Achieved Hb Levels Research Articles

Efficacy and safety of thalidomide in patients with β-thalassemia intermedia and major.

To investigate the short-term and long-term efficacy and safety of thalidomide in the treatment of intermediate and severe β-thalassemia. We analyzed patients with intermediate and severe β-thalassemia treated at our hospital from February 2019 to February 2024. Patients who received treatment for more than 3 months were included. The efficacy of thalidomide was assessed by comparing changes in hemoglobin (Hb), ferritin, bilirubin, and Hb electrophoresis before and after treatment. Adverse drug reactions during treatment were also recorded. A total of 42 β-thalassemia patients were included, with thalidomide dosages ranging from 75 to 150 mg/d. The response rates at 1, 3, and 6 months of treatment were 73.8% (31/42), 75.0% (24/32), and 94.7% (18/19), respectively. The increase in Hb levels was primarily attributed to fetal hemoglobin (HbF). After 1 month of treatment, the HbF percentage increased from a baseline of 34.04 ± 27.58% to 56.25 ± 28.40% (P < .001). At 3 and 6 months, HbF further increased to 67.21 ± 27.12% (P < .001) and 73.93 ± 22.96% (P < .001), respectively. The average duration of thalidomide treatment was 25.3 ± 9.2 months (range: 4-60 months), with 6 patients treated for over 60 months and 18 patients for over 48 months. Two homozygous patients who failed thalidomide treatment achieved Hb levels above 100 g/L and discontinued transfusion therapy after 3 months of hydroxyurea treatment. The most common adverse reaction was somnolence, which was mild and tolerable. Thalidomide demonstrates significant and sustained therapeutic effects in β-thalassemia patients. The adverse reactions are mild and tolerable, allowing patients to continue treatment.

MO540CARDIOVASCULAR OUTCOMES ASSOCIATED WITH ACHIEVED HAEMOGLOBIN LEVEL IN POOLED PHASE 3 STUDIES OF ROXADUSTAT IN NON-DIALYSIS-DEPENDENT PATIENTS WITH ANAEMIA

Abstract Background and Aims Randomised clinical trials evaluating anaemia correction using erythropoietin-stimulating agents (ESAs) in chronic kidney disease (CKD) patients have demonstrated an association between ESA use and increased risk of cardiovascular (CV) complications and mortality. Although the mechanism for this increased risk remains unclear, possibilities include rapid rates of rise (ROR) in haemoglobin (Hb), exposure to high ESA dose and dose escalation, a high Hb target range, and off-target effects of ESAs. Thus, current recommendations generally state that Hb levels should be maintained between 10 and 12 g/dL. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), is used for the treatment of anaemia of CKD; roxadustat stimulates endogenous production of erythropoietin and enhances iron availability, thereby supporting red blood cell production. In this pooled analysis, we explored the relationship between 1) achieved Hb levels and 2) preliminary data for ROR of Hb and subsequent incidence rates of CV events in non–dialysis-dependent (NDD) CKD patients who received roxadustat. Method We analysed pooled data from four phase 3 studies in NDD patients (placebo-controlled: ALPS, ANDES, OLYMPUS; ESA-controlled: DOLOMITES) with anaemia of CKD who received any dose of roxadustat. The reported events occurred during the treatment period and within 7 days of the last dose of roxadustat. Incidence rates of adjudicated major adverse CV events (MACE: all-cause mortality [ACM], myocardial infarction, and stroke), MACE+ (MACE plus heart failure and unstable angina requiring hospitalisation), and ACM were examined relative to 1) most recent Hb level before the event and 2) the preliminary data for ROR of Hb within the 4 weeks of treatment immediately prior to the event. Results Overall, 2709 patients were randomised and received roxadustat. Incidence rates of MACE, MACE+, and ACM were 3- or 4-fold higher in patients with lower reported Hb levels (Hb &amp;lt;10 g/L) compared with those who achieved Hb ≥10 g/dL. Incidence rates of MACE, MACE+, and ACM were similar or lower in patients with a maximum rise of &amp;gt;2 g/dL in Hb within the 4-week period prior to the event compared to those with a change of ≤2 g/dL within the same period (Table). However, it should be noted that patient-exposure years (PEY) were low for the subgroup of patients with ROR &amp;gt;2 g/dL (∼3.3% of overall PEY), and patients with a decreasing Hb were included in the ≤2 g/dL/4 weeks subgroup. Conclusion In this analysis of roxadustat-treated patients with NDD CKD, incidence rates of MACE, MACE+, and ACM were lower in patients who achieved target Hb levels of 10-12 g/dL compared with patients who achieved Hb &amp;lt;10 g/dL. Risk of MACE, MACE+, or ACM did not appear to be associated with the proximal preliminary data for ROR of Hb; however, further characterisation of the ROR of Hb and ROR in relation to baseline Hb are warranted.

