Use Of Erythropoiesis-stimulating Agents Research Articles

The Impact of the Risk Evaluation Mitigation Strategy for Erythropoiesis-Stimulating Agents on Their Use and the Incidence of Stroke in Medicare Subjects with Chemotherapy-Induced Anemia with Lung and/or Breast Cancers.

Erythropoiesis-stimulating agents (ESAs), found to be effective in reducing anemia in chemotherapy-treated cancer patients, also are associated with an increased risk of cardiovascular events, including stroke. In an attempt to mitigate the risk, the Food and Drug Administration implemented a Risk Evaluation Mitigation Strategy (REMS) in February 2010. The purpose of this study is to evaluate change over time in the incidence of stroke among these patients before and after implementation of REMS. A retrospective data analysis using the Medicare 5% Sample Dataset, 2008-2011, was performed. Patients had to be 65 years of age or older at the start of at least 1 year of continuous enrollment and to have lung and/or breast cancers along with chemotherapy-induced anemia (CIA) in both pre-REMS and post-REMS periods (1Q2008 through 4Q2009 and 1Q2010 through 4Q2011, respectively). Logistic regression was used to evaluate differences in proportions of patients who received ESAs and experienced a stroke pre and post REMS. The pre-REMS cohort included 1252 eligible patients prescribed ESAs; the post-REMS cohort included 949 patients. No statistically significant change in stroke incidence was observed post REMS among patients with CIA who received ESAs. There was a 29.5% decrease in ESA use in patients with lung cancer and a 27.8% decrease in patients with breast cancer. Both were statistically significant. Results adjusted for baseline characteristics and comorbid conditions were similar. There was a statistically significant decrease in ESA use in patients with breast and/or lung cancers post REMS; no statistically significant reduction in the incidence of stroke was observed regardless of cancer type.

Trends in Anemia Management Practices in Patients Receiving Hemodialysis and Peritoneal Dialysis: A Retrospective Cohort Analysis

Background/Aims: Recent changes in clinical practice guidelines and reimbursement policies may have affected the use of anemia-related medications and red blood cell (RBC) transfusions in peritoneal dialysis (PD) and hemodialysis (HD) patients. We sought to compare patterns of erythropoiesis-stimulating agents (ESA) and intravenous (IV) iron use, achieved hemoglobin levels, and RBC transfusion use in PD and HD patients. Methods: In quarterly cohorts of prevalent dialysis patients receiving persistent therapy (>3 months), 2007-2011, with Medicare Parts A and B coverage, we assessed ESA and IV iron use and dose, RBC transfusions, and hemoglobin levels. Quarterly transfusion rates were calculated. Results: Observable PD and HD patients numbered 14,958 and 221,866 in Q1/2007 and 17,842 and 256,942 in Q4/2011. Adjusted ESA use was lower in PD (71.4-80.1%) than in HD (86.9-92.0%) patients, decreasing from 80.1% (Q1/2010) to 71.4% (Q4/2011) in PD patients, and from 92.0 to 86.9% in HD patients. The mean adjusted ESA dose decreased by 67.5% in PD and 58.4% in HD patients. IV iron use tended to increase, peaking at 39.3% for PD (Q3/2011) and 80.5% for HD (Q2/2011) patients. Adjusted mean hemoglobin levels fell from 11.7 to 10.6 mg/dl in PD and from 12.0 to 10.7 mg/dl in HD ESA users; adjusted transfusion rates increased from 2.4 to 3.0 per 100 patient-months in PD and from 2.6 to 3.3 in HD patients. Conclusions: In patients receiving persistent dialysis, dose and frequency of ESA administrations decreased during the period 2007-2011. Mean hemoglobin levels decreased by more than 1 g/dl, while transfusion rates increased by approximately 25%.

