Harms of off-label erythropoiesis-stimulating agents for critically ill people.
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ABSTRACT:
SUBMITTER: Mesgarpour B
PROVIDER: S-EPMC6373621 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundErythropoiesis-stimulating agents are used to treat anemia in patients with cancer. However, their safety and effectiveness is controversial. We did a systematic review of the clinical efficacy and harms of these agents in adults with anemia related to cancer or chemotherapy.MethodsWe conducted a systematic review of published and unpublished randomized controlled trials (RCTs) using accepted methods for literature searches, article selection, data extraction and quality assessment. We included RCTs involving anemic adults with cancer. We compared the use of erythropoiesis-stimulating agents with nonuse and assessed clinical outcomes (all-cause mortality, cardiovascular events and hypertension, health-related quality of life, blood transfusions and tumour response) and harms (serious adverse events) between groups.ResultsWe identified 52 trials (n = 12 006) that met our selection criteria. The pooled all-cause mortality during treatment was significantly higher in the group receiving erythropoiesis-stimulating therapy than in the control group (relative risk [RR] 1.15, 95% confidence interval [CI] 1.03 to 1.29). Compared with no treatment, use of erythropoiesis-stimulating agents led to clinically detectable improvements in disease-specific measures of quality of life. It also reduced the use of blood transfusions (RR 0.64, 95% CI 0.56 to 0.73). However, it led to an increased risk of thrombotic events (RR 1.69, 95% CI 1.27 to 2.24) and serious adverse events (RR 1.16, 95% CI 1.08 to 1.25).InterpretationUse of erythropoiesis-stimulating agents in patients with cancer-related anemia improved some disease-specific measures of quality of life and decreased the use of blood transfusions. However, it increased the risk of death and serious adverse events. Our findings suggest that such therapy not be used routinely as an alternative to blood transfusion in patients with anemia related to cancer.
| S-EPMC2683210 | biostudies-literature
Project description:Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.
| S-EPMC4302692 | biostudies-other
Project description:Anemia, complicating the course of chronic kidney disease, is a significant parameter, whether interpreted as subjective impairment or an objective prognostic marker. Renal anemia is predominantly due to relative erythropoietin (EPO) deficiency. EPO inhibits apoptosis of erythrocyte precursors. Studies using EPO substitution have shown that increasing hemoglobin (Hb) levels up to 10-11 g/dL is associated with clinical improvement. However, it has not been unequivocally proven that further intensification of erythropoiesis stimulating agent (ESA) therapy actually leads to a comprehensive benefit for the patient, especially as ESAs are potentially associated with increased cerebro-cardiovascular events. Recently, new developments offer interesting options not only via stimulating erythropoeisis but also by employing additional mechanisms. The inhibition of activin, a member of the transforming growth factor superfamily, has the potential to correct anemia by stimulating liberation of mature erythrocyte forms and also to mitigate disturbed mineral and bone metabolism as well. Hypoxia-inducible factor prolyl hydroxylase inhibitors also show pleiotropic effects, which are at the focus of present research and have the potential of reducing mortality. However, conventional ESAs offer an extensive body of safety evidence, against which the newer substances should be measured. Carbamylated EPO is devoid of Hb augmenting effects whilst exerting promising tissue protective properties. Additionally, the role of hepcidin antagonists is discussed. An innovative new hemodialysis blood tube system, reducing blood contact with air, conveys a totally different and innocuous option to improve renal anemia by reducing mechanical hemolysis.
| S-EPMC5592888 | biostudies-other
Project description:Minimal effective concentration (MEC) was proposed to explain why subcutaneous (SC) administration of erythropoietin (EPO) induces a higher hemoglobin (HGB) increase than intravenous (IV) administration. It has been further used to explain the paradox that erythropoiesis-stimulating agent (ESA) with lower receptor binding affinity may have higher in vivo activity. We have developed a pharmacokinetic and pharmacodynamic (PK/PD) model with incorporation of the operational model of agonism to characterize the data from two clinical trials. By using model-based simulations, we demonstrate that SC route is more efficacious than IV route and explain the paradoxical behavior of ESAs. We determined that MEC can be quantified by C50, which represents the concentration of an ESA producing its half-maximal effect of stimulating the proliferation of erythroid precursor cells. The model used may allow joint PK/PD modeling of data from different ESAs, and provide a platform for dosing regimen optimizations and future clinical study designs.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e62; doi:10.1038/psp.2013.39; published online 7 August 2013.