POS-258 CARDIOVASCULAR OUTCOMES AND EXPLORATORY ANALYSES BY ACHIEVED HB LEVELS IN THE POOLED PHASE 3 ROXADUSTAT STUDIES OF NON-DIALYSIS-DEPENDENT PATIENTS WITH ANEMIA OF CHRONIC KIDNEY DISEASE

Increasing severity of anemia among patients with non-dialysis dependent (NDD) chronic kidney disease (CKD) is associated with decreased survival (Levin et al. Nephrol Dial Trans. 2006). Previous studies (NHCT, CHOIR, CREATE and TREAT) showed that ESA treatment to high Hb targets could increase mortality and cardiovascular (CV) events (Besarab et al. N Engl J Med. 1998; Singh et al. N Engl J Med. 2006; Drüeke et al. N Engl J Med. 2006; Pfeffer et al. N Engl J Med. 2009). In secondary analyses, this increased risk was associated with higher ESA doses rather than achieved Hb levels (Szczech et al. Kidney Int 2008). Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates a coordinated erythropoietic response by increasing endogenous EPO production, decreasing hepcidin, and increasing iron availability. We examined the associations between achieved Hb levels and CV outcomes in NDD patients with anemia of CKD treated with roxadustat. Pooled data from three pivotal, phase 3, randomized, double-blind, placebo-controlled studies of roxadustat for the treatment of anemia in patients with NDD-CKD were assessed. Primary efficacy endpoint for the US FDA submission was the mean change from baseline in Hb averaged over Weeks 28 to 52, regardless of rescue therapy, in all three pivotal studies. Key CV safety endpoints included time to first major adverse CV event (MACE, consisting of death, MI, and stroke) and time to first MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization); these adjudicated CV events were evaluated based on ITT analysis. Exploratory analyses included incidence rates of adjudicated MACE and MACE+ among patients randomized to roxadustat, evaluated based on 1) Hb level immediately before the event and 2) maximum Hb level in the first 12 treatment weeks (during the period of anemia correction). For this analysis, events occurring within 12 weeks following randomization were excluded. Hb level immediately before the event was defined as the most recent Hb value occurring prior to the event. The ITT population included 4277 patients with NDD-CKD (2391 roxadustat, 1886 placebo). Mean baseline Hb was 9.10 g/dL in both treatment groups. Mean (SD) changes in Hb from baseline averaged over Weeks 28–52, regardless of rescue therapy, were +1.85 (0.94) and +0.13 (1.01) g/dL in the pooled roxadustat and placebo groups (least squares mean [LSM] treatment difference: 1.72 [95% CI: 1.65, 1.79; P<0.001]); results for the individual studies were similar to the pooled data. The HR for time to MACE was 1.08 (95% CI 0.94, 1.24) for roxadustat vs. placebo and 1.04 (95% CI 0.91, 1.18) for MACE+. In the roxadustat-treated patients, the MACE and MACE+ rates were highest when Hb was <8 g/dL and decreasing as Hb increased to ≥10 g/dL, which includes categories of Hb levels 10–<11, 11–<12, and ≥12 g/dL (Table). In the NDD-CKD population, roxadustat corrected anemia and generally maintained Hb to 11±1 g/dL during weeks 28-52. Risk of MACE and MACE+ in patients treated with roxadustat were comparable to placebo in NDD patients. MACE and MACE+ incidence rates were lowest when achieved Hb levels were ≥10 g/dL.

POS-284 CARDIOVASCULAR OUTCOMES AND EXPLORATORY ANALYSES BY ACHIEVED HB LEVELS IN POOLED PHASE 3 TRIALS OF ROXADUSTAT IN DIALYSIS-DEPENDENT PATIENTS WITH ANEMIA OF CHRONIC KIDNEY DISEASE

