The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer treatment-induced anaemia (including review of technology appraisal no. 142): a systematic review and economic model
Louise CrathorneNicola HuxleyMarcela HaasovaTristan SnowsillTracey Jones-HughesMartin HoyleSimon BriscoeHelen CoelhoLinda LongAntonieta Medina‐LaraRubén Mújica-MotaMark NapierChris Hyde
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Abstract:
Anaemia is a common side effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions to improve cancer treatment-induced anaemia (CIA). To investigate the effectiveness and cost-effectiveness of ESAs in anaemia associated with cancer treatment (specifically chemotherapy). The following databases were searched from 2004 to 2013: The Cochrane Library, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, British Nursing Index, Health Management Information Consortium, Current Controlled Trials and ClinicalTrials.gov. The US Food and Drug Administration and European Medicines Agency websites were also searched. Bibliographies of included papers were scrutinised for further potentially includable studies. The clinical effectiveness review followed principles published by the NHS Centre for Reviews and Dissemination. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care, placebo or other ESAs. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL) and adverse events (AEs) were evaluated. When appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment with no ESA treatment. The model comprised two components: one evaluating short-term costs and quality-adjusted life-years (QALYs) (while patients are anaemic) and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. Of 1457 titles and abstracts screened, 23 studies assessing ESAs within their licensed indication (based on start dose administered) were included in the review. None of the RCTs were completely aligned with current European Union licenses. The results suggest a clinical benefit from ESAs for anaemia-related outcomes and an improvement in HRQoL scores. The impact of ESAs on AEs and survival remains highly uncertain, although point estimates are lower, confidence intervals are wide and not statistically significant. Base-case incremental cost-effectiveness ratios (ICERs) for ESA treatment compared with no ESA treatment ranged from £ 19,429 to £ 35,018 per QALY gained, but sensitivity and scenario analyses demonstrate considerable uncertainty in these ICERs, including the possibility of overall health disbenefit. All ICERs were sensitive to survival and cost. The relative effectiveness of ESAs was not addressed; all ESAs were assumed to have equivalent efficacy. No studies were completely aligned with their European labelling beyond the starting dose evaluated. There is questionable generalisability given that the included trials were published >20 years ago and there have been many changes to chemotherapy as well as to the quality of supportive treatment. Trial quality was moderate or poor and there was considerable unexplained heterogeneity for a number of outcomes, particularly survival, and evidence of publication bias. Adjustments were not made to account for multiple testing. ESAs could be cost-effective when used closer to licence, but there is considerable uncertainty, mainly because of unknown impacts on overall survival. This study is registered as PROSPERO CRD42013005812. The National Institute for Health Research Health Technology Assessment programme.Keywords:
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ABSTRACT. The regulation of erythropoiesis during the first three months of life was studied in 30 premature infants who had haemoglobin concentrations which were lower than in term infants of the same postdelivery age. Erythropoietin and erythropoiesis inhibitors were measured by means of an exhypoxic polycythaemic mouse bioassay. The percentage of haemoglobin F was determined as well. An increased erythropoietin level was detected only in six infants older than six weeks, whose blood haemoglobin concentration was lower than 100 g/l, while in serum from other babies erythropoietin was undetectable by the method used. Erythropoiesis inhibitors were present in 80% of the samples tested. The results presented indicate that in premature infants erythropoiesis is regulated through erythropoietin and that inhibitors of erythropoiesis take part in this regulation as well, but that the haemoglobin level at which erythropoietin is increased is lower in preterm infants than in term babies.
