epoetin-alfa and Myocardial-Ischemia

Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties.. A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020).. Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; COVID-19; Epoetin Alfa; Erythropoietin; Expert Testimony; Forecasting; Guideline Adherence; Hematinics; Hematologic Neoplasms; Hematopoiesis; Humans; Iron; Medicine; Meta-Analysis as Topic; Multicenter Studies as Topic; Myocardial Ischemia; Neoplasms; Observational Studies as Topic; Pandemics; Practice Guidelines as Topic; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Renal Dialysis; Renal Insufficiency, Chronic; SARS-CoV-2; Venous Thromboembolism

Transient ST-segment depression measured on ambulatory ECG monitors has been described as representing silent ischemia. Patients who demonstrate silent ischemia have been reported to show increased mortality compared to patients without silent ischemia. We undertook this study to determine if the correction of anemia in End Stage Renal Disease (ESRD) patients from (+/- = standard deviation) 30 +/- 3 to 42 +/- 3 with the use of Epoietin alfa would result in decreased silent ischemia in patients with clinically evident ischemic heart disease or congestive heart failure.. Thirty one ESRD patients with congestive heart failure or patients with clinically-evident ischemic heart disease were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoietin alfa to 42 +/- 3% and patients in Group B were maintained with a hematocrit of 30 +/- 3% throughout the course of the study. All patients had a 24 hour Holter monitor recording at baseline and at 28 weeks after randomization (when they had reached their target hematocrit). Significant silent ischemia was considered to be present if patients demonstrated at least 60 seconds of > or = 1 mm ST segment depression.. Fifteen patients were randomized to Group A and 16 patients were randomized to Group B. The mean hematocrit increased in group A from 29.1 +/- 2.4% to 40.8 +/- 5.2% after 30 weeks. The mean hematocrit in Group B remained stable at 30 +/- 3% throughout the course of the study. Ten patients demonstrated silent ischemia at baseline. At follow up patients in group A demonstrated a mean of 1.7 +/- 4.9 minutes of ischemia compared to 1.1 +/- 3.4 minutes in group B. These were not significantly different. A similar number of patients in group A and Group B required adjustments in their anti-anginal medication during the course of the study.. It is possible to increase hematocrit to near normal levels in hemodialysis with the administration of exogenous Epoietin alfa. The increase in hematocrit form 30 +/- 3% to 42 +/- 3% is not associated with a change in the level of silent ischemia these patients demonstrate.

Topics: Anemia; Electrocardiography; Electrocardiography, Ambulatory; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hematocrit; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Prognosis; Recombinant Proteins; Renal Dialysis

Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30+/-3% to 42+/-3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the "Normal hematocrit Study".. Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42+/-3% and patients in Group B were maintained with a hematocrit of 30+/-3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded.. The mean hematocrit increased in Group A from 29.1+/-2.4% to 40.8+/-5.2% after 30 weeks. The hematocrit in Group B remained stable at 30+/-3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study.. It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30+/-3% to 42+/-3% is not associated with increased blood pressure.

Topics: Adult; Aged; Anemia; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Recombinant Proteins; Reference Values; Renal Dialysis; Treatment Outcome

In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis.. We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction.. After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group.. In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended.

Topics: Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Prospective Studies; Recombinant Proteins; Renal Dialysis

To compare the effectiveness of dynamic anemia management strategies by applying the parametric g-formula to electronic health records.. Patients with end-stage renal disease from the US Renal Data System who had congestive heart failure or ischemic heart disease and were undergoing hemodialysis in outpatient dialysis facilities between 2006 and 2010.. We explicitly emulated a target trial of three ‎erythropoietin dosing strategies (aimed at achieving a low, middle, or high hematocrit) and estimated the observational analog of the per-protocol effect.. Of 156,945 eligible patients, 41,970 died during the 18-month follow-up. Compared to the low-hematocrit strategy, the estimated risk of death was 4.6 (95% CI 4.4-4.9) percentage points higher under the high-hematocrit strategy and 1.8 (95% CI 1.7-1.9) percentage points higher under the mid-hematocrit strategy. The corresponding risk differences for a composite outcome of death and myocardial infarction were similar.. An explicit emulation of a target trial using electronic health records, combined with the parametric g-formula, allowed comparison of real-world dynamic strategies that have not been compared in randomized trials.

Topics: Anemia; Dose-Response Relationship, Drug; Electronic Health Records; Epoetin Alfa; Heart Failure; Hematocrit; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Outcome and Process Assessment, Health Care; Randomized Controlled Trials as Topic; Renal Dialysis; Research Design