Lower hemoglobin (Hb) in patients on dialysis is associated with increased risk of hospitalization and mortality (Lacson et al. Am J Kidney Dis. 2009). Previous studies (NHCT, CHOIR, CREATE and TREAT) showed that ESA treatment to high Hb targets could increase mortality and cardiovascular (CV) events (Besarab et al. NEJM 1998; Singh et al. NEJM 2006; Drüeke et al. NEJM. 2006; Pfeffer et al. NEJM 2009). In secondary analyses, this increased risk was associated with higher ESA doses rather than achieved Hb levels (Szczech et al. Kidney Int 2008). Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates a coordinated erythropoietic response by increasing endogenous EPO production, decreasing hepcidin and increasing iron availability. We examined the associations between achieved Hb levels and CV outcomes in patients with anemia of dialysis-dependent (DD) chronic kidney disease (CKD) treated with roxadustat. Pooled data from three pivotal, phase 3, randomized, open-label, epoetin alfa–controlled studies of roxadustat for the treatment of anemia in patients with DD-CKD were assessed. Patients requiring dialysis and anemia treatment were 1:1 randomized to receive roxadustat or epoetin alfa. Primary efficacy endpoint for the US FDA submission was the mean change from baseline in Hb averaged over Weeks 28-52, regardless of rescue therapy, in all three pivotal studies. Key CV safety endpoints included time to first major adverse CV event (MACE, consisting of death, MI, and stroke) and time to first MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization); these adjudicated CV events were evaluated for the treatment period and within 7 days of the last dose of study medication (OT+7). Exploratory analyses included incidence rates of MACE and MACE+ among patients randomized to roxadustat, evaluated based on 1) Hb level immediately before the event, defined as the most recent central laboratory Hb value that preceded the onset of the event, and 2) maximum Hb level in the first 12 treatment weeks. For this analysis, events occurring within 12 weeks following randomization were excluded. The ITT population included 3890 patients (1943 roxadustat and 1947 epoetin alfa). Mean baseline Hb was 9.6-9.7 g/dL. Mean (SD) changes in Hb from baseline averaged over Weeks 28–52, regardless of rescue therapy, were 1.22 (1.49) and 0.99 (1.51) g/dL in the roxadustat and epoetin alfa groups, respectively (least squares mean treatment difference: 0.26 [95% CI: 0.20, 0.33; P<0.0001]). Comparing roxadustat with epoetin alfa, HR for MACE was 0.96 (95% CI 0.82, 1.13) & MACE+ HR was 0.86 (0.74, 0.98; P=0.028) in the pooled population. In roxadustat-treated patients, the MACE and MACE+ rates were highest when Hb was <8 g/dL, decreasing as Hb increased to ≥10 g/dL, which includes categories of Hb levels 10–<11, 11-<12, and ≥12 g/dL (Table). In the DD-CKD population, roxadustat generally maintained Hb to 11±1 g/dL during weeks 28-52. Risk of MACE in roxadustat-treated patients was not increased compared to epoetin alfa. Furthermore, roxadustat lowered the risk of MACE+ compared to epoetin alfa. In roxadustat-treated patients, MACE and MACE+ incidence rates were lowest when achieved Hb levels were ≥10 g/dL.

Physical health-related quality of life at higher achieved hemoglobin levels among chronic kidney disease patients: a systematic review and meta-analysis

BackgroundThe impact of anemia treatment with erythropoietin stimulating agents (ESA) on health-related quality of life (HRQOL) in chronic kidney disease (CKD) patients is controversial, particularly regarding optimal hemoglobin (Hb) target ranges.MethodsWe conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCT) with ESA to estimate the effect of different achieved Hb values on physical HRQOL and functionality. We searched PubMed, EMBASE, CENTRAL, PEDro, PsycINFO and Web of Science databases, until May 2020. Two authors independently extracted data from studies. We included observational and RCTs that enrolled CKD patients undergoing anemia treatment with ESA with different achieved Hb levels among groups. We excluded studies with achieved Hb < 9 g/dL. For the meta-analysis, we included RCTs with control groups achieving Hb 10–11.5 g/dL and active groups with Hb > 11.5 g/dL. We analyzed the standardized mean difference (SMD) between groups for physical HRQOL.ResultsAmong 8496 studies, fifteen RCTs and five observational studies were included for the systematic review. We performed the meta-analysis in a subset of eleven eligible RCTs. For physical role and physical function, SMDs were 0.0875 [95% CI: − 0.0025 – 0.178] and 0.08 [95% CI: − 0.03 – 0.19], respectively. For fatigue, SMD was 0.16 [95% CI: 0.09–0.24]. Subgroup analysis showed that trials with greater achieved Hb had greater pooled effects sizes — 0.21 [95% CI: 0.07–0.36] for Hb > 13 g/dL vs. 0.09 [95% CI: 0.02–0.16] for Hb 11.5–13 g/dL. Proportion of older and long-term diabetic patients across studies were associated with lower effect sizes.ConclusionAchieved hemoglobin higher than currently recommended targets may be associated with small but potentially clinically significant improvement in fatigue, but not in physical role or physical function. Younger and non-diabetic patients may experience more pronounced benefits of higher Hb levels after treatment with ESAs.

SUN-095 INTERNATIONAL VARIATION IN CLINIC HEMOGLOBIN TARGETS AND ACHIEVED HEMOGLOBIN LEVELS IN ADVANCED CKD: RESULTS FROM THE CKD OUTCOMES AND PRACTICE PATTERNS STUDY (CKDOPPS)

