Use Of Erythropoiesis-stimulating Agents Research Articles

Luspatercept Response in ESA-NaïVe/RS+ Patients and RS- Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS)

Background: Management of anemia is a common therapeutic challenge in patients with myelodysplastic syndromes (MDS). Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014).Aims: This is an ongoing, phase 2, multicenter, open-label study to evaluate the effects of luspatercept in patient (pts) with low-intermediate risk MDS. Endpoints included erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, safety, and pt-reported QoL.Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), no prior HMA, and no current lenalidomide or erythropoiesis-stimulating agent (ESA). An expansion cohort of up to 56 patients was added to this phase 2 study to evaluate response to luspatercept in pts who do not qualify for the phase 3 MEDALIST trial (for RS+ positive patients with baseline EPO ≥ 200 U/L and ≥ 2U RBC/8 weeks). These include pts with low transfusion burden (< 4U RBC/8 weeks) who are either 1) ring sideroblast (RS)+ (≥ 15% RS in bone marrow) with baseline EPO ≤ 200 U/L and no prior ESA use, or 2) RS- with any baseline EPO level and any prior ESA use. Patients are treated with 1.0 mg/kg of luspatercept every 3 weeks for up to 5 doses, with titration up to 1.75 mg/kg. Patients may rollover to an open-label extension study for up to an additional 2 years of treatment.Results: Results for the initial patient cohorts have demonstrated a high proportion of HI-E and RBC-TI responses in RS+ patients. Data for the additional ESA-naïve RS+ patients with low EPO levels and RS- patients with 3 months of treatment will be presented at the meeting.Conclusions: Erythroid response to luspatercept has been demonstrated in RS+ patients with lower-risk MDS and is being explored in ESA-naïve RS+ patients with low EPO levels and RS- patients. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). DisclosuresDonovan:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

Comparing Eras: Assessing Treatment Trends before and after Ruxolitinib Approval

Background: Ruxolitinib is a JAK1/2 inhibitor that gained FDA approval for treatment of intermediate and high-risk myelofibrosis (MF) in 2011. Prior to ruxolitinib, a variety of treatments were used for myelofibrosis, with variable efficacy. Even in the ruxolitinib era, treatment decisions are primarily focused on symptom management, as no treatment, other than allogeneic hematopoietic stem-cell transplant (allo-HSCT) has shown to have a strong disease-modifying effect. Ruxolitinib significantly improves splenomegaly and constitutional symptoms associated with MF. Here, we aim to compare MF treatments before and after ruxolitinib approval to assess treatment patterns and impact on clinical outcomes. We hypothesized that an increased use of ruxolitinib after its FDA-approval would affect those with constitutional symptoms and/or splenomegaly and correlate with decreased use of other treatments aimed at these symptoms.Methods: This was a single institution, retrospective study of all patients with a diagnosis of MF who were seen at our center between 2/2001 and 6/2016. The World Health Organization 2016 definition of primary myelofibrosis (PMF) was used for confirmation of diagnosis. Initial treatment was defined as first treatment after diagnosis of MF. Specific phenotypes were assigned retrospectively based on chart review reflecting the patient's initial complaints which led to diagnosis.Results: We identified 312 eligible patients. This group was divided into two cohorts: those diagnosed prior to the ruxolitinib era (cohort PRE, n = 177) and those diagnosed in the ruxolitinib era (cohort POST, n = 135). Demographics (gender, race, age at diagnosis) and presenting features were comparable between the cohorts. In the PRE cohort, JAK2 inhibitor use occurred in the setting of a clinical trial as well as in patients who were diagnosed prior to ruxolitinib approval, but first received treatment after its approval. In this cohort, 25% of patients received a JAK2 inhibitor, with 36% of these patients receiving it as frontline therapy (see figure 1). This compared to 44% of POST patients who received a JAK-2 inhibitor, with 69% receiving it in the frontline setting. POST patients were, more likely to receive ruxolitinib overall (OR 2.28, p = 0.001) and as first-line therapy (OR 4.49, p < 0.0001). POST patients were less likely to receive an erythropoiesis-stimulating agent (ESA) overall (OR 0.40, p = 0.0003) and as first line therapy (OR 0.51, p = 0.02). Thalidomide was also less commonly used in the POST patients (OR 0.34, P = 0.003). The use of hydroxyurea was similar between cohorts.When stratified based on the presence of constitutional symptoms (CS) and/or splenomegaly (S), patients most commonly received an ESA, JAK-2 inhibitor, or hydroxyurea as frontline therapy (see figure 2). When both CS and S were present, patients more commonly received the latter two options. Patients presenting with CS and S were more likely to receive ruxolitinib as first line therapy in the POST cohort compared to the PRE (OR 5.5, p = 0.0004); however, the use of first line hydroxyurea was not significantly different between the PRE and POST cohorts (p = 0.28). In all, ten separate frontline treatments were used in the symptomatic PRE cohort while only five were utilized in POST patients.In patients presenting without constitutional symptoms or splenomegaly, there was no difference in initial treatment strategy in the PRE and POST cohorts, and ruxolitinib was rarely utilized in this patient population.No difference in overall survival (OS) was noted between the two cohorts.Conclusion:After FDA-approval, ruxolitinib has emerged as the most common first-line treatment option for MF, specifically in patients with constitutional symptoms and splenomegaly, with decreased up-front use of thalidomide, ESAs and hydroxyurea. Patients presenting without constitutional symptoms or splenomegaly were no more likely to received ruxolitinib in the post-approval era, indicating a preference for alternative treatment options in this group. Longer follow up is needed to assess survival impact of frontline ruxolitinib use in our patient population. [Display omitted] [Display omitted] DisclosuresSweet:Karyopharm: Honoraria, Research Funding; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

