Fatigue visual analogue scale score correlates with quality of life in cancer patients receiving epoetin alfa (Sandoz) for chemotherapy-induced anaemia: The CIROCO study.

PURPOSE: Available tools to measure fatigue and health-related quality of life (HRQoL) in cancer patients are often difficult to use in clinical practice. The fatigue visual analogue scale (VAS) provides a simple method to assess fatigue. This study evaluated the correlation between HRQoL and fatigue perceived by cancer patients undergoing chemotherapy. METHODS: This was a non-interventional prospective study of adult cancer patients in France presenting with chemotherapy-induced anaemia (CIA) treated with epoetin alfa (Sandoz). Data were collected using an electronic case report form at study inclusion (T0), after 2-3 chemotherapy cycles (T1) and after 4-6 cycles (T2). RESULTS: The study included 982 patients from September 2015 to October 2017. Overall, there was a negative correlation between fatigue VAS and HRQoL. The overall haemoglobin (Hb) change between T0 and T2 was +17.8 % (± 18.1 %). Fatigue assessed by both patients and physicians showed a clinically significant improvement during the study. Global HRQoL also increased. CONCLUSION: Treatment of CIA with epoetin alfa (Sandoz) improved Hb levels, fatigue, and HRQoL, with a correlation observed between fatigue VAS score and HRQoL. Fatigue VAS could act as a simple alternative to more complex methods to measure HRQoL; however, further analyses are required to confirm this association.

An updated meta-analysis on the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor treatment of anemia in nondialysis-dependent chronic kidney disease.

BACKGROUND: Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses. METHODS: A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted via RevMan 5.3 software using a random-effects model. Stata (version 15.0) was used to analyze the publication bias. RESULTS: Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety. CONCLUSIONS: HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

EPO and the athlete biological passport: Hematological results from a placebo-controlled, boosting and microdose EPO administration in male recreational athletes.

Hematological results in the context of the Athlete Biological Passport (ABP) from a placebo-controlled EPO administration study are provided here. Twelve participants administered eight subcutaneous boosting doses of epoetin alfa (at 40 IU/kg) over the course of 20 days. After a 10-day washout period, the same volunteers administered six microdoses (900 IU), intravenously, over 13 days. A blinded placebo cohort followed the same dosing pattern, administering saline instead of EPO. All participants supplemented with oral iron, daily, throughout the entirety of the study. In the EPO cohort, as expected, significant changes from baseline were identified in IRF, RET#, RET%, RDW, HCT, HGB, and RBC. No meaningful changes were identified in the placebo cohort population. From the ABP perspective, atypical passport findings (ATPF) were identified in 49% of the samples collected during the boosting and initial washout phases, and 24% of the samples during the microdosing and final washout phases. ATPFs from this cohort were flagged as late as Day 70, the final day of the study. Only a single ATPF was identified from all samples collected from the placebo cohort. ABPs from all volunteers in the study are provided as an avenue to visually convey differences in magnitude and timing of the hematological changes caused by EPO on the individual level. These data are expected to provide important content for Athlete Passport Management Units and ABP expert panels alike.

Retacrit®, Biosimilar of Epoetin Alfa, in Chemotherapy-Induced Anemia in Routine Practice: Impact of Iron Supplementation.

INTRODUCTION: The aim of the study was to evaluate in real-life conditions the effectiveness and safety of a biosimilar of epoetin alfa (Retacrit®) in chemotherapy-induced anemia and the impact of iron supplementation. METHODS: This was a longitudinal, observational, prospective study of 12-16 weeks conducted in 195 French centers. The primary endpoint was the achievement of target Hb (with an increase of Hb ≥1 g/dL) or an increase of Hb ≥2 g/dL, in the absence of transfusion in the previous 3 weeks. RESULTS: 2,076 patients (women, 50.6%; mean age, 67.0 years) with malignant diseases (solid tumors, 79.8%; lymphomas, 12.7%; multiple myeloma, 6.6%) were analyzed. A total of 655 patients received oral iron (40.5%), intravenous iron (58.9%), or both (0.6%). At inclusion, 10.0% and 18.2% of patients without and with iron supplementation had serum ferritin <100 µg/L, respectively. Transferrin saturation (TSAT) ≤20% was more frequent in patients with supplementation (76.6%) than without supplementation (33.9%). The mean weekly doses of epoetin alfa biosimilar and planned duration of treatment were comparable regardless of iron supplementation. The primary endpoint was achieved in 70.5% and 70.2% of patients without and with iron supplementation, respectively. Three (0.1%) serious thromboembolic events related to treatment with epoetin alfa biosimilar were reported. CONCLUSION: Epoetin alfa biosimilar was effective and well tolerated for treating chemotherapy-induced anemia. Patients in subgroup with iron supplementation had lower TSAT at inclusion compared to subgroup without supplementation. Comparable mean Hb levels were achieved in both subgroups. The rate of patients with iron supplementation through the intravenous route was however insufficient.