| S-EPMC3828003 | biostudies-literature
Project description:Oxygen is essential for life, and the body has developed an exquisite method to collect oxygen in the lungs and transport it to the tissues. Hb contained within red blood cells (RBCs), is the key oxygen-carrying component in blood, and levels of RBCs are tightly controlled according to demand for oxygen. The availability of oxygen plays a critical role in athletic performance, and agents that enhance oxygen delivery to tissues increase aerobic power. Early methods to increase oxygen delivery included training at altitude, and later, transfusion of packed RBCs. A breakthrough in understanding how RBC formation is controlled included the discovery of erythropoietin (Epo) and cloning of the EPO gene. Cloning of the EPO gene was followed by commercial development of recombinant human Epo (rHuEpo). Legitimate use of this and other agents that affect oxygen delivery is important in the treatment of anaemia (low Hb levels) in patients with chronic kidney disease or in cancer patients with chemotherapy-induced anaemia. However, competitive sports was affected by illicit use of rHuEpo to enhance performance. Testing methods for these agents resulted in a cat-and-mouse game, with testing labs attempting to detect the use of a drug or blood product to improve athletic performance (doping) and certain athletes developing methods to use the agents without being detected. This article examines the current methods to enhance aerobic performance and the methods to detect illicit use.
| S-EPMC2439521 | biostudies-other
Project description:IntroductionImpaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients.MethodsIn this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index.ResultsOf the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (β = -0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 μg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables.ConclusionSerum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.
| S-EPMC9263417 | biostudies-literature
Project description: Not available
| S-EPMC7014351 | biostudies-literature
Project description:Secondary hyperparathyroidism (SHPT) is common in end-stage renal disease (ESRD) patients, and it can suppress erythropoiesis. We aimed to investigate the relationship between the consumption of erythropoiesis-stimulating agents (ESAs) and parathyroidectomy (PTX) in ESRD patients with SHPT and to determine the predictors for anemia improvement. The current standard of chronic kidney disease anemia therapy relies on the prescription of iron supplementation, and ESA. We retrospectively analyzed 81 ESRD patients with PTX at Ditmanson Medical Foundation Chiayi Christian Hospital from July 2004 to Dec 2018. The requirement of ESA therapy markedly declined from a dose of 41.6 (interquartile range [IQR], 0-91.2) to 10.3 (IQR, 0-59.5, p = 0.001) unit/kg/week. In addition, 63.7% of patients required iron replacement therapy preoperatively and the proportion reduced to 52.5% after PTX (p < 0.001). The hemoglobin (Hb) level showed an insignificant change from a median value of 10.7 g/dL (9.5-11.6 g/dL) before PTX to 10.5 g/dL (9.6-11.2 g/dL) at 6 months after PTX. A preoperative Hb level ≤ 10 mg/dL (odds ratio [OR], 20.1; 95% confidence interval [CI], 4.71-125, p < 0.001) and transferrin saturation (TSAT) < 25% (OR, 12.8; 95% CI, 2.51-129, p < 0.001) were predictors for anemia improvement. Our study demonstrated that PTX markedly decreased the requirement of ESA. Patients with a low preoperative Hb level or low TSAT showed an increase in the Hb level after PTX. PTX may be considered not only for SHPT with refractory anemia but also for high ESA-dependent patients.
| S-EPMC9499136 | biostudies-literature
Project description:Purpose of reviewThe use of erythropoiesis-stimulating agents (ESAs) such as erythropoietin and darbepoetin in preterm and term infants has been studied for over 20 years. Recent investigations have explored the potential neuroprotective effects of ESAs. We review the recent clinical trials and experimental animal models that provide evidence in support of using ESA to improve the neurodevelopmental outcomes in term and preterm infants.Recent findingsContinued work using animal models have confirmed the neuroprotective properties of ESAs, including promotion of oligodendrocyte development in the face of neuronal injury. Clinical studies in term and preterm infants have reported the neuroprotective effects following ESA administration, and improved neurodevelopmental outcomes have been reported in the studies of preterm infants.SummaryESAs show great promise in preventing and treating brain injury in term and preterm infants.
| S-EPMC4504847 | biostudies-literature
Project description: Not available
| S-EPMC6486170 | biostudies-literature