Change of EPO treatment from subcutaneous epoetin to intravenous epoetin or darbepoetin alpha

This prospective, two-arm, clinical trial assesses the effectiveness in maintaining the levels of haemoglobin (Hb) between 11 and 13 g/d1 and the safety of changing the administration route (from subcutaneous to intravenous) of epoetin (rHuEPO) alpha at equidose versus a changeover to darbepoetin alpha, taking the exact equivalence in peptide mass between the two as referent in patients with chronic renal insufficiency (CRI) in haemodialysis. A total of 112 patients previously treated with epoetin and no dose modification during the 8 weeks prior to the study and stable levels of Hb were included. Of these, 92.1% finished the follow-up period (24 weeks). After changing the administration route of rHuEPO, a significant increase in the resistance index (REI, weekly dose per kilogram of weight/levels of hemoglobin) was observed with mean values of 2.73 (p < 0.018) and 4.37 (p < 0.001) after 16 and 24 weeks respectively, requiring an increase of the dose greater than 15% over the baseline in 6 1.1% of the patients. The changeover to, darbepoetin alpha, independently of the administration route, was accompanied by a decrease in REI starting in the 8th week (mean levels of 0.012, 0.018 and 0.023 after 8, 16 and 24 weeks respectively), significant (p < 0.001) at the 3 cutoff points of the study. The conversion factor increased significantly up to 1:260 in week 24. Both erythropoietic stimulating factors (EST) were well tolerated and no unexpected side effects were observed. In conclusion, treatment of anaemia with darbepoetin alpha in patients with CRI in haemodialysis previously treated with rHuEPO proved to be more effective than the use of epoetin intravenously, significantly improving the resistance index. In addition, the treatment with darbepoetin alpha was well tolerated in these patients.     

Treatment of renal anemia with darbepoetin alfa administered once every other week in predialysis patients with chronic kidney disease and previously treated with epoetin alfa

Darbepoetin alfa is an erythropoiesis-stimulating glycoprotein with up to 3 times longer half-life than recombinant human erythropoietin (rHuEPO) in humans. The aim of this study was to assess the efficacy and safety of darbepoetin alfa given once every other week as treatment of anemia in predialysis patients with chronic renal failure (CRF) previously treated with once-weekly epoetin alfa. A total of 42 CRF patients were included, all of whom had previously been treated with epoetin alfa and showed stable hemoglobin (Hb) levels without dose changes during the last 8 weeks prior to enrolment in this study. All patients received s.c. darbepoetin alfa once every other week at doses calculated from the protein mass equivalence between rHuEPO and darbepoetin alfa. Follow-up lasted for 24 weeks. Dose adjustments were conducted to preserve target Hb levels between 11 and 13 g/dl. Thirty-nine patients completed the 24 weeks of study. Hb levels increased during follow-up [mean values of 0.39 (p < 0.002), 0.58) (p < 0.001), and 0.83 g/dl (p < 0.001) at 8, 16 and 24 weeks, respectively] despite reducing the darbepoetin alfa dose up to 15% at 24 weeks [from 0.192 microg/kg body weight to 0.185, 0.178 and 0.163 at 8, 16, and 24 weeks, respectively (p < 0.001)]. No adverse events related to darbepoetin alfa were reported. In conclusion, these results show s.c. administration of darbepoetin alfa once every other week was superior to weekly epoetin alfa as a maintenance treatment for anemia in predialysis CRF patients, since the former provided higher Hb levels. Moreover, darbepoetin alfa administration was safe in these patients.     