A prospective observational study of effectiveness and safety of iron isomaltoside in patients with chronic renal failure and iron deficiency anemia .

The aim of this study was to investigate the effectiveness, safety, and tolerability of iron isomaltoside in routine practical care of iron deficiency anemia (IDA) in patients with chronic renal failure. The study included 698 patients with IDA on dialysis or with nondialysis chronic kidney disease (CKD) stages 3 - 5 designated by their physicians for treatment with iron isomaltoside. Data were recorded at baseline and after 3 and 9 months. Effectiveness data included measurement of hemoglobin (Hb), hematocrit, i-iron, transferrin saturation (TSAT), and i-ferritin. Safety data included adverse events and safety laboratory variables. Following administration of a mean cumulative dose of 2,574 mg isomaltoside over 9months, initial average Hb increased from 11.0g/dL to 11.6g/dL, TSAT from 19.4% to 28.3%, and i-ferritin from 320µg/L to 642µg/L, demonstrating a positive effect of iron isomaltoside on iron deficiency. In addition, there was a significant reduction in the use of erythropoiesis-stimulating agents (ESAs) (regarding epoetinα, initial mean dose 40,688IU/month, final dose 35,665IU/month, -13.7%, p<0.001). No drug-related adverse events were reported. Furthermore, safety parameters including i-phosphate indicated no abnormal changes. Iron isomaltoside demonstrated very good effectiveness and tolerability in patients with stage 3-5 CKD, including an ESA saving effect. .

PCN197 - Cost-Related Medication Nonadherence Among Elderly Medicare Cancer Survivors Using Erythropoiesis-Stimulating Agents

Use of erythropoiesis-stimulating agents (ESAs) poses a significant economic burden to elderly Medicare cancer survivors. The burden of high drug expense, especially for the elderly, is one of the major reasons to not adhere to prescription regimens. The objectives of this study were to 1) provide national estimates on the prevalence of cost-related medication nonadherence (CRN), 2) to examine the association between ESA use and CRN, and 3) identify predictors of CRN among elderly Medicare cancer survivors using ESAs. This study was a pooled cross-sectional study of the Medicare Current Beneficiary Survey from 2006 to 2011. ESA users were defined as having at least one prescription of darbepoetin or epoetin in Medicare Part B or D. Self-reported CRN was the main outcome and was measured based on responses to four survey questions: taking smaller doses of prescriptions, skipping doses to make prescriptions last longer, delaying obtaining prescriptions because of cost, and not obtaining prescriptions because cost too much. Weighted logistic regression was conducted to identify predicators of CRN. ESA users had higher prevalence of CRN (9.82% vs. 6.98%, P=0.0307), compared to ESA non-users. ESA use was associated with CRN (OR: 1.46, 95% CI: 1.03-2.07). Among elderly Medicare cancer survivors using ESAs, predictors of CRN included high out-of-pocket (OOP) costs of ESAs ($100 to $500 per year, OR: 4.37, 95% CI: 1.17-16.30; $500 to $1,000 per year, OR: 17.39, 95% CI: 5.10-59.31; and >$1,000 per year, OR: 14.30, 95% CI: 4.04-50.55), disability status (OR: 2.47, 95% CI: 1.14-5.36), and without low-income subsidy (OR: 5.13, 95% CI: 1.60-16.42). Centers for Medicare and Medicaid Services and healthcare providers should adopt new strategies for better access to prescribed regimens for patients with risks of nonadherence due to high OOP medical and prescription drug costs.

