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Factors affecting the doses of roxadustat vs darbepoetin alfa for anemia treatment in hemodialysis patients.
Akizawa, T, Yamaguchi, Y, Majikawa, Y, Reusch, M
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2021;(5):575-585
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Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.
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Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients.
Akizawa, T, Tanaka-Amino, K, Otsuka, T, Yamaguchi, Y
American journal of nephrology. 2021;(9):702-713
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INTRODUCTION Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. METHODS Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. RESULTS Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses. DISCUSSION/CONCLUSION The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.
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Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial.
Trenkwalder, C, Winkelmann, J, Oertel, W, Virgin, G, Roubert, B, Mezzacasa, A, ,
Movement disorders : official journal of the Movement Disorder Society. 2017;(10):1478-1482
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BACKGROUND Compromised iron status is important in restless legs syndrome pathophysiology. We compared the efficacy and tolerability of ferric carboxymaltose (single intravenous dose) versus placebo for restless legs syndrome treatment in iron-deficient nonanemic patients. METHODS Patients with moderate to severe restless legs syndrome and serum ferritin < 75 μg/L (or serum ferritin 75-300 μg/L and transferrin saturation < 20%) were randomized to ferric carboxymaltose (1000 mg iron) or placebo. Mean change difference between ferric carboxymaltose and placebo in International Restless Legs Syndrome Severity Scale score from baseline to week 4 was the primary end point; week 12 was a secondary end point. RESULTS Ferric carboxymaltose treatment (n = 59) led to nonsignificant improvement over placebo (n = 51) in International Restless Legs Syndrome Severity Scale score at week 4 (difference [95% confidence interval], -2.5 [-5.93 to 1.02], P = 0.163), reaching significance by week 12 (-4.66 [-8.59 to -0.73], P = 0.021). CONCLUSIONS In patients who responded to treatment, ferric carboxymaltose may require more time to stabilize restless legs syndrome than previously assumed. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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The Ferumoxytol for Anemia of CKD Trial (FACT)-a randomized controlled trial of repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis: background and rationale.
Macdougall, IC, Dahl, NV, Bernard, K, Li, Z, Batycky, A, Strauss, WE
BMC nephrology. 2017;(1):117
Abstract
BACKGROUND Iron deficiency anemia (IDA) is a common manifestation of chronic kidney disease (CKD), affecting most patients on hemodialysis and imposing a substantial clinical burden. Treatment with iron supplementation increases hemoglobin levels and can reduce the severity of anemia in patients with CKD. While correcting anemia in these patients is an important therapeutic goal, there is a lack of long-term trials directly comparing intravenous iron therapies in patients with CKD receiving hemodialysis. METHODS/DESIGN The Ferumoxytol for Anemia of CKD Trial (FACT) is a 13-month, open-label, randomized, multicenter, international, prospective study with 2 substudies. Entry criteria for the main study include adults with IDA (defined as hemoglobin <11.5 g/dL [<115.0 g/L] and a transferrin saturation <30%), serum ferritin <800 ng/mL (<1798 pmol/L), and receiving hemodialysis for ≥3 months. Patients are randomized to receive ferumoxytol (1.02 g over 2 doses) or iron sucrose (1.0 g over 10 doses) during the initial 5-week treatment period. Those with persistent/recurrent IDA over the 11-month observation period will receive additional 5-week treatment periods, as appropriate. The primary efficacy endpoint of the main study is the mean change in hemoglobin from Baseline to Week 5 for each treatment period. The secondary efficacy endpoints include the mean change in transferrin saturation from Baseline to Week 5 and the proportion of patients with a hemoglobin increase of ≥1.0 g/dL at any time from Baseline to Week 5. Safety will be assessed through an examination of the adverse event profile over the course of the study. An "oxidative stress" substudy in approximately 100 patients will assess the effects of treatment on biomarkers of oxidative stress/inflammation during the initial 5-week treatment period, and a magnetic resonance imaging substudy in approximately 70 patients will assess the potential for iron deposition in target tissues over 24 months. DISCUSSION FACT fulfills the need for a long-term comparative trial in patients with IDA and CKD receiving hemodialysis. The efficacy and safety results will provide useful information for guiding therapy in this population. Two hundred ninety-six patients have been enrolled, and completion of the main study is expected soon. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01227616 (registered October 22, 2010); EudraCT number: 2010-022133-28.
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Resistance to erythropoiesis-stimulating agents is associated with arterial microcalcification in early hemodialysis patients.