Erythropoietin-stimulating agent-resistant vitamin B6 deficiency anemia in a pediatric patient on hemodialysis.

BACKGROUND: Vitamin B6 is a rate-limiting coenzyme that plays an important role in the biosynthesis of heme and the incorporation of iron into protoporphyrin. Its deficiency is often seen in chronic kidney disease (CKD), particularly those requiring dialysis and following administration of erythropoietin-stimulating agent (ESA). CASE- DIAGNOSIS/TREATMENT: A 16-year-old African-American male with stage 5 CKD on chronic hemodialysis experienced a decrease in hemoglobin over a 3-month period from 11 to 6.5 g/dl while receiving ESA, resulting in multiple blood transfusions. His transferrin saturation was 41%, ferritin level 706 [80-388] ng/mL, mean corpuscular volume (MCV) 87 [78-98] µm3, corrected reticulocytes count 2.3% [0.2-1.8%], and vitamin B6 1.2 [5.3-46.7] µg/L. Bone marrow biopsy was normocellular (65%) with erythroid hyperplasia and rare dyserythropoiesis. Prussian blue staining showed increased iron storage. Supplemental vitamin B6 (100 mg daily) was initiated at hemoglobin 7.3 g/dL with correction of anemia. Eighteen months later, his hemoglobin is 11.7 g/dL, transferrin saturation 45%, with no additional blood transfusions. CONCLUSIONS: Vitamin B6 deficiency anemia should be considered in any pediatric patient on hemodialysis who does not respond to standard ESA and iron therapy.

Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment.

Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity of iron stores (absolute iron deficiency) or a relative (functional) deficiency which prevents the use of available iron stores. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood losses, impaired iron absorption, and chronic inflammation. The traditional biomarkers used for the diagnosis of iron-deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent challenges in the detection and monitoring of IDA in these patients. Here, we review the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the literature that has informed the current practice guidelines for the treatment of IDA in CKD, and we summarize the available oral and intravenous (IV) iron formulations for the treatment of IDA in CKD. Two important issues are addressed, including the potential risks of a more liberal approach to iron supplementation as well as the potential risks and benefits of IV versus oral iron supplementation in patients with CKD.

Total Knee Arthroplasty Is Safe in Jehovah's Witness Patients-A 12-Year Perspective.

Despite the evolution of blood management protocols, total knee arthroplasty (TKA) occasionally requires allogeneic blood transfusion. This poses a particular challenge for Jehovah's Witnesses (JW) who believe that the Bible strictly prohibits the use of blood products. The aim of this study was to compare JW and a matched-control cohort of non-JW candidates undergoing TKA to assess the safety using modern blood management protocols. Fifty-five JW patients (63 knees) who underwent TKA at our institution between 2005 and 2017 were matched to 63 non-JW patients (63 knees). Patient demographics, intraoperative details, and postoperative complications including in-hospital complications, revisions, and 90-day readmissions were collected and compared between the groups. Additionally, subgroup analysis was performed comparing JW patients who were administered tranexamic acid (TXA) between the two groups. Baseline demographics did not vary significantly between the study cohorts. The mean follow-up was 3.1 years in both the JW and non-JW cohorts. Postoperative complications, including in-hospital complications (7.9 vs. 4.8%; p = 0.47), revision TKA (1.6 vs. 1.6%; p = 1.00), and 90-day readmission (1.6 vs. 4.8%; p = 0.31) were not significantly different between the JW and non-JW groups. Subgroup analysis demonstrated JW patients who received TXA had a significantly lower decline in postoperative hemoglobin (Hgb) (8.6 vs. 14.0%; p < 0.01). At a follow-up of up to 12 years, JW patients who underwent TKA have outcomes equivalent to non-JW patients without the need for transfusion. Our findings support that surgeons are more likely to optimize JW patients preoperatively with iron and folate supplementation. Despite these variations in preoperative optimization efforts, no significant difference with regard to Hgb or hematocrit levels was demonstrated. Level of evidence is III, retrospective observational study.

