Objective Ascites is the most common complication of liver cirrhosis and is associated with increased morbidity and mortality. We aimed to describe hospital-based healthcare resource utilisation (HCRU) and costs in patients with ascites requiring drainage in England. Methods Patients with cirrhosis and ascites requiring paracentesis between April 2016 and March 2019 were retrospectively identified from Hospital Episode Statistics (HES). First paracentesis was defined as index event. Patients were followed up for 12 months, until death, liver transplant or transjugular intrahepatic portosystemic shunt insertion; classified as non-recurrent if no further paracentesis was reported, recurrent if >= 1 further paracentesis was reported or refractory if >= 3 paracenteses <28 days apart were reported. Demographics, clinical characteristics, encounters, liver-related complications and costs were gathered. HES analysis was validated by thorough case-note review at University Hospitals Plymouth applying similar methodology. Results A total of 3558 non-recurrent, 873 recurrent and 529 refractory ascites patients were identified in HES. Mean age was 58.8 years, most (63.2%) were men. HCRU and complications increased with ascites severity. Patients with refractory ascites required over two times as many inpatient admissions/year than recurrent patients (13.8 vs 5.4) and over 30% more outpatient visits (16.0 vs 11.8). Average cost/patient/year also increased with severity (10 pound 440 vs 25 pound 854 vs 40 pound 244). Demographics, HCRU and complications in the audit cohort support the findings in the HES cohort. Conclusions This study reinforces the unmet need for improved treatments for patients with cirrhosis-related ascites who face repeated admissions and increasing complications, and the high-cost burden of managing these cases places on the National Health Service.

Introduction Immune thrombocytopenia (ITP) is an autoimmune condition characterised by platelet destruction and insufficient platelet production. The American Society of Hematology ITP guidelines recommend rituximab, splenectomy, and thrombopoietin receptor agonists (TPO-RAs) as primary treatment options in patients with chronic ITP (Neunert C, et al. 2019). Fostamatinib, a spleen tyrosine kinase inhibitor, is approved for the treatment of chronic ITP in patients who have had an insufficient response to a previous treatment (FDA 2018, EMA 2020). Recent real-world evidence suggests that fostamatinib is used after a previous TPO-RA line (Hughes DM, et al. 2021). The objective of this network meta-analysis (NMA) was to estimate the relative efficacy of fostamatinib compared with current standard treatments after TPO-RAs in patients with refractory chronic ITP for overall platelet response. Methods A systematic literature review was conducted in 2019 and updated in July 2021. Six identified studies informed the NMA, including 2 placebo-controlled trials of fostamatinib (Bussel J, et al. 2018), 2 placebo-controlled trials of rituximab (Arnold DM, et al. 2012, Ghanima W, et al. 2015), 1 randomised trial of 3 rituximab regimens (Zwaginga JJ, et al. 2015) and 1 non-randomised study of 2 rituximab regimens (Zaja F, et al. 2012) (Figure 1). No studies assessing additional comparators of interest were found that could inform the NMA. The outcome of interest was overall platelet response, however definitions varied across studies in terms of platelet count thresholds and assessment time points, and several analyses were therefore performed to investigate sensitivity in variation in outcome definition. Analysis 1 used the published definitions for each study. Analysis 2 used an alternative standardised definition (platelet count >30,000/µL by week 4) for the fostamatinib trials, and the published definitions for each of the remaining studies. Analysis 3 used the alternative standardised definition for all studies and was restricted to those with results available: Bussel 2018 and Ghanima 2015. Possible treatment effect modifiers were evaluated by 8 British haematologists via a Delphi panel. None were identified and it was assumed that the differing baseline characteristics between studies did not have a significant impact on the outcome of interest. Random-effect models were employed in the analyses. The Odds Ratio (OR) for outcome occurrence of each treatment compared to fostamatinib together with the 95% credible intervals (CrI), 95% prediction intervals (PrI), median rank and probability of being the best treatment were