PUK22 - Renal Anemia Treatment in the Us- How Payer Policies and Physician Preferences Drive Prescribing and How will the Emerging Oral HIF-PH Inhibitors Influence Payers and Physicians?

Novel oral hypoxia inducible factor-prolyl hydroxylase inhibitors (HIF-PHi) offer a more convenient therapeutic option over erythropoiesis-stimulating agents (ESAs), which are administered intravenously for the treatment of renal anemia (RA). However, HIF-PHi could result in increased expenditures in an environment of tightening healthcare budgets for US insurers and dialysis centers. This research explores how payers and physicians interact and how reimbursement decisions impact the prescribing and uptake of RA therapies in chronic kidney disease-nondialysis (CKD-ND) and dialysis patients. In February 2016, 100 US nephrologists were surveyed regarding their current and expected prescribing of ESAs, IV iron and future prescribing of HIF-PHi for treating RA. 30 managed care organization pharmacy directors/medical directors were also surveyed. 59% of physicians report pressure from their dialysis units regarding RA treatment. Payers employ a wide range of measures to control access to premium-priced ESAs. 33%-48% of payers quoted prior authorization (PA) as the main control across ESAs. However, PA can be overcome as payers want to ensure that drugs are used according to the FDA label and are prescribed by specialists. 32% of nephrologists reported they would prescribe HIF-PHi over ESAs in CKD-ND due to its less invasive route of administration. Assuming availability, nephrologists expect HIF-PHi to capture approximately 38% of their RA patients. The main market access challenge HIF-PHi will face is likely an anticipated high price compared with ESAs—and thus unfavorable tiering. However, 67% of payers indicate they would place HIF-PHi on tier 1 if priced at a 20% discount to ESAs. Opportunity exists for HIF-PHi, partly due to the intravenous administration of ESAs and increased scrutiny of costs at dialysis centers. Although nephrologists expect to decrease their ESA use following the launch of HIF-PHi, these agents will need to convincingly demonstrate cost-effectiveness to secure optimum reimbursement status.

Negative Relationship between Erythropoietin Dose and Blood Lead Level in Patients Undergoing Maintenance Hemodialysis

The adverse effects of increased blood lead levels have been well discussed. Several antioxidant agents have been reported to offer protection from lead toxicity and to reduce blood lead levels (BLL). Given that erythropoietin (EPO) also has antioxidant properties, the aim of this cross-sectional study was to assess the role of EPO and other clinical variables on BLL in hemodialysis (HD) patients. We recruited 931 maintenance hemodialysis (MHD) patients who had undergone HD for at least 6 months and who had ever received blood lead level (BLL) study. Use of erythropoiesis-stimulating agents followed the The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) Clinical Practice Guideline. We estimated demographic, hematological, nutritional, inflammatory, biochemical, and dialysis-related data based on this study. In the group with EPO, 7% had high BLL. In the group without EPO, 22% had high BLL. From the stepwise liner regression, urban areas, hemodialysis duration, and clearance of urea (KT/Vurea) were positively associated with log BLL. In contrast, diabetes (DM), and monthly EPO dose were negatively associated with log BLL. This study showed that EPO dose might be negatively associated with blood lead levels in patients on maintenance hemodialysis.

Initiation of erythropoiesis-stimulating agents and outcomes: a nationwide observational cohort study in anaemic chronic kidney disease patients.