Preoperative Epoetin-α with Intravenous or Oral Iron for Major Orthopedic Surgery: A Randomized Controlled Trial.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Preoperative administration of epoetin-α with iron is commonly used in anemic patients undergoing major orthopedic surgery, but the optimal route of iron intake is controversial. The aim of this study was to compare the clinical effects of erythropoietin in combination with oral or intravenous iron supplementation. METHODS: This study was a prospective, randomized, single-blinded, parallel arm trial. Patients scheduled for elective hip or knee arthroplasty with hemoglobin 10 to 13 g/dl received preoperative injections of erythropoietin with oral ferrous sulfate or intravenous ferric carboxymaltose. The primary endpoint was the hemoglobin value the day before surgery. RESULTS: One hundred patients were included in the analysis. The day before surgery, hemoglobin, increase in hemoglobin, and serum ferritin level were higher in the intravenous group. For the intravenous and oral groups, respectively, hemoglobin was as follows: median, 14.9 g/dl (interquartile range, 14.1 to 15.6) versus 13.9 g/dl (interquartile range, 13.2 to 15.1), group difference, 0.65 g/dl (95% CI, 0.1 to 1.2; P = 0.017); increase in hemoglobin: 2.6 g/dl (interquartile range, 2.1 to 3.2) versus 1.9 g/dl (interquartile range, 1.4 to 2.5), group difference, 0.7 g/dl (95% CI, 0.3 to 1.1; P < 0.001); serum ferritin: 325 µg/l (interquartile range, 217 to 476) versus 64.5 µg/l (interquartile range, 44 to 107), group difference, 257 µg/l (95% CI, 199 to 315; P < 0.001). The percentage of patients with nausea, diarrhea, or constipation was higher in the oral group, 52% versus 2%; group difference, 50% (95% CI, 35 to 64%; P < 0.0001). CONCLUSIONS: After preoperative administration of erythropoietin, body iron stores and stimulation of the erythropoiesis were greater with intravenous ferric carboxymaltose than with oral ferrous sulfate supplementation.

EPOR2/ßcR2-independendent effects of low-dose epoetin-α in porcine liver transplantation.

Ischemia-reperfusion injury (IRI) remains a key component of graft damage during transplantation. Erythropoietin (EPO) induces anti-inflammatory and anti-apoptotic effects via the EPOR2/ßcR2 complex, with a potential risk of thrombosis. Previous work indicates that EPO has EPOR2/ßcR2-independent protective effects via direct effects on the endothelium. As the EPOR2/ßcR2 receptor has a very low affinity for EPO, we aimed to test the hypothesis that EPO doses below the level that stimulate this receptor elicit cytoprotective effects via endothelial stimulation in a porcine liver transplantation model. Landrace pigs underwent allogenic liver transplantation (follow-up: 6 h) with a portojugular shunt. Animals were divided into two groups: donor and recipient treatment with low-dose EPO (65 IU/kg) or vehicle, administered 6 h before cold perfusion and 30 min after warm reperfusion. Fourteen of 17 animals (82.4%) fulfilled the inclusion criteria. No differences were noted in operative values between the groups including hemoglobin, cold or warm ischemic time. EPO-treated animals showed a significantly lower histopathology score, reduced apoptosis, oxidative stress, and most important a significant up-regulation of endothelial nitric oxide (NO) synthase (eNOS). Donor and recipient treatment with low-dose EPO reduces the hepatic IRI via EPOR2/ßcR2-independent cytoprotective mechanisms and represents a clinically applicable way to reduce IRI.

Is There a Role for Preoperative Iron Supplementation in Patients Preparing for a Total Hip or Total Knee Arthroplasty?