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Background: Two erythropoiesis-stimulating agents (ESAs), epoetin alfa and darbepoetin alfa, are approved for the treatment of chemotherapy-induced anemia in patients with cancer. Randomized controlled trials indicate that the drugs are similarly efficacious, but that the duration of clinical benefit (DCB) ranges from 2 to 7 days for epoetin alfa and from 7 to 21 days for darbepoetin alfa, depending on dose. Given equivalent efficacy, payers are increasingly interested in understanding the cost differences for these 2 drugs. Objective: To examine the impact of different methodological approaches on the cost comparison between epoetin alfa and darbepoetin alfa users, with cancer from a payer perspective. Methods: Episodes of care (episode) were constructed for cancer patients treated with ESAs, using MarketScan claims data. Episodes started with the first ESA claim and ended on the last ESA claim or the claim before a 42-day or longer gap in ESA therapy. Each episode was augmented with an estimated DCB based on the last dose in the episode. Cost was reimbursed amount observed in the claims database. Adjusted weekly cost was estimated using generalized linear models to control for difference in clinical and demographic differences across epoetin alfa and darbepoetin alfa episodes. Results: Episodes were created in 324 darbepoetin alfa and 342 epoetin alfa users. Darbepoetin alfa users tended to be younger, had more comorbidities, and had advanced cancer (all p < 0.001). After accounting for DCB, the average weekly cost of darbepoetin alfa was significantly lower than that of epoetin alfa ($619 vs $940; p < 0.001). After multivariate adjustment, darbepoetin alfa had lower costs than epoetin alfa in the base case and all alternative approaches. Conclusions: To reduce the risk of potential bias, DCB and different patient characteristics should be taken into account when using retrospective claims data to conduct cost comparisons between agents that have significant differences in dosing schedule.
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SUMMARY: This study aimed to compare the within‐patient variability in haemoglobin levels in haemodialysis patients receiving intravenous epoetin alfa or intravenous darbepoetin alfa. Data on haemodialysis patients were extracted from the Renal Anaemia Management database from 2003 to 2004. The variance in haemoglobin was calculated for each patient with more than five haemoglobin observations ( n = 3619). A mixed model was fitted to the within‐patient variances and weighting was based on the number of observations minus 1 for each patient. The model took into account the situation where patients had data on both agents and could therefore act as their own control. The mean within‐patient variance in haemoglobin levels for patients receiving darbepoetin alfa was 24% (95% CI: 18%, 31%) greater than that for patients receiving epoetin alfa ( P < 0.0001). The mean haemoglobin level for patients receiving darbepoetin alfa was 11.33 g/dL (95% CI: 11.27, 11.40) compared with 11.43 g/dL (95% CI: 11.39, 11.46) for patients receiving epoetin alfa ( P < 0.01). There was greater within‐patient fluctuation in haemoglobin levels in patients receiving darbepoetin alfa compared with epoetin alfa. The implications of haemoglobin fluctuations on patient outcomes and resource use require further study.
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Objective: The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in chronic kidney disease (CKD) and to identify determinants of the variation in epoetin alfa: darbepoetin alfa dose ratios across studies.Methods: A systematic review of the literature for comparative switch and non-switch studies of epoetin alfa and darbepoetin alfa treatments in CKD for the period 2000–2005 was performed. Two reviewers independently assessed the quality of the information. Data on the study design and outcomes were collected for each selected study. The dose ratio from epoetin alfa to darbepoetin alfa was calculated for each study, and the results were reported stratified by study characteristics. To control for differences in study design and characteristics that could explain the variability in the relative dosages of the two agents across studies, multivariate regression analysis was conducted. Based on these results, a dose conversion ratio for Canada was estimated.Results: A total of 21 studies involving 16 378 patients exposed to epoetin alfa or darbepoetin alfa in CKD were identified. Univariate analysis of the dose ratios indicated a mean dose ratio of 217:1 (IU of epoetin alfa:µg of darbepoetin alfa). Results from the multivariate analysis demonstrated that the study design (i.e., switch study versus straight comparison studies) and geographical coverage (i.e., United States) affected the results. Based on the multivariate analysis, the dose conversion ratio between epoetin alfa and darbepoetin alfa for Canada was 169:1.Conclusions: Despite limitations associated with switching studies and the limited total number of studies available, this systematic review based on aggregated results provides further evidence to the clinical community that the dose conversion ratio for epoetin alfa:darbepoetin alfa in CKD patients in Canada is approximately 169:1. At that ratio, treatment with epoetin alfa is 11–18% cheaper than treatment with darbepoetin alfa in Canada.
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