Risks of Venous Thromboembolism, Stroke, Heart Disease, and Myelodysplastic Syndrome Associated With Hematopoietic Growth Factors in a Large Population-Based Cohort of Patients With Colorectal Cancer

PurposeTo determine the relationship between the receipt of colony-stimulating factors (CSFs) with erythropoiesis-stimulating agents (ESAs) and the risk of developing venous thromboembolism (VTE), stroke, heart disease, and myelodysplastic syndrome (MDS) in patients with colorectal cancer. MethodsWe studied 80,925 patients diagnosed with colorectal cancer at age ≥ 65 years in 1992-2009 from the nationwide 16 areas of the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. Cumulative incidence and the time to events Cox hazard regressions were used to explore the risks of outcomes in association with the receipt of CSFs and ESAs. ResultsPatients who received chemotherapy (CT) with both CSF and ESA were 58% more likely to develop VTE than those who received CT without CSF and ESA (hazard ratio, 1.58; 95% confidence interval, 1.43-1.76). The risk of stroke appeared to be not associated with the use of CSF and ESA, whereas the risk of heart disease was only significantly elevated in those patients who did not receive CT but received ESA. The risk of acute myeloid leukemia or MDS was significantly increased 4- to 9-fold in patients who received ESA, regardless of receipt of CT or CSF. ConclusionThe use of ESAs was significantly associated with a substantially increased risk of MDS in patients with colorectal cancer. The use of CSFs and ESAs was also significantly associated with a moderately increased risk of VTE and a slightly elevated risk of heart disease.

Risk Score to Predict 1-Year Mortality after Haemodialysis Initiation in Patients with Stage 5 Chronic Kidney Disease under Predialysis Nephrology Care.

BackgroundFew risk scores are available for predicting mortality in chronic kidney disease (CKD) patients undergoing predialysis nephrology care. Here, we developed a risk score using predialysis nephrology practice data to predict 1-year mortality following the initiation of haemodialysis (HD) for CKD patients.MethodsThis was a multicenter cohort study involving CKD patients who started HD between April 2006 and March 2011 at 21 institutions with nephrology care services. Patients who had not received predialysis nephrology care at an estimated glomerular filtration rate (eGFR) of approximately 10 mL/min per 1.73 m2 were excluded. Twenty-nine candidate predictors were selected, and the final model for 1-year mortality was developed via multivariate logistic regression and was internally validated by a bootstrapping technique.ResultsA total of 688 patients were enrolled, and 62 (9.0%) patients died within one year of HD initiation. The following variables were retained in the final model: eGFR, serum albumin, calcium, Charlson Comorbidity Index excluding diabetes and renal disease (modified CCI), performance status (PS), and usage of erythropoiesis-stimulating agent (ESA). Their β-coefficients were transformed into integer scores: three points were assigned to modified CCI≥3 and PS 3–4; two to calcium>8.5 mg/dL, modified CCI 1–2, and no use of ESA; and one to albumin<3.5 g/dL, eGFR>7 mL/min per 1.73 m2, and PS 1–2. Predicted 1-year mortality risk was 2.5% (score 0–4), 5.5% (score 5–6), 15.2% (score 7–8), and 28.9% (score 9–12). The area under the receiver operating characteristic curve was 0.83 (95% confidence interval, 0.79–0.89).ConclusionsWe developed a simple 6-item risk score predicting 1-year mortality after the initiation of HD that might help nephrologists make a shared decision with patients and families regarding the initiation of HD.

Chemotherapy-associated anemia in patients with lung cancer: an epidemiological, retrospective and multicenter study.

Providing epidemiological data and treatment of anemia in lung cancer patients undergoing first-line chemotherapy. Epidemiological, observational, retrospective and multicenter study carried out at 30 sites throughout Spain. The prevalence of anemia (hemoglobin [Hb] level <12 g/dl) was 18.3% and the incidence 80.7%. Mean Hb levels were 13.4 g/dl (95% Cl: 13.2-13.6) and 11.5 g/dl (95% Cl: 11.3-11.7) at starting and at the end of chemotherapy, respectively. Of the 294 patients with anemia, 174 (59.2%) were treated. Erythropoiesis-stimulating agents were given to 90.2% patients, alone in 31.6% and combined iron in 39.7%, transfusion in 9.2% and iron and transfusion in 9.8%. These results suggest an appropriate and rational use of erythropoiesis-stimulating agents in the treatment of chemotherapy-associated anemia in lung cancer patients. [corrected].

