Erythropoiesis-stimulating Agents Usage Research Articles

The Influence of Precursor Depletion and dose Regimens on Resistance to Erythropoiesis-Stimulating Agents: Insights from Simulations with Instantaneous Dose-Adaptation Algorithm

Erythropoiesis-stimulating agents (ESAs) have been a common treatment for anemia associated with chronic kidney disease (CKD), while 10–20 % of patients continue to suffer from persistent anemia despite receiving ESA treatments. Our previous findings suggested that intensive ESA usage can cause resistance by depleting the erythroid precursor cells. Here, we used a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model of ESAs and conducted simulations to evaluate the influence of dose regimens and other factors (such as administration route, individual PK/PD parameters, types of ESAs, and disease status) on ESA resistance with instantaneous dose adaptations in healthy populations and anemic patients. The simulated results show that instantaneous dose-adaptation can reduce ESA resistance, but up to 30 % of subjects still ended up developing ESA resistance in healthy populations. The Smax is markedly higher in hypo-responders than in normal-responders, while hypo-responders possess fewer precursors and experience a faster decline compared to normal-responders. There is a ceiling effect of increasing ESA dosage to improve HGB responses and reduce ESA resistance, and the limit is lower in anemic patients compared to healthy populations. Subcutaneous administrations and ESAs with longer half-lives lead to stronger HGB responses and less resistance at equivalent doses. Taken together, this study indicates that precursor depletion contributes to ESA resistance and dose regimens can greatly influence the occurrence of ESA resistance. Furthermore, ESA treatment for patients showing ESA resistance should avoid continuously increasing doses and instead consider stimulating the renewal of precursors.

#3648 INDIVIDUALIZED ANEMIA THERAPY IMPROVES HEMOGLOBIN OUTCOMES AND DECREASES EPOETIN BETA DRUG EXPOSURE IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Anemia is a common complication in hemodialysis (HD) patients. Its treatment with erythropoiesis-stimulating agents (ESAs) is challenging due to a nonlinear dose-response relationship and time delays between ESA administration and hemoglobin (Hgb) response. Anemia treatment protocols are frequently used in clinical settings. However, high variability of patient-specific disease characteristics complicate attainment and maintenance of desired Hgb levels. We developed a novel fully personalized ESA dose recommendation tool and present clinical results of a multi-center, randomized controlled trial (RCT) using this software. Method We conducted an RCT in adult HD patients in six dialysis facilities in the US. Patients were randomized 1:1 and treated with our personalized ESA dose recommendation tool for twenty-six weeks (intervention group) or continued to be treated using an anemia protocol that was used as part of standard of care in those clinics (control group). The recommendation tool utilized a physiology-based model of anemia to estimate patient-specific physiological key characteristics, such as red blood cell lifespan, to create a patient-individual model from recent routine clinical data (gender, height, weight, Hgb measurements, and ESA treatment). These key characteristics and model-based outcome predictions were used to generate patient-specific ESA dose recommendations to stabilize Hgb levels in a target window of 10–11 g/dL. Dose recommendations were disseminated to the anemia managers of patients enrolled in the study for evaluation and further decision-making (Figure 1). This procedure was repeated biweekly with updated clinical data. Results Ninety-six patients were enrolled in the RCT. Patients were included in the statistical analysis when they remained in the clinical study for at least 30 days (n = 45 control group, n = 46 intervention group). We evaluated outcome measures showing efficacy and efficiency of the treatment in achieving target Hgb levels. Hgb-related outcomes were significantly different between the two study groups, with an improved Hgb control in the intervention arm, manifesting in a reduction of the Hgb distance to target by more than 30%. Epoetin-beta utilization in the intervention group was decreased by over 20%, while iron-related parameters showed no difference between the two arms (Table 1). Acceptance rate of dose recommendations was high; roughly 95% of the recommendations were accepted and implemented by the clinical staff. Conclusion A therapy software for personalized anemia management was developed for use with epoetin beta. The model-based ESA dose recommendation tool was evaluated in a clinical RCT in HD patients. Hgb control improved significantly in the group using the novel software tool, while ESA usage decreased, thus providing more efficient anemia management for the individual patient while reducing epoetin-beta drug exposure.

