. METHODS: Cost-effectiveness was calculated for FCM versus FD, IS, and oral iron individually in terms of the additional cost per additional responder, defined as haemoglobin normalisation or an increase of ≥2 g/dL in haemoglobin levels, in a model developed in Microsoft Excel. Relative efficacy inputs were taken from a previously published network meta-analysis, since there is currently no single head-to-head trial evidence comparing all therapy options. Costs were calculated in 2020 pounds sterling (GBP) capturing the costs of iron preparations, healthcare professional time, and consumables. RESULTS: The analysis suggested that FCM may be the most effective intervention, with 81% of patients achieving a response. Response rates with FD, IS, and oral iron were 74%, 75%, and 69%, respectively. Total costs with FCM, FD, IS, and oral iron were GBP 296, GBP 312, GBP 503, and GBP 56, respectively. FCM was found to be more effective and less costly than both FD and IS, and therefore was considered dominant. Compared with oral iron, FCM was associated with an incremental cost-effectiveness ratio of GBP 2045 per additional responder. CONCLUSIONS: FCM is likely to be the least costly and most effective IV iron therapy in the UK setting. Compared with oral iron, healthcare payers must decide whether the superior treatment efficacy of FCM is worth the additional cost.

Linear and loglinear structural mean models to evaluate the benefits of an on-demand dosing regimen.

BACKGROUND: Structural mean models can be used to estimate treatment efficacy when drug exposure varies. We applied structural mean model to evaluate the clinical benefits of a proton pump inhibitor prescribed to be taken as needed to alleviate epigastric pain. We also investigated a new diagnostic approach to evaluate model assumptions. METHODS: All patients were suffering from nonerosive reflux disease or functional ulcer-like dyspepsia and were prescribed a proton pump inhibitor to be taken as needed for relief of epigastric pain. The primary endpoint was a score variable that expresses the magnitude of gastro-intestinal symptoms at 8 weeks after randomization. We developed linear and loglinear versions of the structural mean models to derive an unbiased estimator of the reduction in symptom score as a function of exposure to the test drug. Semi-parametric models based on splines and corresponding simultaneous confidence bands identified the presence of potential interactions between drug exposure and baseline covariates. RESULTS: The on-demand dosing regimen generated a wide range of drug exposure. Application of SMM showed that the potential treatment-induced reduction in symptom score was much greater than the average treatment reduction observed in this population of patients. Our diagnostic tool was useful for detecting the interaction between drug exposure and baseline covariates. LIMITATIONS: Analysis could only be performed over the first 2 months after randomization because, afterwards, many patients dropped out from the placebo group. CONCLUSIONS: The structural mean model approach allows one to estimate treatment efficacy in the presence of variable drug exposure. Similar results were obtained using linear and loglinear structural mean model.

Outcomes Associated with Treatment of Chronic Pain with Tapentadol Compared with Morphine and Oxycodone: A UK Primary Care Observational Study.

INTRODUCTION: This study compared adverse outcomes and resource use for patients with a diagnosis of pain treated with tapentadol prolonged-release (PR) versus those treated with morphine controlled-release (CR) and oxycodone CR. METHODS: Data were sourced from the Clinical Practice Research Datalink (CPRD), a database derived from UK primary care. Patients prescribed tapentadol PR between May 2011 and December 2016 were selected and matched to two groups of controls treated with either morphine CR or oxycodone CR on gender, age, pain duration, pain site, pain aetiology, Charlson index and prior analgesia. Times to first adverse event (constipation or nausea/vomiting) were compared within a Cox proportional hazards model. Rates of primary care contacts, accident and emergency contacts and, for a subset of patients linked to Hospital Episode Statistics (HES), inpatient admissions and outpatient contacts were compared using incidence rate ratios (IRRs) derived from Poisson regression. RESULTS: A total of 1907 patients prescribed tapentadol PR were identified and 1791 (93.9%) had a pain diagnosis. Of these 1246 (65.3%) were matched to morphine controls and 829 (43.4%) to oxycodone controls. Compared to controls, gastrointestinal adverse events with tapentadol PR treatment were reduced; aHR = 0.532 (0.402-0.703; p < 0.001) versus morphine CR and 0.517 (0.363-0.735; p < 0.001) versus oxycodone CR. Compared with morphine CR, primary care contacts [IRR = 0.831 (0.802-0.861)], accident and emergency attendance [0.739 (0.572-0.951)], outpatient contacts [0.917 (0.851-0.989)] and inpatients contacts [0.789 (0.664-0.938)] were reduced. For oxycodone, the respective figures were 0.735 (0.703-0.768), 0.971 (0.699-1.352), 0.877 (0.799-0.962) and 0.748 (0.601-0.932). CONCLUSION: Tapentadol PR was associated with significantly fewer adverse gastrointestinal events than morphine CR and oxycodone CR in patients with a diagnosis of pain. There was also significantly reduced primary and secondary care resource use. As with all observational studies, potential bias due to residual confounding and confounding by indication should be considered. FUNDING: Grünenthal Ltd.

Cost-effectiveness of tapentadol prolonged release compared with oxycodone controlled release in the UK in patients with severe non-malignant chronic pain who failed 1st line treatment with morphine.

OBJECTIVES: The aim of this analysis was to assess the cost-effectiveness of tapentadol PR (prolonged release) compared with oxycodone CR (controlled release) in severe non-malignant chronic pain patients in whom controlled release morphine was ineffective or not tolerated. METHODS: A Markov model was developed to assess costs and benefits over a 1-year time horizon from the National Health Service perspective in the UK. Patients could either continue on 2nd line therapy or switch to 3rd line opioid due to lack of efficacy or poor tolerability. Patients failing also 3rd line therapy entered the final absorbing health state (4th line). Data on tolerability, efficacy, and utilities for tapentadol and oxycodone were obtained from the three comparative phase III clinical trials. Costs of resource consumption associated with opioid treatment were derived from a retrospective database analysis of anonymized patient records. RESULTS: The model results predicted that initiating 2nd line therapy with tapentadol leads to higher effectiveness and lower costs vs oxycodone. For the overall population included in the clinical trials, mean annual costs per patient when treated with tapentadol and oxycodone were £3543 and £3656, respectively. Treatment with tapentadol, while cheaper than oxycodone, was more effective (0.6371 vs 0.6237 quality-adjusted life years (QALYs) for tapentadol and oxycodone, respectively), meaning that tapentadol dominated oxycodone. For the sub-group of opioid-experienced patients with severe pain at baseline the ranking in terms of costs and QALYs remained unchanged. Extensive sensitivity analyses showed that conclusions about the cost-effectiveness are consistent. CONCLUSIONS: The cost-effectiveness study suggested that initiating 2nd line treatment in patients with severe non-malignant chronic pain in the UK with tapentadol instead of oxycodone improves patients' quality-of-life and is less costly. Key limitations when interpreting the results are the use of different sources to populate the model and restricted generalizability due to data extrapolation.