Ferumoxytol for iron deficiency anemia in patients undergoing hemodialysis. The FACT randomized controlled trial
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BACKGROUND: Patients with chronic kidney disease (CKD) undergoing dialysis often require intravenous iron for iron deficiency anemia (IDA). MATERIALS AND METHODS: The Ferumoxytol for Anemia of CKD Trial (FACT), a randomized, multicenter, open-label, phase 4 study, compared the long-term safety and efficacy of ferumoxytol with iron sucrose for the treatment of IDA in patients with CKD undergoing hemodialysis. Patients with IDA and CKD undergoing hemodialysis were randomized 2:1 to ferumoxytol 1.02 g (2 × 510 mg) or iron sucrose 1.0 g (10 × 100 mg) for a 5-week treatment period (TP). Over 11 months, patients underwent additional 5-week TPs whenever IDA (hemoglobin < 11.5 g/dL and transferrin saturation < 30%) was detected. The primary efficacy endpoint was mean change in hemoglobin from baseline to week 5 for each TP. Adverse events were recorded during the study. RESULTS: Overall, 293 patients received ferumoxytol (n = 196) or iron sucrose (n = 97). Ferumoxytol was noninferior to iron sucrose regarding hemoglobin change from baseline to week 5. The mean change in hemoglobin in the ferumoxytol and iron sucrose groups was 0.5 and 0.4 g/dL, respectively, in TP 1 (least-squares mean difference, 0.13; 95% confidence interval, -0.11 to 0.36) and 0.6 and 0.3 g/dL, respectively, in TP 2 (0.30; 0.06 - 0.55). Treatment-related and serious adverse events were similar in both groups; no new safety signals emerged. CONCLUSION: Long-term administration of ferumoxytol has noninferior efficacy and a similar safety profile to iron sucrose when used to treat IDA in patients with CKD undergoing hemodialysis.
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Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial.

Few trials have examined rates of hypersensitivity reactions (HSRs) with intravenous iron formulations used to treat iron deficiency anemia (IDA). This randomized, multicenter, double-blind clinical trial compared the safety, and efficacy of ferumoxytol versus ferric carboxymaltose (FCM), focusing on rates of HSRs and hypotension as the primary end point. Patients with IDA of any etiology in whom oral iron was unsatisfactory or intolerable received ferumoxytol (n = 997) or FCM (n = 1000) intravenously over ≥15 minutes on days 1 and 8 or 9 for total respective doses of 1.02 g and 1.50 g. Composite incidences of moderate-to-severe HSRs, including anaphylaxis, or moderate-to-severe hypotension from baseline to week 5 (primary safety end point) were 0.6% and 0.7% in the ferumoxytol and FCM groups, respectively, with ferumoxytol noninferior to FCM. No anaphylaxis was reported in either group. The secondary safety end point of incidences of moderate-to-severe HSRs, including anaphylaxis, serious cardiovascular events, and death from baseline to week 5 were 1.3% and 2.0% in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Least-squares mean changes in hemoglobin at week 5 were 1.4 g/dL and 1.6 g/dL in the ferumoxytol and FCM groups, respectively (noninferiority test P < .0001). Incidence of hypophosphatemia was 0.4% for ferumoxytol and 38.7% for FCM.

Correction to: 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.

Following publication of the original article [1], the authors reported that one of the authors' name is spelled incorrectly. In this Erratum the incorrect and correct author name are shown. The original publication of this article has been corrected.

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.

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.

Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome.

Some, but not all, intravenous iron formulations have been recognized to induce renal phosphate wasting syndrome. Most commonly this has been reported following treatment of iron deficiency anemia (IDA) with ferric carboxymaltose (FCM). A search of PubMed identified relevant randomized controlled trials (RCTs), and case studies evaluating hypophosphatemia (HPP) resulting from intravenous iron treatment. While more recent larger comparative RCTs have confirmed that the majority of patients receiving FCM, especially those with normal renal function, may experience severe HPP, complete documentation is hampered by inconsistent reporting of serum phosphate in such trials. Similarly, while case series and RCTs have documented the persistence of HPP for several weeks or even months, the lack of studies lasting beyond 5-6 weeks has constrained full understanding of the duration of effect. Clinical trials have established that the mechanism involves the bone/metabolic axis with the elevation of intact fibroblast growth factor 23 playing the central role. Reports continue to accumulate of the clinical consequences of severe HPP which are, most commonly, bone abnormalities following repetitive dosing. Case reports and studies, however, have also shown that symptomatic hypophosphatemia can occur after a single FCM dose. The frequency of such events remains unknown, in part due to lack of awareness of hypophosphatemia coupled with the fact that the most common acute symptoms of HPP (fatigue and weakness) are the same for IDA and for many of the chronic diseases that cause IDA. Changes to US and European prescribing information for FCM should raise awareness of the potential for HPP and need to monitor patients at risk for it.