Erythropoiesis-stimulating agents and incident malignancy in chronic kidney and end-stage renal disease: Apopulation-based study.

Research investigating incident malignancy risk in erythropoiesis‐stimulating agent (ESA) users with chronic kidney disease (CKD) is lacking. We aimed to compare the incident cancer risk between ESA and non‐ESA users with CKD or end‐stage renal disease (ESRD). In this retrospective cohort study, all adults newly diagnosed with CKD or ESRD between 2000 and 2012 were enrolled. The study population included 98,748 patients. After case–control matching, 7115 patients were included. The defined daily dose (DDD) of ESA was used as the unit for measuring the amount of ESA prescribed. The primary outcome was the risk of incident malignancy. The secondary outcomes were incident malignancy risk in different tertiles of cumulative ESA doses and the risk of different types of cancers. The risk of incident malignancy was 1.84 times higher with ESA treatment than without ESA treatment (hazard ratio, 1.84; 95% confidence interval, 1.43–2.36; p < 0.001). The malignancy risk was positively correlated with the cumulative dose of ESA (p‐for‐trend = 0.001) and a significant difference in the high annual cumulative DDD cohort (hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.76–3.25; p < 0.001). The risk of genitourinary malignancy was 12.55 times higher with ESA treatment than without ESA treatment (HR, 12.55; 95% CI, 5.78–27.24; p < 0.001). ESA usage is associated with an increased risk of malignancy, particularly genitourinary cancers, in patients with CKD or ESRD. Clinicians should be aware of the occurrence of malignancy, and keep ESA dosage as low as possible.

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Direct healthcare costs of chronic kidney disease management in Italy: What cost-savings can be achieved with higher biosimilar uptake and more appropriate use of erythropoiesis-stimulating agents?

Erythropoiesis-stimulating agents (ESAs), are used for treating chronic kidney disease (CKD)-related anemia, contributing to CKD costs. The study was aimed at investigating direct healthcare costs of CKD patients treated with ESAs and the potential savings achievable by increasing the use of biosimilars and preventing inappropriate ESA use. A multi-center, cohort study was conducted using claims databases of five large Italian geographic areas. Yearly mean direct healthcare costs per patient were estimated, stratifying by CKD stage. The total yearly cost and potential savings related to ESA use were estimated: (a) considering 25/50/75% of originator ESA substitution with biosimilars; (b) eliminating inappropriate ESA dispensing. During the study period, the ESA-related yearly mean cost represented 17% of total yearly costs in stage I-III, decreasing to 13% in stage IV-V and 6% in dialysis. Among originator users, assuming a 25% of biosimilar uptake, the annual cost-savings of ESA treatment would represent 10.5% of total ESA costs in CKD stage I-V and 7.7% in dialysis. Among incident ESA users for which hemoglobin levels were available, 9% started inappropriately ESA treatment, increasing to 62.0% during the first year of maintenance therapy. Hypothesizing prevention of the first inappropriate ESA dispensing, the total yearly cost-savings would amount to €35 772, increasing to €167 641 eliminating the inappropriate dispensing during maintenance therapy. Higher use of lowest cost ESA, prevention of inappropriate ESA use as well as other strategies aimed at slowing down the progressive renal impairment are essential for minimizing clinical and economic burden of CKD.

PUK36 DIRECT HEALTHCARE COSTS OF CHRONIC KIDNEY DISEASE MANAGEMENT IN ITALY: HOW MUCH SAVING CAN BE ACHIEVED WITH LARGER BIOSIMILAR UPTAKE?