estimated and are displayed in forest plots for each analysis. ORs<1 indicate reduced response relative to fostamatinib. All analyses were performed following the guidance of the National Institute for Health and Care Excellence Decision Support Unit and were implemented with WinBUGS and R. Results In analysis 1, pairwise comparisons indicated that fostamatinib was statistically significantly more effective than placebo and all rituximab regimens with ORs for comparators vs. fostamatinib ranging from 0.11 to 0.20 (Figure 2A). In analysis 2, fostamatinib was associated with improved response vs. placebo and all rituximab regimens (OR range 0.14 - 0.25) but statistical significance was only reached vs. placebo and rituximab 4 x 100 mg/week (Figure 2B). In analysis 3, pairwise comparisons suggested increased efficacy of fostamatinib relative to placebo and rituximab 4 x 375 mg/m2/week with ORs of 0.25 and 0.34, respectively. However, OR was only statistically significant vs. placebo (Figure 2C). The probability of fostamatinib being the most effective treatment ranged 0.91 - 0.97 across analyses; median rank for fostamatinib was 1 in all analyses (Figure 2). The between study standard deviations indicated moderate heterogeneity in treatment effects between studies. Conclusions The results from all analyses indicate that fostamatinib was associated with improved overall platelet response relative to rituximab at all regimens evaluated (4 x 375 mg/m2/week, 2/4 x 375 mg/m2/week, 2 x 750 mg/m2/week, 4 x 100 mg/week), and placebo. The use of rituximab offered no additional benefit with regards to achieving a platelet response than being on placebo. Fostamatinib may be a better alternative than rituximab to increase platelet counts in patients with refractory chronic ITP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The development of cirrhotic ascites is associated with significant complications and costs. We previously developed a discrete event simulation (DES) to assess the cost-effectiveness of long-term albumin (LTA; 40g twice/week for 2 weeks, 40g/week thereafter) in addition to standard medical treatment (SMT) in a UK patient cohort, based on patient characteristics and healthcare resource use (HCRU) from Hospital Episode Statistics (HES) and outcomes from the ANSWER trial. We estimated the cost-saving per patient treated with LTA was £8,820. We aimed to validate our model and the HES inputs, by performing a detailed notes-based audit of patients with cirrhotic ascites at University Hospitals Plymouth NHS Trust. All patients undergoing LVP between March 2016-June 2018 were identified. Patients were excluded if ascites was not due to cirrhosis or there was insufficient follow-up data and classified as non-recurrent (if no further LVP or liver-related complications occurred in the follow-up), recurrent (if at least one LVP/complication occurred during the follow-up) and refractory (if ≥3 LVP with ≤28 days between them occurred). Demographic/clinical characteristics at baseline and over 12-month follow-up were collected from patient records. Patients with recurrent ascites were considered eligible for LTA. Working on the premise that LTA may not be practical for all patients, the cost-effectiveness of treating 50% of the cohort with LTA+SMT vs SMT was assessed using the previously developed DES. Unit costs from NHS tariffs and the list price for albumin were used. Reductions in event probabilities associated with LTA were based on ANSWER trial data. Eighty-seven patients underwent an index LVP for cirrhotic ascites: 34 with non-recurrent, 31 with recurrent and 22 with refractory ascites. All patient groups were predominantly male with alcohol-related liver disease. Patient characteristics are included in table 1. Our model estimated that treating 15/31 recurrent ascites patients with LTA+SMT would avoid 28 inpatient encounters, two cases of RA and three deaths at 12 months. Despite the increased overall cost of £167,272 due to albumin administration (based on list price of albumin and outpatient visit cost for administration), the reduction in complications and HCRU would lead to an overall estimated cost-saving of £194,340 (£1,805/patient). Our audit of patients with recurrent ascites validates our previous HES analysis; we found similar HCRU and event rates to previous HES data inputs and this DES supports the conclusion that treating patients with recurrent ascites with LTA would improve survival and lead to cost-savings through reduction of complications and HCRU.