The Labile Side of Iron Supplementation in CKD.

The practice of intravenous iron supplementation has grown as nephrologists have gradually moved away from the liberal use of erythropoiesis-stimulating agents as the main treatment for the anemia of CKD. This approach, together with the introduction of large-dose iron preparations, raises the future specter of inadvertent iatrogenic iron toxicity. Concerns have been raised in original studies and reviews about cardiac complications and severe infections that result from long-term intravenous iron supplementation. Regarding the iron preparations specifically, even though all the currently available preparations appear to be relatively safe in the short term, little is known regarding their long-term safety. In this review we summarize current knowledge of iron metabolism with an emphasis on the sources and potentially harmful effects of labile iron, highlight the approaches to identifying labile iron in pharmaceutical preparations and body fluids and its potential toxic role as a pathogenic factor in the complications of CKD, and propose methods for its early detection in at-risk patients.

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.

Risk evaluation mitigation strategy: impact of application of the Food and Drug Adminstration's strategy on use of erythropoiesis-stimulating agents and transfusion in patients with chemotherapy-induced anaemia

The Food and Drug Administration (FDA) instituted a risk evaluation mitigation strategy (REMS) for erythropoiesis-stimulating agent (ESA) use in patients with cancer in February 2010. Implementation of REMS was considered likely to reduce ESA use and increase red blood cell transfusions. We aimed to quantify ESA and transfusion use pre- and post-REMS. A retrospective data analysis was conducted using the Medicare 5% Sample Database from 2008 through 2011. Patients were 66years of age or older and had lung and/or breast cancers along with chemotherapy-induced anaemia. Patients initiated chemotherapy in pre-REMS and post-REMS periods (1Q2008 through 4Q2009 and 1Q2010 through 4Q2011, respectively). Logistic regression was used to evaluate differences in proportions of patients receiving ESAs and transfusions pre-REMS and post-REMS. The pre-REMS group included 1526 patients and the post-REMS group included 1689 patients. ESA use in patients with lung cancer decreased 30·2% from pre- to post-REMS and 33·1% in patients with breast cancer. Both decreases were statistically significant. Transfusion rates increased 22·1% from the pre-REMS period to the pre-REMS period in patients with breast cancer (P<0·0001), but there was no statistically significant change over time in patients with lung cancer. Erythropoiesis-stimulating agent use decreased in patients with both lung and breast cancer (P<0·0001), and transfusion rates increased significantly post-REMS in patients with breast cancer (P<0·0001) but not in those with lung cancer.

Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis

New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin α, epoetin β, darbepoetin α, biosimilars). A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control. Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03-1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94-1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87-1.16) for ESA compared with control. After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.

Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD.

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders.

Clinical Outcomes With Use of Erythropoiesis Stimulating Agents in Patients With the HeartMate II Left Ventricular Assist Device