BACKGROUND: Several treatment modalities exist for the treatment of perioperative anemia. We determined the effect of oral iron supplementation on preoperative anemia, and the use of blood-conserving interventions before total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: A total of 3435 total joint arthroplasties (1461 THAs and 1974 TKAs) were analyzed during 2 phases of a blood conservation program. The first phase used erythropoietin alfa (EPO) or intravenous (IV) iron for patients at risk for perioperative anemia. The second phase included these interventions, as well as preoperative iron supplementation. The effect on preoperative hemoglobin (Hb) and serum ferritin, as well as EPO and IV iron utilization, was determined. RESULTS: Oral iron therapy increased preoperative Hb level by 6 g/L (P < .001) and 7 g/L (P < .001) in the hip and knee cohorts, respectively. Serum ferritin level rose by 80 µg/L (P < .001) and 52 µg/L (P < .001) in the hip and knee cohorts, respectively. The number of patients with an Hb level <130 g/L was significantly reduced (P < .001 for both cohorts), as were patients with serum ferritin levels <35 µg/L (P = .002 for hip and P < .001 for knee cohorts). Utilization of EPO reduced from 16% to 6% (P < .001) and 18% to 6% (P < .001) in the hip and knee cohorts, respectively. Utilization of IV iron reduced from 4% to 2% (P = .05) and 5% to 2% (P < .001) in the hip and knee cohorts, respectively. CONCLUSION: Oral iron therapy reduced the burden of perioperative anemia and reduced utilization of other blood-conserving therapies before THA and TKA. Future research should delineate the cost-effectiveness of oral iron therapy.

Ceftriaxone-Induced Hemolytic Anemia in a Jehovah's Witness.

BACKGROUND Drug-induced immune hemolytic anemia (DIIHA) is a rare condition that may result from the administration of an antibiotic, most notably the cephalosporin class, commonly used in both the adult and pediatric populations. A delay in recognition by a provider may lead to continuation of the offending agent and possibly result in fatal outcomes. CASE REPORT We report the case of a 65-year-old woman on ceftriaxone infusions after being diagnosed with acute mitral valve endocarditis 3 weeks prior, which presented with severe anemia and bilateral transient vision loss. Being a Jehovah's Witness, the patient refused blood product transfusions and was managed with alternative therapies. The etiology of the symptoms was suspected to be a hemolytic anemia directly related to her ceftriaxone infusions. CONCLUSIONS This report demonstrates the importance of close vigilance while prescribing drugs known to cause hemolytic anemia. Although rare, drug-induced immune hemolytic anemia caused by ceftriaxone may be a potentially fatal condition, but with early recognition and withdrawal of the offending agent, successful treatment may ensue. Serological tests should be utilized to obtain a definitive diagnosis.

Anemia in nephrotic syndrome: approach to evaluation and treatment.

Nephrotic syndrome is one of the most common glomerular diseases that affect in children. Complications may occur in nephrotic syndrome as a result of the disease itself as well as its treatment. Most of these complications result from excessive urinary protein losses, and control of proteinuria is the most effective treatment strategy. Anemia is one of the many complications seen in patients with persistent nephrotic syndrome and may occur as a result of excessive urinary losses of iron, transferrin, erythropoietin, transcobalamin and/or metals. This leads to a deficiency of substrates necessary for effective erythropoiesis, requiring supplementation in order to correct the anemia. Supplementation of iron and erythropoietin alone often does not lead to correction of the anemia, suggesting other possible mechanisms which need further investigation. A clear understanding of the pathophysiologic mechanisms of anemia in nephrotic syndrome is necessary to guide appropriate therapy, but only limited evidence is currently available on the precise etiologic mechanisms of anemia in nephrotic syndrome. In this review we focus on the current state of knowledge on the pathogenesis of anemia in nephrotic syndrome.

Impact of a blood management protocol on transfusion rates and outcomes following total hip and knee arthroplasty.

Introduction Preoperative anaemia remains undertreated in the UK despite advice from national agencies to implement blood conservation measures. A local retrospective audit of 717 primary hip/knee replacements in 2008-2009 revealed 25% of patients were anaemic preoperatively. These patients experienced significantly increased transfusion requirements and length of stay. We report the results of a simple and pragmatic blood management protocol in a district general hospital. Methods Since 2010 patients at our institution who are found to be anaemic when listed for hip/knee replacement have been offered iron supplementation and/or erythropoietin depending on haemoglobin and ferritin levels. In this study, postoperative blood transfusions, length of stay and readmissions were assessed retrospectively for all patients undergoing elective primary hip/knee replacement in 2014 and compared with the baseline findings. Results During the 12-month study period, 406 patients were eligible for inclusion and none were excluded. Eighty-nine patients (22%) were anaemic preoperatively and sixty-five received treatment. The transfusion rate fell from the baseline levels of 23.0% and 6.7% to 4.3% and 0.5% for hip and knee replacements respectively (p<0.001). The median length of stay reduced from 6 to 3 days (p<0.001) for both hip and knee replacements. The rate for readmissions within 90 days fell from 13.5% to 8.9% (p<0.05). Conclusions Preoperative anaemia is common in patients listed for hip/knee replacement and it is associated strongly with increased blood transfusion. The introduction of a blood management protocol has led to significant reductions in transfusion and length of stay, sustained over a four-year period. This suggests that improved patient outcomes, conservation of blood stocks and cost savings can be achieved.