To investigate the effect and mechanism of recombinant human erythropoietin (rhEPO) on angiogenesis in chronic ischemic porcine myocardium.. A ameroid constrictor was placed around the proximal circumflex branch of the left coronary artery in 12 Bama miniatures' swine artery by thoracoscopy. Electrocardiogram and coronary angiography were used to confirm the establishment of myocardial ischemia. The animals were divided into rhEPO treatment group (n = 6) and negative control group (n = 6). Treatment group received subcutaneous injection of rhEPO at 1, 3, 7, 14, 21 days, control group received saline. The expression of vascular endothelial growth factor (VEGF) in serum was assessed by ELISA. Ultrasonography and coronary angiography were assessed 28 days after therapy. Western blot was used to detect the expression of VEGF, phosphorylated protein kinase B (p-Akt) and phosphorylated extracellular signal regulated kinases (p-Erk). The degree of angiogenesis was assessed by immunohistochemical analysis.. Serum VEGF rose significantly in both control and treatment groups, peaking at 3 days and then returning to the near-baseline level at 28 days, but the two groups showed no significant difference at each time point (P > 0.05). Echocardiographic measurements showed that the left ventricular systolic function of animals in treatment group increase significantly after rhEPO therapy. the expression levels of VEGF, p-Akt and p-Erk had markedly increased, which resulted in a 2.5-fold increased of VEGF, 1.1-fold increased of p-Akt, 1.5-fold increased of p-Erk (t = 37.721, 10.907, 12.957, all P = 0.000). there were significant increase in capillary density and arteriole density in the two groups ((944 ± 98) %/mm² vs. (569 ± 102) %/mm², (73 ± 13) %/mm² vs. (45 ± 10) %/mm², t = 4.214, 2.869, P = 0.016, 0.023).. rhEPO can promote angiogenesis and arteriogenesis and improve the left ventricular systolic function in porcine model of chronic myocardial ischemia. The potential mechanism is to up-regulated the expression of p-Akt and p-Erk.

Topics: Animals; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Humans; Male; Myocardial Ischemia; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Swine; Swine, Miniature; Vascular Endothelial Growth Factor A

Nitrosative stress caused by ischemia contributes to poor functional recovery in hearts. A previous study showed that recombinant human erythropoietin (EPO) activates the Janus-tyrosine kinase 2/extracellular signal-regulated kinase (Jak2/ERK) pathway to protect myocardium against ischemia/reperfusion (IR) injury. However, it is not clear how pro-survival signals triggered by EPO affect the nitric oxide (NO) system in post-ischemic myocardial tissue.. Isolated rat hearts were subjected to IR injury and changes in protein expression in the myocardium were evaluated by immunostaining.. Compared with untreated hearts, EPO-treated IR hearts showed significant improvements in contractility and reduced myocardial injury and infarction; this was associated with attenuated caspase-3 activation. Excess formation of NO metabolites and nitrotyrosine, which cause nitrosative stress, was markedly suppressed by EPO. The mechanism underlying EPO-mediated alleviation of nitrosative stress was related to an increase in arginase II expression and to the suppression of heat shock protein 90 (HSP90)-dependent upregulation of endothelial and inducible NO synthase (NOS). Myocardial EPO content was restored after EPO treatment, which in turn recruited signal transducer and activator of transcription (STAT) 3 protein and induced ERK signaling downstream of Jak2, which increased arginase II levels and suppressed HSP90 expression, respectively. Inhibition of STAT3 and ERK specifically reversed the effects of EPO on arginase II and HSP90 expression.. These results indicate that EPO triggers the Jak2-STAT3/ERK pathway to restore the balance between arginase and NOS and, thus, reduces nitrosative stress. This may form the basis of myocardial protection following IR.

Topics: Animals; Arginase; Blotting, Western; Epoetin Alfa; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Female; HSP90 Heat-Shock Proteins; Immunohistochemistry; In Vitro Techniques; Janus Kinase 2; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Reactive Nitrogen Species; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; STAT3 Transcription Factor

Erythropoietin (EPO) has been thought to be capable of potentiating protection of jeopardized myocardium by reperfusion in evolving myocardial infarction. However, diversity in study design and measurements of infarct size in studies evaluating EPO has led to inconsistent results. We sought to characterize the effect of EPO on infarct size after myocardial ischemia and reperfusion with the use of assessment of left-ventricular (LV) creatine kinase (CK) depletion and echocardiography.. Acute coronary occlusion was induced in 10-week-old C57BL6 mice by left anterior descending coronary artery ligation for 3 h followed by 72 h of reperfusion. EPO (10,000 U/kg) or an equivalent amount of saline vehicle alone was injected intraperitoneally before ligation or immediately after the onset of reperfusion. Assays of residual LV CK activity and calculation of LV CK depletion were performed on LV homogenates harvested 72 h after onset of reperfusion for measurement of infarct size, and echocardiography was performed immediately before harvest of tissue for measurement of function.. Mice administered EPO before ligation had similar infarct size (37.1+/-4.1%) and echo scores (22.9+/-0.4) compared with those in corresponding control mice administered saline (35.29+/-1.9 and 21.3+/-1.1%, respectively). Mice administered EPO after reperfusion had similar infarct size (39.1+/-4.8%) and echo scores (19.5+/-1.0) compared with those in corresponding control mice administered saline (40.3+/-4.9 and 21.5+/-1.9%, respectively).. EPO does not protect ischemic myocardium such that reperfusion after 3 h can yield additional salvage.

Topics: Animals; Biomarkers; Creatine Kinase; Disease Models, Animal; Echocardiography, Doppler; Epoetin Alfa; Erythropoietin; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Recombinant Proteins; Time Factors; Ventricular Function, Left