ObjectivesThis study evaluated clinical outcomes associated with erythropoiesis stimulating agent (ESA) use in left ventricular assist devices (LVAD)–supported patients. BackgroundUse of ESAs in patients with LVADs may minimize blood transfusions and decrease allosensitization. ESAs increase thrombotic events, which is concerning because LVADs are sensitive to pump thrombosis (PT). MethodsWe retrospectively reviewed 221 patients at our center who received a HeartMate II (Thoratec Corp., Pleasanton, California) LVAD between January 1, 2009 and June 6, 2013. Patients were divided into those who received ESAs during index admission (n = 121) and those who did not (n = 100). Suspected PT was defined as evidence of thrombus in the LVAD or severe hemolysis (lactate dehydrogenase >1,000 mg/dl or plasma-free hemoglobin >40 mg/dl). Outcomes were compared between cohorts using inverse probability-weighted analyses. ResultsDuring a mean follow-up of 14.2 ± 11.9 months, suspected PT occurred in 37 patients (ESA 23%, no ESA 12%; p =0.03). The ESA cohort received ESAs 13.9 ± 60.9 days after LVAD implantation. At 180 days, event-free rates for suspected PT were ESA 78.6% versus no ESA 94.5% (p < 0.001). ESA use had higher rates of suspected PT (hazard ratio [HR]: 2.35; 95% confidence interval [CI]: 1.38 to 4.00; p = 0.002). For every 100-unit increase in cumulative ESA dosage, the hazard of suspected PT increased by 10% (HR: 1.10; 95% CI: 1.04 to 1.16; p < 0.001). After inverse probability weighting, ESA use was associated with a significantly higher rate of all-cause mortality (HR: 1.62; 95% CI: 1.12 to 2.33; p = 0.01). ConclusionsESA use in LVAD patients is associated with higher rates of suspected PT.

Regaining the response to erythropoietin following azacitidine in chronic myelomonocytic leukemia previously evolved from refractory anemia.

Regaining the response to erythropoietin following azacitidine in chronic myelomonocytic leukemia previously evolved from refractory anemia.

Target Hemoglobin May Be Achieved with Intravenous Iron Alone in Anemic Patients with Cardiorenal Syndrome: An Observational Study

Background: The treatment of anemia in patients with cardiorenal syndrome (CRS) is based mainly on intravenous (IV) iron therapy and/or erythropoiesis-stimulating agents (ESAs). There are concerns about the safety of ESAs due to a potentially higher risk for stroke and malignancy. Objective: We aimed to explore whether IV iron alone is sufficient to improve anemia in CRS patients and to define the predictors of treatment response. Methods: We retrospectively analyzed data of 81 CRS patient treated for anemia at our clinic. All patients received IV iron for 6 weeks. A subset of patients was additionally given subcutaneous ESAs. The end point was the improvement from baseline in hemoglobin (Hb) and ferritin levels at week 7. Results: We retrieved the files of 81 patients; 34 received IV iron alone and 47 were given IV iron and ESAs (the combination group). The Hb levels significantly increased in both groups (in the IV iron alone group: 10.6 ± 1.1 to 11.9 ±1.1 g/dl, p < 0.001; in the combination group: 10.2 ± 0.9 to 12.4 ± 1.3 g/dl, p < 0.001), but more pronouncedly in the combination group (2.17 vs. 1.24 g/dl; p = 0.001). The platelet count decreased significantly in the IV iron alone group but was unchanged in the combination group. Eighty percent of patients attained a Hb target of 11 g/dl, with no significant difference between the two groups (73.5 vs. 85.1%; p = 0.197). Low baseline Hb was the only predictor of a favorable outcome to treatment. Conclusion: Our observational study suggests that IV iron treatment without ESAs may substantially raise the Hb level to ≥11 g/dl in CRS patients. This treatment strategy may reduce the use of ESAs and hence its potential adverse effects.

Use of CME to impact self-reported changes in the evaluation and management of anaemia in geriatric patients

