Iron Deficiency in Heart Failure and Effect of Dapagliflozin: Findings From DAPA-HF.

BACKGROUND: Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline. METHODS: Iron deficiency was defined as a ferritin level <100 ng/mL or a transferrin saturation <20% and a ferritin level 100 to 299 ng/mL. Additional biomarkers of iron metabolism, including soluble transferrin receptor, erythropoietin, and hepcidin were measured at baseline and 12 months after randomization. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. RESULTS: Of the 4744 patients randomized in DAPA-HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P<0.0001). The effect of dapagliflozin on the primary outcome was consistent in iron-deficient compared with iron-replete patients (hazard ratio, 0.74 [95% CI, 0.58-0.92] versus 0.81 [95% CI, 0.63-1.03]; P-interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo. CONCLUSIONS: Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03036124.

Eritropoyetina como agente eritropoyético y no eritropoyético: consideraciones terapéuticas / Erythropoietic and non-erythropoietic functions of erythropoietin: therapeutic considerations / Eritropoietina como agente eritropoiético e não eritropoiético: considerações terapêuticas / Erythropoietic and non-erythropoietic functions of erythropoietin: therapeutic considerations

La producción de glóbulos rojos es controlada continuamente para suplir la desaparición de las células envejecidas y garantizar un aporte de oxígeno adecuado a todo el organismo. La citoquina pleitrópica eritropoyetina (Epo), originalmente definida por su rol en la eritropoyesis para prevenir la muerte programada de progenitores eritroides en la médula ósea, ha demostrado un rol antiapoptótico protector sobre diversos tejidos no hematopoyéticos. A la reconocida eficacia del tratamiento con eritropoyetina recombinante humana (rhuEpo) para contrarrestar la anemia que acompaña a patologías muy diversas, se agregan algunos aspectos que impiden lograr los resultados terapéuticos esperados, ya sea por resistencia al tratamiento o por el desarrollo de efectos adversos. Con el fin de prevenir estos efectos, así como reducir las dosis de rhuEpo en tratamientos crónicos se han desarrollado nuevos agentes que presentan modificaciones estructurales de la Epo, o bien alteraciones en las propiedades/actividad de la Epo nativa. Dado que, actualmente, los resultados sobre los efectos de la Epo sobre morbilidad/ mortalidad en diversas patologías no están suficientemente claros, nuevas investigaciones serán útiles para resolver dudas sobre la efectividad de la eritropoyetina y sus derivados o agentes alternativos con el fin de proveer bases sólidas para el desarrollo de ensayos clínicos concluyentes.

Erythropoietin (Epo), the cytokine required for promoting erythropoiesis through the proliferation and differentiation of erythroid cells, has been reported to act as a pleiotropic cytokine beyond the hematopoietic system. In contrast with the potentially beneficial effects attributed to recombinant human erythropoietin (rhuEpo), research has advanced to indicate that mortality and morbidity rates are increased in some patient groups when treated with rhuEpo. Some cardiac and systemic conditions may predispose to adverse events, and other factors, such as proinflammatory agents, may lead to resistance to erythropoietin treatment. Many compounds are currently under investigation in order to avoid these unwanted effects and to reduce the rhuEpo dose during chronic therapies. They are either erythropoiesis-stimulating agents different from erythropoietin or structurally modified erythropoietins with altered properties and activities. In recent reports, contrasting data have raised several concerns regarding the effectiveness of erythropoietin treatment to prevent adverse events. Therefore, much investigation is needed to provide a solid basis for the development of conclusive clinical trials.

A produção de glóbulos vermelhos é controlada continuamente para suprir o desaparecimento das células envelhecidas e garantir uma contribuição de oxigênio adequado a todo o organismo. A citocina pleiotrópica eritropoietina (Epo), originalmente definida por seu papel na eritropoiese para prevenir a morte programada de progenitores eritroides na medula óssea, tem demonstrado um papel anti-apoptótico protetor sobre diversos tecidos não hematopoiéticos. Adicionam-se à reconhecida eficácia do tratamento com eritropoietina recombinante humana (rhuEpo), para contra-arrestar a anemia que acompanha patologias muito diversas, alguns aspectos que impedem alcançar os resultados terapêuticos esperados, quer seja por resistência ao tratamento ou pelo desenvolvimento de efeitos adversos. Com o fim de prevenir estes efeitos, bem como reduzir as doses de rhuEpo em tratamentos crônicos foram desenvolvidos novos agentes que apresentam modificações estruturais da Epo, ou então alterações nas propriedades/atividade da Epo nativa. Devido a que, atualmente, os resultados sobre os efeitos da Epo sobre morbidade/mortalidade em diversas patologias não estão suficientemente claros, novas pesquisas serão úteis para resolver dúvidas sobre a efetividade da eritropoietina e seus derivados ou agentes alternativos visando a fornecer bases sólidas para o desenvolvimento de ensaios clínicos concludentes.

