Erythropoiesis-stimulating Agents Therapy Research Articles

Treatment with Erythropoiesis Stimulating Agents in Patients with Chronic Kidney Disease Complicated by Cancer

Anemia, commonly seen in patients with chronic kidney disease (CKD), is due to a relatively reduced production of erythropoietin by renal interstitial fibroblasts. The development of cancer in patients with kidney disease puts them at a higher risk of developing severe anemia along with its antecedent problems. The treatment of anemia in patients with cancer has changed substantially in recent years. This is partly due to results from a large number of published studies that indicate an increased risk of mortality and tumor progression with erythropoiesis-stimulating agents (ESA) therapy, which may have been overstated, on careful review of the literature. In the nephrology literature, studies exploring the normalization of hemoglobin with erythropoietin treatment have found increased cardiovascular and thromboembolic events, and risk of death. Many CKD and dialysis patients receive ESA to maintain a hemoglobin goal in the range of 9-11.5 g/dL. In patients with kidney disease, a cancer diagnosis makes the treatment of anemia challenging. In this review, we discuss the pathobiology of anemia in kidney disease, the benefits and risks of ESA treatment in CKD patients with cancer, and provide recommendations on ESA treatment for clinicians taking care of this unique subset of patients.

Evaluation of the Impact of a New Synthetic Vitamin E-Bonded Membrane on the Hypo-Responsiveness to the Erythropoietin Therapy in Hemodialysis Patients: A Multicenter Study

Background: Oxidative stress has been related to hypo-response to erythropoiesis-stimulating agents (ESAs) in hemodialysis (HD) patients. The aim of this study was to verify whether vitamin E (ViE) on a synthetic polysulfone dialyzer can improve ESA responsiveness. Methods: This controlled, multicenter study involved 93 HD patients on stable ESA therapy, who were randomized to either ViE-coated polysulfone dialyzer or to a low-flux synthetic dialyzer. The primary outcome measure was the change in ESA resistance index (ERI) from baseline. Results: Mean ERI decreased in the ViE group by 1.45 IU/kg*g/dl and increased in the control group by 0.53 IU/kg*g/dl, with a mean difference of 1.98 IU/kg*g/dl (p = 0.001 after adjusting for baseline ERI, as foreseen by the study protocol). Baseline ERI was inversely related to its changes during follow-up only in the control group (R² = 0.29). Conclusions: The ViE dialyzer can improve ESA response in HD patients. Changes in ERI during follow-up are independent from baseline ERI only in the ViE group. Video Journal Club ‘Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=453442.

Low versus high dose erythropoiesis-stimulating agents in hemodialysis patients with anemia: A randomized clinical trial.

The increased risks of death and adverse events with erythropoiesis-stimulating agent (ESA) therapy targeting a higher hemoglobin level are established. It is uncertain whether the adverse effects of ESA therapy are related to dose and are mitigated when a fixed low ESA dose is used. We conducted a multicenter, prospective randomized open-label, blinded-endpoint (PROBE) trial to evaluate fixed low versus high dose ESA therapy on patient outcomes. We intended to recruit 2104 hemodialysis patients >18 years with anemia or receiving ESA treated at dialysis clinics in Italy. The intervention was fixed low (4000 IU epoetin alfa equivalent weekly) or high (18,000 IU epoetin alfa equivalent weekly) dose ESA for 12 months. Primary outcomes were serum transferrin, ferritin, albumin, C-reactive protein and ESA dose. Secondary outcomes were the composite of death or cardiovascular event, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, cardiovascular hospitalization, and quality of life. Study recruitment was terminated after inclusion of 656 participants with convergence of ESA dose between groups during follow up. Fixed low dose ESA had uncertain effects on serum ferritin (delta of delta (DD) 3.9 ng/ml, 95% CI -85.0 to 92.8), transferrin (9.2 mg/dl, -6.3 to 24.8), transferrin saturation (3.7%, -5.0 to 12.3), serum albumin (-0.03 g/dl, -0.2 to 0.1), or C-reactive protein (-0.6 mg/l, -3.3 to 2.1). In addition, fixed dose therapy had inconclusive effects on the composite endpoint of mortality and cardiovascular events (hazard ratio [HR] 0.95, 95% CI 0.66 to 1.37), death (0.98, 0.64 to 1.52), nonfatal myocardial infarction (0.52, 0.18 to 1.52), nonfatal stroke (no events), hospital admission for cardiovascular causes (0.93, 0.50 to 1.72) or health-related quality of life. A fixed low ESA dose in hemodialysis patients has uncertain effects on serum parameters, mortality, cardiovascular events, and quality of life. Hemoglobin targets may be so entrenched in nephrology practice that a trial of ESA dose is no longer possible.

