Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.

BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. STUDY DESIGN: Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. SETTING & PARTICIPANTS: Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. INTERVENTION: Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. OUTCOMES: Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). MEASUREMENTS: Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). RESULTS: Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. LIMITATIONS: Short treatment duration and small sample size. CONCLUSIONS: In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.

Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial.

BACKGROUND: Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly. METHODS: Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11-13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50-53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953. RESULTS: Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups. CONCLUSIONS: Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa.

Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial.

BACKGROUND: C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, was developed to provide stable control of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease. We examined its efficacy for Hb level correction when administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients. STUDY DESIGN: Open-label, multicenter, randomized, parallel-group, phase 3 study. SETTING & PARTICIPANTS: Dialysis patients (age >or= 18 years). INTERVENTION: Patients (n = 181) were randomly assigned (3:1) to receive intravenous C.E.R.A. once every 2 weeks or epoetin 3 times weekly. OUTCOMES & MEASUREMENTS: The primary end point was Hb level response rate (increase in Hb level >or= 1 g/dL [10 g/L] versus baseline and Hb level >or= 11 g/dL [110 g/L] without blood transfusion during the 24-week correction period) in the intent-to-treat population. RESULTS: Hb response rates (intent-to-treat population) were 93.3% with C.E.R.A. and 91.3% with epoetin. Similar results were found in the per-protocol population. Peak mean Hb levels were 12.28 +/- 1.13 (SD) g/dL (122.8 +/- 11.3 g/L) with C.E.R.A. and 12.19 +/- 1.24 g/dL (121.9 +/- 12.4 g/L) with epoetin. Mean change in Hb levels from baseline to the end of the correction period were 2.70 +/- 1.45 g/dL (27 +/- 14.5 g/L) with C.E.R.A. and 2.56 +/- 1.31 g/dL (25.6 +/- 13.1 g/L) with epoetin. Both treatments were generally well tolerated. LIMITATIONS: Open-label study design, 3:1 randomization, limited peritoneal dialysis population, descriptive statistics, and lack of formal prespecified comparison to epoetin. CONCLUSIONS: Intravenous C.E.R.A. once every 2 weeks may be as safe and effective as 3-times-weekly epoetin for correcting anemia in dialysis patients. These results show the utility of intravenous C.E.R.A. administered once every 2 weeks in erythropoiesis-stimulating agent-naive dialysis patients.

Antimicrobial locks: putting the lock on catheter infections.

Infectious complications resulting from catheter use in the hemodialysis population remain as the significant cause of morbidity and mortality in this patient population. Because conservation of vascular access sites remains a therapeutic mainstay for chronic hemodialysis patients, clinical investigators have evaluated the safety and efficacy of catheter preservation with antimicrobial lock solutions instilled into the lumens of catheters to treat and prevent infectious complications. The recommended treatment of catheter-related bacteremia includes administration of systemic antibiotics with catheter removal. To date, 4 studies in the hemodialysis population have evaluated the use of systemic antibiotics with an antimicrobial lock solution for treatment of catheter-related bacteremias to amplify the success of catheter salvage. The use of antimicrobial lock solutions for the treatment of catheter-related bacteremia has resulted in successful catheter salvage in approximately 69% of patients, with the remainder requiring catheter removal following a lack of clinical improvement after 48 hours. The antimicrobial lock has also been studied as a prophylactic measure to prevent catheter-related bacteremia. Six studies in the hemodialysis population have evaluated the use of an antimicrobial lock for the prevention of catheter-related bacteremia with an overall 64%-100% reduction in the frequency of catheter-related bacteremia. Although the use of antimicrobial lock for prophylaxis has demonstrated efficacy in clinical trials, its long-term consequences, including potential impact on antimicrobial resistance, are unknown. The objectives of this review are to evaluate the current body of evidence espousing the utilization of an antimicrobial lock solution in tunneled cuffed and uncuffed catheters that are utilized during chronic intermittent hemodialysis.

Iron sucrose: the oldest iron therapy becomes new.

Several parenteral iron preparations are now available. This article focuses on iron sucrose, a hematinic, used more widely than any other for more than five decades, chiefly in Europe and now available in North America. Iron sucrose has an average molecular weight of 34 to 60 kd, and after intravenous (IV) administration, it distributes into a volume equal to that of plasma, with a terminal half-life of 5 to 6 hours. Transferrin and ferritin levels can be measured reliably 48 hours after IV administration of this agent. Iron sucrose carries no "black-box" warning, and a test dose is not required before it is administered. Doses of 100 mg can be administered over several minutes, and larger doses up to 300 mg can be administered within 60 minutes. The efficacy of iron sucrose has been shown in patients with chronic kidney disease (CKD) both before and after the initiation of dialysis therapy. Iron sucrose, like iron gluconate, has been associated with a markedly lower incidence of life-threatening anaphylactoid reactions and may be administered safely to those with previously documented intolerance to iron dextran or iron gluconate. Nonanaphylactoid reactions, including non-life-threatening hypotension, nausea, and exanthema, also are extremely uncommon with iron sucrose. Management of patients with the anemia of CKD mandates that we carefully examine the effectiveness and safety of this oldest of iron preparations and the accumulating present-day data regarding it and contemporaneous agents.

Access monitoring is worthwhile and valuable.

During the past several years, a limited number of small clinical trials have questioned the role of surveillance in the management of vascular accesses, since the prolongation of access longevity until replacement was not altered. Although prolongation of access life span is an important endpoint, it is not the only one. Reduction in thrombotic events reduces the risks to the patient resulting from loss of access patency. The body of evidence suggests that the detection of stenosis and prevention of thrombosis are valuable. When a test indicates the likely presence of a stenosis, venography or fistulography should be used to definitely establish the presence and the degree of the stenosis. In most cases, angioplasty should be performed if the stenosis is greater than 50% by diameter. The value of routine use of any surveillance technique for detecting anatomic stenosis alone without concomitant functional assessment by measurement of access flow, venous pressure, recirculation, or other physiologic parameter has not been established. Stenotic lesions should not be repaired merely because they are present. If such correction is performed, then intra-procedural studies of access flow or intra-access pressure prior to and following percutaneous transluminal angioplasty should be conducted to demonstrate a functional improvement with a 'successful' percutaneous transluminal angioplasty.

Preventing vascular access dysfunction: which policy to follow.

In the USA, three Clinical Performance Measures are currently in place: increasing the number of autologous arteriovenous fistulas (AVFs) among incident hemodialysis patients to 50% and to 40% in prevalent hemodialysis patients; to foster the surveillance of accesses with preemptive correction of problems before accesses thrombose or fail, and to reduce the use of catheters in prevalent patients to less than 10%. Reduction of catheters will automatically result from initiatives that increase the construction of AVFs and preemptive monitoring and surveillance of accesses for dysfunction. Therefore, policies that promote the latter two vascular access aspects are most important to develop and follow. Of these two, however, the most impact will be made by promoting a policy to increase AVF creation in the timeliest manner possible. Strategies and resources needed to achieve these policies are presented. The need for a team approach is emphasized.