Oral zinc supplementation reduces the erythropoietin responsiveness index in patients on hemodialysis.

BACKGROUND: In hemodialysis (HD) patients, zinc depletion caused by inadequate intake, malabsorption, and removal by HD treatment leads to erythropoiesis-stimulating agent (ESA) hyporesponsiveness. This study investigated the effects of zinc supplementation in HD patients with zinc deficiency on changes in the erythropoietin responsiveness index (ERI). METHODS: Patients on HD with low serum zinc levels (<65 µg/dL) were randomly assigned to two groups: The polaprezinc group (who received daily polaprezinc, containing 34 mg/day of zinc) (n = 35) and the control group (no supplementation) (n = 35) for 12 months. All the 70 patients had been taking epoetin alpha as treatment for renal anemia. ERI was measured with the following equation: Weekly ESA dose (units)/dry weight (kg)/hemoglobin (g/dL). RESULTS: There were no significant changes in hemoglobin levels within groups or between the control and polaprezinc groups during the study period. Although reticulocyte counts were increased immediately after zinc supplementation, this change was transient. Serum zinc levels were significantly increased and serum copper levels were significantly decreased in the polaprezinc group after three months; this persisted throughout the study period. Although there was no significant change in the serum iron or transferrin saturation levels in the polaprezinc group during the study period, serum ferritin levels significantly decreased following polaprezinc treatment. Further, in the polaprezinc group, ESA dosage and ERI were significantly decreased at 10 months and nine months, respectively, as compared with the baseline value. Multiple stepwise regression analysis revealed that the change in the serum zinc level was an independent predictor of lowered ERI. CONCLUSIONS: Zinc supplementation reduces ERI in patients undergoing HD and may be a novel therapeutic strategy for patients with renal anemia and low serum zinc levels.

Suppression of erythropoiesis by dietary nitrate.

In mammals, hypoxia-triggered erythropoietin release increases red blood cell mass to meet tissue oxygen demands. Using male Wistar rats, we unmask a previously unrecognized regulatory pathway of erythropoiesis involving suppressor control by the NO metabolite and ubiquitous dietary component nitrate. We find that circulating hemoglobin levels are modulated by nitrate at concentrations achievable by dietary intervention under normoxic and hypoxic conditions; a moderate dose of nitrate administered via the drinking water (7 mg NaNO3/kg body weight/d) lowered hemoglobin concentration and hematocrit after 6 d compared with nonsupplemented/NaCl-supplemented controls. The underlying mechanism is suppression of hepatic erythropoietin expression associated with the downregulation of tissue hypoxia markers, suggesting increased pO2. At higher nitrate doses, however, a partial reversal of this effect occurred; this was accompanied by increased renal erythropoietin expression and stabilization of hypoxia-inducible factors, likely brought about by the relative anemia. Thus, hepatic and renal hypoxia-sensing pathways act in concert to modulate hemoglobin in response to nitrate, converging at an optimal minimal hemoglobin concentration appropriate to the environmental/physiologic situation. Suppression of hepatic erythropoietin expression by nitrate may thus act to decrease blood viscosity while matching oxygen supply to demand, whereas renal oxygen sensing could act as a brake, averting a potentially detrimental fall in hematocrit.

C-Terminally fused affinity Strep-tag II is removed by proteolysis from recombinant human erythropoietin expressed in transgenic tobacco plants.