Early low-dose erythropoiesis-stimulating agent therapy and progression of moderate chronic kidney disease: a randomized, placebo-controlled trial.

It is unknown whether early intervention with low-dose erythropoiesis-stimulating agents (ESAs) in non-anaemic patients delays progression of chronic kidney disease (CKD). In a single-blind, 24-month trial, adults with estimated glomerular filtration rate (eGFR) 30–59 mL/min/1.73 m2 and either Type 2 diabetes mellitus or previous kidney transplantation were randomized to low-dose continuous erythropoiesis receptor activator (CERA; monthly dose 30–75 µg; n = 115) or placebo (n = 120). The primary endpoint was the annual change in eGFR (abbreviated Modification of Diet in Renal Disease formula). Mean (standard deviation) eGFR was 40.7 (9.8) mL/min/1.73 m2 versus 39.8 (9.2) mL/min/1.73 m2 at baseline for CERA and placebo, respectively, and 39.0 (11.6) g/dL versus 39.7 (10.6) g/dL at the final visit. The median (interquartile range) annual reduction in eGFR was 0.5 (−2.2, 3.8) mL/min/1.73 m2 with CERA versus 0.4 (−2.0, 3.2) mL/min/1.73 m2 with placebo (P = 0.657). No significant difference in the annual change in eGFR was observed between treatment groups in the subpopulations with Type 2 diabetes or kidney transplant. Adverse events with a suspected relation to study drug occurred in 22.0% and 16.2% of patients randomized to CERA or placebo, respectively, and adverse events led to study drug discontinuation in 11.0% and 8.5% of patients. Patients with moderate CKD and Type 2 diabetes or previous kidney transplantation showed stable renal function that was unaffected by administration of low-dose ESA. In addition, there was no clinically meaningful effect of 2-year low-dose ESA treatment on albuminuria, an important surrogate marker of kidney injury.

Predictive factors for anemia response to erythropoiesis‐stimulating agents in myelofibrosis

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat the anemia of myelofibrosis (MF), but information on the predictors of response is limited. Results of ESA therapy were analyzed in 163 MF patients with severe anemia, most of whom had inadequate erythropoietin (EPO) levels (<125U/L) at treatment start. According to the revised criteria of the International Working Group for Myelofibrosis Treatment and Research, anemia response was achieved in 86 patients (53%). Median response duration was 19.3months. In multivariate analysis, baseline factors associated with a higher response rate were female sex (P=.007), leukocyte count ≥10×109 /L (P=.033), and serum ferritin <200ng/mL (P=.002). Patients with 2 or 3 of the above features had a significantly higher response rate than the remainder (73% vs 28%, respectively; P<.001). Over the 373 patient-years of follow-up on ESA treatment, nine patients developed thrombotic complications (six arterial, three venous), accounting for 2.41 events per 100 patient-years. Survival time from ESA start was longer in anemia responders than in non-responders (P=.011). Besides the already established predictive value of EPO levels, these data can help to identify which MF patients are more likely to benefit from ESA treatment.

Target-based Anemia Management with Erythropoiesis Stimulating Agents (Risks and Benefits Relearned) and Iron (Still More to Learn).

The FDA first licensed erythropoiesis stimulating agents (ESA) for use in patients with ESRD in 1989. Hemoglobin targets for treatment with ESAs were established at the outset on the basis of descriptive pre-ESA literature and Phase I-III data in patients with ESRD. Postrelease literature in ESA-treated patients accumulating over time initially supported improvement in indices of both cardiovascular and other organ function as well as quality of life with therapy. Recommended treatment targets for hemoglobin would evolve further in the United States from four iterations of evidence- and opinion-based practice guidelines appearing between 1997 and 2007. Several randomized, controlled trials published from 1998 to 2009 examined normalization and near-normalization of hemoglobin in patients with both ESRD and CKD; they raised fundamental questions as to the safety of robust correction of anemia. These findings, taken together with subsequent actions of the FDA in ESA labeling and CMS's quality expectations for hemoglobin in payment for dialysis treatments, would result in a comprehensive reassessment of the hemoglobin targets in ESA therapy. A marked decrease in both national ESA utilization and hemoglobin attainment has ensued as a result. This discussion addresses the history of the striking changes in enthusiasm for hemoglobin-targeted anemia therapy from 1989 to the present, and similarly examines the evolution of ferritin-targeted iron administration, which has followed different-and markedly slower-historical development.