Uncertainties regarding the ideal target for hemoglobin (Hb) and difficulties in the management in chronic kidney disease (CKD) patients may lead to variations in anemia practice patterns. Using data from CKDOPPS clinics in Brazil (BR), Germany (GE), and the United States (US) (2013-2018), we describe clinic-level targets for Hb and their associations with achieved Hb levels in patients with advanced CKD receiving anemia treatment. CKDOPPS is an international prospective cohort study of stage 3-5 non-dialysis CKD patients from national samples of nephrology clinics. Patients with eGFR <30ml/min/1.73m2 at study enrollment were included in this analysis. Clinic-level Hb upper and lower targets were collected from nephrologist surveys and averaged if multiple nephrologists in a clinic responded to the survey. Baseline anemia treatment status of individual patients was defined based on their use of either erythropoietin stimulating agents, intravenous or oral iron IV. We collected data within +/- 3 months from study enrollment, and observed values of Hb obtained using the average of available measurements within 3-15 months after the enrolment in patients treated for anemia. A total of 44 clinics reported Hb targets: BR (12), GE (15), US (17). We observed variations in the lower limits of Hb targets across countries: 91% of Brazilian facilities established 10+ g/dL as the lower cutoff, whereas around 40% of facilities in the US and Germany had <9.5g/dL. Upper limits were typically established at 12g/dL across all facilities (Figure: a). The mean Hb in clinics with 10+ lower Hb targets were 10.7, 11 and 11.5 g/dL in the US, Brazil and Germany, respectively. Patients from clinics reporting higher Hb lower-limits (Hb>10g/dL) had higher Hb levels in response to anemia treatment across countries (Figure: b). We observed variation in lower limits of Hb targets across CKDOPPS clinics. Since patients treated in facilities across countries with higher Hb lower-limit targets displayed higher Hb levels, target Hb appeared to be positively associated with anemia control.

De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease.

Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naïve patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. One-hundred sixteen pediatric ESA-naïve subjects (aged 1-18years) with CKD stages 3-5D and hemoglobin (Hb) <10g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0g/dl over 25weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQL™) in children ≥2years. In both groups, mean Hb concentrations increased to ≥11.0g/dl over the first 3months of treatment and remained stable within the 10.0-12.0g/dl target range. The median time to achieve hemoglobin ≥10g/dl was slightly longer for subjects <12years (QW and Q2W, both 28days) vs. those ≥12years (23 and 22days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQL™ scores showed modest increases. Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naïve pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0g/dl.

Effect of anemia correction to the modestly high hemoglobin level in patients with chronic kidney disease on left ventricular hypertrophy

Background and purposeTo assess effects of long-term anemia management on left ventricular hypertrophy in patients with chronic kidney disease (CKD) not on dialysis, we performed secondary outcome analyses of a randomized controlled study that evaluated effects of anemia management with erythropoiesis stimulating agents in this population. Methods and subjectsSubjects [hemoglobin (Hb)<10.0g/dL, 2.0≤serum creatinine<6.0mg/dL] were randomized either to high Hb (11.0≤target Hb≤13.0g/dL with darbepoetin alfa), or to low Hb group (9.0≤target Hb≤11.0g/dL with recombinant human erythropoietin), and followed up to 48 weeks. Data from echocardiographic evaluation and values of neurohumoral factors associated with heart failure were assessed in subjects whose data were evaluable both at the baseline and at the end point. ResultsThe high Hb group achieved target range Hb levels (12.1±1.1g/dL, at 32 weeks, N=111), which was significantly higher (p<0.001) than the low Hb group (N=95). Though blood pressure and renal function changes were similar between the groups, left ventricular diastolic dimension was significantly decreased only in the high Hb group (p<0.001), and the change in left ventricular mass index (LVMI) correlated coarsely but significantly with the achieved Hb levels (r=0.147, p=0.032). The higher Hb levels were associated with greater reduction in LVMI and left ventricular wall thickness, and the lower Hb levels with the greater increase in human arterial- or brain natriuretic polypeptide levels. ConclusionsAnemia correction targeting modestly higher Hb levels better preserves cardiac function in CKD patients not on dialysis.

Changes in erythropoiesis-stimulating agent (ESA) dosing and haemoglobin levels in US non-dialysis chronic kidney disease patients between 2005 and 2009

Recent clinical trials in cancer patients treated with erythropoiesis-stimulating agents (ESAs) and in CKD patients treated to haemoglobin (Hb) targets above the labeled range of 10-12 g/dL with ESAs raised safety concerns regarding ESA therapy. Subsequently, product labeling was revised including addition of a black-box warning and removal of many quality of life claims not supported by current standards, and there were changes in reimbursement and anaemia guidelines. The extent to which these events influenced ESA dosing and Hb levels in patients with chronic kidney disease not on dialysis (CKD-NOD) is not known. We used data collected in a series of cross-sectional surveys between March 2005 and July 2009. Patients with CKD-NOD were selected from a random sample of free-standing US nephrology clinics. Information on demographics, insurance information, laboratory data and ESA use was abstracted from medical records by site investigators. We evaluated ESA treatment (use and dosing) and Hb levels over time and used multivariate linear regression to assess changes in ESA doses and Hb levels over time adjusting for case-mix differences. Between 2005 and 2009, 15 836 CKD-NOD patients were sampled. During this period, ESA use declined from 60 to 46%, and the mean dose declined from 176 to 136 mcg/month; the largest decline in use and in dose occurred beginning in 2007. Simultaneously, the mean (standard deviation) Hb level in ESA-treated patients declined from 11.5 (1.4) to 10.6 (1.2) g/dL, though the decline was most pronounced starting in 2007. As the mean Hb declined, the percent of treated patients with an Hb > 12 g/dL dropped from 27 to 12%, and the mean dose in this sub-population declined from 173 to 111 mcg/month. The emergence of safety concerns and the subsequent changes in product labeling, reimbursement and clinical practice guidelines all appear to have influenced physician dosing practices resulting in less frequent use of ESAs, lower ESA doses and lower achieved Hb levels in CKD-NOD patients.