KEY MESSAGE: C -terminally fused Strep -tag II is removed from rhuEPO expressed in tobacco plants. The finding suggests that direct fusion of purification tags at the C -terminus of rhuEPO should be avoided. Asialo-erythropoietin (asialo-EPO), a desialylated form of EPO, is a potent tissue-protective agent. Recently, we and others have exploited a low-cost plant-based expression system to produce recombinant human asialo-EPO (asialo-rhuEPO(P)). To facilitate purification from plant extracts, Strep-tag II was engineered at the C-terminus of EPO. Although asialo-rhuEPO(P) was efficiently expressed in transgenic tobacco plants, affinity purification based on Strep -tag II did not result in the recovery of the protein. In this study, we investigated the stability of Strep-tag II tagged asialo-rhuEPO(P) expressed in tobacco plants to understand whether this fused tag is cleaved or inaccessible. Sequencing RT-PCR products confirmed that fused DNA sequences encoding Strep-tag II were properly transcribed, and three-dimensional protein structure model revealed that the tag must be fully accessible. However, Western blot analysis of leaf extracts and purified asialo-rhuEPO(P) revealed that the Strep-tag II was absent on the protein. Additionally, no peptide fragment containing Strep-tag II was identified in the LC-MS/MS analysis of purified protein further supporting that the affinity tag was absent on asialo-rhuEPO(P). However, Strep-tag II was detected on asialo-rhuEPO(P) that was retained in the endoplasmic reticulum, suggesting that the Strep-tag II is removed during protein secretion or extraction. These findings together with recent reports that C-terminally fused Strep-tag II or IgG Fc domain are also removed from EPO in tobacco plants, suggest that its C-terminus may be highly susceptible to proteolysis in tobacco plants. Therefore, direct fusion of purification tags at the C-terminus of EPO should be avoided while expressing it in tobacco plants.

Biosimilars: the science of extrapolation.

Despite the establishment of a specific approval pathway, the issuance of detailed scientific guidelines for the development of similar biological medicinal products (so-called "biosimilars") and the approval of several biosimilars in the European Union, acceptance of biosimilars in the medical community continues to be low. This is especially true in therapeutic indications for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. This article addresses the concerns frequently raised in the medical community about the use of biosimilars in such extrapolated indications and explains the underlying scientific and regulatory decision making including some real-life examples from recently licensed biosimilars.

Efficacy of subcutaneous epoetin-zeta on anemia in renal transplant recipients: a single-center experience.

BACKGROUND: Persistent or "de novo" anemia (plasma hemoglobin<11 g/dL) may complicate the graft outcome in a significant number of renal transplant recipients. We describe a single-center experience with epoetin-zeta (EPO-Z), the biosimilar form for epoetin-alfa. METHODS: Twenty patients were included in the study, 10 in treatment with different erythropoiesis-stimulating agents (ESA) and shifted to EPO-Z (shift group) and 10 who started EPO-Z treatment for anemia (naive group). All the patients had stable renal function and normal values of main inflammation markers and were prospectively followed up for 12 months. Iron supplements were administered during the study, as needed. RESULTS: In the shift group, mean plasma hemoglobin levels>11 g/dL were maintained for the entire 1-year follow-up period, with average EPO-Z doses 3.4% higher than the corresponding doses of previous ESA; in the naive group, the target value was reached between the first and third months and remained stable throughout the study. Mean corpuscular volume did not vary in either group. No change was observed in glomerular filtration rate, nor in proteinuria or in main laboratory data. No drug-related side effect was reported. CONCLUSIONS: EPO-Z may be considered a valid alternative to different ESAs in renal transplant recipients, with an interesting pharmaco-economic profile, considering its lower cost.

Use of Aspirin in normalization of recombinant human erythropoietin-mediated hyper-reactivity of platelets in rats.

OBJECTIVES: The cytokine erythropoietin is the primary stimulator of erythropoiesis and recombinant human erythropoietin (rHuEPO), which is widely used in the treatment of anemia associated with advanced chronic kidney disease (CKD). Adverse cardiovascular outcomes have been observed during clinical trials of anemia correction with rHuEPO in CKD patients. We investigated the effects of short-term, high-dose treatment with rHuEPO on platelet reactivity and effects of aspirin on platelet reactivity in healthy rats. MATERIALS AND METHODS: Animals received three daily dose of rHuEPO (25 µg/kg s.c.). Platelets were isolated after 48 h of last dose of rHuEPO to study the arachidonic acid-induced platelet aggregation. Aspirin (75 mg/kg p.o.) was given to animals just before 1 h of isolation of platelets. RESULTS: In rats, treatment with rHuEPO increased platelet reactivity and platelet count. The increased platelet reactivity was paralleled by decreased time-to-occlusion (TTO) in arterial thrombosis model, and decreased bleeding time after tail transection in rats. Treatment with rHuEPO followed by single dose of aspirin showed significant reduction in TTO and bleeding time as compared with aspirin-treated group. CONCLUSIONS: These findings suggest that rHuEPO increases platelet reactivity and aspirin normalizes the hyper-reactive platelet and may reduce the cardiovascular events associated with rHuEPO in CKD patients.