Phase III clinical trials with darbepoetin: implications for clinicians

Anemia occurring in patients with renal failure on dialysis has been shown to both increase transfusion requirements and decrease functional status and quality of life. As a result, treatment of these patients with an erythropoietic agent such as epoetin alfa or darbepoetin alfa has become established as an essential part of optimal patient care. Anemia resulting from cancer or chemotherapy is a common problem in oncology, and has been shown similarly to increase transfusion risk and decrease patient reported outcomes. For reasons that are not clear, but may include either frequently encountered slow response or nonresponse and higher doses and hence higher costs, treatment of anemia in oncology has not become a standard treatment for all patients. Erythropoietic agents (epoetin alfa and darbepoetin alfa) have been used to improve anemia-related fatigue and quality of life in cancer patients. Epoetin is administered 1 to 3 times per week whereas darbepoetin, with up to a 3-fold greater half-life, is given once every 1 or 2 weeks. Recent data demonstrate that darbepoetin can be administered as infrequently as every 3 weeks with comparable erythropoietic efficacy. Several studies have been carried out to determine the optimum schedule of dosing to obtain maximum patient benefit. Following treatment with darbepoetin, antibodies to darbepoetin were not detected, no unusual adverse event was seen with darbepoetin, and the mean increase in hemoglobin remained unchanged when the dosing interval was increased from 1 to 2 weeks. The safety and efficacy of darbepoetin was also determined in patients with solid tumors receiving chemotherapy; the lowest clinically effective dose was determined to be 3.0 and 5.0 microg/kg every 2 weeks with a 66 and 84% response, respectively. No additional benefit was seen with higher doses. A multicenter study evaluated the safety and efficacy of darbepoetin administered either weekly, every 3 weeks, or every 4 weeks in anemic patients with cancer who were not receiving chemotherapy or radiotherapy. The results indicated that with weekly dosing, 70% of patients showed an increase in hemoglobin. The dose of 4.5 microg/kg/week resulted in 100% hematopoietic response. In a randomized, active control, pilot trial, front-loading darbepoetin followed by lower doses or less frequent doses also appears to be efficacious and may decrease the time to response. At the present time, darbepoetin improves anemia, reduces requirements for transfusion, and improves the quality of life for these patients. To compare efficacy of these erythropoietic agents it is important to analyze the data using intent to treat rather than analysis of patients who complete the study. This way a true evaluation of the change of hemoglobin can be assessed corresponding both to dose and an improvement in the QOL.     

Improvement of anemia in hemodialysis patients treated by hemodiafiltration with high-volume on-line-prepared substitution fluid

BACKGROUND: Hemodiafiltration (HDF) is associated with a lower incidence of neuropathy, carpal tunnel syndrome, joint pain, and partial correction of anemia. HDF with on-line-prepared substitution fluid (OL HDF), as compared with conventional hemodialysis, increases the treatment tolerance and, as compared with standard HDF, avoids storage problems and allows a higher substitution volume at low cost. METHODS: Thirty-two hemodialysis patients treated by OL HDF for at least 9 months were studied. Hemoglobin, hematocrit, iron metabolism, serum albumin, dialysis dose and dry body weight were determined under a settled condition with regular hemodialysis 3 months before the transfer to OL HDF. The same parameters were analyzed 3, 6 and 9 months after the beginning of the new treatment modality. RESULTS: During OL HDF, hemoglobin values significantly increased in patients without addition of recombinant human erythropoietin (rHuEPO): baseline vs. 6 months 11 +/- 1.7 vs. 12 +/- 1.8 g/dl (p < 0.01); baseline vs. 9 months 11 +/- 1.7 vs. 12 +/- 1.6 g/dl (p < 0.05). In patients on a maintenance dose of rhuEPO, this could be significantly reduced, while the target hemoglobin levels were maintained (10.6 +/- 0.9 g/dl): baseline 99.8 +/- 50.4 U/kg/week, 3rd month 76.2 +/- 43 U/kg/week, 6th month 64.3 +/- 37 U/kg/week, and 9th month 59.4 +/- 38.6 U/kg/week (p = 0.007, p = 0.0006, and p = 0.0007, respectively, vs. baseline). Iron metabolism, dialysis dose, dry body weight and serum albumin levels did not significantly change during the follow-up period. Further, a stability of the rHuEPO supplementation was observed in 14 patients followed up for 24 months. CONCLUSIONS: OL HDF influences anemia and rHuEPO dose. It allows considerable anemia correction in patients without rHuEPO treatment, while it significantly reduces rHuEPO doses in those on rHuEPO treatment as compared with standard hemodialysis. The rHuEPO costs are consequently reduced.     

