Safety and clinical outcome of erythropoiesis-stimulating agents in patients with ST-elevation myocardial infarction: a meta-analysis of individual patient data.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events. METHODS: A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with ≥30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality. RESULTS: Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (±131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06). CONCLUSIONS: Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients.

Long term effects of epoetin alfa in patients with ST- elevation myocardial infarction.

PURPOSE: The HEBE III trial showed that epoetin alfa administration in patients with a first ST-elevation myocardial infarction (STEMI) did not improve left ventricular function at 6 weeks after primary percutaneous coronary intervention (PCI). The long term effects of erythropoiesis- stimulating agents on cardiovascular morbidity and mortality are unknown, therefore we evaluated clinical events at 1 year after PCI. METHODS: A total of 529 patients with a first STEMI and successful primary PCI were randomized to standard optimal medical treatment (N = 266) or an additional bolus of 60,000 IU epoetin alfa administered intravenously (N = 263) within 3 h after PCI. Analyses were performed by intention to treat. RESULTS: At 1 year after STEMI, 485 patients had complete follow-up. The rate of the composite end point of all-cause mortality, re-infarction, target vessel revascularization, stroke and/or heart failure was 6.4 % (N = 15) in the epoetin alfa group and 9.6 % (N = 24) in the control group (p = 0.18). Thromboembolic events were present in 1.3 % (N = 3) of patients in the epoetin alfa group and 2.4 % (N = 6) in the control group. There was no evidence of benefit from epoetin alfa administration in subgroups of patients. CONCLUSIONS: Administration of a single bolus of epoetin alfa in patients with STEMI does not result in a reduction of cardiovascular events at 1 year after primary PCI. There was a comparable incidence of thromboembolic complications in both treatment groups, suggesting that epoetin alfa administration is safe at long term.

Inflammation and anaemia in a broad spectrum of patients with heart failure.

AIMS: Anaemia in heart failure (HF) is associated with a poor prognosis. Although inflammation is assumed to be an important cause of anaemia, the association between anaemia and inflammatory markers in patients with HF has not been well established. METHODS: Data from a multicentre randomised clinical trial, in which patients were eligible if they were >18 years of age and admitted for HF (New York Heart Association II-IV), were used. In a subset of 326 patients, haemoglobin (Hb), haematocrit, high sensitivity C-reactive protein (hsCRP), interleukin-(IL) 6, soluble tumour necrosis factor receptor (sTNFR)-1 and erythropoietin (Epo) were measured at discharge and the primary endpoint was all-cause mortality. Follow-up was 18 months. RESULTS: Anaemia (Hb <13 g/dl (men) and <12 g/dl (women)) was present in 40% (130/326) of the study population. Median levels of IL-6, hsCRP and sTNFR-1 were significantly higher in anaemic patients than in non-anaemic patients. Logistic regression demonstrated that each increase in hsCRP values (OR 1.58 per SD log hsCRP; 95% CI 1.09 to 2.29; p=0.016) and each increase in sTNFR-1 values (OR 1.62 per SD log sTNFR-1; 95% CI 1.24 to 2.11; p<0.001) were independently associated with anaemia. Epo (HR 1.31 per log Epo; 95% CI 1.01 to 1.69; p=0.041) and sTNFR-1 (HR 1.47 per log sTNFR-1; 95% CI 1.16 to 1.86; p=0.001) levels were independently associated with outcome. CONCLUSION: Anaemia is present in 40% of patients hospitalised for HF and is independently associated with inflammation.

Vitamin D status and outcomes in heart failure patients.

AIMS: Vitamin D status has been implicated in the pathophysiology of heart failure (HF). The aims of this study were to determine whether a low vitamin D status is associated with prognosis in HF and whether activation of the renin-angiotensin system (RAS) and inflammatory markers could explain this potential association. METHODS AND RESULTS: We measured 25-hydroxy-vitamin D (25(OH)D), plasma renin activity (PRA), interleukin-6 (IL-6), C-reactive protein (CRP), and the incidence of death or HF rehospitalization in 548 patients with HF. Median age was 74 (64-80) years, left ventricular ejection fraction was 30% (23-42), and mean follow-up was 18 months. Low 25(OH)D levels were associated with female gender (P< 0.001), higher age (P= 0.002), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P< 0.001). Multivariable linear regression analysis showed that PRA (P= 0.048), and CRP levels (P= 0.006) were independent predictors of 25(OH)D levels. During follow-up, 155 patients died and 142 patients were rehospitalized. Kaplan-Meier analysis showed that lower 25(OH)D concentration was associated with an increased risk for the combined endpoint (all-cause mortality and HF rehospitalization; log rank test P= 0.045) and increased risk for all-cause mortality (log rank test P= 0.014). After adjustment in a multivariable Cox regression analysis, low 25(OH)D concentration remained independently associated with an increased risk for the combined endpoint [hazard ratio (HR) 1.09 per 10 nmol/L decrease; 95% confidence interval (CI) 1.00-1.16; P= 0.040] and all-cause mortality (HR 1.10 per 10 nmol/L decrease; 95% CI 1.00-1.22; P= 0.049). CONCLUSION: A low 25(OH)D concentration is associated with a poor prognosis in HF patients. Activation of the RAS and inflammation may confer the adverse effects of low vitamin D levels.