In 2012, new clinical guidelines were introduced for use of erythropoiesis-stimulating agents (ESA) in chronic kidney disease (CKD) patients, recommending lower haemoglobin (Hb) target levels and thresholds for ESA initiation. These changes resulted in lower blood levels in these patients. However, there is limited evidence on just when ESA should be initiated and the safety of a low Hb initiation policy. In this observational inception cohort study, Swedish, nephology-referred, ESA-naïve CKD patients (n = 6348) were enrolled when their Hb dropped below 12.0 g/L, and they were followed for mortality and cardiovascular events. Four different ESA treatments were evaluated applying dynamic marginal structural models: (i) begin ESA immediately, (ii) begin ESA when Hb <11.0 g/dL, (iii) begin ESA when Hb <10.0 g/dL and (iv) never begin ESA in comparison with 'current practice' [the observed (factual) survival of the entire study cohort]. The adjusted 3-year survival following ESA begun over a range of Hb (from <9.0 to 12.0 g/dL) was evaluated, after adjustment for covariates at baseline and during follow-up. Overall, 36% were treated with ESA. Mortality during follow-up was 33.4% of the ESA-treated and 27.9% of the non-treated subjects. The adjusted 3-year survival associated with ESA initiation improved for subjects with initial Hb <9.0 to 11 g/dL and then decreased again for those with Hb above 11.5 g/dL. Initiating ESA at Hb <11.0 g/dL and <10.0 g/dL was associated with improved survival compared with 'current practice' [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.79-0.89 and 0.90; 95% CI 0.86-0.94, respectively] and did not increase the risk of a cardiovascular event (HR 0.93; 95% CI 0.87-1.00). In non-dialysis patients with CKD, ESA initiation at Hb < 10.0-11.0 g/dL is associated with improved survival in patients otherwise treated according to guidelines.

Spectrum and Burden of Erythropoiesis-Stimulating AgentHyporesponsiveness Among Contemporary HemodialysisPatients.

Hemodialysis patients with erythropoiesis-stimulating agent (ESA) hyporesponsiveness have been a topic of active research. However, there have been no studies of ESA hyporesponsiveness among US patients following the dramatic change in anemia management that resulted from the 2011 changes in ESA product labeling and bundling of dialysis remuneration. Retrospective observational study. We studied prevalent hemodialysis patients treated at a large dialysis organization in calendar years 2012 to 2013 (N=98,972). ESA hyporesponsiveness, defined as 2 consecutive hemoglobin measurements< 10g/dL (every other week) with contemporaneous ESA dose > 7,700U/treatment. Patients with ESA hyporesponsiveness were identified during the first quarter of 2012 and followed up through 2013 using intention-to-treat principles. Associations between the study exposure (ESA hyporesponsiveness) and mortality, missed hemodialysis treatments, ESA and iron use, and hemoglobin levels were determined using generalized estimating equations adjusting for imbalanced baseline covariates. At baseline, 12,361 (12.5%) patients were identified as having ESA hyporesponsiveness. The mean hemoglobin level among patients with ESA hyporesponsiveness was ∼1g/dL lower than in patients without ESA hyporesponsiveness at baseline, narrowing over follow-up to 0.4g/dL. Initially, mean ESA use was approximately 3-fold greater for patients with ESA hyporesponsiveness than for those without ESA hyporesponsiveness, decreasing to 2-fold greater at study end; iron use and missed hemodialysis treatment rates were also greater among patients with ESA hyporesponsiveness throughout. ESA hyporesponsiveness was associated with enhanced mortality risk versus non-ESA hyporesponsiveness: adjusted incidence rate ratios were estimated at 2.24 (95% CI, 1.93-2.60) in the second quarter, gradually decreasing to 1.48 (95% CI, 1.18-1.84) by study end. It is possible that an alternative ESA hyporesponsiveness definition may be optimal. As such, the associations we observed may be conservative estimates of true relationships. When using a contemporary definition at one point in time, ESA hyporesponsiveness was potently and persistently associated with greater mortality, greater iron and ESA use, and lower hemoglobin levels compared to non-ESA hyporesponsiveness.

Possible Inhibitory Effect of Erythropoiesis-Stimulating Agents at the Predialysis Stage on Early-Phase Coronary Events after Hemodialysis Initiation