慢性腎臓病 (CKD) における腎性貧血管理の現況

Patients with chronic kidney disease (CKD) are frequently complicated by renal anemia as renal function declines. However, clinical guidelines on erythrocyte stimulating agents (erythropoietin : EPO) for such patients have not been established. Current clinical practice for EPO administration is based on the recommendations of the Japanese health insurance regulations, which have not always been supported by clinical evidence. The study subjects were 49 patients with CKD staged above 3 who had developed renal anemia requiring EPO. These patients were treated with EPO S. C. at the dose of 6,000 IU/week together with iron supplementation as deemed necessary for more than 24 weeks. The hemoglobin (Hb) value was 9.2 +/- 1.0 g/dL at the start, 10.9 +/- 1.6 g/dL at the peak (n = 49, p < 0.001 the start vs. the peak), and 9.0 +/- 1.6 g/dL at the commencement of dialysis (n = 49, p < 0.001 the peak vs. the commencement of dialysis). Seventy-one percent (35/49) of the patients achieved Hb levels over 10 g/dL, and 51% (25/49) achieved Hb levels over 11 g/dL. Conversely, 28% (14/49) of the patients failed to reach an Hb level over 10 g/dL. Factors explaining the good response to EPO (good responders were defined as those achieving Hb levels over 11 g/dL) had shown high Hb levels at the start (Logistic multiple regression analysis, p = 0.03) along with low creatinine concentration at the start (Cox's proportional hazard models, p = 0.015). Transferrin saturation (TSAT) at the start was 33.6 +/- 13.6%, 34.0 +/- 19.9% at the peak, and 24.7 +/- 11.6% at the commencement of dialysis, showing a significant reduction in TSAT at the commencement of dialysis compared to that at the start (n = 49, p = 0.0383, the start vs. the commencement of dialysis). Serum ferritin concentration was 140.7 +/- 139.5 pg/mL at the start, 107.9 +/- 110.8 pg/mL at the peak, and 131.9 +/- 112.4 pg/mL at the commencement of dialysis, indicating an absence of significant differences among the three time points. The current health insurance regulations in Japan seem to be inappropriate in that the permitted EPO dosage of 6,000 IU/week might not be sufficient to achieve the target Hb level of more than 11 g/dL in most patients with CKD. To more efficiently achieve renoprotection, both early and timely initiation of EPO and reconsideration of the recommended EPO dosage appear to be warranted.

Blood and Resource Utilization in Cancer Patients with Chemotherapy-Induced Anemia (CIA) in the Pre- and Post-National Coverage Determination (NCD) Timeframes: Results From An Electronic Medical Record Study.