Hypophosphatemia Associated with Intravenous Iron Therapies for Iron Deficiency Anemia: A Systematic Literature Review.

BACKGROUND: Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed condition with a significant impact on quality of life. Oral iron supplementation is often poorly tolerated or yields inadequate response, requiring the use of intravenous iron (IVI) in some patients. Administration of certain IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to adverse events including serious fatigue and osteomalacia. OBJECTIVE: The purpose of this study was to systematically assess the prevalence, clinical consequences, and reporting of treatment-emergent hypophosphatemia within literature investigating IVI therapies marketed in the United States (US). METHODS: A systematic literature review (SLR) was conducted using the PubMed database to identify publications reporting serum phosphate levels or rates of hypophosphatemia within adult IDA patient populations receiving current US-marketed IVIs. RESULTS: The SLR yielded 511 unique publications, with 40 records meeting the final inclusion criteria. Most studies did not report phosphate monitoring methodology or an explicit definition of hypophosphatemia. Hypophosphatemia rates ranged from 0.0% to 92.1% for ferric carboxymaltose (FCM), 0.0% to 40.0% for iron sucrose, 0.4% for ferumoxytol, and 0.0% for low-molecular-weight (LMW) iron dextran. Randomized controlled studies described hypophosphatemia as "asymptomatic" or did not report on other associated sequelae. Eleven case reports detailed treatment-emergent hypophosphatemia in patients treated with FCM. Patients with acute hypophosphatemia primarily developed severe fatigue; those with repeated FCM dosing developed chronic hypophosphatemia associated with osteomalacia and bone deformities. CONCLUSION: Studies analyzed in this SLR reported a range of hypophosphatemia rates, with the highest consistently seen in patients treated with FCM. Across the clinical literature, there appeared to be minimal standardization of phosphate monitoring and definitions of hypophosphatemia. Although multiple cases have documented serious clinical consequences of hypophosphatemia associated with certain IVIs, current trials neither consistently nor adequately assess the frequency and severity of treatment-emergent hypophosphatemia and may underestimate its prevalence.

Health-related quality of life in patients with iron deficiency anemia: impact of treatment with intravenous iron.

Most physicians appear to be aware of the health consequences of advanced anemia, especially in the acute setting, frequently responding with a not inconsequential therapeutic default of transfusion. In contrast, the profound impact that chronic anemia, of any degree, may have on a patient's performance is underappreciated. The focus of this review is to 1) delineate the consistent and broad impact of anemia on patient quality of life as documented by multiple well-validated patient-reported outcome instruments and 2) demonstrate the essential normalization of the debilitation as assessed by these instruments following the administration of intravenous iron.

Cost-effectiveness analysis of intravenous ferumoxytol for the treatment of iron deficiency anemia in adult patients with non-dialysis-dependent chronic kidney disease in the USA.