A single dose of erythropoietin in ST-elevation myocardial infarction.

AIMS: Cardioprotective effects of erythropoietin (EPO) have been shown in experimental and smaller clinical studies. We performed a prospective, multicentre, randomized trial to assess the effects of a single high dose of EPO after primary coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods and results Patients with a successful PCI for a first STEMI were randomized to receive either standard medical care alone, or in combination with a single bolus with 60,000 IU i.v. of epoetin alfa within 3 h after PCI. Primary endpoint was left ventricular ejection fraction (LVEF) after 6 weeks, assessed by planar radionuclide ventriculography. Pre-specified secondary endpoints included enzymatic infarct size and major adverse cardiovascular events. A total of 529 patients were enrolled (EPO n = 263, control n = 266). At baseline (before EPO administration), groups were well-matched for all relevant characteristics. After a mean of 6.5 (± 2.0) weeks, LVEF was 0.53 (± 0.10) in the EPO group and 0.52 (± 0.11) in the control group (P = 0.41). Median area under the curve (inter-quartile range) after 72 h for creatinine kinase was 50 136 (28 212-76 664)U/L per 72 h in the EPO group and 53 510 (33 973-90 486)U/L per 72 h in the control group (P = 0.058). More major adverse cardiac events occurred in the control than in the EPO group (19 vs. 8; P = 0.032). Conclusion A single high dose of EPO after a successful PCI for a STEMI did not improve LVEF after 6 weeks. However, the use of EPO was related to less major adverse cardiovascular events and a favourable clinical safety profile. CLINICAL TRIAL REGISTRATION INFORMATION: NCT00449488; http://www.clinicaltrials.gov/ct2/show/NCT00449488?term=voors&rank=2.

Endogenous erythropoietin and outcome in heart failure.

BACKGROUND: Endogenous erythropoietin is increased in patients with heart failure (HF). Previous small-scale data suggest that these erythropoietin levels are related to prognosis. This study aims to analyze the clinical and prognostic value of erythropoietin levels in relation to hemoglobin in a large cohort of HF patients. METHODS AND RESULTS: In patients hospitalized for HF, endogenous erythropoietin levels were measured at discharge and after 6 months. In anemic patients, the relation between erythropoietin and hemoglobin levels was determined by calculating the observed/predicted ratio of erythropoietin levels. We studied data from 605 patients with HF. Mean age was 71+/-11 years; 62% were male; and mean left ventricular ejection fraction was 0.33+/-0.14. Median erythropoietin levels were 9.6 U/L at baseline and 10.5 U/L at 6 months. Higher erythropoietin levels at baseline were independently related to an increased mortality at 18 months (hazard ratio, 2.06; 95% confidence interval, 1.40 to 3.04; P<0.01). In addition, persistently elevated erythropoietin levels (higher than median at baseline and at 6 months) were related to an increased mortality risk (hazard ratio, 2.24; 95% confidence interval, 1.02 to 4.90; P=0.044). The observed/predicted ratio was determined in a subset of anemic patients, 79% of whom had erythropoietin levels lower than expected and 9% had levels higher than expected on the basis of their hemoglobin. Multivariate Cox regression analysis revealed that a higher observed/predicted ratio was related to an increased mortality risk (hazard ratio, 3.52; 95% confidence interval, 1.53 to 8.12; P=0.003). CONCLUSIONS: Erythropoietin levels predict mortality in HF patients, and persistently elevated levels have an independent prognostic value. In anemic HF patients, the majority had a low observed/predicted ratio. However, a higher observed/predicted ratio may be related to an independent increased mortality risk.

Erythropoietin levels in heart failure after an acute myocardial infarction: determinants, prognostic value, and the effects of captopril versus losartan.