Abstract 2472Poster Board II-449 Background:The Centers for Medicare & Medicaid Services issued erythropoiesis-stimulating agent (ESA) coverage limitations for cancer patients with CIA in July 2007 restricting ESA administration to those with hemoglobin (Hb) less than 10 g/dL and contingent on specific achieved Hb levels. Data assessing CIA patients regardless of ESA treatment pre- and post-NCD are scarce. This study evaluated Pre- and Post-NCD data in patients with CIA from a single oncology clinic in the northeastern United States to understand anemia treatment patterns, hematologic outcomes, and resource utilization. The oncology clinic, which is a part of a multi-specialty capitated integrated medical group, implemented the ESA NCD policy in September 2007. Methods:Medical, laboratory, and administrative claims data between 1/2005 and 4/2008 were retrospectively analyzed. Assessed patients had a diagnosis of malignant cancer (ICD-9-CM 140.XX-208.xx), received chemotherapy, and were anemic (Hb < 11 g/dL) during the chemotherapy treatment period. Patients diagnosed with myelodysplasia, acute leukemia, or chronic kidney disease who received dialysis, and those enrolled in ESA clinical trials were excluded. Data were categorized and analyzed in two time frames (Pre-NCD: 07/06-05/07, Post-NCD: 09/07-04/08). Baseline characteristics, ESA treatment patterns, hematologic outcomes (transfusion and available Hb levels), and resource utilization were assessed during the 20 week observation period following the index date of Hb < 11 g/dL. Results:359 patients were identified (241 Pre-NCD; 118 Post-NCD). Baseline age, gender, race, weight, height, and distribution of tumor type were similar between groups. In the Post-NCD group, a significantly higher proportion of patients had comorbidities of congestive heart failure, coronary artery disease, and chronic obstructive pulmonary disease. The Post-NCD group had a significantly lower proportion of patients treated with ESAs (Pre-NCD 64%, Post-NCD 47%, p=0.0023). Among patients on ESA therapy (≥ 2 ESA injections), there was a trend toward shorter duration of ESA treatment in the Post-NCD arm [mean (SD): Pre-NCD 57.9 days (39.1), Post-NCD 47.3 days (38.1), p=0.08]. As noted in the table below, transfusion-independent Hb levels were lower in the Post-NCD group at baseline, Week 8, and Week 12. The proportion of patients transfused and blood utilization were similar in the Pre- and Post-NCD groups. The average number of oncology/hematology visits per patient was lower in the Post-NCD group [mean (SD): Pre-NCD 8.8 (5.9), Post-NCD 7.4 (6.5), p=0.01], however, a significantly higher proportion of patients in the Post-NCD period had a hospital admission (Pre-NCD 37.8%, Post-NCD 50.8%, p=0.02) or an emergency room (ER) visit (Pre-NCD 44.8%, Post-NCD 55.9%, p=0.048).Mean Hemoglobin, g/dL (SD)Pre-NCDPost-NCDp-valueBaselinen=24110.3 (0.07)n=11810.2 (0.63)0.0353Week 4n=16610.8 (1.17)n=7310.8 (1.18)0.8191Week 8n=15111.3 (1.39)n=5910.8 (1.39)0.039Week 12n=12811.6 (1.45)n=5410.9 (1.22)0.0067Week 16n=12711.5 (1.35)n=5111.4 (1.21)0.4523Week 20n=5911.6 (1.16)n=2511.5 (1.19)0.6279 Conclusion:Data from this single center observational study reported a lower proportion of patients initiated on ESAs, similar blood utilization, and an increased proportion of patients with hospitalization and ER visits in CIA patients with Hb < 11 g/dL in the Post-NCD as compared to the Pre-NCD time period. Further study assessing the impact of CIA NCD policy on healthcare resource utilization in multiple clinical centers is warranted. Disclosures:Burton:Centocor Ortho Biotech Services, LLC: Consultancy, Research Funding. Boulanger:Centocor Ortho Biotech Services, LLC: Consultancy, Research Funding. Larholt:Centocor Ortho Biotech Services, LLC: Consultancy, Research Funding. Pashos:Centocor Ortho Biotech Services, LLC: Consultancy, Research Funding. McKenzie:Centocor Ortho Biotech Services, LLC: Employment. Senbetta:Centocor Ortho Biotech Services, LLC: Employment. Lopez:Centocor Ortho Biotech Services, LLC: Employment. Sundaresan:Centocor Ortho Biotech Services, LLC: Consultancy. Preusse:Centocor Ortho Biotech Services, LLC: Consultancy. Seidler:Centocor Ortho Biotech Services, LLC: Consultancy.

Every-Other-Week Darbepoetin Alfa in the Correction and Maintenance of Haemoglobin Levels in Elderly Patients with Chronic Kidney Disease

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with increased rates of mortality and diminished quality of life in patients with CKD. Although extended dosing with darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), has been shown to be effective in maintaining haemoglobin (Hb) levels in CKD patients, little information is published on the use of darbepoetin alfa in the correction and maintenance of Hb levels in elderly CKD patients naive to ESA therapy. This post hoc subanalysis of data from two clinical trials was conducted to investigate the efficacy and safety profile of de novo every-other-week (q2w) darbepoetin alfa in elderly patients with CKD-associated anaemia (not on dialysis), as compared with that of a younger (aged <65 years) patient cohort. This analysis was based on data obtained from two open-label, single-arm, multicentre studies of similar design. Patients were aged >or=18 years and naive to previous ESA therapy. Darbepoetin alfa administration was initiated at 0.75 microg/kg and titrated according to individual patient requirements to achieve and maintain Hb levels between 11.0 and 13.0 g/dL. The proportion of patients who achieved the primary endpoint, Hb >or=11.0 g/dL (study 1), and an Hb level between 11.0 and 13.0 g/dL (study 2) at weeks 4, 8 and 12 weeks and at the end of the study were determined. The results of this subanalysis were stratified by age (<65, 65-74 and >or=75 years). A total of 203 patients were enrolled in the two studies; 60% were female, 84 (41%) were aged <65 years, 57 (28%) were aged 65-74 years and 62 (31%) were aged >or=75 years. The proportion of patients who achieved Hb levels of >or=11.0 g/dL in study 1 and 11.0-13.0 g/dL in study 2 at week 20 were 93%, 96% and 92%, respectively, for the three age groups. Weight-adjusted q2w darbepoetin alfa doses were similar between the age groups and stable throughout the study period. The mean (standard deviation) Hb levels at week 21 were 12.0 (1.2), 12.7 (1.1) and 12.6 (1.0) g/dL in subjects aged <65, 65-74 and >or=75 years, respectively. The median (standard error) time to reach the primary endpoint was 5.0 (4.7), 5.0 (5.7) and 5.0 (5.7) weeks for subjects aged <65 years, 65-74 years and >or=75 years, respectively. The safety profiles of q2w darbepoetin alfa in both the older and younger age-groups were consistent with those expected for patients with CKD not receiving dialysis. The results of this study suggest that ESA-naive subjects aged <65, 65-74 and >or=75 years of age with CKD (not receiving dialysis) who received q2w darbepoetin alfa were able to achieve and maintain Hb levels at 11.0-13.0 g/dL. The de novo q2w treatment regimen with darbepoetin alfa described in the present report may help optimize anaemia management in CKD-associated anaemia patients, including those in the older adult population.