Tratamiento de la anemia perioperatoria de la fractura de cadera / Treatment of perioperative anemia in hip fracture

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Erythropoietic agents and the elderly.

Erythropoietin (Epo) is a peptide hormone that stimulates erythropoiesis. There are several agents in clinical use and in development that either act as ligands for the cell surface receptors of Epo or promote Epo production, which stimulates erythropoiesis. These are known as erythropoietic agents. The agents already in use include epoetin alfa, epoetin beta, and darbepoetin alfa. Newer agents under active investigation include continuous erythropoietin receptor activator (CERA) or proline hydroxylase inhibitors that increase hypoxia-inducible factor-1 (HIF-1), thereby stimulating Epo production and iron availability and supply. Erythropoietic agents have been shown to promote neuronal regeneration and to decrease post-stroke infarct size in mouse models. They have also been reported to shorten survival when used to treat anemia in many cancer patients and to increase thromboembolism. In contrast, rapid decrease of Epo levels as observed in astronauts and high-altitude dwellers upon rapid descent to sea level leads to the decrease of erythroid mass, a phenomenon known as "neocytolysis." The relative decrease in the serum Epo level is known to occur in some subjects with otherwise unexplained anemia of aging. Anemia by itself is a predictor of poor physical function in the elderly and is a significant economic burden on society. One out of every five persons in the United States will be elderly by 2050. Erythropoietic agents, by preventing and treating otherwise unexplained anemias of the elderly and anemia associated with other disease conditions of the elderly, have the potential to improve the functional capacity and to decrease the morbidity and mortality in the elderly, thereby alleviating the overall burden of medical care in society.

Erythropoiesis-stimulating agents: favorable safety profile when used as indicated.

BACKGROUND AND PURPOSE: Several studies with erythropoiesis-stimulating agents (ESAs) have raised a number of safety issues. Therefore, a discussion of available data in light of the current EORTC guidelines 2006 on the use of ESAs in anemic patients is warranted. METHODS: Literature is reviewed with respect to experimental and clinical data on the effect of ESA therapy on tumor growth both in the preclinical setting and on patient survival. RESULTS: Studies showing an adverse effect of ESA therapy on patient survival generally exhibit considerable methodological deficiencies. Moreover, they investigated treatment situations for which ESAs are not approved and/or did not involve recommended baseline ("intervention") or target hemoglobin levels. CONCLUSION: When used as indicated, ESAs are valuable and safe drugs for the treatment of anemia and do not negatively affect patient survival. In particular, the data situation confirms the importance and correctness of the EORTC guidelines 2006 and their recently updated version. It is therefore recommended that these guidelines continue to be strictly followed in the treatment of chemotherapy-induced anemia.

Optimización del uso de Agentes estimulantes del Receptor de la Eritropoyetina (AREs) en pacientes con neoplasias hematológicas basado en el nivel de hemoglobina reticulocitaria / Optimizing the use of Erythropoietin-Receptor stimulating Agents (ERAs) in patients with hematopoietic malignancies based on the level of reticulocyte hemoglobin