Chronic kidney disease (CKD) is a growing public health issue worldwide. Erythropoiesis stimulating agents (ESAs) are used to treat CKD-related anemia, contributing to CKD management costs. However, 20-30% of ESA costs can be reduced using biosimilars. Our objective was to investigate direct healthcare costs of CKD patients treated with originator or biosimilar ESAs and potential savings achievable by increasing use of biosimilars. A multi-center, retrospective (2009-2014), cohort study was conducted using claims databases of five large geographic areas in Italy (8 million residents). Incident CKD-ESA users with at least 1-year ESA use, were included in the study. Yearly mean/patient direct healthcare costs were estimated, by CKD stage. Total annual cost and potential savings due to ESA use were estimated considering 25%, 50% and 75% of ESA substitution with biosimilar epo-alpha. During the study period 7,810 CKD patients started ESA treatment (epo-alfa reference product: 1,139, 14.6%; epo-alfa biosimilars: 1,204, 15.4%; other still patented ESAs: 5,467, 70.0%). Of these, 2,921 (37.4%) had information on CKD stage (I-III: 40%; IV-V: 27%; dialysis: 33%). ESA-related annual mean cost/patient represented 17% (€1,551; 95% Confidence Interval €1,471-€1,631) of total cost/year in stage I-III, decreasing to 13% (€1,493; €1,413-€1,573) in stage IV-V and 6% (€2,045; €1,946-€2,144) in dialysis patients. 15% of incident ESA users, started ESA biosimilar during the study period (mean ESA cost/patient/year: €1,051). Among ESA-originator users, assuming 25% biosimilar uptake, the annual cost-saving on ESA treatment would represent 10.5% of total ESA costs in CKD stage I-V and 7.7% in dialyzed patients. Assuming 75% biosimilar uptake cost-savings would increase to 31.5% in CKD stage I-V and 23.0% in dialysis. CKD patients management, especially after initiation of dialysis, is very costly. ESA use contributes partially to the direct healthcare costs of CKD. Larger use of ESA biosimilars would substantially reduce drug expenditure in CKD patients.

In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study

BackgroundEvidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice.MethodsDuring the years 2009–2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out.Results`In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0–1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2–2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1–2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2–0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3–0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness.ConclusionsThe study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients’ quality of life.

Anemia and mortality in patients with nondialysis-dependent chronic kidney disease

BackgroundA combination of safety concerns and labeling changes impacted use of erythropoiesis-stimulating agents (ESAs) in renal anemia. Data regarding contemporary utilization in pre-dialysis chronic kidney disease (CKD) are lacking.MethodsElectronic healthcare records and medical claims data of pre-dialysis CKD patients were aggregated from a large US managed care provider (2011–13). ESA use patterns, characteristics, and outcomes of ESA-treated/untreated patients were quantified.ResultsAt baseline, 109/32,308 patients (0.3%) were ESA users. Treated patients were older, had more advanced CKD (58.8% vs 5.4% with stage 4/5 vs 3) and greater prevalence of comorbid diabetes, hypertension, heart failure, and peripheral vascular disease. An additional 266 patients initiated ESA: hemoglobin at initiation was 8–10 g/dL in 193 of these and >10 g/dL in the remainder; 61.7% had stage 4/5 CKD; prevalence of cardiovascular disease was high (50.8% heart failure; 25.2% prior myocardial infarction; 24.1% prior stroke). During follow-up, rates of death and cardiovascular events were higher in baseline ESA users and ESA naives versus non-users.ConclusionsESA use in pre-dialysis CKD patients was exceedingly rare and directed disproportionately to older, sicker patients; these patients had high rates of death and cardiovascular events. These data provide context for contemporary use of ESA in pre-dialysis CKD.

Serum Hepcidin and Iron Indices Affect Anemia Status Differently According to the Kidney Function of Non-Dialysis Chronic Kidney Disease Patients: Korean Cohort Study For Outcome in Patients with Chronic Kidney Disease (KNOW-CKD)