Introduction Decompensated cirrhosis is a major cause of morbidity and mortality in the United Kingdom (UK).1 The development of ascites complicating cirrhosis frequently represents the first manifestation of decompensation, is a hallmark of advanced liver disease and frequently a prelude to other complications. Refractory ascites (RA), characterised by early recurrence after initial paracentesis, is associated with a worse prognosis.2 The objective of the present study was to describe healthcare resource utilisation and costs incurred by cirrhotic patients following presentation to the South West Liver Unit with large volume ascites requiring paracentesis. Methods A retrospective study using the Hospital Episode Statistics (HES) data from University Hospitals Plymouth was performed. Patients with decompensated cirrhosis and ascites based on liver disease ICD-10 codes (K70-K77) requiring paracentesis (T46) between January-2015 and February-2020 were identified and healthcare resource utilisation/costs assessed over the following 12 months or until Transjugular Intrahepatic Portosystemic Shunt (TIPS) insertion, liver transplant, diagnosis of RA or death. RA was defined by the need for 2 or more paracenteses in a month. The subset of patients who developed RA were followed up for 12 additional months. Outpatient visits, elective and non-elective admissions and mortality were quantified and costed for the overall population and the sub-group who developed RA. Results HES data identified a cohort of 524 cirrhotic patients with ascites. Mean age was 61.8 years and 57.8% were male. 12-month mortality was 22.3%. 3489 outpatient visits, 509 elective day cases, 284 elective admissions and 969 non-elective admissions were required. The mean cost per patient was £12,176 per year. A total of 1061 paracenteses were performed during the 12-month follow-up. RA developed in 129 (24.6%) cases. Patients with RA were more likely to require hospitalisation (421 day cases, 421 non-elective and 206 elective admissions), had more outpatient appointments (1693) and a greater requirement for paracenteses (618 procedures) during the subsequent 12 months. This resulted in a greater mean cost per patient (£23,810 per year). Conclusions The development of ascites in cirrhotic patients is associated with significant healthcare resource utilisation and high mortality. One in four patients developed refractory ascites within 12 months of first paracentesis and in these patients hospitalisation rates, outpatient appointments and paracentesis more than doubled, with a significant increase in associated cost. Future treatment strategies that can reduce the likelihood of developing RA may help mitigate costs and ease the burden on both health systems and patients. References Sepanlou SG, Safiri S, Bisignano C, et al. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet Gastroenterology & Hepatology 2020;5(3):245–66. Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on the consensus conference of the international ascites club. Hepatology 2003;38(1):258–66.

Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of >4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: Age ≥18;Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);failure of ≥1 prior treatment for wAIHA;Haptoglobin ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN;Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to <10 g/dL, subject must be on a permitted wAIHA treatment AND have symptoms associated with anemia. Exclusion Criteria include: Presence of other forms of AIHA;Uncontrolled or insufficiently controlled hypertension;Neutrophil count <1,000/µL,Platelet count <30,000/μL (unless patient has Evans syndrome);Transaminase levels >1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy; duration of hemoglobin response; and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patients have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. Figure Disclosures Cooper: Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Numerof:Rigel: Current Employment, Current equity holder in publicly-traded company. Tong:Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter:Incyte: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Shionogi: Consultancy; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria.

Immune thrombocytopenia (ITP) is a rare condition characterized by thrombocytopenia and variable bleeding severity. After acute management with steriods and intravenous immunoglobulin (IVIG), the next line therapies include medical treatments: immunosuppressive therapy such as rituximab, mycophenolate mofetil (MMF), thrombopoietin receptor agonists or surgical treatments. The choice of therapy depends on the time course of the disease, severity, patient choice and comorbidities. The evidence for comparative efficacy between different treatment modalities is lacking in the literature, in particular the immunosuppressive therapies MMF and rituximab.