Los agentes estimulantes del Receptor de la Eritropoyetina (AREs) se usan en el tratamiento de la anemia de hemopatías malignas (HM). Sin embargo, la tasa de respuestas es variable por diversos factores como el déficit funcional de hierro (DFF). El nivel de hemoglobina (Hb) reticulocitaria es un parámetro fácil de obtener que ha mostrado su utilidad en el diagnóstico del DFF. El objetivo de este estudio fue identificar qué pacientes con HM tratados con AREs presentan DFF y si la Hb reticulocitaria predice la respuesta hemoglobínica en estos enfermos. Se incluyeron 42 pacientes con diagnostico de Mieloma Múltiple (n=17), Linfoma no Hodgkin (n=14), Linfoma de Hodgkin (n=3), Leucemia Linfática Crónica (n=4), Síndrome Mielodisplásico (n=2), Leucemia Linfoblástica Aguda (n=1) y Leucemia Mieloblástica Aguda (n=1). Veinticinco fueron tratados con Epoetina-beta, diez y seis con Darbepoetina y uno con Epoetina alfa.La respuesta fue favorable en el 28%, 53% y 58% de lospacientes a las 3, 6 y 12 semanas de tratamiento, respectivamente. Se detectó DFF en el 17% de los pacientes. En cuanto a la respuesta, no hubo diferencias estadísticamente significativas entre los pacientes con y sin DFF, si bien, a mitad de tratamiento, fue ligeramente superior en el grupo sin DFF (57% vs 43%, p>0.05). El nivel basal de Hb reticulocitaria se correlacionó con el grado de respuesta global a las 12 semanas de finalizar el tratamiento. Así, el 79% de los pacientes respondedores tenían una Hb reticulocitaria inicial >36·5 pg, mientras que este porcentaje bajó al 30% en los no respondedores (p = 0.024)En resumen, la Hb reticulocitaria es un método sensible ypreciso para detectar DFF en pacientes con HM bajo tratamiento con AREs. Además, un nivel elevado de Hb reticulocitaria basal es un parámetro que se asocia con respuesta favorable al tratamiento

The Erythropoietin-Receptor stimulating Agents (ERAs) areindicated in the supportive treatment of the anemia in hematological malignancies (HM). However, the response rate is variable due to factors such as the functional iron deficiency (FID). The level of the reticulocyte hemoglobin (RHb) is an easy-to-obtain parameter very useful for the diagnostic of the FID.The purpose of this study was to evaluate which patientswith HM treated with ERAs present FID. In addition, wetried to asses if the level of RH predicts the response in these patients.We included 42 patients with the following diagnostics:Multiple Myeloma (n= 17), Non Hodgkin Lymphoma(n=14), Hodgkin Lymphoma (n=3), Chronic lymphocyticLeukemia (n=4), Myelodisplastic syndrome (n=2), Acutelymphoblastic Leukemia (n=1), and Acute mieloblasticLeuKemia (n=1). Twenty five of them were treated withEpoetin beta, sixteen with darbepoetin alfa and one withEpoetin alfa at standard doses. The response was favorable in 28%, 53% and 58% of patients at the third, sixth and twelfth week of the treatment, respectively. FID was detected in 17% of the patients. Theresponse rate was not statistical significant different between patients with and without FID, although it was slightly superior in the group without FID (57% vs. 43%, p>0.05). Seventy nine percent of patients with a favorable response at twelve weeks showed an initial RH >36·5 pg, while this percentage was only 30% in patients who did not respond (p=0.024).In conclusion, RH is a sensitive and specific method to detect FID in patients with HM who are treated with ERAs.Furthermore, the high level of RH at the baseline is a predictor of favorable response of treatment, in these patients

Anemia e insuficiencia renal: eficacia de su control / Anemia and renal failure: efficacy of its control

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In vivo evidence that erythropoietin protects neurons from ischemic damage.

Erythropoietin (EPO) produced by the kidney and the liver (in fetuses) stimulates erythropoiesis. In the central nervous system, neurons express EPO receptor (EPOR) and astrocytes produce EPO. EPO has been shown to protect primary cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity. Here we report in vivo evidence that EPO protects neurons against ischemia-induced cell death. Infusion of EPO into the lateral ventricles of gerbils prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous EPO was also confirmed by counting synapses in the hippocampal CA1 region. Infusion of soluble EPOR (an extracellular domain capable of binding with the ligand) into animals given a mild ischemic treatment that did not produce neuronal damage, caused neuronal degeneration and impaired learning ability, whereas infusion of the heat-denatured soluble EPOR was not detrimental, demonstrating that the endogenous brain EPO is crucial for neuronal survival. The presence of EPO in neuron cultures did not repress a NMDA receptor-mediated increase in intracellular Ca2+, but rescued the neurons from NO-induced death. Taken together EPO may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.