Effect of epoetin zeta for correction of renal anemia in hemodialysis patients with thalassemia minor

Two patients with thalassemia minor and end-stage renal failure on hemodialysis were treated with epoetin zeta (Silapo, Retacrit; STADA, Germany), a medicinal product that was developed and registered as biosimilar to epoetin alfa. Dosing was titrated individually for two patients to achieve a stable hemoglobin (Hb) concentration of 10.5-12.0 g/dL. One patient was treated intravenously with epoetin zeta; the other patient was treated subcutaneously. After 12 weeks of therapy both patients achieved Hb levels within the target range, confirming the effi cacy of epoetin zeta in patients with thalassemia minor.

Transfusion outcomes in erythropoiesis-stimulating agent (ESA)-treated cancer chemotherapy patients based on achieved hemoglobin (Hb) levels

6637 Background: Recently, Medicare ESA coverage policy has been changed mandating ESA administration be limited to specific achieved Hb levels. To assess the clinical implications of these changes in ESA coverage policy, data from an ongoing ESA registry were evaluated. Methods: Observational data from an ongoing, prospective registry of ESA-treated patients in 55 US oncology clinics between 12/03–11/07 were analyzed. Hospital- and community-based outpatient practices were included. Data were analyzed from adult chemotherapy-treated oncology patients with ≥2 ESA doses and Hb level <10g/dL prior to ESA administration. Transfusion-related outcomes were categorized into three cohorts based on mean Hb values achieved during ESA treatment: 9.1–10, 10.1–11, or 11.1–12g/dL. Results: 330 patients met inclusion criteria with 36%, 45%, and 19% categorized into mean achieved Hb levels of 9.1–10, 10.1–11, and 11.1–12g/dL, respectively. Patients with lower mean achieved Hb levels were associated with greater transfusion requirements, including a higher proportion of patients requiring transfusion and higher blood utilization based on units/study patient (Table). Logistic regression analysis suggested that as the mean hemoglobin achieved increases, the risk of transfusion decreases (Odds Ratio= 0.580, 95% CI 0.401, 0.839). Conclusion: Lower mean achieved Hb level during ESA treatment was associated with increased transfusion requirements in cancer chemotherapy patients. Such findings are informative to decision-makers on the transfusion implications of limiting ESA coverage to defined Hb levels. Hb Cohort 9.1–10 g/dL (n=118) 10.1–11 g/dL(n=149) 11.1–12 g/dL (n=63) Mean (SD) Hb achieved, g/dL 9.6 (0.24) 10.5 (0.27) 11.4 (0.28) % Patients Transfused 39% 23% 19% Mean (SD) units/study patient 1.3 (2.2) 0.6 (1.2) 0.5 (1.1) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ortho Biotech Ortho Biotech Ortho Biotech