Levocarnitine Injections Decrease the Need for Erythropoiesis-Stimulating Agents in Hemodialysis Patients with Renal Anemia

Aims: The aim of this study was to evaluate the efficacy of levocarnitine injection for renal anemia in hemodialysis patients. Methods: In this randomized controlled clinical trial, we randomly assigned patients on maintenance hemodialysis at our hospital to receive levocarnitine injections (n = 30) or no injection (n = 30) and monitored the patients during 12 months of treatment. In the treatment group, patients received an injection of levocarnitine 1,000 mg 3 times weekly after hemodialysis sessions. All patients received recombinant human erythropoietin as an erythropoiesis-stimulating agent (ESA). Response to ESA therapy was determined by calculating the erythropoietin responsiveness index (ERI; ESA dose·kg^-1·g^-1· dL^-1·week^-1). Results: (1) The target levels of hemoglobin and hematocrit were maintained during the study period in both the levocarnitine group and the control group. (2) The dose of ESAs required to maintain these levels decreased gradually in the levocarnitine group and was significantly lower at 6 and 12 months than at study initiation. Furthermore, the dose of ESAs was significantly lower than that in the control group at 12 months. (3) The ERI showed a significant decrease at 6 and 12 months in the levocarnitine group, with a significant difference between the 2 groups at 12 months. Conclusion: Our results suggest that levocarnitine administration can reduce the dose of ESAs required in patients with renal anemia on hemodialysis and improve the response to ESA therapy.

Erythropoiesis-stimulating Agents in Critically Ill Trauma Patients: A Systematic Review and Meta-analysis.

To perform a meta-analysis of all relevant randomized controlled trials assessing the effect of erythropoiesis-stimulating agents (ESAs) in critically ill trauma patients. ESAs have effects beyond erythropoiesis. The administration of the ESA epoetin alfa to critically ill trauma patients has been associated with a reduction in mortality. We performed a systematic review and meta-analysis with trial sequential analysis. We searched Medline, Medline in Process, and other nonindexed citations, EMBASE, and the Cochrane Database from inception until September 9, 2015, for randomized controlled trials comparing ESAs to placebo (or no ESA). We identified 9 eligible studies that randomly assigned 2607 critically ill patients after trauma to an ESA or placebo (or no ESA). Compared with placebo (or no ESA), ESA therapy was associated with a substantial reduction in mortality [risk ratio (RR) 0.63, 95% confidence interval (CI) 0.49-0.79, P = 0.0001, I = 0%). In patients with traumatic brain injury, ESA therapy did not increase the number of patients surviving with moderate disability or good recovery (RR 1.00, 95% CI 0.88-1.15, P = 0.95, I = 0%). With the dosing regimens employed in the included studies, ESA therapy did not increase the risk of lower limb proximal deep venous thrombosis (RR 0.97, 95% CI 0.72-1.29, P = 0.78, I = 0%). The administration of ESAs to critically ill trauma patients is associated with a significant improvement in mortality without an increase in the rate of lower limb proximal deep venous thrombosis. Given the worldwide public health significance of these findings research to validate or refute them is required.

Transfusion Burden and Outcomes in Patients with Low- or Unspecified-Grade Myelodysplastic Syndromes Treated with Erythropoiesis-Stimulating Agents: Analysis of a United States Commercial Claims Database