Objective. The Third US National Health and Nutrition Examination Survey (NHANES III) prompted the recognition of geriatric anaemia as a public health concern since ~10% of people aged 65 years or older were anaemic. The objective of this study was to design and implement a continuing medical education (CME) event that motivates and guides Primary Care Health Practitioners (PCHPs) to adopt medical practices that improve outcomes among geriatric patients with anaemia by employing effective diagnostic workup. Research design and methods. A total of 4196 PCHPs participated in 11 highly interactive 75-minute live conferences conducted throughout the US from 2011 through 2013 that featured case-based interactive discussions on the workup of microcytic, normocytic, and macrocytic anaemia by a PCHP and local haematologist expert. A standardised diagnostic algorithm for geriatric anaemia was used and distributed as a handout at the live activity. A reinforcing mobile application based on this algorithm was introduced in 2012. Main outcome measures. Data from participants were gathered immediately after the event, 10–12 weeks post-event, and 1–3 years post-event. Outcomes were evaluated according to Moore's levels. Chi-squared analyses compared the proportion of respondents who committed to one or more of the five major behavioural changes over time. Results. The Chi-squared test analysed data from each of the three timelines for five medical behavioural changes. A comparison of participants’ responses showed that there was a significant increase in the proportion of responders committing to behavioural change #1, “Avoid indiscriminant use of erythropoiesis-stimulating agents” and #5, “Refer patients with unexplained mild anaemia to a haematologist” from post-event to 1–3 years (p<0.001) (see Table 2). The proportion of respondents who committed to the other three behavioural changes remained consistent over time, suggesting that actual change in medical practice occurred at 1–3 years. Conclusions. This proof of concept study validates the use of case-based CME involving a highly interactive discussion between PCHP and specialist, used in conjunction with a standardised diagnostic algorithm as effective in improving PCHP knowledge, competence, and self-reported performance improvement. This study lays the groundwork for follow-up studies using objective performance measures.

Considerations and challenges in defining optimal iron utilization in hemodialysis.

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.

Trends in Anemia Treatment Among Patients with Non-Myeloid Malignancies Treated with Chemotherapy

Background: Anemia is a common complication of chemotherapy that can cause clinically important symptoms and reduced quality of life. It is unclear how management of chemotherapy induced anemia (CIA) has evolved over time given the changes in the US prescribing information, reimbursement, and implementation of a risk evaluation and mitigation strategy (REMS) for the use of erythropoiesis-stimulating agents (ESAs).Objective: To describe treatment trends and current treatment patterns for anemia during chemotherapy in 2000 to 2013.Methods: Patients diagnosed with incident breast, lung, colorectal, ovarian or gastric cancer who developed moderate to severe anemia (i.e., grade II-IV based on the CTCAE grading system, or hemoglobin <10 g/dl) during chemotherapy were identified from Kaiser Permanente Southern California Health Plan. We estimated the proportions of anemia episodes with the following CIA treatment modalities: use of ESA, red blood cell (RBC) transfusion, iron, folate or B12 nutritional therapy or no treatment by anemia severity in three calendar periods: January 2000-Dec 2006 (P1), January 2007-24 March 2010 (P2), 25 March 2010-June 2013 (P3). We also estimated the most recent hemoglobin concentrations in the 7 days before ESA and RBC transfusion. Differences between calendar periods were assessed for proportions treated and for hemoglobin concentration prior to CIA treatment. Standard errors were estimated with use of the generalized estimating equations.Results: A total of 7,266 patients were included in this study (3,374 breast, 1,751 lung, 1,406 colorectal, 503 ovarian and 232 gastric cancer). Overall, 16% of the patients were diagnosed at stage I, 31% at stage II, 30% at stage III and 23% at stage IV. The mean age at diagnosis was 60 years. The observed grade II-IV anemia episodes were 1741 (7,159 pts) in P1, 880 (3,285 pts) in P2, and 1011 (3699 pts) in P3. Figures 1 and 2 show the proportion of various CIA treatment modalities by CIA severity. Proportion of anemia episodes with ESA use decreased from 2006 to 2013 (P1: 28%; P2: 21%; and P3: 3%). An increased trend of transfusion use was observed (P1: 8%; P2: 14%; and P3: 16%), with the greatest increase observed in grade III CIA (P1: 21%; P2: 41%; and P3: 54%). There was also an increase in the proportion of untreated CIA (P1: 66%; P2: 68%; and P3: 80%). When we examined the level of hemoglobin concentration prior to CIA intervention, there was a slight decrease in the hemoglobin concentrations prior to ESA use across calendar periods [mean (SD): 9.7 (1.1) g/dl in P1; 9.6 (1.1) in P2; 9.1 (1.2) in P3, p<0.01], but no difference was found for hemoglobin concentrations prior to RBC transfusion [mean (SD): 8.3 (1.3) in P1; 8.4 (1.5) in P2; 8.4 (1.3) in P3]. Iron, folate or B12 nutritional therapy was more common in severe CIA (i.e. grade III-IV, Figure 2), with a small decreasing trend in use across calendar periods (P1: 10%; P2: 8%; and P3: 7%).Similar trends for CIA treatment modalities across the three calendar periods were observed when we restricted the analyses to stage 4 cancer (Figure 3).Conclusion: The study indicates that along with the decreased utilization of ESA, utilization of RBC transfusion has increased significantly over the calendar periods in patients diagnosed with five solid tumors. Approximately 80% of patients with moderate to severe anemia (Hg < 10g/dL) in patients of these common solid tumors remained untreated in most recent calendar period (March 25, 2010–June 30, 2013). DisclosuresChao:Amgen Inc.: Research Funding. Xu:Amgen Inc.: Research Funding. Sattayapiwat:Amgen Inc.: Research Funding. Page:Amgen Inc.: Employment, stockholder Other. Cannavale:Amgen Inc.: Research Funding. Rodriguez:Amgen Inc.: Research Funding. Bohac:Amgen Inc.: Employment, stockholder Other. Xu:Amgen Inc.: Employment, stockholder Other.

