Erythropoiesis-stimulating agents (ESA) are medications which stimulate the bone marrow to make red blood cells. They are used to treat anemia due to end stage kidney disease, chemotherapy, major surgery, or certain treatments in HIV/AIDS. In these situations they decrease the need for blood transfusions. The different agents are more or less equivalent. They are given by injection.
Common side effects may include joint pain, rash, vomiting, and headache. Serious side effects may include heart attacks, stroke, increased cancer growth, or pure red cell aplasia. It is unclear if use is safe during pregnancy. They work similar to naturally occurring erythropoietin.
They were first approved for medical use in the United States in 1989. It is on the World Health Organization's List of Essential Medicines. Commercially available agents include epoetin alfa and darbepoetin alfa, and biosimilars. Use among athletes is prohibited by the World Anti-Doping Agency.
Medical uses ESAs are used to maintain hemoglobin at the lowest level necessary to avoid red blood cell transfusions. Owing to the risk of thromboembolism or death, ESAs should only be used in cancer patients receiving palliative, or non-curative, chemotherapy. It is not clear whether ESA use leads to clinically significant improvements in fatigue or quality of life in cancer patients. Medical speciality professional organizations do not recommend the use of ESAs in people with chronic kidney disease (CKD) who have hemoglobin levels greater than 10 g/dL and do not have anemia symptoms. In chronic kidney disease, the effects of individual ESAs on most outcomes, including mortality, cardiovascular events, and the need for blood transfusion, remain uncertain, with much of the evidence base at high risk for bias.
In preterm babies ESAs may help reduce the need for red blood cell transfusions.
The 2020 Cochrane Anaesthesia Review Group review of erythropoietin (EPO) plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non‐cardiac surgery demonstrated that patients were much less likely to require red cell transfusion and in those transfused, the volumes were unchanged (mean difference -0.09, 95% CI -0.23 to 0.05). Pre-op hemoglobin (Hb) concentration was increased in those receiving 'high dose' EPO, but not 'low dose'.
There is no evidence that one agent is better than another in the setting of CKD.
Failure ESAs may fail to achieve an adequate therapeutic response when one or more of the following is present:Burtis, C.A.; Ashwood, E.R. and Bruns, D.E. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 5th Edition. Elsevier. pp 1554 Occult blood loss and/or iron deficiency Vitamin B12 or folate deficiency Infection and inflammation Inadequate dialysis Hyperparathyroidism Aluminum toxicity Patient adherence Hypothyroidism Primary disease activity Transplant rejection Malignancy Pure red cell aplasia
Types
The following types of ESAs are available: Erythropoietin (Epo) Epoetin alfa (Procrit, Epogen) Epoetin beta (NeoRecormon) Epoetin zeta (Silapo, Retacrit) Darbepoetin alfa (Aranesp) Methoxy polyethylene glycol-epoetin beta (Mircera)
Available forms
Recombinant erythropoietin has a variety of glycosylation patterns giving rise to alpha, beta, delta, and omega forms:
epoetin alfa: Darbepoetin (Aranesp) Darbecept (Celon labs) Epocept (Lupin pharma) Nanokine (Nanogen Pharmaceutical biotechnology, Vietnam) Epofit (Intas pharma) Epogen, made by Amgen Epogin Eprex, made by Janssen-Cilag Binocrit, made by Sandoz PDpoetin, made by pooyeshdarou biopharmaceutical company IRAN Procrit Bioyetin, made by Probiomed Abseamed (Medice Arzneimittel Pütter GmbH Co. KG) epoetin beta: NeoRecormon, made by Hoffmann–La Roche Recormon Methoxy polyethylene glycol-epoetin beta (Mircera) by Roche epoetin delta: Dynepo trademark name for an erythropoiesis stimulating protein, by Shire plc epoetin omega: Epomax epoetin zeta (biosimilar forms for epoetin alpha): Silapo (STADA Arzneimittel AG) Retacrit (Hospira, Pfizer Europe MA EEIG) Miscellaneous: Epocept, made by Lupin Pharmaceuticals EPOTrust, made by Panacea Biotec Ltd Erypro Safe, made by Biocon Ltd. Repoitin, made by Serum Institute of India Limited Vintor, made by Emcure Pharmaceuticals Epofit, made by Intas pharma Erykine, made by Intas Biopharmaceutica Wepox, made by Wockhardt Biotech Espogen, made by LG life sciences. ReliPoietin, made by Reliance Life Sciences Shanpoietin, made by Shantha Biotechnics Ltd Zyrop, made by Cadila Healthcare Ltd. EPIAO (rHuEPO), made by Shenyang Sunshine Pharmaceutical Co.. LTD. China Cinnapoietin, made by CinnaGen biopharmaceutical Iran.
Darbepoetin alfa, which early literature during its development often termed as novel erythropoiesis-stimulating protein (NESP), is a form created by five substitutions (Asn-30, Thr-32, Val-87, Asn-88 and Thr-90) that create two new N-glycosylation sites. This glycoprotein has a longer terminal half-life, meaning it is possible to administer it less frequently.