BACKGROUND: In patients with chronic heart failure, erythropoietin (Epo) levels are increased and related to a poor prognosis. Furthermore, Epo levels in these patients show a weak correlation with hemoglobin levels. METHODS: This is a retrospective analysis of a subgroup of the OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) trial in which serum Epo levels were measured at baseline, at 1 month, and at 1 and 2 years in 224 patients with an acute myocardial infarction complicated by signs or symptoms of heart failure. We investigated the determinants and the prognostic role of elevated Epo levels in these patients, and we studied the change in Epo levels by either captopril or losartan. RESULTS: The correlation between Epo and hemoglobin at baseline (r = 0.348, P < .001) and after 1 month (r = 0.272, P < .001) disappeared after 1 year of follow up (r = 0.129, P = .102). At 1 year, C-reactive protein was the only factor associated with Epo levels. Higher Epo levels at baseline were independently related to a higher mortality during 2 years of follow-up (hazard ratio 2.84, P = .014). In the captopril group, logEpo levels decreased from 1.19 (+/-0.26) to 0.95 (+/-0.20) mIU/mL, and in the losartan group from 1.19 (+/-0.27) to 1.01 (+/-0.17) mIU/mL (P = .036 between groups). CONCLUSION: In this substudy of the OPTIMAAL trial, the correlation between Epo and hemoglobin disappeared in early post-acute myocardial infarction heart failure patients. Furthermore, elevated Epo levels at baseline predicted increased mortality.

Effects of erythropoietin after an acute myocardial infarction: rationale and study design of a prospective, randomized, clinical trial (HEBE III).

BACKGROUND: Preclinical studies have consistently shown that erythropoietin (EPO), administered after an acute myocardial infarction (AMI), reduces infarct size and improves left ventricular function. Furthermore, EPO promotes endothelial progenitor cell growth, which increases angiogenesis. A recent pilot study in patients with AMI suggested that a single bolus of EPO was safe and well tolerated. METHODS: The HEBE III is a multicenter, prospective, randomized, open-label trial with blinded evaluation of the primary end point. The primary objective is to study the effect on left ventricular ejection fraction (LVEF) of a single bolus of EPO, administered directly after a primary percutaneous coronary intervention (PCI) for a first AMI. A total of 466 patients with thrombolysis in myocardial infarction 0/1 flow before the PCI procedure and 2/3 flow after a successful PCI are randomly assigned to either receive standard medical care or a single bolus with 60,000 IU of EPO on top of standard medical care within 3 hours of the PCI procedure. Primary end point of the study is LVEF after 6 weeks, assessed by planar radionuclide ventriculography. IMPLICATIONS: If an improvement of LVEF with a single bolus of EPO is demonstrated, this simple approach might further improve clinical outcome of patients with AMI.

Erythropoietin stimulates normal endothelial progenitor cell-mediated endothelial turnover, but attributes to neovascularization only in the presence of local ischemia.

PURPOSE: We aimed to evaluate whether ischemia is required for erythropoietin (EPO) induced stimulation of endothelial progenitor cells (EPCs) and their related effects on endothelial and cardiac function. METHODS: Bone marrow of rats was replaced by transgenic cells to allow tracking of EPCs. Ischemic heart failure was induced by left coronary artery ligation to induce myocardial infarction (MI) and control rats received a sham procedure. Three weeks after surgery, rats were randomized to receive EPO (darbepoetin alfa 40 microg/kg per 3 weeks) or vehicle and were sacrificed 9 weeks after surgery. RESULTS: In all treated groups, EPO significantly increased circulating EPCs and their incorporation into the endothelium of the ischemic and non-ischemic hearts as well as in the control organs; kidney and liver. This was associated with significantly improved endothelial function, which was strongly correlated with circulating EPCs (R = 0.7, p < 0.01). However, additional EPCs preferentially homed to the ischemic MI borderzone (p < 0.01) resulting in specific EPO-induced improvement of cardiac microvascularization and performance only in ischemic hearts (all p < 0.05). The differential stimulation of neovascularization by EPO was associated with increased EPO-receptor and VEGF expression in ischemic hearts only. CONCLUSIONS: In general, EPO stimulates normal endothelial progenitor cell-mediated endothelial turnover, but improves cardiac microvascularization and function only in the presence of ischemia.

Erythropoietin in chronic heart failure.

In patients with chronic heart failure (CHF), anemia is common and is associated with adverse outcome. Correction of anemia by erythropoiesis-stimulating proteins would thus seem attractive. Endogenous erythropoietin (Epo) levels are increased in CHF and are associated with severity of the disease and with increased mortality. Furthermore, Epo levels poorly correlate with hemoglobin levels, suggesting that elevated Epo levels are not only driven by anemia, but by the condition of CHF as well. Several experimental studies have demonstrated ancillary cardioprotective effects of the recombinant form of Epo, including reduced apoptosis and increased neovascularization. Three early, small studies and 3 subsequent phase 2 trials found that erythropoiesis-stimulating proteins in anemic CHF patients were safe overall and potentially beneficial. Currently, a large phase 3, randomized, clinical trial is ongoing that evaluates the effects of darbepoetin alpha on morbidity and mortality in CHF.