Won, HS, Choi, SJ, Yun, YS, Shin, OR, Ko, YH, Kim, YS, Yoon, SA, Kim, YO
BioMed research international. 2014;:731296
Abstract
The aim of this study was to evaluate the relationship between arterial microcalcification (AMiC) and erythropoiesis-stimulating agents (ESA) hyporesponsiveness in hemodialysis patients. The presence of AMiC was confirmed by pathologic examination of von Kossa-stained arterial specimens acquired during vascular access surgery. We assessed the ESA hyporesponsiveness index (EHRI), defined as the weekly ESA dose per kilogram body weight divided by the hemoglobin level. AMiC was detected in 33 (40.2%) of 82 patients. Patients with diabetes had a higher incidence of AMiC than patients without diabetes. The serum levels of albumin and cholesterol were higher in patients without AMiC than in patients with AMiC. The serum levels of intact parathyroid hormone were lower in patients with AMiC than in patients without AMiC. The serum levels of phosphate and calcium-phosphorus product did not differ between the two groups. The mean EHRI value was higher in patients with AMiC than in patients without AMiC. In multivariate analyses, ESA hyporesponsiveness and diabetes showed a significant association with AMiC. In conclusion, ESA hyporesponsiveness may be a clinical relevant parameters related to AMiC in hemodialysis patients.
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Pharmacokinetics and safety of deferasirox in subjects with chronic kidney disease undergoing haemodialysis.
Maker, GL, Siva, B, Batty, KT, Trengove, RD, Ferrari, P, Olynyk, JK
Nephrology (Carlton, Vic.). 2013;(3):188-93
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AIM: Treatment of chronic kidney disease (CKD) includes parenteral iron therapy, and these infusions can lead to iron overload. Secondary iron overload is typically treated with iron chelators, of which deferasirox is one of the most promising. However, it has not been studied in patients with CKD and iron overload. METHODS A pilot study was conducted to evaluate the pharmacokinetics and safety of deferasirox in eight haemodialysis-dependent patients, who were receiving intravenous iron for treatment of anaemia of CKD. Deferasirox was administered at two doses (10 mg/kg and 15 mg/kg), either acute (once daily for 2 days) or steady-state (once daily for 2 weeks). RESULTS A dose of 10 mg/kg in either protocol was not sufficient to achieve a plasma concentration in the therapeutic range (acute peak 14.1 and steady-state 22.8 μmol/L), while 15 mg/kg in either protocol maintained plasma concentration well above this range (acute peak 216 and steady-state 171 μmol/L). Plasma concentration observed at 15 mg/kg was well above that expected for this dose (40-50 μmol/L), although no adverse clinical events were observed. CONCLUSION This study highlights the need to profile drugs such as deferasirox in specific patient groups, such as those with CKD and iron overload.
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Role of residual renal function in phosphate control and anemia management in chronic hemodialysis patients.
Penne, EL, van der Weerd, NC, Grooteman, MP, Mazairac, AH, van den Dorpel, MA, Nubé, MJ, Bots, ML, Lévesque, R, ter Wee, PM, Blankestijn, PJ, et al
Clinical journal of the American Society of Nephrology : CJASN. 2011;(2):281-9
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BACKGROUND AND OBJECTIVES There is increasing awareness that residual renal function (RRF) has beneficial effects in hemodialysis (HD) patients. The aim of this study was to investigate the role of RRF, expressed as GFR, in phosphate and anemia management in chronic HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Baseline data of 552 consecutive patients from the Convective Transport Study (CONTRAST) were analyzed. Patients with a urinary output≥100 ml/24 h (n=295) were categorized in tertiles on the basis of degree of GFR and compared with anuric patients (i.e., urinary output<100 ml/24 h, n=274). Relations between GFR and serum phosphate and erythropoiesis-stimulating agent (ESA) index (weekly ESA dose per kg body weight divided by hematocrit) were analyzed with multivariable regression models. RESULTS Phosphate levels were between 3.5 and 5.5 mg/dl in 68% of patients in the upper tertile (GFR>4.13 ml/min per 1.73 m2), as compared with 46% in anuric patients despite lower prescription of phosphate-binding agents. Mean hemoglobin levels were 11.9±1.2 g/dl with no differences between the GFR categories. The ESA index was 31% lower in patients in the upper tertile as compared with anuric patients. After adjustments for patient characteristics, patients in the upper tertile had significantly lower serum phosphate levels and ESA index as compared with anuric patients. CONCLUSIONS This study suggests a strong relation between RRF and improved phosphate and anemia control in HD patients. Efforts to preserve RRF in HD patients could improve outcomes and should be encouraged.
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Do two intravenous iron sucrose preparations have the same efficacy?