Iron Supplementation Adjunct to Erythropoiesis Stimulating Agents Is Cost Saving for Chemotherapy-Related Anemia in the Era of Biosimilars

▪Background: International guidelines recommend erythropoiesis stimulating agents (ESA) to improve chemotherapy-related anemia (CRA), however, two meta-analyses proved that intravenous iron (II) improves the chance of obtaining a response to ESA by 28% (Gafter-Gvili 2013, Petrelli 2012). Recently, biosimilar ESAs have been approved for CRA, we therefore aimed at comparing the cost-effectiveness of different therapeutic strategies for CRA eventually including II and/or biosimilar ESAs.Methods: A decision model was built comparing 5 strategies: no ESA, brand ESA, brand ESA plus II, biosimilar ESA, biosimilar ESA plus II. Ferric gluconate was assumed to be administered 125 mg per week for 6 weeks overall: 4 infusions were planned in days different from chemotherapy administration. ESA was started at hemoglobin values lower than 11 g/dl. The model included a Markov tree of 13 health states representing hemoglobin level during 26 therapy weeks. Weekly probability of hemoglobin improvement by 1 g/dL was estimated to be 10% with ESA and 15% with ESA plus II but null without ESA. The efficacy of biosimilar ESA was assumed to be the same as ESA. Weekly probability of death was assumed to be 0.4% (Pedrazzoli 2008). The rate of severe events during II infusion was assumed to be 0.2% per week without fatal events. Quality of life at different hemoglobin levels was driven from literature. The economic analysis was run in the perspective of the Health Care System and of the society. II administration was charged €50 and blood transfusion €400. Indirect costs for iron infusions and transfusions planned in days not devoted to chemotherapy was estimated to be €100 for transportation and care-giver time. Based on local data, the per-unit cost of biosimilar ESA versus brand ESA was considered to be 1 in 5.All the analyses were run TreeAgePro2014. Microsimulations and first-order MonteCarlo analysis were run.Results: ESA improve quality-adjusted survival of patients from 14.51 to 14.82 quality-adjusted weeks but II adjunct increased the gain to 15.20 weeks. In the perspective of the health-care system, the management of cancer-related anemia without ESA costs €1,550, while ESA therapy increased the costs by €618 (biosimilars) and €2,933 (brand); ESA plus II increased the costs by €359 and €2,437, respectively. Therefore, the adjunct of II reduced overall health-care costs by €259 in the biosimilar strategy and €496 in the brand ESA strategy. Societal costs similarly increased with ESA use, but the increment was lower: €584 with biosimilar ESA and €2,866 with brand ESA. II allowed to achieve minimal savings in the biosimilar strategy, while savings were €288 in the brand ESA strategy. Savings to the health-care system and to the society were even higher (further €300 to the healthcare-system and €90 to the society) in the hypothesis that liposomial oral iron (30 mg per day for 60 days) achieved similar results as II, at €1 per day charged to the patient (in Italy liposomal iron it is not refunded). Ferric carboxymaltose 750 mg single administration at a cost of €280 might compete with multiple ferric gluconate administrations. Finally, we explored the efffect of threshold hemoglobin: starting ESA at hemoglobin levels lower than 10 g/dl instead of 11 g/dl allowed to reduce health-care costs of ESA therapy by €172, but quality of life was increased by only 0.14 and 0.59 weeks, without and with II, respectively.Conclusions: Rational allocation of health-care resources imposes to choose the most convenient therapeutic strategy among those recommended by practice guidelines. Intravenous iron allows to save health-care and society resources and to improve quality of life by a more rapid hematopoietic response to ESA. Different iron formulations need to be tested in association with ESA in this setting in order to improve the efficiency of avilable therapeutic strategies. Cost-effectiveness analyses should be shared by clinicians and hospital pharmacy to adopt the most effective and efficient therapeutic strategies. DisclosuresNo relevant conflicts of interest to declare.