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by 1 or more peripheral blood cytopenias.Anemia is the most common cytopenia associated with low-grade MDS (based on the International Prognostic Scoring System). Erythropoiesis-stimulating agents (ESA) are commonly used as frontline treatment of anemia in patients (pts) with low-grade MDS; red blood cell transfusions are also important in supportive care. The present database analysis was conducted to understand the transfusion burden and outcomes among pts in the United States who were diagnosed with low- or unspecified-grade MDS and treated with ESA.Methods: A retrospective analysis of theOptum integrated claims and Electronic Medical Record database ("Optum Database") identified pts aged ≥ 18 years with an index diagnosis of MDS (low-grade, ICD 9 code: 238.72; high-grade, ICD 9 code: 283.73; del(5q), ICD 9 code: 238.74; or unspecified-grade, ICD 9 code: 238.75) between 2006 and 2014 who had 365 days of retrospective data preceding index diagnosis. Pts with baseline acute myeloid leukemia were excluded. Demographics and clinical outcomes were analyzed by descriptive summary. Kaplan-Meier survival analysis was performed to define overall survival (OS) and time to transfusion dependence or transfusion independence.Results: Among the 8,493 pts in the Optum Database who met the inclusion criteria, MDS was categorized as low-grade in 2,136 (25.2%), high-grade in 367 (4.3%), del(5q) in 198 (2.3%), and unspecified-grade in 5,792 (68.2%); median follow-up was 2.3 years. In each MDS category, roughly half of pts were male, and the majority were white and non-Hispanic. Median ages at diagnosis were 75, 74, 74, and 76 years, and 977 (46%), 224 (61%), 83 (42%), and 2,071 (36%) received ≥ 1 treatment in the low-grade, high-grade, del(5q), and unspecified-grade MDS categories, respectively. Frontline therapy with ESA was the mainstay of treatment for pts with low-grade (n = 732; 75%) and unspecified-grade (n = 1,284; 62%) MDS. Average durations of frontline treatment with ESA were 228.1 and 204.5 days in pts with low-grade and unspecified-grade MDS, respectively. Median OS among low- and unspecified-grade MDS pts receiving frontline ESA was 5.4 and 4.6 years, respectively. Of the pts who received frontline ESA, 53 (7.2%) with low-grade and 107 (8.3%) with unspecified-grade MDS were transfusion dependent (≥ 2 transfusions in the 16 weeks prior to treatment initiation). Transfusion dependence in pts receiving frontline ESA was associated with shorter median OS vs transfusion independence (1.7 years vs 5.7 years in low-grade MDS, P < 0.0001; 1.7 years vs 5.2 years in unspecified-grade MDS, P < 0.0001;Figure 1). Among the 160 frontline ESA pts with low-/unspecified-grade MDS who were transfusion dependent, 108 (68%) became transfusion independent (defined as ≥ 60 days without transfusion; 37 of 53 with low-grade MDS; 71 of 107 with unspecified-grade MDS); median time to transfusion independence was 137 and 139 days in pts with low-grade and unspecified-grade MDS, respectively. Most pts with low- or unspecified-grade MDS who received frontline ESA (52% and 51%, respectively) went on to receive second-line treatment, and treatment with ESA was the most common second-line therapy (42% and 40%, respectively). 163 (8.7%) of post-front-line ESA pts were transfusion dependent. Among pts with low-/unspecified-grade MDS who received second-line therapy, median OS was shorter for those who were transfusion dependent after frontline treatment with ESA vs those who were transfusion independent (1.97 years vs 4.5 years, respectively, P < 0.001). 92 (56%) of these transfusion-dependent pts became transfusion independent in a median of 181 days.Conclusions: ESA therapy was the most common treatment approach, both frontline and second-line, for pts with low- or unspecified-grade MDS; however, treatment with ESA did not always eliminate the need for transfusion. Similar to previous reports in pts with low-grade MDS, survival outcomes were substantially worse if pts were transfusion dependent prior to frontline or second-line treatment or became transfusion dependent following frontline treatment. These data indicate the critical importance for treatments to reduce transfusion burden among pts with MDS, in both the frontline and relapsed settings. [Display omitted] DisclosuresMehra:Janssen: Employment, Equity Ownership. Potluri:Janssen Research & Development, LLC: Other: Contracted to perform research; SmartAnalyst, Inc.: Employment. He:Janssen Global Services, LLC: Employment, Equity Ownership. Rizo:Janssen Research & Development, LLC: Employment, Equity Ownership. Mundle:Janssen Research & Development, LLC: Employment, Equity Ownership. Bussolari:Janssen Research & Development, LLC: Employment, Equity Ownership.

Dynamics of the erythropoiesis stimulating agent resistance index in incident hemodiafiltration and high-flux hemodialysis patients

Hyporesponsiveness to erythropoiesis-stimulating agent therapy in dialysis patients is poorly understood. Some studies report an improvement in the erythropoiesis-stimulating agent resistance index (ERI) with hemodiafiltration (HDF) versus high-flux hemodialysis (HD). We explored ERI dynamics in 38,340 incident HDF and HD patients treated in 22 countries over a 7-year period. Groups were matched bypropensity score at baseline (6 months after dialysis initiation). The follow-up period (mean of 1.31 years) was stratified into 1 month intervals with delta analyses performed for key ERI-related parameters. Dialysis modality, time interval, and polycystic kidney disease were included in a linear mixed model with the outcome ERI. Baseline ERI was nonsignificantly higher in HDF versus HD treatment. ERI decreased significantly faster in HDF-treated patients than inHD-treated patients, was decreased in both HD and HDF when patients were treated with intravenous darbepoetin alfa, but only in HDF when treated with intravenous recombinant human erythropoietin (rHuEPO). A clear difference between HD- and HDF-treated patients could only be found for patients with high baseline ERI and assigned to intravenous rHuEPO treatment. A significant advantage in terms of lower ERI for patients treated by HDF was found. Sensitivity analysis limited this advantage for HDF to those patients treated with intravenous rHuEPO (not darbepoetin alfa or subcutaneous rHuEPO) and to patients with a high baseline ERI. Thus, our results allow more accurate planning for future clinical trials addressing anemia management in dialysis patients.