Kinetics of haematopoietic recovery after dose-intensive chemo/radiotherapy in mice: optimized erythroid support with darbepoetin alpha

Despite its frequency and impact on clinical outcomes, anaemia in cancer patients remains poorly understood and suboptimally treated. The definition of optimum treatment schedules with erythropoietic agents requires a suitable model of chemotherapy-induced progressive anaemia. This study investigated novel strategies such as once-per-chemotherapy-cycle dosing, synchronization between erythroid supportive care and chemotherapy, and definition of the optimum timing of erythroid support. A murine model of carboplatin chemotherapy/radiotherapy (CRT)-induced anaemia was used, which caused progressive anaemia across multiple cycles. Weekly administration of recombinant human erythropoietin (rHuEPO) was effective, but the longer-acting darbepoetin alpha resulted in superior responses. In all animals, anaemia became progressive and more refractory across cycles because of accumulated bone marrow damage. Exploiting a specific enzyme-linked immunosorbent assay, which could distinguish between darbepoetin alpha and endogenous erythropoietin, the effect of CRT upon the pharmacokinetics of darbepoetin alpha showed that clearance of darbepoetin alpha, and presumably erythropoietin, was at least partially dependent on a chemotherapy-sensitive pathway. Scheduling data suggested that administration of erythropoietic agents prior to chemotherapy was more effective than administration after chemotherapy. There was no evidence that erythropoietic agents exacerbated anaemia, even when administered immediately prior to CRT in an attempt to "prime" erythroid cells for the effects of CRT.     

Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination therapy

In hepatitis C virus (HCV)-infected patients who develop anemia during combination therapy, erythropoietic growth factors maintain higher drug treatment levels compared to ribavirin dose reduction, which may lead to an increase in treatment response rates. This study estimated the cost-effectiveness of growth factor therapy in maintaining anemic HCV-infected patients on target drug levels during combination therapy. A decision analysis using a Markov model was developed with 7 health states: Sustained viral response, chronic HCV, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Data sources included population-based studies of growth factor therapy, previously published estimates of costs and natural history of hepatitis C, and recent prospective studies. Our reference case was a 45-year-old Caucasian man with HCV infection (genotype 1, 2, or 3) who developed anemia while undergoing combination therapy with ribavirin and pegylated interferon. We compared growth factor injections (darbepoetin alpha or epoetin alpha) during combination therapy with standard ribavirin dose reduction. Compared to a ribavirin dose reduction strategy, the cost of darbepoetin per additional quality-adjusted life-year was 34,793 dollars for genotype 1 and 33,832 dollars for genotypes 2 or 3 versus 60,600 dollars and 64,311 dollars for epoetin. For all genotypes, the results were sensitive to changes in the cure rates of HCV therapy, the utility of chronic HCV, the costs of growth factors, and the age at which therapy is begun. In conclusion, use of erythropoietic growth factors, specifically darbepoetin, for patients with anemia occurring during HCV combination therapy appears to be cost-effective for genotypes 1, 2, or 3.     

Recombinant human erythropoietin in very elderly patients with myelodysplastic syndromes: results from a retrospective study

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80–99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6–10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) pa-tients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p?=?0.004), ferritin <200 ng/ml (p?=?0.017), Hb >8 g/dl (p?=?0.034), and a high-dose rHuEPO treatment (p?=?0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5–68.4) in responders versus 30.6 months (95 % CI 7.3–53.8) in resistant patients (p?=?0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.     

JR‐131, a Biosimilar of Darbepoetin Alfa,for the Treatment of Hemodialysis Patients With Renal Anemia: A Randomized,Double‐Blinded,Parallel‐Group Phase 3 Study

The aim of this study was to compare the efficacy and safety of intravenous JR‐131, a darbepoetin alfa biosimilar, to darbepoetin alfa in hemodialysis patients with renal anemia. In this 24‐week, multicenter, randomized, double‐blinded, parallel‐group phase 3 study, 334 hemodialysis patients with renal anemia who had been receiving darbepoetin alfa were randomized to either JR‐131 or darbepoetin alfa group. The initial dose was set based on the darbepoetin alfa dose during the observation period. The primary endpoint was change in hemoglobin level from baseline to end of treatment. The 95% confidence interval of the difference in the change in hemoglobin level between the groups was ?0.19 to ?0.20 g/dL, within the equivalent margin of ?0.5 to 0.5 g/dL. No notable treatment‐emergent adverse events were observed in either group. JR‐131 was therapeutically equivalent to darbepoetin alfa, and the safety profile of JR‐131 was similar to that of darbepoetin alfa.     