Poor ESA Responders As Defined By Week 4 Hemoglobin Response Have Greater ESA Dosing but Worse Cardiovascular Outcomes in Patients with Anemia of Chronic Kidney Disease (CKD) Not on Dialysis

Erythropoiesis-stimulating agents (ESAs) reduce transfusion use in patients with anemia of CKD (A-CKD) but ESA use is associated with worse cardiovascular outcomes in all trials to date. Several studies indicate that patients with A-CKD who have initial poor responses to ESAs have even worse cardiovascular outcomes than others. No specific baseline characteristics identify poor ESA responders. If these patients could be identified early in their therapy, their anemia management might be altered to reduce their known greater risks of major adverse cardiovascular events (MACE). A standardized and early definition of poor ESA responders is desirable but has not been established.We analyzed three groups of patients with anemia of CKD not on dialysis (A-CKD-NOD), for their initial response to ESA therapy, ESA dosing over time, and subsequent MACE outcomes. One group consisted of all patients in the TREAT trial receiving darbepoetin alfa (n=1981; New Engl J Med 2009 and 2010). The other two groups consisted of all patients in the phase 3 trials of the ESA peginesatide for A-CKD-NOD (New Engl J Med 2013), based on the ESA to which they were randomized. Patients receiving peginesatide (n=600) comprised one group, and the control group receiving darbepoetin alfa therapy (n=304) comprised the third group (for this group, events are too few for further analysis). In all patients, peginesatide was given once monthly and darbepoetin was given every two weeks, initially at a prespecified dose and then titrated to achieve and maintain target hemoglobin (Hgb) levels of 11-12 g/dL. All analyses used the patient populations with both baseline and week 4-5 Hgb values. Peginesatide was non-inferior to darbepoetin in raising Hgb in the trials. Our analyses compared early Hgb responses at week 4-5 for each patient with later Hgb levels, cumulative ESA dosage, and with primary outcomes of MACE (time to first event of stroke, myocardial infarction, or death) for each group. Patient level data was available for all patients, and all data has been reported publically. All outcomes were assessed by blinded independent review. The relationships between MACE outcomes and the hemoglobin response were assessed using three methods: Kaplan-Meier analysis with log-rank test, adjusted Cox model with model selection, and bootstrap simulations.Results: In all groups, patients’ baseline Hgb was 10-10.5 g/dL. No individual or composite baseline characteristics were predictive for defining a poor responder group. “Poor responders” for each group, identified by week 4-5 Hgb values, remained poor responders at week 12. The average Hgb level after 12 weeks remained marginally lower in the poor responder group. Over time, the poor responder group received more ESA dose yet achieved lower Hgb increments and sustained more MACE events. TableStudy groupsCKD not on dialysisNPoor responder: Hgb increment from baselinen (%)Relative Risk for MACE for poor vs better responderPeginesatide6000.3 g/dL or less112 (19)2.56Darbepoetin (TREAT trial)19810.1 g/dL or less451 (23)1.22In exploratory analyses, patients with little or no increment in Hgb at 4 weeks on ESA therapy, defined by having 0.3 g/dL Hgb increment with peginesatide or 0.1 g/dL or less Hgb increment with darbepoetin, have the greatest risk for MACE outcomes and should be studied prospectively for alternatives to continuing or escalating usual ESA therapy, to determine if the poor responder findings are prognostic or predictive (or both). The risk of a MACE outcome is less common but not eliminated among better responders. In sensitivity analyses, by using additional adverse outcomes (such as onset of heart failure or of hospitalization) in composite models, more events are identified and allow for greater precision for risk estimates but may not be as reliable clinically as are MACE events.This work is independent and does not represent views of any government agency. DisclosuresNo relevant conflicts of interest to declare.

