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Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are oral alternatives to current standard-of-care treatments for anaemia in chronic kidney disease (CKD). We conducted network meta-analyses to indirectly compare clinical outcomes for three HIF-PHIs in dialysis and non-dialysis populations with anaemia in CKD., Methods: The evidence base comprised phase III, randomised, controlled trials evaluating daprodustat, roxadustat, or vadadustat. Three outcomes were evaluated: efficacy [change from baseline in haemoglobin (Hgb)], cardiovascular safety [time to first major adverse cardiovascular event (MACE)] and quality of life [change from baseline in 36-Item Short Form Health Survey (SF-36) Vitality score]. Analyses were performed separately for all patients and for erythropoiesis-stimulating agent (ESA) non-users at baseline (non-dialysis population) or prevalent dialysis patients (dialysis population). Bayesian Markov Chain Monte Carlo methods with non-informative priors were used to estimate the posterior probability distribution and generate pairwise treatment comparisons. Point estimates (medians of posterior distributions) and 95% credible intervals (CrI) were calculated., Results: Seventeen trials were included. In non-dialysis patients, there were no clinically meaningful differences between the three HIF-PHIs with respect to Hgb change from baseline [all patients analysis (total n  = 7907): daprodustat vs. roxadustat, 0.09 g/dL (95% CrI -0.14, 0.31); daprodustat vs. vadadustat, 0.09 g/dL (-0.04, 0.21); roxadustat vs. vadadustat, 0.00 g/dL (-0.22, 0.22)] or risk of MACE [all patients analysis (total n  = 7959): daprodustat vs. roxadustat, hazard ratio (HR) 1.16 (95% CrI 0.76, 1.77); daprodustat vs. vadadustat, 0.88 (0.71, 1.09); roxadustat vs. vadadustat, 0.76 (0.50, 1.16)]. Daprodustat showed a greater increase in SF-36 Vitality compared with roxadustat [total n  = 4880; treatment difference 4.70 points (95% CrI 0.08, 9.31)]. In dialysis patients, Hgb change from baseline was higher with daprodustat and roxadustat compared with vadadustat [all patients analysis (total n  = 11 124): daprodustat, 0.34 g/dL (0.22, 0.45); roxadustat, 0.38 g/dL (0.27, 0.49)], while there were no clinically meaningful differences in the risk of MACE between the HIF-PHIs [all patients analysis (total n  = 12 320): daprodustat vs. roxadustat, HR 0.89 (0.73, 1.08); daprodustat vs. vadadustat, HR 0.99 (0.82, 1.21); roxadustat vs. vadadustat, HR 1.12 (0.92, 1.37)]. Results were similar in analyses of ESA non-users and prevalent dialysis patients., Conclusions: In the setting of anaemia in CKD, indirect treatment comparisons suggest that daprodustat, roxadustat, and vadadustat are broadly clinically comparable in terms of efficacy and cardiovascular safety (precision was low for the latter), while daprodustat may be associated with reduction in fatigue to a greater extent than roxadustat., Competing Interests: A.S. is an employee of GSK. R.D.L. has received research support from Bristol Myers Squibb, GSK, Medtronic, and Pfizer; and consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, GSK, Medtronic, Merck, Pfizer, and Portola. C.P.K. has received consulting fees from Abbott, Akebia, AstraZeneca, Bayer, Boehringer Ingelheim, Cara Therapeutics, CSL Behring, CSL Vifor, GSK, Pharmacosmos, ProKidney, Rockwell, Takeda, and Tricida, outside of the submitted work. A.C. has received research grants from CSL Vifor; consultancy fees from Astellas, AstraZeneca, Boehringer Ingelheim, CSL Vifor, GSK, Novo Nordisk, and Otsuka; speaker fees from Amgen, Astellas, AstraZeneca, Bayer, CSL Vifor, GSK, Novo Nordisk, and Sanofi (Mexico) and travel support from Astellas, AstraZeneca, and GSK, outside the submitted work. AC is also a member of the Catalan Registry of Renal Patients (RMRC). S.A.M was an employee of GSK at the time of the study. N.B. is an employee of, and shareholder in, GSK. T.J.K. is an employee of, and shareholder in, GSK. V.G.-H. is an employee of Analysis Group, Inc., which received funding from GSK to conduct this research. R.A. is an employee of Analysis Group, Inc., which received funding from GSK to conduct this research. R.R.C. is an employee of and shareholder in GSK. K.L.J. has received consulting fees from GSK, Vifor, and Akebia. A.J.S. has received consultancy fees from Analysis Group, Inc. I.D. has received research grants from Sanofi, NIHR Clinical Research Network (West Midlands, UK), and Kidney Research UK; and honoraria for advisory boards and speaker meetings from GSK, AstraZeneca, Sanofi, and Vifor., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Rationale & Objective: Since the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences., Study Design: Retrospective observational cohort study., Setting & Participants: US Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014., Predictors: Erythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic., Outcomes: Associations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups., Analytical Approach: Baseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ 2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model., Results: Of 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P  < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days., Limitations: Only US Medicare patients were included and different hyporesponder definitions may have influenced the results., Conclusions: This study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients., (© 2020 The Authors.)

Background: A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1-infected patients., Methods: A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed., Results: Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions., Conclusion: Three clinical trials of DTG have demonstrated comparable or superior efficacy and safety to DRV, RAL, and EFV in HIV-1-infected treatment-naive patients. This network meta-analysis suggests DTG is also favorable or comparable to other commonly used third agents (ATV/r, LPV/r, RPV, and EVG/c).

Objectives: The objective of this study was to assess the potential for cost-effectiveness of new technologies for chronic obstructive pulmonary disease (COPD) over the period from 2001 to 2010., Methods: Lung function outcomes and drug prices were observed for a UK COPD population over the period from 2001 to 2010. Cost-effectiveness was assessed at regular intervals on the basis of an established cost-effectiveness model, and the maximum price a technology providing cure could achieve under the current cost-effectiveness rules was estimated., Results: The results of this study show that although the scope for clinical improvement in COPD was still considerable, during the 10 years studied, the potential for cost-effectiveness at each point in time was dependent on momentary market characteristics, such as the changing price of comparators and improvements in clinical effectiveness. As a result, the analysis demonstrates that the future cost-effectiveness of a technology in development depends on the manner pricing and clinical effectiveness evolve throughout time., Conclusions: Because any predictions will be short-lived and dependent on a number of uncertain factors, we conclude that producing accurate forecasts on the potential for cost-effectiveness of new therapies earlier during the development process is especially difficult under the current static cost-effectiveness framework., (Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

This NICE technology appraisal guidance considers the clinical and cost effectiveness of the use of alteplase for acute ischaemic stroke.