Rottembourg, J, Kadri, A, Leonard, E, Dansaert, A, Lafuma, A
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2011;(10):3262-7
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BACKGROUND Intravenous (i.v.) iron sucrose similar (ISS) preparations are available but clinical comparisons with the originator iron sucrose (IS) are lacking. METHODS The impact of switching from IS to ISS on anaemia and iron parameters was assessed in a sequential observational study comparing two periods of 27 weeks each in 75 stable haemodialysis (HD) patients receiving i.v. iron weekly and an i.v. erythropoiesis-stimulating agent (ESA) once every 2 weeks. Patients received IS in the first period (P1) and ISS in the second period (P2). RESULTS Mean haemoglobin value was 11.78 ± 0.99 g/dL during P1 and 11.48 ± 0.98 g/dL during P2 (P = 0.01). Mean serum ferritin was similar for both treatment periods (P1, 534 ± 328 μg/L; P2, 495 ± 280 μg/L, P = 0.25) but mean TSAT during P1 (49.3 ± 10.9%) was significantly higher than during P2 (24.5 ± 9.4%, P <0.0001). The mean dose of i.v. iron per patient per week was 45.58 ± 32.55 mg in P1 and 61.36 ± 30.98 mg in P2 (+34.6%), while the mean ESA dose was 0.58 ± 0.52 and 0.66 ± 0.64 μg/kg/week, respectively (+13.8%). Total mean anaemia drug costs increased in P2 by 11.9% compared to P1. CONCLUSIONS The switch from the originator IS to an ISS preparation led to destabilization of a well-controlled population of HD patients and incurred an increase in total anaemia drug costs. Prospective comparative clinical studies are required to prove that ISS are as efficacious and safe as the originator i.v. IS.
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Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia.
Steensma, DP, Sloan, JA, Dakhil, SR, Dalton, R, Kahanic, SP, Prager, DJ, Stella, PJ, Rowland, KM, Novotny, PJ, Loprinzi, CL
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(1):97-105
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PURPOSE Functional iron deficiency may impair response to erythropoiesis-stimulating agents (ESAs) in iron-replete patients with chemotherapy-associated anemia (CAA). This study evaluated whether coadministration of parenteral iron improves ESA efficacy in patients with CAA. PATIENTS AND METHODS This prospective, multicenter, randomized trial enrolled 502 patients with hemoglobin (Hb) less than 11 g/dL who were undergoing chemotherapy for nonmyeloid malignancies. All patients received darbepoetin alfa once every 3 weeks and were randomly assigned to receive either ferric gluconate 187.5 mg intravenously (IV) every 3 weeks, oral daily ferrous sulfate 325 mg, or oral placebo for 16 weeks. RESULTS There was no difference in the erythropoietic response rate (ie, proportion of patients achieving Hb ≥ 12 g/dL or Hb increase ≥ 2 g/dL from baseline): 69.5% (95% CI, 61.9% to 76.5%) of IV iron-treated patients achieved an erythropoietic response compared with 66.9% (95% CI, 59.1% to 74.0%) who received oral iron and 65.0% (95% CI, 57.2% to 72.3%) who received oral placebo (P = .75). There were also no differences in the proportion of patients requiring red cell transfusions, changes in quality of life, or the dose of darbepoetin administered. Adverse events (AEs) tended to be more common in the IV iron arm: grade 3 or higher AEs occurred in 54% (95% CI, 46% to 61%) of patients receiving IV iron compared with 44% (95% CI, 36% to 52%) who received oral iron and 46% (95% CI, 38% to 54%) who received oral placebo (P = .16). CONCLUSION In patients with CAA, addition of IV ferric gluconate to darbepoetin failed to provide additional benefit compared with oral iron or oral placebo.
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Impact of iron-folic acid supplementation on cognitive abilities of school girls in Vadodara.
Sen, A, Kanani, SJ
Indian pediatrics. 2009;(2):137-43
Abstract
OBJECTIVES To assess impact of daily and intermittent iron-folate (IFA) supplementation on cognition of underprivileged primary schoolgirls in Vadodara. DESIGN Experimental-control longitudinal study. SETTING Municipal primary schools. PARTICIPANTS Schoolgirls (n=161) in the age group of 9 - 13 years. INTERVENTION Participants at three randomly selected schools were given IFA tablets (100 mg elemental iron + 0.5 mg folic acid) either once weekly or twice weekly or daily for one year. The fourth was the control school. OUTCOME MEASURES Digit span, maze test, visual memory test, and clerical task scores. RESULTS IFA supplementation given daily and twice-weekly significantly improved cognition in most tests; the effect was not seen in once-weekly or control groups. In daily and twice weekly IFA groups, positive change in cognition test scores was relatively higher in girls with good compliance(< 70 % dose) vs. poor compliance; in anemic (hemoglobin < 11 g/dL) vs non-anemic girls and in those with higher hemoglobin (Hb) gain (< 1g/dL) vs. lower Hb gain. CONCLUSION Twice weekly IFA supplementation is comparable to daily IFA in terms of beneficial effects on cognition in young adolescent girls.