Background/Aims: No studies have examined the association among serum hepcidin, iron indices, or anemia status based on the kidney function of non-dialysis chronic kidney disease (CKD) patients. Methods: We reviewed data of 2238 patients from a large-scale multicenter prospective Korean study (2011–2016) and excluded 198 patients with missing data regarding serum hepcidin, hemoglobin, transferrin saturation (TSAT), ferritin, and usage of erythropoiesis-stimulating agents (ESA) or supplemental iron and 363 patients using ESA or supplemental iron. Finally, 1677 patients were included. Results: The mean patient age was 53.5 years, and 65.4% were men. TSAT and serum hepcidin were significantly associated with anemia status, whereas serum ferritin was not, regardless of anemia severity. For patients with an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m², a 10% increase of TSAT was associated with hemoglobin <13 g/dL (odds ratio [OR], 0.628; 95% confidence interval [CI], 0.515-0.765; P<0.001) and hemoglobin <11.5 g/dL (OR, 0.672; 95% CI, 0.476-0.950; P=0.024), whereas a 10-ng/mL increase of serum hepcidin was associated with hemoglobin <11.5 g/dL (OR, 1.379; 95% CI, 1.173-1.620; P<0.001) and hemoglobin <10.0 g/dL (OR, 1.360; 95% CI, 1.115-1.659; P=0.002) for patients with eGFR <45 mL/min/1.73 m² according to multivariate logistic analysis. Conclusions: TSAT was associated with less severe anemia in early CKD patients. Serum hepcidin was associated with more severe anemia in advanced CKD patients.

Predictors of adherence to a new erythropoiesis-stimulating agent inpatient ordering policy: A cross-sectional study.

BackgroundErythropoiesis-stimulating agents (ESAs) are recommended for treating anemia in patients with chronic kidney disease and end-stage renal disease. However, misappropriate and over-use of these agents can be costly and unnecessary in some settings.ObjectiveThe primary aim was to identify predictors of adherence to a newly approved ESA inpatient ordering policy. The secondary aims were to evaluate the impact of a 5-day delay in the initiation of ESA therapy on ESA usage, hemoglobin (Hb) levels, and costs.MethodsThis retrospective observational record review included a sample of adult patients admitted to four tertiary care hospitals from November 1, 2013 to August 31, 2014. Multivariable logistic and linear regression analyses were used to calculate the odds of adherence to the new ESA inpatient ordering policy and the impact of this policy on discharge Hb level, respectively.ResultsA total of 242 patients were included. The majority of the prescribers (77%) adhered to the new ESA ordering policy. Hemoglobin (OR = 1.306; 95% CI: 1.03–1.65) and ferritin (OR = 3.91; 95% CI: 1.23–12.51) levels at admission and length of hospital stay were positively correlated with the odds of patients receiving ESAs after day 5 (OR = 1.12; 95% CI:1.05–1.20). Furthermore, adherence to the new policy did not have a significant impact on discharge Hb level (β = 0.02349; P = 0.895).ConclusionsPrescribers were adherent to a 5-day delay in the initiation of ESA therapy policy which resulted in a reduction in ESA usage, did not impact the discharge Hb levels, and was proven to be cost effective.

Developing a classification system for haemoglobin management in patients with end-stage renal disease on haemodialysis: a secondary data analysis

BackgroundOngoing discussion on anaemia management and target haemoglobin (Hb) levels in patients on haemodialysis with erythropoietin treatment require a systematic approach in evaluating current practice. Aim of the present study...

Comparative effectiveness and safety of erythropoiesis-stimulating agents (biosimilars vs originators) in clinical practice: a population-based cohort study in Italy

ObjectivesTo evaluate the benefit/risk profile of epoetin α biosimilar with the erythropoiesis-stimulating agents (ESAs) originators when administered to naïve patients from clinical practice.DesignPopulation-based observational cohort study.SettingAll residents in the Lazio...