Regulation of platelet count by erythropoiesis-stimulating agents - iron axis in hemodialysis patients.

Higher doses of erythropoiesis-stimulating agents (ESAs) contribute to atherothrombotic cardiovascular disease in hemodialysis (HD) patients. Thrombocytosis is associated with increased mortality in ESA-treated HD patients. We investigated variables affecting platelet count and its variability (platelet count increment [Δplatelet count]) in HD patients. This retrospective longitudinal and observational study of HD outpatients was carried out over 3 years. The outcome was independent determinants of platelet count and Δplatelet count, which were associated with iron indices, ESA dose, and C-reactive protein. In univariate regression analysis, V-shaped relationship was observed between platelet count and transferrin saturation (TSAT), ferritin, serum iron, and hemoglobin (Hb) with the bottom of 0.21, 330 ng/mL, 49 µg/dL, and 10.3 g/dL, respectively. Mixed-effect multivariate regression analysis revealed that TSAT (inversely), Hb ≤10.3 g/dL (inversely), C-reactive protein, and ESA dose were independently associated with platelet count. Δplatelet count was independently and inversely correlated with ΔTSAT and directly correlated with Δferritin. TSAT was independently and inversely associated with ESA dose. ESA dose was directly correlated with iron dose and inversely correlated with TSAT, ferritin ≤330 ng/mL, and Hb ≤10.3 g/dL. ESA dose and TSAT were correlated in determining platelet count and Δplatelet count. Targets of iron indices that reflect iron supply sufficient to avoid platelet count increment and variability may be >21% of TSAT and 300 ng/mL of serum ferritin for appropriate ESA therapy in HD patients.

Impact of a Patient Blood Management Program and an Outpatient Anemia Management Protocol on Red Cell Transfusions in Oncology Inpatients and Outpatients.

Patient blood management (PBM) programs are associated with reduced transfusion usage, reduced hospital costs, and improved patient outcomes. The application of PBM principles in patients with malignant disease might achieve similar results. However, this population presents unique challenges. The aim of the present study was to investigate the impact of a PBM program on blood usage and patient outcomes in cancer patients, particularly in the setting of restricted use of erythropoiesis-stimulating agents (ESAs). A retrospective observational study was performed of patients admitted with a primary diagnosis of malignancy treated at Eastern Maine Medical Center as inpatients or outpatients, or both, from January 2008 through July 2013. The proportion of inpatients and outpatients receiving ESAs decreased from 2.9% in 2008 to 1.1% in 2013 (p < .001). During the same period, an increase occurred in the mean dose of intravenous (IV) iron from 447 mg (95% confidence interval [CI], 337-556) to 588 mg (95% CI, 458-718). The mean red blood cell (RBC) units transfused per inpatient and outpatient episode decreased from 0.067 to 0.038 unit (p < .001). In inpatients, significant increases occurred in the proportion of single-unit RBC transfusions (p < .001) and patients infused with IV iron (p = .02), and significant decreases in the mean pretransfusion hemoglobin (p = .02) and RBC transfusion rate (p = .04). In-hospital mortality and length of stay did not change significantly during this period. Despite the decreased use of ESA therapy, the implementation of a PBM program and outpatient anemia management protocol in cancer patients at our medical center was associated with significant reductions in RBC usage.

Erythropoiesis-stimulating agent slows the progression of chronic kidney disease: a possibility of a direct action of erythropoietin

Background Controversy exists regarding the renoprotective effect of erythropoiesis-stimulating agent (ESA) in progressive chronic kidney disease (CKD) with renal anemia. In this study, we examined whether ESA therapy has a renoprotective effect in progressive CKD. Methods The subjects in this retrospective observational study were 68 non-dialysis dependent CKD patients with renal anemia. We compared the progression rate (PR), defined by the slope of the linear regression line of estimated glomerular filtration rate, measured during 6 months just before and after the start of ESA therapy. We also investigated the factors affecting renoprotective efficacy of ESA therapy against the progression of CKD. Results Median (interquartile range) PR decreased significantly from 6.2 (3.7–12.7) to 4.0 (−0.3 to 7.3) mL/min/1.73 m2/year after the start of ESA therapy. Blood pressure levels and rate of medication with renin-angiotensin system inhibitors were comparable between the two periods. Next, we investigated the factors affecting renoprotective efficacy of ESA therapy against the progression of CKD. Thirty patients were good renal responders, defined as those with the ratio of post-/pre-PR of <0.5 and the difference of pre- minus post-PR >5.0 mL/min/1.73 m2/year, and 38 patients were poor renal responders who did not meet the definition of good renal responders. Multivariable logistic regression analysis showed that weekly ESA dose, but not increase in hemoglobin level, was a significant and independent determinant of the renoprotective effect of ESA. Conclusion ESA therapy slows the progression of CKD and part of the effect might be attributed to the direct renoprotective action of ESA.