OBJECTIVE: Ferumoxytol has demonstrated superior efficacy compared with oral iron in treating iron deficiency anemia in chronic kidney disease (CKD) patients. However, an economic evaluation of ferumoxytol has not been conducted. The aim of this study was to analyze the cost-effectiveness of treating iron deficiency anemia in adult non-dialysis-dependent CKD patients with ferumoxytol as compared with oral iron, alone or in combination with erythropoietin-stimulating agents (ESAs). METHODS: A decision analytic model compared health outcomes and costs associated with 5-week outpatient treatment of adult non-dialysis-dependent CKD patients with ferumoxytol or oral iron, each as monotherapy or in combination with ESAs in the USA. Direct costs include the following: drug acquisition and administration, adverse events, and medical management. Efficacy was determined as mean increase in hemoglobin (g/dL) from baseline over the 5-week period. Clinical inputs were derived from patient-level data from two Phase III randomized controlled trials of ferumoxytol vs. oral iron in non-dialysis-dependent CKD patients, and cost inputs from RED BOOK™ and Centers for Medicare and Medicaid Services data. Sensitivity analyses were performed to identify cost drivers and assess the stability of results. RESULTS: The 5-week treatment cost was $2,489, $5,216, $1,298, and $4,263 per patient for ferumoxytol, ferumoxytol with ESAs, oral iron, and oral iron with ESAs, respectively. The corresponding incremental costs per g/dL increase in hemoglobin, relative to ferumoxytol alone, were $398, $3,558, and $4,768 per patient. Efficacy was the main driver of cost-effectiveness for all treatments. Adverse event and medical management costs were the principal drivers of oral iron monotherapy costs, while drug acquisition substantially contributed to the overall cost for the remaining treatments. CONCLUSION: These results suggest that ferumoxytol is a cost-effective treatment for iron deficiency anemia in non-dialysis-dependent CKD patients over a 5-week period compared with oral iron with or without ESAs. Ferumoxytol is more cost-effective as monotherapy.

Comparative safety of intravenous Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia: rationale and study design of a randomized double-blind study with a focus on acute hypersensitivity reactions.

BACKGROUND: Intravenous (IV) iron is often used to treat iron deficiency anemia in patients who are unable to tolerate or are inadequately managed with oral iron. However, IV iron treatment has been associated with acute hypersensitivity reactions. The comparative risk of adverse events (AEs) with IV iron preparations has been assessed by a few randomized controlled trials, which are most often limited by small patient numbers, which lack statistical power to identify differences in low-frequency AE such as hypersensitivity reactions. MATERIALS AND METHODS: Ferumoxytol versus Ferric Carboxymaltose for the Treatment of Iron Deficiency Anemia (FIRM) is a randomized, double-blind, international, multicenter, Phase III study designed to compare the safety of ferumoxytol and ferric carboxymaltose (FCM). The study includes adults with hemoglobin <12.0 g/dL (females) or <14.0 g/dL (males), transferrin saturation ≤20% or ferritin ≤100 ng/mL within 60 days of dosing, and a history of unsatisfactory or nontolerated oral iron therapy or in whom oral iron therapy is inappropriate. Patients are randomized (1:1) to ferumoxytol 510 mg or FCM 750 mg, each given intravenously on days 1 and 8. Primary end points are the incidence of moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. All potential hypersensitivity and hypotensive reactions will be adjudicated by a blinded, independent Clinical Events Committee. A secondary safety end point is the composite frequency of moderate-to-severe hypersensitivity reactions, including anaphylaxis, serious cardiovascular events, and death. Secondary efficacy end points include mean change in hemoglobin and mean change in hemoglobin per milligram of iron administered from baseline to week 5. Urinary excretion of phosphorus and the occurrence of hypophosphatemia after IV iron administration will be examined as well as the mechanisms of such hypophosphatemia in a substudy. CONCLUSION: FIRM will provide data on the comparative safety of ferumoxytol and FCM, two IV iron preparations with similar dosing schedules, focusing on moderate-to-severe hypersensitivity reactions, including anaphylaxis, and moderate-to-severe hypotension. The study plans to enroll 2000 patients and is expected to complete in 2017.

Efficacy and safety of IV ferumoxytol for iron deficiency anemia in patients with cancer.

PURPOSE: Iron deficiency anemia (IDA) is common in cancer patients due to blood loss and inflammation. Many do not tolerate oral iron or adequately respond. Intravenous (IV) iron is commonly used as an adjunct to erythropoiesis-stimulating agents; data on the use of IV iron monotherapy in these patients are limited. This study aimed to evaluate IV ferumoxytol for the treatment of cancer patients with IDA with a history of unsatisfactory oral iron therapy or in whom oral iron could not be used. PATIENTS AND METHODS: This post hoc analysis of pooled data from two multicenter, randomized, controlled, Phase III trials evaluating IV ferumoxytol (510 mg ×2) vs placebo or iron sucrose (200 mg ×5) included a subgroup of 98 patients with cancer that the investigator identified as the primary cause of their IDA, or with cancer whose IDA was attributed to another comorbid condition (ferumoxytol, n=75; iron sucrose, n=13; placebo, n=10). Gastrointestinal cancers were most common (42), followed by breast (14), cervix (ten), and lung (nine). The primary endpoint was the mean change in hemoglobin (Hgb) from baseline to week 5. RESULTS: At week 5, both ferumoxytol and iron sucrose produced significant increases in Hgb from baseline (1.8 g/dL [P<0.0001] and 1.9 g/dL [P=0.002], respectively). During the studies, 45 patients received chemotherapy, 19 with platinum-based regimens. Erythropoiesis-stimulating agent doses were neither increased >20% nor initiated in any treatment group. Overall rates of adverse events and serious adverse events in the cancer subgroup mirrored those in the overall study population. CONCLUSION: Monotherapy with IV iron appears to be an effective option for cancer patients with IDA who do not respond to or cannot tolerate oral iron therapy.