A Single Institution Retrospective Analysis of the Effect of Erythropoiesis Stimulating Agents in Patients with Multiple Myleoma

Background: Erythropoiesis Stimulating Agents (ESAs) are FDA approved for chemotherapy induced anemia and anemia of chronic kidney disease. These indications are more frequent in patients with multiple myeloma. Use of ESAs has been associated with an increased risk of heart attack, stroke, venous thromboembolism (VTE), and all-cause mortality. In patients with cancer, ESA's have been associated with worse progression free survival (PFS) and overall survival (OS) Previous research regarding ESA use in patients with multiple myeloma has been limited and conflicting. In this study, we evaluate the effects of ESA use in patients with multiple myeloma. Additionally, we examined the frequency of ESA usage after the 2007 FDA safety update revising product labeling for ESAs.Methods: A retrospective chart review was conducted on patients diagnosed with active multiple myeloma between January 1st, 2000 and December 31st, 2015 at Gundersen Health System in La Crosse Wisconsin. Collected data include patient demographics, medications, lab tests, comorbidities, and the dates of any VTE, stroke, or myocardial infarction. Both a logistic regression and a matched case-control analysis were used to compare rates of complications in patients using ESAs to those that did not. ESA effect on median survival time was also calculated for each International Staging System (ISS) stage of disease.Results:There were 278 patients included for demographic analysis (Table 1), of which 268 were included in the logistic regression analysis and 124 (62 pairs) in the matched case-control analysis.A logistic regression model constructed via stepwise selection found that bone lesions at diagnosis (Odds Ratio (OR): 2.5 [1.2-5.1]), antiplatelet drug use (OR: 3.7 [1.2-11.3]) and ESA use (OR: 4.7 [2.2-9.9]) were associated with increased risk of VTE in our patient population. Use of an Angiotensin Converting Enzyme (ACE) inhibitor (OR: 0.4 [0.2-0.9]) was associated with a decreased risk of VTE. Increased odds of VTE with ESA usage (OR: 5.9 [1.9 - 18.8]) were also noted in the matched case-control analysis. There was no association found between rate of stroke and ESA usage in either logistic or matched case-control analysis. No significant association between ESA use and overall survival was noted in either logistic or matched case-control analysis.When comparing outcomes based upon pre and post FDA revised product labeling, we found a 50% reduction in ESA usage within our institution. In this same time period, the percentage of patients with multiple myeloma developing VTEs has been significantly reduced (18.6% vs 12.8% [p<0.007]).Conclusions: In our population, the use of ESAs in multiple myeloma patients was associated with increased risk of VTE. No significant association between ESA use and overall survival was noted. The observed decrease in both ESA use and rate of VTE in patients with myeloma after the 2007 revised safety labelling by the FDA may reflect practice changes in response to this revision at our institution. Further study in a prospective large multicenter dataset with further control of confounding variables is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

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.

Naturally nonanemic dialysis patients: Who are they?

Introduction Not only anemia, but also erythropoiesis stimulating agent (ESA)s for treating anemia may adversely affect prognosis of chronic hemodialysis patients. Various features of naturally (with no ESA usage) nonanemic patients may be useful for defining several factors in the pathogenesis of anemia. Methods Data, retrieved from the European Clinical Database (EuCliD)-Turkey on naturally nonanemic prevalent chronic hemodialysis patients (n: 201) were compared with their anemic (those who required ESA treatment) counterparts (n: 3948). Findings Mean hemoglobin values were 13.5 ± 0.8 and 11.5 ± 0.9 g/dL in nonanemic and anemic patients, respectively (P < 0.001). Nonanemia status was associated with younger age, male gender, longer dialysis vintage, nondiabetic status, more frequent hepatitis-C virus seropositivity and more frequent arteriovenous fistula usage. Serum ferritin and CRP levels and urea reduction ratio were higher in ESA-requiring patients. One (99%) and two (95.3%) years survival rates of the "naturally nonanemic" patients were superior as compared to anemics (91.0% and 82.6%, respectively), (P < 0.001). Discussion "Naturally nonanemic" status is associated with better survival in prevalent chronic hemodialysis patients; underlying mechanisms in this favorable outcome should be investigated by randomized controlled trials including large number of patients.