Model Predictive Control of Erythropoietin Administration in the Anemia of ESRD

Variable hemoglobin (Hb) response to erythropoiesis-stimulating agents (ESAs) may result in adverse outcomes. New methods are needed to determine the appropriate dose of ESA to maintain the target Hb level. (1) Observational study to develop an algorithm for model predictive control (MPC) by using an artificial neural network model of Hb response to ESA. (2) Computer simulation to test MPC versus a conventional anemia management protocol (AMP). (3) Clinical trial to test MPC. The MPC was developed from historic data from 186 long-term hemodialysis patients at the University of Louisville, KY. Testing by simulation occurred in 60 hypothetical patients generated from random sampling of the 186 patients. The trial included 9 hemodialysis patients who received ESA doses based on MPC recommendations over 6 months. Management by means of MPC or AMP. OUTCOME OF INTEREST: Achieved Hb level and variability measured by means of the difference between achieved Hb level and target Hb level of 11.5 g/dL and erythropoietin dose. In the trial, Hb level deviation from target was compared in the same subjects between the study (last 4 of 6 months on MPC) and control (4 months on AMP immediately proceeding the study period) periods. In simulation, achieved Hb levels were 12.3 +/- 0.6 g/dL for AMP and 11.6 +/- 0.4 g/dL for MPC (P < 0.001), mean SDs were 0.75 +/- 0.30 g/dL for AMP and 0.60 +/- 0.21 g/dL for MPC (P < 0.01), and mean absolute differences from target were 0.8 +/- 0.6 g/dL for AMP and 0.3 +/- 0.3 g/dL for MPC (P < 0.001). In the trial, achieved Hb levels were 11.9 +/- 1.1 g/dL for AMP and 11.8 +/- 0.6 g/dL for MPC (P = 0.8), mean SDs were 0.86 +/- 0.60 g/dL for AMP and 0.64 +/- 0.33 g/dL for MPC (P = 0.4), and mean absolute differences from target were 1.19 +/- 0.79 g/dL for AMP and 0.79 +/- 0.50 g/dL for MPC (P = 0.02). MPC of ESAs may result in improved anemia management.

Response: Epoetin Alfa for Treatment of Anemia in HIV-Infected Patients

To the Editor: In Paul Bellman's letter regarding our recent review article,1 he raises an important issue regarding the potential of epoetin alfa to induce thrombotic vascular events (TVEs) and to have an adverse impact on survival. This phenomenon was observed in several studies exploring the investigational use of recombinant human erythropoietin in cancer patients in whom hemoglobin (Hb) levels rose beyond the usual target of 12 g/dL. Epoetin alfa and beta products were both involved. The US Food and Drug Administration (FDA) held an Oncology Drug Advisory Committee (ODAC) meeting on May 4, 2004 to review this issue. Ortho Biotech Products, LP (OBP), along with the manufacturers of other erythropoietin products, worked closely with the FDA to ensure that the product labeling for all erythropoietin products included appropriate information regarding the benefits and risks for patients. Amgen and OBP, distributors of erythropoietin products in the United States, issued letters to health care professionals advising them of the important safety information regarding TVEs and survival.2,3 In addition, to ensure consistency with labeling for other products in the class, changes to Hb rate of rise and target levels were made to the epoetin alfa prescribing information.4 Mention of this issue was not included in our article because the ODAC discussion was ongoing while the manuscript was in press. The dosage and administration of epoetin alfa in HIV-infected patients treated with zidovudine was not affected by the outcome of the ODAC meeting. The product label for HIV-infected patients recommends that treatment be discontinued if Hb exceeds 13 g/dL and resumed only after Hb drops to 12 g/dL. The dose should be reduced by 25% when treatment is resumed and then titrated to maintain the desired Hb level. Dr. Bellman also points out that the dyslipidemia associated with the use of highly active antiretroviral therapy (HAART) could theoretically put HIV patients who are treated with epoetin alfa at greater risk of developing thrombotic complications; however, our review of the literature did not yield any such reports despite the widespread use of epoetin alfa in patients on HAART regimens. Dr. Bellman further states that we have provided recommendations in our article to the effect that epoetin alfa therapy should be used to achieve Hb levels >12 g/dL. In fact, we made no such recommendations. Our intent was to review the medical literature and to report accurately the results of published trials that have furthered our understanding of anemia in the HIV population and the role of epoetin alfa therapy. Dr. Bellman may have misinterpreted the definitions of anemia used in epidemiologic studies as guidance for the management of patients in his practice. The reference that he cites describing the safety of epoetin alfa in HIV-infected patients refers to a report of 4 placebo-controlled trials. To our knowledge, this report represents the only published placebo-controlled trials of epoetin alfa in HIV patients. Subsequent trials of epoetin alfa examining different dosing strategies have confirmed that the adverse event profile of epoetin alfa is generally consistent with those described in the prescribing information.5,6 Dr. Bellman is correct in his observation that speculation regarding future uses of epoetin alfa in the HIV-infected population mentioned in our review was largely supported by data derived from animal models, and this is clearly delineated in the article. We reviewed these data to satisfy the basic science interests of the readers of the Journal of Acquired Immune Deficiency Syndromes and to suggest potential areas for future research. The balance of Dr. Bellman's commentary refers to publications outside the scope of our review. He suggests that the authors have not provided adequate disclosure of their relationships with commercial interests. The authors disagree with Dr. Bellman's opinion and have disclosed any potential conflict. They, furthermore, were not involved in the selection of this article for publication. We can assure Dr. Bellman that our research interests and publications are driven by the desire to optimize the care of our HIV patients. David H. Henry, MD* Paul A. Volberding, MD† Gerhard Leitz, MD, PhD‡ *Pennsylvania Hospital Philadelphia, PA †University of California, San Francisco San Francisco, CA ‡Ortho Biotech Clinical Affairs, LLC Bridgewater, NJ