Ferumoxytol versus iron sucrose treatment: a post-hoc analysis of randomized controlled trials in patients with varying renal function and iron deficiency anemia.

BACKGROUND: Iron deficiency anemia is highly prevalent in patients with chronic kidney disease and is often treated with intravenous iron. There are few trials directly comparing the safety and efficacy of different intravenous iron products. METHODS: This post-hoc analysis pooled data from 767 patients enrolled in two randomized, controlled, open-label trials of similar design comparing the treatment of iron deficiency anemia with ferumoxytol and iron sucrose across patients with all stages of renal function. One trial was conducted in adults with CKD either on or not on dialysis and the second in adults with IDA of any underlying cause and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used who had normal to no worse than moderately impaired renal function. Patients were categorized by chronic kidney disease stage (i.e., estimated glomerular filtration rate), and the primary efficacy endpoint was the mean change in hemoglobin from Baseline to Week 5. RESULTS: The overall incidence of adverse events was numerically lower in ferumoxytol-treated patients compared to those treated with iron sucrose (42.4 vs. 50.2 %, respectively); the incidence of treatment-related adverse events was generally similar between the two treatment groups (13.6 vs. 16.0 %, respectively). Adverse events of Special Interest (i.e., hypotension, hypersensitivity) occurred at lower rates in those treated with ferumoxytol compared to those treated with iron sucrose (2.5 vs. 5.3 %, respectively). Overall, mean hemoglobin increased in both treatment groups, regardless of degree of renal insufficiency, although greater increases were seen among those with less severe kidney damage. Mean increases in hemoglobin from Baseline to Week 5 were significantly greater with ferumoxytol than with iron sucrose treatment in the subgroup with an estimated glomerular filtration rate ≥90 mL/min (Least Squares mean difference = 0.53 g/dL; p < 0.001). There were no other consistent, significant differences in hemoglobin levels between treatment groups for the other chronic kidney disease categories except for isolated instances favoring ferumoxytol. CONCLUSIONS: The efficacy and safety of ferumoxytol is at least comparable to iron sucrose in patients with varying degrees of renal function. TRIAL REGISTRATION: (CKD-201; ClinicalTrials.gov identifier: NCT01052779; registered 15 January, 2010), (IDA-302; ClinicalTrials.gov identifier: NCT01114204; registered 29 April, 2010).

Ferumoxytol versus placebo in iron deficiency anemia: efficacy, safety, and quality of life in patients with gastrointestinal disorders.

INTRODUCTION: Iron deficiency anemia (IDA) is common in patients with gastrointestinal (GI) disorders and can adversely affect quality of life. Oral iron is poorly tolerated in many patients with GI disorders. Ferumoxytol is approved for the intravenous treatment of IDA in patients with chronic kidney disease. This study aimed to evaluate the efficacy and safety of ferumoxytol in patients with IDA and concomitant GI disorders. PATIENTS AND METHODS: This analysis included 231 patients with IDA and GI disorders from a Phase III, randomized, double-blind, placebo-controlled trial evaluating ferumoxytol (510 mg ×2) versus placebo in patients who had failed or were intolerant of oral iron therapy. The primary study end point was the proportion of patients achieving a ≥20 g/L increase in hemoglobin (Hgb) from baseline to Week 5. Other end points included mean change in Hgb, proportion of patients achieving Hgb ≥120 g/L, mean change in transferrin saturation, and patient-reported outcomes (PROs). RESULTS: Significantly more patients with IDA receiving ferumoxytol achieved a ≥20 g/L increase in Hgb versus placebo (82.1% vs 1.7%, respectively; P<0.001). Mean increase in Hgb (28.0 g/L vs -1.0 g/L, respectively; P<0.001) significantly favored ferumoxytol treatment. Ferumoxytol-treated patients demonstrated significantly greater improvements than placebo-treated patients relative to their very poor baseline PRO scores posttreatment, including improvements in the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and various domains of the 36-Item Short-Form Health Survey. Ferumoxytol-treated patients had a low rate of adverse events. CONCLUSION: In this study, ferumoxytol was shown to be an efficacious and generally well-tolerated treatment option for patients with IDA and underlying GI disorders who were unable to use or had a history of unsatisfactory oral iron therapy.