The Impact of Lowering Haemoglobin Targets on Patterns of Erythropoiesis-Stimulating Agent Use in Patients on Haemodialysis

Background/Aims: Haemoglobin (Hb) targets have been reduced in patients receiving haemodialysis (HD). We have investigated the impact of new guidance on current practices and costs. Methods: Anaemia management in all patients undergoing thrice-weekly HD was retrospectively reviewed. Hb targets were compared against Kidney Disease: Improving Global Outcomes 2012 recommendations. The impact of new guidance was assessed by comparing anaemia parameters pre- and post-guideline publication. Results: Two hundred and ninety two patients, with a mean age of 64 years were included. The Hb target range was achieved in 44% patients and was above target in 51%. In a sub-group of 230 patients, the mean Hb did not differ during Q4-2011 and Q4-2012. A reduction in erythropoiesis-stimulating agent (ESA) use was observed. ESA efficiency (Hb/ESA) increased in the later period (6.08 vs. 6.41 g/l/μg) and was associated with a 3% cost reduction. Conclusion: Introduction of guidelines lowering Hb targets in HD patients led to more efficient ESA usage and cost-savings. Anaemia treatment, however, remains unnecessarily aggressive in some patients. Further reductions in Hb and ESA dose are achievable.

Use of Erythropoietin-Stimulating Agents (ESA) in Patients With End-Stage Renal Failure Decided to Forego Dialysis: Palliative Perspective

Normochromic normocytic anemia is a common complication in chronic kidney disease (CKD) and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) act to replace endogenous erythropoietin for patients with end-stage renal disease having anemia. Today, ESAs remain the main tool for treating anemia associated with CKD. In current practice, the use of ESA is not limited to the patients on renal replacement therapy but has extended to nondialysis patients under palliative care (PC). Current evidence on ESA usage in patients with CKD decided to forego dialysis often have to take reference from studies conducted in other groups of patients with CKD, including pre-dialysis patients and those on renal replacement therapy. There is paucity of studies targeting use of ESAs in renal PC patients. Small-scale retrospective study in renal PC patients had suggested clinical advantage of ESAs in terms of hemoglobin improvement, reduction in fatigue, and hospitalization rate. With the expected growth in elderly patients with CKD decided to forego dialysis and manage conservatively, there remains an urgent need to call for large-scale prospective trial in exploring efficacy of ESAs in this population, targeting on quality of life and symptoms improvement outcome. This article also reviews the mechanism of action, pharmacology, adverse effects, and clinical trial evidence for ESA in patients with CKD under renal PC.

Darbepoetin Hits a Double As Epoetin Hits a Home Run in Response to the 2007 FDA Black Box Warning