Treatment of anemia with epoetin in kidney transplant recipients

The aim of this study was to analyze the prevalence and efficacy of renal anemia treated with epoetin in maintenance kidney transplant recipients in Slovenia. By the end of 2009, 107 out of 537 patients (19.9%) had been treated with epoetin. A cohort of 49 patients (45.8%) were analyzed in detail: 11 patients received epoetin alpha, 18 epoetin beta, 10 darbepoetin alpha, and 10 patients received methoxy polyethylene glycol-epoetin beta. The median epoetin dose was 0.36 μg/kg body weight per week. The median serum laboratory parameters were as follows: hemoglobin 120 g/L, hematocrit 0.36, ferritin 332 ng/mL, transferrin saturation 34%, serum creatinine 145 μmol/L, serum albumin 41 g/L, intact parathyroid hormone 79 ng/L, and C-reactive protein 3 mg/L. We concluded that the prevalence of renal anemia in kidney transplant recipients treated with epoetin was approximately 20%, and laboratory parameters suggested that the treatment of renal anemia in this study cohort was optimal.     

Darbepoetin alfa effectively maintains hemoglobin concentrations at extended dose intervals relative to intravenous rHuEPO in Japanese dialysis patients

Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its three-fold longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. In this multicenter, open-label study, 513 dialysis patients maintained on stable rHuEPO therapy were switched to KRN321 at extended dose intervals. Those receiving rHuEPO two (n = 144, 28.1%) or three times (n = 305, 59.5%) per week were switched to KRN321 once per week, and those receiving rHuEPO once per week (n = 64, 12.5%) were switched to KRN321 once every two weeks. The doses of KRN321 (10-120 microg) were titrated to maintain Hb concentrations at 10-13 g/dL and, if possible, within 11-12 g/dL for up to 52 weeks. If the Hb concentration remained between 10.5 and 12 g/dL, conversion of the dosing frequency from once per week to once every two weeks was allowed. Hemoglobin concentrations were maintained regardless of the dosing interval. The percentage of patients with Hb values within 11-12 g/dL was 23.6% at week 0, 41.3% at week 7, 46.1%-51.9% between weeks 11 and 22 and 45.6% at week 52. KRN321 was well tolerated and the safety profile was consistent with previous trials conducted for KRN321. KRN321, when administered at extended dose intervals, is well tolerated and effective Hb concentrations are attained in Japanese hemodialysis patients.     

Association of Erythropoietin Dose and Route of Administration with Clinical Outcomes for Patients on Hemodialysis in the United States

Background and objectives

Recombinant human erythropoietin (epoetin) is used routinely to increase blood hemoglobin levels in patients with ESRD and anemia. Although lower doses of epoetin are required to achieve equivalent hemoglobin responses when administered subcutaneously rather than intravenously, standard practice has been to administer epoetin to patients on hemodialysis intravenously. Randomized trials of alternative epoetin treatment regimens in patients with kidney failure have shown that risks of cardiovascular complications and death are related to the dose levels of epoetin used. Therefore, given the dose-sparing advantages of subcutaneous epoetin administration, the possibility that treatment of patients on hemodialysis with subcutaneous epoetin might be associated with more favorable outcomes compared with intravenous treatment was investigated.

Design, setting, participants, & measurements

A retrospective cohort study of 62,710 adult patients on hemodialysis treated with either intravenous or subcutaneous epoetin-α and enrolled in the Centers for Medicare and Medicaid Services ESRD Clinical Performance Measures Project from 1997 to 2005 was carried out. Risks of death and/or hospitalization for cardiovascular complications (adverse composite event outcomes) during 2 years of follow-up were determined in relationship to epoetin dose and route of administration (intravenous versus subcutaneous) by multivariate Cox proportional hazard modeling adjusted for demographics and clinical parameters.

Results

Epoetin doses used to achieve equivalent hemoglobin responses in study patients were, on average, 25% higher when epoetin was administered intravenously rather than subcutaneously (as expected). Moreover, adverse composite event outcomes were found to be significantly more likely to occur during follow-up for patients on hemodialysis managed with intravenous rather than subcutaneous epoetin (adjusted hazard ratio for adverse events within 1 year [intravenous versus subcutaneous] was 1.11 [95% confidence interval, 1.04 to 1.18]).

Conclusions

This study finds that treatment of patients on hemodialysis with subcutaneous epoetin is associated with more favorable clinical outcomes than those associated with intravenous epoetin treatment.     

CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesis-stimulating agent for the treatment of anemia

Anemia is a common and debilitating condition in patients with chronic kidney disease and patients with cancer. Over the last 10 to 15 years, the introduction of erythropoietic therapy has transformed the management of anemia in both these conditions. The first therapeutic agent to be used for the stimulation of erythropoiesis was recombinant human erythropoietin (epoetin). At the turn of this century, darbepoetin alfa, a second-generation erythropoietic agent, became available. Darbepoetin alfa contains two additional N-linked carbohydrate chains, which confer greater metabolic stability in vivo. More recently, a third-generation molecule, Continuous Erythropoietin Receptor Activator (CERA), incorporating a large polymer chain, has been developed. CERA has an elimination half-life in humans that is considerably longer than the half-life of either epoetin or darbepoetin alfa. CERA may also have different receptor binding characteristics and pharmacology from other erythropoietic agents; these characteristics are the subject of ongoing investigation. CERA is currently in phase III clinical trials.     

Use of agents stimulating erythropoiesis in digestive diseases

Anemia is the most common complication of inflammatory bowel disease （IBD）. Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron deficiency in IBD. There is also a variable compo- nent of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin （rHuEPO）, which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as first choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit （11-12 g/dL）. New formulations of intravenous iron （iron carboxymaltose） and the new generation of erythropoietic agents （darbepoetin and continuous erythropoietin receptor activator） will allow better dosing with the same efficacy and safety.     

Study of immutable variables determining rHuEPO dose requirements on hemodialysis patients

Patients receiving recombinant human erythropoietin (rHuEPO) therapy show wide variability in their responsiveness to the drug. Variables that affect rHuEPO dose requirements can be broadly divided into modificable and immutable characteristics. Most of the scientific research on rHuEPO hyporesponsiveness has focused on modificable variables (iron status, dialysis adequacy), while immutable variables such as gender, etiology of chronic renal failure (CRF) and age have been insufficiently explored. A cross sectional study was performed in order to evaluate if immutable patient characteristics determine rHuEPO dose requirements among 215 patients (52% males; mean age 66 +/- 14 years) on hemodialysis (HD) for more than twelve months. Data were collected at 10 hemodialysis units in Aragon. Patients were divided into three groups according to their gender, their cause of CRF (diabetic nephropathy, vascular nephropathy, tubulointerstitial nephropathy and primary glomerulonephritis) and their age (younger than 60 years, from 60 to 75 years, older than 75 years). Despite a similar dose of rHuEPO, women had lower mean hemoglobin (11.1 +/- 1.5 versus 11.6 +/- 1.7 g/dl; p = 0.0258) than men. The greater hemoglobin in men than women may be attributed to greater serum albumin in men (3.5 +/- 0.3 versus 3.7 +/- 0.3 mg/dl; p = 0.0001). Requirements of rHuEPO were higher in the patients with etiology of primary glomerulonephritis compared with those with the other etiologies, even those with diabetic nephropathy (p = 0.0374). The rHuE-PO doses required to obtain similar hemoglobin levels were higher in patients younger than 60 years (p = 0.0249). We conclude that women, patients with primary glomerulonephritis as cause of CRF, and patients younger than 60 years showed the highest requirements of rHuEPO doses.     

A 24‐Week Anemia Correction Study of Daprodustat in Japanese Dialysis Patients

Daprodustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor developed for treating anemia of chronic kidney disease. This 24‐week, phase 3, open‐label study (NCT02829320) evaluated whether daprodustat could achieve and maintain target hemoglobin levels in Japanese hemodialysis patients with anemia not receiving an erythropoiesis‐stimulating agent. Twenty‐eight patients received daprodustat 4 mg once daily for 4 weeks, after which doses were adjusted to achieve a hemoglobin target of 10.0 to 12.0 g/dL (inclusive). Baseline mean hemoglobin was 9.10 g/dL and mean change from baseline at 4 weeks was 0.79 g/dL (95% CI, 0.53 to 1.05). Mean hemoglobin levels reached the target range by week 8 and were maintained within this range through week 24. Daprodustat 4 mg once daily increased hemoglobin over the first 4 weeks. Throughout the 24‐week study, daprodustat achieved and maintained hemoglobin within the target range and no new safety concerns were identified in hemodialysis patients not receiving erythropoiesis‐stimulating agents.     