Background: We examined whether the use of erythropoiesis-stimulating agents (ESAs) to correct anemia at the predialysis stage could inhibit early-phase coronary events after hemodialysis initiation. Methods: We enrolled 242 patients with chronic kidney disease who had received continued medical treatments and initiated maintenance hemodialysis from 1 September 2000 to 31 December 2014 at Toujinkai Hospital. Patients with a previous history of blood transfusion or any cardiovascular events or interventions were excluded. The coronary events were followed for 1 year after initiation of hemodialysis. Results: Coronary events occurred in 51 of 242 patients: 10 patients had acute coronary syndrome [9 with percutaneous coronary intervention (PCI), 1 without intervention], and 41 had elective coronary revascularization (38 PCI and 3 coronary artery bypass graft). ESA was administered in 118 of 242 patients (48.8%). In stepwise logistic analysis, coronary events were positively associated with nonuse of ESA at the predialysis stage (odds ratio 2.66, p = 0.005) and diabetes mellitus (odds ratio 5.33, p < 0.001). When dividing the patients into 4 subgroups by blood hemoglobin (Hb) level (8.5 g/dl) and the use/nonuse of ESA, coronary event-free survival rates were higher (p = 0.005) in those with Hb ≥8.5 g/dl, ESA+ (86.6%, n = 82) and tended to be higher (p = 0.055) in those with Hb <8.5 g/dl, ESA+ (86.1%, n = 36) than in patients with Hb <8.5 g/dl, ESA- (68.6%, n = 86) in a Kaplan-Meier analysis. Conclusions: The use of ESA to correct anemia at the predialysis stage may inhibit early-phase coronary events after hemodialysis initiation.

On-label and off-label prescribing patterns of erythropoiesis-stimulating agents in inpatient hospitalsettings in the US during the period ofmajorregulatory changes.

A number of policy and labeling interventions aimed at reducing inappropriate prescribing of erythropoiesis-stimulating agents (ESAs) were implemented in the U.S. between 2006 and 2010. These interventions included the addition of an FDA Black Box Warning to ESA labeling, the implementation of a Risk Evaluation and Mitigation Strategy program, and the adoption of payment restrictions by the Centers for Medicare and Medicaid Services (CMS). The impact of these safety interventions on different types of ESA prescribing (on-label, off-label; evidence-based, not evidence-based) has not been investigated in a single study. The objective of this study was to explore the prescribing patterns of ESAs for on- and off-label indications in the U.S. hospital inpatients during the period of major policy and labeling changes. A retrospective analysis of ESAs utilization patterns was conducted using Cerner Health Facts® database from January 1, 2005 to June 30, 2011. The study population consisted of adult patients admitted to hospitals during the study period who received at least one ESAs order. Indications for ESA use were assigned based on ICD-9CM diagnosis codes, procedure codes, and medication records. ESA use was then classified based on FDA-approval and the strength of scientific evidence supporting its use. Indication categories included (1) on-label use (ONS); (2) off-label use, supported (OFS); and (3) off-label use, unsupported (OFU). Descriptive statistics were used to examine ESA use by patient, hospital, and physician characteristics and over time. ESAs were most frequently prescribed for ONS (48.7%), followed by OFU (42.7%) and OFS indications (8.6%). Of all off-label use, 83.2% were for unsupported indications. Between 2005 and 2010, the percent of inpatient visits with ESA use decreased for supported indications, both on-label (-63.2%) and off-label (-78.2%), but increased for unsupported indications (80%). OFU use surpassed ONS use as the most common type of ESA use in2009. Total and ONS ESA use decreased markedly, while OFU ESA use continued to increase during the period of major policy and labeling changes.

Pediatric Patient Blood Management Programs: Not Just Transfusing Little Adults.

Red blood cell transfusions are a common life-saving intervention for neonates and children with anemia, but transfusion decisions, indications, and doses in neonates and children are different from those of adults. Patient blood management (PBM) programs are designed to assist clinicians with appropriately transfusing patients. Although PBM programs are well recognized and appreciated in the adult setting, they are quite far from standard of care in the pediatric patient population. Adult PBM standards cannot be uniformly applied to children, and there currently is significant variation in transfusion practices. Because transfusing unnecessarily can expose children to increased risk without benefit, it is important to design PBM programs to standardize transfusion decisions. This article assesses the key elements necessary for a successful pediatric PBM program, systematically explores various possible pediatric specific blood conservation strategies and the current available literature supporting them, and outlines the gaps in the evidence suggesting need for further/improved research. Pediatric PBM programs are critically important initiatives that not only involve a cooperative effort between pediatric surgery, anesthesia, perfusion, critical care, and transfusion medicine services but also need operational support from administration, clinical leadership, finance, and the hospital information technology personnel. These programs also expand the scope for high-quality collaborative research. A key component of pediatric PBM programs is monitoring pediatric blood utilization and assessing adherence to transfusion guidelines. Data suggest that restrictive transfusion strategies should be used for neonates and children similar to adults, but further research is needed to assess the best oxygenation requirements, hemoglobin threshold, and transfusion strategy for patients with active bleeding, hemodynamic instability, unstable cardiac disease, and cyanotic cardiac disease. Perioperative blood management strategies include minimizing blood draws, restricting transfusions, intraoperative cell salvage, acute normovolemic hemodilution, antifibrinolytic agents, and using point-of-care tests to guide transfusion decisions. However, further research is needed for the use of intravenous iron, erythropoiesis-stimulating agents, and possible use of whole blood and pathogen inactivation. There are numerous areas where newly formed collaborations could be used to investigate pediatric transfusion, and these studies would provide critical data to support vital pediatric PBM programs to optimize neonatal and pediatric care.