A prospective observational study of early intervention with erythropoietin therapy and renal survival in non-dialysis chronic kidney disease patients with anemia: JET-STREAM Study.

BackgroundThere is limited data showing that early treatment for anemia could prolong renal survival in non-dialysis chronic kidney disease (CKD) patients. We therefore investigated the relationship between hemoglobin (Hb) levels at initiation of epoetin beta therapy and renal outcome in non-dialysis CKD patients with anemia.MethodsIn this prospective, multi-center, observational study, non-dialysis CKD patients with anemia who were naïve to erythropoiesis-stimulating agents (ESAs) were divided into three groups based on their Hb levels at initiation of epoetin beta therapy (Group I: 10 ≤ Hb < 11 g/dL, Group II: 9 ≤ Hb < 10 g/dL, and Group III: Hb < 9 g/dL). The primary endpoint was time to first occurrence of any renal event. For the primary analysis, an inverse probability weighted Cox regression model was used to adjust time-dependent selection bias in the artificially censored data.ResultsA total of 1113 patients were eligible for primary endpoint analysis. Risk of renal events was significantly higher in Group III compared with Group I (HR, 2.52; 95 % CI, 1.98–3.21; P < 0.0001); although not significant, the risk was also higher in Group II compared with Group I (HR, 1.48; 95 % CI, 0.91–2.40; P = 0.11).ConclusionInitiation of ESA therapy when Hb levels decreased below 11 g/dL but not below 10 g/dL could be more effective at reducing the risk of renal events in non-dialysis CKD patients with anemia compared with initiation of ESA therapy at below 9 g/dL or even 10 g/dL.

Safety concerns about intravenous iron therapy in patients with chronic kidney disease.

Anaemia in chronic kidney disease (CKD) is managed primarily with erythropoiesis-stimulating agents (ESAs) and iron therapy. Following concerns around ESA therapy, intravenous (IV) iron is being administered more and more worldwide. However, it is still unclear whether this approach is safe at very high doses or in the presence of very high ferritin levels. Some observational studies have shown a relationship between either high ferritin level or high iron dose and increased risk of death, cardiovascular events, hospitalization or infection. Others have not been able to confirm these findings. However, they suffer from indication biases. On the other hand, the majority of randomized clinical trials have only a very short follow-up (and thus drug exposure) and are inadequate to assess the mortality risk. None of them have tested the role of different iron doses on hard end points. With the lack of clear evidence coming from well-designed and large-scale studies, several data suggest that excessive iron therapy may be toxic in several aspects, ranging from iron overload to tissue damage from labile iron. A number of experimental and clinical data suggest that either excessive iron therapy or iron overload may be a possible culprit of atherogenesis. The process seems to be mediated by oxidative stress. Iron therapy should also be used cautiously in the presence of active infections, since iron is essential for bacterial growth. Recently, the European Medicines Agency officially raised concerns about rare hypersensitivity reactions following IV iron administration. The balance has been in favour of benefits. In several European countries, this has created a lot of confusion and somewhat slowed the run towards excessive use. Altogether, IV iron remains a mainstay of anaemia treatment in CKD patients. However, in our opinion, its excessive use should be avoided, especially in patients with high ferritin levels and when ESA agents are not contraindicated.

Anaemia and early phase cardiovascular events on haemodialysis.

Although the mechanism of the cardio-renal anaemia syndrome (CRAS) has been elucidated in considerable detail over the past decade, cardiovascular disease (CVD) remains a leading cause of death among patients with end-stage kidney disease (ESKD) undergoing haemodialysis, and these patients' cardiovascular mortality is greater than that of the general population. Recent studies have reported that the CVD risk increases with advancing chronic kidney disease (CKD) stage. Furthermore, the incidence of cardiovascular events is highest during the first week after dialysis initiation, with increased risk in incident haemodialysis patients. This accumulated evidence demonstrates that how patients are managed during the pre-dialysis phase may have important implications on long-term outcomes in ESKD. Anaemia, a non-traditional risk factor for CVD, advances exponentially along with declining kidney function due to insufficient erythropoietin production. Anaemia causes functional abnormalities of the heart, as represented by cardiac hypertrophy, which results from increased cardiac workload induced by an increased preload. Left ventricular hypertrophy (LVH), a traditional risk factor for CVD, is especially associated with advanced CKD stage and could be a major risk factor for cardiovascular complications such as ischaemic heart disease, heart failure, and sudden cardiac death. In ESKD, anaemia develops more severely and requires a higher amount of erythropoiesis-stimulating agent (ESA) therapy before dialysis initiation. This suggests that improvement in anaemia management during the pre-dialysis phase may have a beneficial effect on cardiac hypertrophy and contribute to reducing the CVD risk after initiating haemodialysis.