Kinetics of reticulocyte maturity fractions and indices and iron status during therapy with epoetin beta (recombinant human erythropoietin) in cardiac surgery patients

We evaluated the changes in reticulocyte maturity fractions and indices, as measured by flow cytometry, during preoperative treatment with recombinant human erythropoietin (epoetin beta) in cardiac surgery patients. A total of 72 patients was enrolled in this double-blind, randomized, placebo-controlled clinical trial and assigned to the two treatment groups (5 × 500 U/kg bodyweight epoetin beta or placebo intravenously over 14 days preoperatively). Therapy with epoetin beta produced continuous increases in hematocrit/hemoglobin, in the most mature fraction of reticulocytes (LR), and in reticulocyte count. In the first treatment week there were parallel increases in the fraction of most immature reticulocytes (HR) and in the reticulocyte mean cell volume. During the second week of treatment the reticulocyte mean cell hemoglobin content (CHr) decreased, but CHr was independent of all iron parameters, affecting neither the reticulocyte fractions nor the hematocrit/hemoglobin increase. The total preoperative rise in hematocrit correlated with the rises in LR fraction (P = 0.0270) and reticulocyte count (P = 0.0486) during the first week of treatment. Whereas in the epoetin beta patients the preoperative change in HR fraction showed negative correlations with transferrin saturation at baseline (P = 0.0058) and with the preoperative change in iron (P = 0.0113), the preoperative change in the LR fraction correlated positively with transferrin at baseline (P = 0.0115). Postoperatively, the reticulocyte parameters revealed that the onset of increased stimulation of erythropoiesis did not occur in the placebo patients until the second postoperative day, whereas erythropoietic activity in the epoetin beta patients was much higher during the postoperative period as well, as a result of the preoperative stimulation of erythropoiesis. The reticulocyte parameters measured by flow cytometry permitted an objective analysis of erythropoietic activity during treatment with epoetin beta and in all patients postoperatively. Further studies in various types of epoetin beta therapy are needed in order to clarify the value of these reticulocyte parameters for identification of iron deficiency and optimization of epoetin beta treatment regimen. Am. J. Hematol. 55:89-96, 1997. © 1997 Wiley-Liss, Inc.     

F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study

Studies on baboons and preliminary observations in three patients with sickle cell anemia (SS) suggested that high doses of pulse administered recombinant human erythropoietin (rHuEPO) stimulate F-reticulocyte production. We now report on the administration of rHuEPO in a double- blind format to ascertain frequency of response and potential precipitation of side effects. Ten patients were enrolled, but one was discontinued due to the indication of a blood transfusion. Of the other nine, five received rHuEPO in escalating doses (from 400 to 1,500 U per kg twice daily [BID] per week), alternating with a placebo, in blinded fashion. The second group, consisting of four patients, followed an identical protocol (except starting dose was 1,000 U/Kg, BID per week) and were iron supplemented during treatment. The criterion of response was a transient doubling (as a minimum) of the steady-state F- reticulocyte level. We found that none of the five patients in the first group responded to rHuEPO, and two of them became iron deficient, as judged by a significant decrease in ferritin. Of the second group, four patients responded with F-reticulocyte increases. In three patients, open label administration of rHuEPO confirmed the effect. We observed seven painful episodes during this study, two during the EPO administration and five during the placebo arm. Three patients were phlebotomized because the hemoglobin level increased 1.5 g/dL more than steady-state levels. Of the six patients followed-up by percent dense cell determinations, one exhibited increased levels during periods of the treatment, whereas the other five showed no change. No anti-rHuEPO antibodies were detected. We conclude that rHuEPO can stimulate F- reticulocyte response in some patients with sickle cell anemia, without apparent negative clinical side effects. The state of iron stores may be critical. Whether higher doses of rHuEPO and/or a different regimen might induce sustained F cells and fetal hemoglobin increases remains to be determined.     

Influence of relative hypoparathyroidism on the responsiveness to recombinant human erythropoietin in hemodialysis patients