Association of erythropoiesis-stimulating agents and the incidence risk of cancer diagnosis among chronic dialysis patients: a nested case-control study.

Erythropoiesis-stimulating agents (ESAs) are the cornerstone of the treatment for anemia in end-stage renal disease (ESRD) patients. Although a correlation has been established between ESAs and increased tumor growth among patients with cancer-related anemia, an association with a higher incidence of cancer among chronic dialysis patients remains relatively unclear. We completed a nested case-control study in a cohort of 4574 patients who began chronic dialysis treatment between 1 January 2001 and 31 December 2007 in Quebec, Canada, utilizing dialysis registry and administrative databases exclusively to extract our data. We excluded patients with a prior diagnosis of cancer. Eligible cases were identified by the time of initial cancer diagnosis obtained from either the hospital's discharge or physician billing form. We then randomly selected up to 10 controls for each case. ESA exposure was evaluated between 6 and 9 months prior to the initial cancer diagnosis. The mean weekly exposure was used to categorize ESA usage as either a low dose (<30 µg/week), moderate dose (30-70 µg/week) or high dose (>70 µg/week). We estimated the association between ESAs and the risk of developing cancer using a multivariable conditional logistic regression. We identified 419 cases of cancer and 3895 matched controls during the study period. The use of ESAs was associated with a higher risk of cancer {odds ratio [OR] 1.04 [95% confidence interval (CI) 1.02-1.07]}. Specifically, patients in the high exposure group (>70 µg/week) had an increased risk of developing cancer [OR 1.77 (95% CI 1.18-2.66)] compared with patients in the unexposed group. High-dose ESA was associated with an increased incidence risk of new cancer diagnosis among chronic dialysis patients.

Artificial intelligence for optimal anemia management in end-stage renal disease

Computational intelligence for the prediction of hemoglobin to guide the selection of erythropoiesis-stimulating agent dose results in improved anemia management. The models used for the prediction result from the use of individual patient data and help to increase the number of hemoglobin observations within the target range. The benefits of using these modeling techniques appear to be a decrease in erythropoiesis-stimulating agent use and a decrease in the number of transfusions. This study confirms the results of previous smaller studies and suggests that additional beneficial results may be achieved.

Effects of the prospective payment system on anemia management in maintenance dialysis patients: implications for cost and site of care

BackgroundThe 2011 expanded Prospective Payment System (PPS) and contemporaneous Food and Drug Administration label revision for erythropoiesis-stimulating agents (ESAs) were associated with changes in ESA use and mean hemoglobin levels among patients receiving maintenance dialysis. We aimed to investigate whether these changes coincided with increased red blood cell transfusions or changes to Medicare-incurred costs or sites of anemia management care in the period immediately before and after the introduction of the PPS, 2009–2011.MethodsFrom US Medicare end-stage renal disease (ESRD) data (Parts A and B claims), maintenance hemodialysis patients from facilities that initially enrolled 100 % into the ESRD PPS were identified. Dialysis and anemia-related costs per-patient-per-month (PPPM) were calculated at the facility level, and transfusion rates were calculated overall and by site of care (outpatient, inpatient, emergency department, observation stay).ResultsMore than 4100 facilities were included. Transfusions in both the inpatient and outpatient environments increased. In the inpatient environment, PPPM use increased by 11–17 % per facility in each quarter of 2011 compared with 2009; in the outpatient environment, PPPM use increased overall by 5.0 %. Site of care for transfusions appeared to have shifted. Transfusions occurring in emergency departments or during observation stays increased 13.9 % and 26.4 %, respectively, over 2 years.ConclusionsInpatient- and emergency-department-administered transfusions increased, providing some evidence for a partial shift in the cost and site of care for anemia management from dialysis facilities to hospitals. Further exploration into the economic implications of this increase is necessary.