A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency anemia in patients with CKD.

BACKGROUND AND OBJECTIVES: Few randomized controlled trials have compared intravenous iron products head to head in CKD patients with iron deficiency anemia. This study compared the efficacy and safety of two intravenous iron products (ferumoxytol [Feraheme injection] and iron sucrose [Venofer]) in patients with CKD and iron deficiency anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this phase II, randomized, open-label, active-controlled, multicenter clinical trial, patients were randomized 1:1 to either 1.02 g ferumoxytol (2 × 510-mg injections) or 1.0 g iron sucrose administered as either a slow injection or infusion (10 doses for dialysis patients and 5 doses for nondialysis patients). Inclusion criteria included hemoglobin<11.0 g/dl, transferrin saturation<30%, and eGFR<60 ml/min per 1.73 m(2) or a diagnosis of underlying CKD (e.g., nephropathy or nephritis). The primary end point was change in hemoglobin from baseline to week 5. RESULTS: In total, 162 patients were randomized. Demographics were balanced between the treatment groups. Adverse event profiles of the two regimens were fairly similar: overall adverse events, 48% ferumoxytol versus 65% iron sucrose; related adverse events, 10% ferumoxytol versus 16% iron sucrose; and adverse events leading to study discontinuation, 1% ferumoxytol versus 5% iron sucrose. Rates of serious adverse events and related serious adverse events were similar between the ferumoxytol and iron sucrose groups: serious adverse events, 9% versus 7%, respectively and related serious adverse events, 1% versus 1%, respectively. Overall, increases in hemoglobin were similar between treatment groups. Based on an ANOVA model adjusted for baseline hemoglobin level and dialysis status, the least squares mean change from baseline to week 5 was 0.8 ± 0.1 g/dl in the ferumoxytol-treated group and 0.7 ± 0.1 g/dl in the iron sucrose group. The difference in the mean change from baseline between the two treatment groups was 0.1 g/dl (95% confidence interval, -0.2 to 0.4). CONCLUSION: In this randomized, controlled trial, ferumoxytol and iron sucrose showed comparable efficacy and adverse events rates.

One-year outcomes from the TAXUS express stent versus cypher stent.

We compared 1-year outcomes in patients treated with paclitaxel-eluting stents (PESs) or sirolimus-eluting stents (SESs) in "real-world" clinical practice. Clinical outcomes were evaluated in 1,558 consecutive, unselected, retrospectively collected patients treated with drug-eluting stents (DESs; PES = 816, SES = 742) at 19 United States centers. The primary end point was 1-year target vessel revascularization (TVR). The study included a prespecified diabetic cohort (PES = 289, SES = 247), for which efficacy comparisons between DESs were analyzed according to vessel diameter and presence of chronic kidney disease. Baseline demographic, angiographic, and procedural characteristics were similar between patients treated with PESs and those treated with SESs. At 1 year, there were no overall statistical differences in death, myocardial infarction, TVR, or stent thrombosis. In the diabetic cohort, however, the cumulative incidence of TVR was significantly lower for patients treated with PESs (3%) compared with SESs (9%, p <0.01), which persisted after adjustment for baseline differences (hazard ratio 0.29, 95% confidence interval 0.12 to 0.67). This decrease in TVR with PES was similar in insulin- and noninsulin-requiring diabetic patients. In multivariate analysis, independent predictors of TVR included diabetes, bifurcation stenting, and overlapping stents; in the diabetic cohort, treatment with SESs was also a multivariate predictor of TVR. In conclusion, in this observational, retrospective analysis of DES-treated patients, PESs and SESs demonstrated similar overall safety and efficacy, but PESs were associated with a significant decrease in 1-year TVR rates in diabetic patients.