Background: Darbepoetin and epoetin are erythropoiesis stimulating agents (ESAs) that have been used to treat chemotherapy related anemia in cancer patients since 2002 and 1993. ESAs reduce rates of blood transfusions in both CKD and cancer patients. In the cancer setting, toxicities for ESAs include venous thromboembolism (VTE), tumor progression, and death. In March 2007, these toxicities were described by FDA in a revised "black box" warning. The warning advised clinicians to use the lowest dose possible of ESAs among persons with chemotherapy associated anemia and to administer ESAs to cancer patients who are receiving chemotherapy for palliation versus the curative setting. While several studies report decreased ESA utilization among cancer patients with chemotherapy-induced anemia following the Black Box warning, these studies have not reported on changes in ESA use for darbepoetin versus epoetin nor have they reported on changes in VTE rates. We report on darbepoetin versus epoetin utilization trends in cancer patients with chemotherapy-associated anemia in addition to VTE and transfusion rates during the years 2002 to 2010.Methods: We merged South Carolina Medicaid data with South Carolina Cancer Registry dataset for the years 2002- 2010. Breast, non-small cell lung and colorectal patients 18 years of age and older evaluated. From the chemotherapy population in this cohort based on tumor registry data, ESA users were identified from medical and pharmacy claims. The final sample contained persons with a first ESA claim after chemotherapy administration among Medicaid persons who are not dually enrolled in Medicare and Medicaid.Results: Of 1,315 chemotherapy patients who received an ESA, 940 (71%) were darbepoetin users and 375 (29%) were epoetin users. In 2002, epoetin and darbepoetien users accounted for 37.5% and 13% of the chemotherapy population respectively. Epoetin users decreased to 13% for 2004-2006 and declined further to 3.4% by 2010. Darbepoetin administration increased to 43.5% in 2005 among cancer patients receiving chemotherapy and decreased to 7.1% among chemotherapy patients by 2010. Among chemotherapy patients who received epoetin, VTE rates were 8% in 2002 and 3% in 2010 (p<0.05). In contrast, among darbepoetin-treated cancer patients, VTE rates were 5.5% in 2002 and 5.1% in 2010. For transfusions among epoetin-treated cancer patients, transfusion rates were between 5% and 7% in the years 2002- 2008, and then increased to 13% in 2009 and 2010. In contrast, among cancer patients who received darbepoetin, transfusion rates were 7% in the years 2002- 2009 and 9% in 2009. For VTEs, logistic regression indicated that epoetin users had a 60% reduction in VTE odds after the black box warning was disseminated in 2007 and darbepoetin users' had a 35% reduction (p<.05). For transfusions, epoetin users had a 158% increase in odds of receiving a transfusion after the black box warning was added in 2007 and darbepoetin users had a 74% increase after the Black Box warning (p<.05). There is also a marked change in per-cycle dose administration for darbepoetin, but not for epoetin users. While darbepoetin treated cancer patients received a significantly higher monthly, epoetin patients received a lower monthly dose after the black box was disseminated, dose (table).Conclusion: Among cancer patients with chemotherapy-associated anemia who received ESAs between 2002 and 2010, darbepeotin users exhibited a decrease in utilization, little to no response in VTEs or transfusion risks, and marked increases in per cycle and per month dosing. In contrast, epoetin users showed decreased utilization, decreased per-cycle and per-month dosing, decreased VTE rates, and increased transfusion rates. The Black Box warning appears to have had differential effects on epoetin- versus darbepoetin-treated cancer patients with chemotherapy associated anemia.Table 1EpoetinDarbepoetin200220072010200320072010Utilization38%9%3%33%35%7%Transfusions2%6%12%4%7%6%VTEs8%4%3%6%7%5%Mean Total Monthly Dose110,026 IU95,507 IU99,625 IU328mcg403mcg452mcgDifferences between epoetin and darbeoetin patients from 2002-2010 DisclosuresNo relevant conflicts of interest to declare.

Trends in haemoglobin, erythropoietin-stimulating agents and iron use in Swedish chronic kidney disease patients between 2008 and 2013.

The guidelines for anaemia management in chronic kidney disease (CKD) patients have changed substantially during the past 10 years. We here evaluate whether these changes are followed by subsequent modifications in physicians' anaemia management in Sweden. We included patients incident to the Swedish Renal Registry for CKD non-dialysis (CKD-ND, referred patients with an estimated glomerular filtration rate <45 mL/min/1.73 m(2)) and haemodialysis (HD) between 2008 and 2013. Time trends in anaemia management were investigated in relation to prescribed medication, laboratory measures and other relevant clinical characteristics. Linear and binominal regression models were used to describe trends across three predefined time periods (2008-09, 2010-11 and 2012-13). Erythropoiesis-stimulating agents (ESAs) use decreased over time among both CKD-ND and HD patients [risk ratio (RR) 2012-13 compared with 2008-09 for CKD-ND 0.88, 95% confidence interval (CI) 0.81-0.96; RR for HD 0.95, 95% CI 0.93-0.97]. Mean ESA dose decreased significantly among HD patients (7% in 2010-11 compared with 2008-09 and another 3% during 2012-13). Over the time periods studied, ESA doses increased slightly in the CKD-ND population. Mean haemoglobin (Hb) levels decreased in CKD-ND patients, among both ESA users and non-users, whereas it decreased to a lesser degree, albeit significantly, among HD ESA users. The risk of having an Hb >120 g/L decreased, especially between 2008-09 and 2010-11. Iron use increased over time, mainly in the HD population, but also among CKD-ND ESA non-users. Changes in guidelines have influenced the clinical anaemia practice of Swedish nephrology care, resulting in lower ESA use and lower Hb levels.