We Give Too Much Intravenous Iron.

Dialysis patients have absolute and functional iron deficiencies. Traditionally, oral iron preparations have been insufficient to maintain iron stores to support erythropoiesis, especially in the setting of the ubiquitous use of erythropoiesis-stimulating agents. This has led to the widespread adoption of intravenous iron protocols designed to maintain iron stores at levels that are much higher than for patients not on dialysis. These protocols are often developed by dialysis providers and may be largely independent of the treating nephrologist. Concerns about multiple risks associated with the use of intravenous iron persist. Despite this, mean ferritin levels in the United States have risen, partly due to more intravenous iron use and partly due to reduced erythropoiesis-stimulating agent use. Questions about the relationship of intravenous iron to infection, cardiac, and hepatobiliary risks remain. The failure of oral iron preparations to maintain iron stores continues to prompt the use of intravenous iron. Recently, studies with oral ferric citrate as a phosphate binder have shown improved iron stores and maintenance of hemoglobin, and studies with soluble ferric pyrophosphate added to dialysate have shown both maintenance of iron stores and hemoglobin. With new iron options that affect iron stores in dialysis patients, the use of intravenous iron and its potential risks may wane.

Strategies for the Management of Postoperative Anemia in Elective Orthopedic Surgery.

To assess the use of oral iron, intravenous (IV) iron, and erythropoiesis-stimulating agents (ESAs) for the prevention and management of perioperative anemia in elective orthopedic surgery patients, and to provide a clinical algorithm for use. A PubMed and MEDLINE search was conducted from 1964 through March 2016 using the following search terms alone or in combination: orthopedic, surgery, elective, anemia, blood transfusion, iron, erythropoiesis-stimulating agents, and erythropoietin. All English-language prospective and retrospective human studies and meta-analyses evaluating oral iron, IV iron, or ESA alone or in combination in elective orthopedic surgery patients were evaluated, provided they reported blood transfusion outcomes. A total of 9 prospective and retrospective studies and 1 meta-analysis were identified and included. In the preoperative setting, administration of oral iron, IV iron, or ESA alone or in combination to correct underlying anemia led to significantly reduced transfusion rates. Transfusion requirements were generally less with combination therapy (ESA + oral or IV iron). In the short-term perioperative or postoperative period, use of oral or IV iron led to conflicting results, with some reporting a statistically significant reduction in blood transfusions, whereas others reported none. In elective orthopedic surgery, IV or oral iron with or without an ESA may provide benefit in prevention of postoperative anemia and results in blood transfusion reduction without significantly increasing the risk of adverse events. These agents should be considered at the lowest effective dose with emphasis on administration prior to planned surgery.

Associations between hematopoietic growth factors and risks of venous thromboembolism, stroke, ischemic heart disease and myelodysplastic syndrome: findings from a large population-based cohort of women with breast cancer.

To determine the risk of venous thromboembolism (VTE), stroke, ischemic heart disease, and myelodysplastic syndrome (MDS) in association with the receipt of colony-stimulating factors (CSFs) and/or erythropoiesis-stimulating agents (ESAs) in women with breast cancer. We studied 77,233 women with breast cancer aged ≥65 in 1992-2009 from the Surveillance, Epidemiology, and End Results-Medicare linked data with up to 19 years of follow-up. Incidence of VTE increased from 9 cases in women receiving no chemotherapy and no CSFs/ESAs to 22.79 cases per 1,000 person-years in those receiving chemotherapy with CSFs and ESAs. Women with chemotherapy who received both CSFs and ESAs (adjusted hazard ratio and 95 % confidence interval 2.01, 1.80-2.25) or received ESAs without CSFs (2.03, 1.74-2.36) were twice as likely to develop VTE than those receiving no chemotherapy and no CSFs/ESAs, whereas those receiving CSF alone without ESA were 64 % more likely to have VTE (1.64, 1.45-1.85). Risk of MDS was significantly increased by fivefold in patients receiving ESA following chemotherapy. Receipts of CSFs and ESAs were significantly associated with an increased risk of VTE in women with breast cancer. Use of ESAs was significantly associated with substantially increased risks of MDS. These findings support those of previous studies.

Erythropoiesis-stimulating agent dosing, haemoglobin and ferritin levels in UK haemodialysis patients 2005-13.