Misuse Erythropoiesis-stimulating agents have a history of use as blood doping agents in endurance sports, such as horseracing, boxing, cycling, rowing, distance running, race walking, snowshoeing, cross country skiing, biathlon, mixed martial arts, and triathlon. The overall oxygen delivery system (blood oxygen levels, as well as heart stroke volume, vascularization, and lung function) is one of the major limiting factors to muscles' ability to perform endurance exercise. Therefore, the primary reason athletes may use ESAs is to improve oxygen delivery to muscles, which directly improves their endurance capacity. With the advent of recombinant erythropoietin in the 1990s, the practice of autologous and homologous blood transfusion has been partially replaced by injecting erythropoietin such that the body naturally produces its own red cells. ESAs increase hematocrit (% of blood volume that is red cell mass) and total red cell mass in the body, providing a good advantage in sports where such practice is banned. In addition to ethical considerations in sports, providing an increased red cell mass beyond the natural levels reduces blood flow due to increased viscosity, and increases the likelihood of thrombosis and stroke. Due to dangers associated with using ESAs, their use should be limited to the clinic where anemic patients are boosted back to normal hemoglobin levels (as opposed to going above the normal levels for performance advantage, leading to an increased risk of death).
Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly test for it, until in 2000, when a test developed by scientists at the French national antidoping laboratory (LNDD) and endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by distinguishing it from the nearly identical natural hormone normally present in an athlete's urine. The first EPO-doping cases were found by the Swiss Laboratory for Doping Analyses.History of the Swiss Laboratory for Doping Analyses , www.doping.chuv.ch (page visited on 11 June 2014).
In 2002, at the Winter Olympic Games in Salt Lake City, Dr. Don Catlin, the founder and then-director of the UCLA Olympic Analytical Lab, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first time in sports. At the 2012 Summer Olympics in London, Alex Schwazer, the gold medalist in the 50-kilometer race walk in the 2008 Summer Olympics in Beijing, tested positive for EPO and was disqualified."FDA Reports New Risks Posed by Anemia Drugs" Associated Press story in The Washington Post (August 8, 2012)
Since 2002, EPO tests performed by US sports authorities have consisted of only a urine or "direct" test. From 2000 to 2006, EPO tests at the Olympics were conducted on both blood and urine. However, several compounds have been identified that can be taken orally to stimulate endogenous EPO production. Most of the compounds stabilize the hypoxia-inducible transcription factors which activate the EPO gene. The compounds include oxo-glutarate competitors, but also simple ions such as cobalt(II) chloride.
Inhalation of a xenon/oxygen mixture activates production of the transcription factor HIF-1-alpha, which leads to increased production of erythropoietin and improved performance. It has been used for this purpose in Russia since at least 2004.
Cycling Recombinant EPO is believed to have come into use in cycling about 1990. In theory, EPO use can increase VO2max by a significant amount, making it useful for endurance sports like cycling. Italian antidoping advocate Sandro Donati has claimed that the history of doping in cycling can be traced to the Italian Dr Francesco Conconi at the University of Ferrara. Conconi had worked on the idea of giving athletes transfusions of their own blood in the 1980s. Donati felt this work "opened the road to EPO . . . because blood doping was a trial to understand the role of EPO".
Dr. Michele Ferrari, a former student and protege of Conconi, had a controversial interview mentioning the drug in 1994, just after his Gewiss–Ballan team had a remarkable performance in the La Flèche Wallonne race. Ferrari told l'Equipe journalist Jean-Michel Rouet that EPO had no "fundamental" effect on performance and that if his riders used it, it would not "scandalize" himself. After the journalist pointed out several riders were suspected of dying from EPO, Ferrari said EPO was not dangerous, and only abuse of it was dangerous, saying, "It's also dangerous to drink 10 liters of orange juice." The 'orange juice' comment has been widely misquoted.10 liters of orange juice: see the article on Water intoxication, for example. Ferrari was fired shortly after, but continued to work in the industry with top riders, allegedly including Lance Armstrong.Juliet Macur: Cycle of Lies: The Fall of Lance Armstrong That same year, Sandro Donati, working for the Italian National Olympic Committee, presented a report accusing Conconi of being linked to the use of EPO in the sport.
In 1997, the Union Cycliste Internationale (UCI) instituted a new rule that riders testing above 50% haematocrit were not only immediately disqualified, but banned from racing for two weeks. Robert Millar, former racer, later wrote for Cycling News that the 50% limit was "an open invitation to dope to that level", pointing out that normally haematocrit levels would start "around 40-42%" and drop during the course of a "grand tour", but after EPO, they were staying at 50% for "weeks at a time". By 1998, EPO use had become widespread, and the Festina affair tarnished the 1998 Tour de France. One manager offered a 270,000-franc-per-month raise to Christophe Bassons if he would use EPO, but Bassons refused.