BACKGROUND/AIM: It has been shown in a few studies examining small patient groups that high levels of intact parathyroid hormone (iPTH) were associated with a less efficient response to recombinant human erythropoietin (rHuEPO). However, the responsiveness to rHuEPO in hemodialysis (HD) patients with relative hypoparathyroidism remains undetermined. This study examines the responsiveness to rHuEPO in HD patients with relative hypoparathyroidism. METHODS: We retrospectively studied 19 nondiabetic patients (mean age 44.3 +/- 8.2 years, age range 29.4-55.6 years) treated with HD for chronic glomerulonephritis. Of the 19 patients, 8 (group A) had iPTH levels <100 pg/ml for the preceding 6 months without administration of 1,25-(OH)(2)-vitamin D(3). Eleven patients had iPTH levels >100 pg/ml (group B). Hematocrit (Hct) and rHuEPO doses were recorded for statistical analysis. RESULTS: In patients of groups A and B, the rHuEPO dose (U/kg/week) was 55.21 +/- 16.23 vs. 84.08 +/- 24.56 (p = 0.01); Hct (%) 33.29 +/- 1.72 vs. 31.43 +/- 2.98 (p = 0.67), and rHuEPO resistance index (weekly rHuEPO dose/Hct) 81.38 +/- 16.64 vs. 155.63 +/- 42.22 (p < 0.001). Furthermore, weekly rHuEPO dose and rHuEPO resistance index correlated positively with serum iPTH levels (R = 0.765, p < 0.001; R = 0.764, p < 0.001), whereas the Hct correlated negatively with serum iPTH levels (R = -0.400, p = 0.045). The alkaline phosphatase level (IU/l) was lower (50.46 +/- 12.87 vs. 69.61 +/- 20.68, p = 0.17) in group A. CONCLUSION: Our observations suggest that the lower the iPTH levels of chronic HD patients, even with relative hypoparathyroidism, the better the responsiveness to rHuEPO.     

The kind of vascular access influences the baseline inflammatory status and epoetin response in chronic hemodialysis patients

BACKGROUND: Arteriovenous grafts (AVG) and tunneled permanent catheters (TPC) are increasingly being used in hemodialysis (HD) patients. However, their role in baseline inflammatory status has not been fully evaluated. Aim of the study was to evaluate the influence of the current kind of vascular access on the baseline inflammatory status, marked by serum C-reactive protein (CRP), and the response to epoetin therapy in a group of iron-replete HD patients, under steady clinical conditions, without evidence of acute infections and/or inflammatory diseases. METHODS: We studied 79 patients who had been on bicarbonate HD for 8-410 months and were receiving epoetin therapy. They all had adequate iron stores and stable hemoglobin (Hb) levels. Exclusion criteria were fever, signs of infection, white blood cell count (WBC) > 10 x 1,000/microl, for at least 4 weeks before study. 48 patients (group A) had arteriovenous fistula (AVF), 18 patients (group B) AVG, 13 patients (group C) TPC. CRP, Hb, transferrin saturation, serum ferritin, WBC, serum albumin, protein catabolic rate, Kt/V, and epoetin dose (U/kg body weight/week) were measured. CRP values were log-transformed to normalize the distribution. RESULTS: Log-transformed CRP values among the 3 groups were significantly different: group A 1.81 +/- 0.48; group B 2.12 +/- 0.50, and group C 3.00 +/- 0.25 (group A vs. B p < 0.003; group B vs. C p < 0.001; group A vs. C p < 0.0001). CRP and the epoetin dose were directly correlated (r = 0.519; p < 0.0001). The epoetin doses among the 3 groups were significantly different. Multiple regression analysis confirmed AVG and TPC as factors independently influencing CRP levels. CONCLUSIONS: AVG and TPC have a higher degree of chronic inflammation than AVF. The epoetin requirement is increased in TPC and AVG compared with AVF.     

Epoetin alpha in elective coronary and valve surgery in Jehovah's Witnesses patients. Experience in 45 patients

BACKGROUND: The religious beliefs of Jehovah's Witnesses who refuse homologous and autologous blood transfusion poses serious problems for surgeons when operating on patients requiring a mean transfusion requirement of =/>2 units of blood. METHODS: After a number of encouraging studies in a randomised sample of patients 2-3 and after the treatment of some Jehovah's Witnesses 1, a group of 45 patients (23 females and 22 males) underwent elective heart surgery between June 1998 and December 2000. The patients, who were all Jehovah's Witnesses, received pre-treatment with epoetin alpha and ferrous sulphate. In the light of recent studies, it was also decided to repeat medullary preconditioning using the same intervals but with a higher dose. The patients underwent surgery involving myocardial revascularisation, mitral and/or aortic valve replacement, associated interventions, valvuloplasty and ascending aortic aneurysms. After obtaining informed and signed consent, the treatment protocol comprised the administration of 140 IU/kg epoetin alpha three times a week for 3 weeks associated with oral ferrous sulphate 3 times a day. Hematochemical levels (hemoglobin, free hemoglobin, hematocrit, ferritin, transferrin, haptoglobin, reticulocytes, iron levels) were monitored from admission to Day Hospital to discharge. RESULTS: No patient in the study required blood transfusion. CONCLUSIONS: The short, medium and long-term follow-up reconfirmed the substantial reliability of this drug linked to the absence of collateral effects.