ABSTRACT Background: Erythropoiesis-stimulating agents (ESAs) with intravenous iron supplementation are the main treatment for anaemia in patients with chronic kidney disease. Although observational studies suggest better outcomes for patients who achieve higher haemoglobin (Hb) levels, randomized controlled trials comparing higher and lower Hb targets have led to safety concerns over higher targets and to changes in treatment guidelines. Methods: Quarterly data from 2005 to 2013 were obtained on 28 936 haemodialysis patients from the UK Renal Registry. We examined trends in ESA use and average dose, Hb and ferritin values over time and Hb according to the UK Renal Association guideline range. Results: The average ESA dose declined over time, with sharper decreases of epoetin seen towards the end of 2006 and from 2009. Average Hb for patients on ESAs was 114.1 g/L [95% confidence interval (CI) 113.7, 114.6] in the first quarter of 2005, which decreased to 109.6 g/L (95% CI 109.3, 109.9) by the end of 2013. Average serum ferritin was 353 µg/L (95% CI 345, 360) at the start of 2005, increasing to 386 µg/L (95% CI 380, 392) in the final quarter of 2013. The percentage of patients with Hb in the range of 100–120 g/L increased from 46.1 at the start of 2005 to 57.6 at the end of 2013. Conclusions: Anaemia management patterns for haemodialysis patients changed in the UK between 2005 and 2013. These patterns most likely reflect clinician response to emerging trial evidence and practice guidelines. Registries play an important role in continued observation of anaemia management and will monitor further changes as new evidence on optimal care emerges.

A Comparison of Clinical Parameters and Outcomes over 1 Year in Home Hemodialysis Patients Using 2008K@home or NxStage System One

The prevalence of home hemodialysis (HHD) in the United States is growing, driven in part by improvements in dialysis machines for home use. We assessed clinical parameters and outcomes in HHD patients using either Fresenius 2008K@home or NxStage System One over 1 year. Patients were 18 years or older and received HHD for ≥30 days between January 1, 2009, and June 30, 2010. A propensity score match was used to control for differences in baseline characteristics, and 2008K@home patients were stratified by frequency of use. Data for outcome measures were analyzed using generalized linear mixed models. Treatment frequency was lower for 2008K@home groups than System One. Mean standardized Kt/V (stdKt/V) was 2.75 for 2008K@home ≥3.5x/week users and 1.99 for System One users (p < 0.001). Erythropoiesis-stimulating agent use tended to be lower for patients using System One. There were no statistically significant differences across groups in serum albumin, calcium, phosphorus, hemoglobin, or parathyroid hormone levels, normalized protein catabolic rate, body mass index, number of hospitalizations, or hospitalized days. Clinical parameters and outcomes for HHD patients using 2008K@home and System One were largely equivalent, although 2008K@home use was associated with higher stdKt/V. Further studies will be required to establish whether these differences in stdKt/V relate to differences in technology, treatment schedule, or a combination thereof.

Epoetin Alfa and Outcomes in Dialysis amid Regulatory and Payment Reform.

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia in patients with CKD, including those receiving dialysis, although clinical trials have identified risks associated with ESA use. We evaluated the effects of changes in dialysis payment policies and product labeling instituted in 2011 on mortality and major cardiovascular events across the United States dialysis population in an open cohort study of patients on dialysis from January 1, 2005, through December 31, 2012, with Medicare as primary payer. We compared observed rates of death and major cardiovascular events in 2011 and 2012 with expected rates calculated on the basis of rates in 2005-2010, accounting for differences in patient characteristics and influenza virulence. An abrupt decline in erythropoietin dosing and hemoglobin concentration began in late 2010. Observed rates of all-cause mortality, cardiovascular mortality, and myocardial infarction in 2011 and 2012 were consistent with expected rates. During 2012, observed rates of stroke, venous thromboembolic disease (VTE), and heart failure were lower than expected (absolute deviation from trend per 100 patient-years [95% confidence interval]: -0.24 [-0.08 to -0.37] for stroke, -2.43 [-1.35 to -3.70] for VTE, and -0.77 [-0.28 to -1.27] for heart failure), although non-ESA-related changes in practice and Medicare payment penalties for rehospitalization may have confounded the results. This initial evidence suggests that action taken to mitigate risks associated with ESA use and changes in payment policy did not result in a relative increase in death or major cardiovascular events and may reflect improvements in stroke, VTE, and heart failure.