Pharmacist collaborative practice agreement for the management of anemia in malignant disease with erythropoiesis-stimulating agents.

Erythropoiesis-stimulating agents (ESAs) reduce transfusions and increase hemoglobin levels in patients with anemia of malignant disease. A medication guideline and pharmacist collaborative practice agreement (CPA) were developed and implemented to standardize ESA prescribing workflow. The use of ESAs in malignant diseases, in accordance with institutional guidelines, was evaluated to ensure safe and effacious use. An observational study was conducted on all ESA doses given throughout a health system's cancer clinics prior to and after implementation of an ESA guideline and pharmacist CPA. The primary outcome measured was ESA therapy initiated in accordance with guidelines before and after the intervention. Secondary outcomes evaluated were nurse and pharmacist satisfaction, vitals recorded prior to dose, and transfusion rates in patients receiving ESA therapy before and after the intervention. In the pre-implementation group, criteria for initiation were not met by any of the 39 patients; prior to therapy, 5.1 % of patients had not had hemoglobin drawn, 23 % of patients had no iron studies completed, and 29.4 % of myelodysplastic syndrome (MDS) patients had no erythropoietin levels drawn. In the post-implementation group, prior to therapy, all patients had hemoglobin levels drawn, 16.67 % did not have iron studies completed, and all MDS patients had erythropoietin levels drawn appropriately. Chemotherapy-induced anemia (CIA) patients in the pre-implementation group had 71.4 % compliance with receiving chemotherapy within 8 weeks of ESA dose, and the post-implementation group had 100 % compliance. An ESA guideline and pharmacist CPA aligned prescribing practices with the NCCN and ASCO guidelines and improved staff satisfaction.

High Hemoglobin Levels Maintained by an Erythropoiesis-Stimulating Agent Improve Renal Survival in Patients with Severe Renal Impairment.

Our goal was to investigate the effect modification of maintaining a high Hb target range through erythropoiesis-stimulating agent therapy on the renal outcome with respect to chronic kidney disease (CKD) stage and concurrent diabetes condition in patients with CKD. We used data from a previously reported randomized controlled trial involving 321 CKD patients not on dialysis, with Hb levels of <10 g/dL, and serum creatinine (Cr) of 2.0 to 6.0 mg/dL, and in which maintaining Hb levels at 11.0-13.0 g/dL with darbepoetin-α (High Hb group) resulted in a greater renal protective effect than maintaining Hb levels at 9.0-11.0 g/dL with epoetin-α (Low Hb group). We conducted a post-hoc analysis of the effects of baseline CKD stage and concurrent diabetic condition on the renal composite endpoint, consisting of death, initiation of renal replacement therapy, and doubling of the serum Cr level. Both groups with stage 4 CKD had a 3-year cumulative renal survival rate of 53.8%, whereas in patients with stage 5 CKD, the rate in the High Hb group (31.0%) was significantly (P = 0.012) higher than that in the Low Hb group (19.1%). The observations made in patients with stage 5 CKD were maintained on further analysis of non-diabetic patients, but were not seen in those with diabetes or stage 4 CKD. These results suggest that in patients with stage 5 CKD, especially those without diabetes, achieving a higher target Hb level with erythropoiesis-stimulating agents is associated with a greater renoprotective effect.

Abstract P5-15-18: Hemoglobin levels and quality of life in patients with breast cancer and symptomatic chemotherapy-induced anemia enrolled in the eAQUA study