Anaemia management in patients with chronic kidney disease: Taiwan practice guidelines.

The introduction of erythropoiesis-stimulating agents (ESAs) markedly improved the lives of many anaemic patients with chronic kidney disease (CKD). In Taiwan, the strategy of management of anaemia in patients with CKD was different from many other parts of the world. In 1996, the National Health Insurance Administration of Taiwan applied a more restrictive reimbursement criteria for ESA use in patients with CKD. ESA is to be initiated when non-dialysis CKD patients have a serum creatinine >6 mg/dL and a hematocrit <28% to maintain a hematocrit level not exceeding 30%. The maximal dose of epoetin-α or β was 20 000 U per month. The target haemoglobin range and dose limitation for ESAs were the same for dialysis CKD patients. Thus, long before randomized controlled trials showing an increased risk for cardiovascular events at nearly normal haemoglobin concentrations and higher ESA doses in CKD, nephrologists in Taiwan had avoided the use of disproportionately high dosages of ESAs to achieve a haemoglobin level of 10-11 g/dL. Moreover, intravenous iron supplementation was encouraged earlier in Taiwan in 1996, when we reached consensus on the diagnostic criteria for iron deficiency (serum ferritin <300 ng/mL and/or transferrin saturation <30%). The experience of CKD anaemia management in Taiwan demonstrated that a reasonable haemoglobin target can be achieved by using the lowest possible ESA dose and intravenous iron supplementation.

Erythropoietin and cancer: the unintended consequences of anemia correction.

Until 1990, erythropoietin (EPO) was considered to have a single biological purpose and action, the stimulation of red blood cell growth and differentiation. Slowly, scientific and medical opinion evolved, beginning with the discovery of an effect on endothelial cell growth in vitro and the identification of EPO receptors (EPORs) on neuronal cells. We now know that EPO is a pleiotropic growth factor that exhibits an anti-apoptotic action on numerous cells and tissues, including malignant ones. In this article, we present a short discussion of EPO, receptors involved in EPO signal transduction, and their action on non-hematopoietic cells. This is followed by a more detailed presentation of both pre-clinical and clinical data that demonstrate EPO’s action on cancer cells, as well as tumor angiogenesis and lymphangiogenesis. Clinical trials with reported adverse effects of chronic erythropoiesis-stimulating agents (ESAs) treatment as well as clinical studies exploring the prognostic significance of EPO and EPOR expression in cancer patients are reviewed. Finally, we address the use of EPO and other ESAs in cancer patients.