Abstract Background: Fatigue associated with chemotherapy-induced anemia (CIA) is common in patients with breast cancer, and can have adverse effects on quality of life (QoL). Erythropoiesis-stimulating agents (ESAs) reduce the need for transfusions and may improve QoL in patients with symptomatic CIA. Information on hemoglobin (Hb) levels and effects of fatigue on QoL in patients with breast cancer and CIA in real-world clinical practice is limited. Methods: The Electronic Assessment of Quality of Life in Patients With Symptomatic CIA (eAQUA) study evaluated improvements in QoL for patients with CIA receiving ESAs who had an increase in Hb of ≥1 g/dL by week 9. This phase 4, international, longitudinal, prospective, observational study enrolled patients with solid tumors who received chemotherapy and had symptomatic anemia. Patients received ESA therapy for up to 13 weeks based on European indication. The primary outcome was the proportion of patients with increase in Hb ≥1 g/dL and improvement in fatigue-related QoL based on the Functional Assessment of Cancer Therapy-Fatigue (FACT-F; scale = 0 to 52 with lower scores indicating worse fatigue) subscale scores and fatigue Visual Analog Scale (VAS; scale = 0 to 100 with higher scores indicating worse fatigue) from baseline to week 9. FACT-F change scores were anchored to VAS change scores to determine the minimally important difference (MID) for improvements in QoL. Patients with a FACT-F change score that was ≥ the MID were considered to have an improvement in QoL. For Hb and QoL outcomes, week 9 data were those assessed closest to on-treatment day 57 (after initiation of ESA) and within on-treatment days 43 to 70 inclusive, to account for different ESA dosing schedules and the observational nature of the study. Secondary outcomes included rates of red blood cell (RBC) transfusions or iron supplementation during the study. Results: Of 1262 patients enrolled in eAQUA, 289 had breast cancer and were included in the full analysis set (FAS; had at least one ESA dose); of these, 152 patients were eligible to be included in the primary analysis set (PAS; had QoL and Hb data available at baseline and week 9). At baseline, mean (standard deviation [SD]) Hb was 9.4 (0.6) g/dL; mean (SD) FACT-F and VAS scores were 27.1 (10.5) and 52.7 (22.8), respectively, in the FAS. Mean (SD) change from baseline at week 9 was 1.3 (1.3) g/dL for Hb; 4.1 (10.8) score change for FACT-F; and 4.7 (25.9) score change for VAS in the FAS. A total of 54 (18.7%) patients in the FAS required an RBC transfusion and 79 (27.3%) received iron supplementation. At week 9, 77 of 152 patients in the PAS had achieved improvement in fatigue-related QoL (50.7%; 95% confidence interval [CI] = 42.7%, 58.6%); 93 patients had increased Hb ≥1 g/dL (61.2%; 95% CI = 53.4%, 68.9%); and 59 patients (38.8%; 95% CI = 31.1%, 46.6%) had achieved both improvement in fatigue-related QoL and increased Hb ≥1 g/dL. Conclusions: In this exploratory subgroup analysis, patients with breast cancer and symptomatic CIA treated with ESAs achieved clinically meaningful improvements in fatigue-related QoL and Hb levels. Citation Format: Mario Airoldi, Dominique Spaeth, Joan Van den Bosch, Charalambos Christofyllakis, Laura Belton, Chet Bohac, Jan-Henrik Terwey, Giuseppe Tonini. Hemoglobin levels and quality of life in patients with breast cancer and symptomatic chemotherapy-induced anemia enrolled in the eAQUA study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-18.

Clinical impact of the ERBP Working Group 2010 Recommendations for the anemia management in chronic kidney disease not on dialysis: ACERCA study

Background and objectiveThe Anemia Working Group of ERBP in 2010 recommended a target hemoglobin (Hb) level in the range of 11-12 g/dL, without intentionally exceeding 13g/dL during the treatment with erythropoiesis stimulating agents (ESAs). This study evaluated if there was a clinical impact of this statement in the anemia management of chronic kidney disease (CKD) patients treated with ESAs not on dialysis in routine clinical practice in Spain. MethodsThis was an observational and cross-sectional study carried out in CKD patients not on dialysis in Spain who initiated ESA treatment (naïve), or were shifted from a previous ESA to another ESAs (converted) since January 2011. ResultsOf 441 patients evaluated, 67.6% were naïve and 32.4% were converted. At the study visit, 42.5% of naïve patients achieved the Hb target of 11-12 g/dL, with a mean Hb of 11.3±1.3 g/dL (vs 10.1±0.9 g/dL at the start of ESA therapy). Only 35.3% of converted patients maintained Hb levels within the recommended target at the study visit. Yet, 8.2% of naïve patients and 7.9% of those converted had Hb levels >13 g/dL. Hb levels were similar across subgroups of patients, regardless of the presence of significant comorbidities. ConclusionsAnemia management in CKD patients treated with ESAs by Spanish nephrologists seems to be aimed at preventing Hb levels <11 g/dL, while <50% of patients were within the narrow recommended Hb target range. This, together with the lack of individualization in Hb targets according to patients’ comorbidities show that there is still room for improvement in renal anemia management in the clinical setting.