Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial. Once-monthly administration of darbepoetin alfa for the treatment of patients with chronic heart failure and anemia: a pharmacokinetic and pharmacodynamic investigation. Effects of eythropoietin administration on mitral regurgitation and left ventricular remodeling in heart failure patients. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. Effects of darbepoetin alpha on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Effects of darbepoetin-alpha on quality of life and emotional stress in anemic patients with chronic heart failure.
This study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia.
                Anemia is common in patients with CHF.
                In a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin > or =9.0 to < or =12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 microg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak VO2 (ml/min), exercise duration, and health-related quality of life.
                Differences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (-0.7 to 1.7) for peak VO2 (p = 0.40), 45 ml/min (-35 to 127) for absolute peak VO2 (p = 0.27), and 108 s (-11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient's Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated.
                In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak VO2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234). In patients with chronic heart failure (CHF), anemia is associated with more severe symptoms and worse prognosis. Erythropoiesis-stimulating proteins (ESPs) increase hemoglobin and may be of therapeutic benefit. We investigated the pharmacokinetics and pharmacodynamics of the long-acting ESP, darbepoetin alfa, administered on 2 occasions 1 month apart to 30 healthy subjects and 33 patients with symptomatic CHF and anemia (hemoglobin<or=12.5 g/dL) in 2 randomized, double-blind, placebo-controlled studies. Subcutaneous (SC) and intravenous administration of 0.75 microg/kg of darbepoetin alfa were compared in a crossover study. The second study compared 2.0, 3.0, and 5.0 microg/kg SC doses with placebo. Darbepoetin alfa (0.75 microg/kg SC) pharmacokinetics were similar in CHF patients and healthy subjects, with a mean (+/-SD) bioavailability of 29 (+/-11)% and 37 (+/-8)%, respectively. In anemic CHF patients, mean (+/-SD) increases in hemoglobin at 4 weeks after the second monthly dose of 2.0, 3.0, and 5.0 microg/kg (SC) of darbepoetin alfa were 2.3 (+/-0.6), 1.4 (+/-1.0), and 2.4 (+/-1.9) g/dL, respectively. Darbepoetin alfa 0.75 microg/kg (SC) given twice, 1 month apart, was insufficient to increase hemoglobin in this study. No severe, drug-related adverse events occurred. Darbepoetin alfa administered once monthly elevates and maintains the hemoglobin concentration in patients with CHF and anemia. The effects of erythropoietin administration on mitral regurgitation in patients with congestive heart failure have not yet been examined. After 2 months, erythropoietin treatment results in a significant reduction in left ventricular volumes and mitral regurgitation severity and improves hemodynamics.
                Copyright 2008 Elsevier Ireland Ltd. All rights reserved. This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization.
                Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron.
                Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV) who had a left ventricular ejection fraction (LVEF) of < or =40% despite maximally tolerated doses of CHF medications and whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups. Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need.
                Over a mean of 8.2+/-2.6 months, four patients in Group B and none in Group A died of CHF-related illnesses. The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B. The LVEF increased by 5.5% in A and decreased by 5.4% in B. The serum creatinine did not change in A and increased by 28.6% in B. The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B. The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B.
                When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen, associated with less hospitalization and renal impairment and less need for diuretics. Anemia is now recognized as being a common finding in CHF and is associated with increased mortality and morbidity. However, it is uncertain whether the anemia is actually causing the worse prognosis or is merely a marker of more severe cardiac disease. Previous intervention studies with subcutaneous (s.c.) beta-EPO in combination with iron have either been uncontrolled or case-controlled studies. We report a randomized, double-blind, placebo-controlled study of the combination of s.c. EPO and oral iron versus oral iron alone in patients with anemia and resistant CHF.
                The present study examines, in patients with advanced congestive heart failure (CHF) and anemia, the effects of beta-erythropoietin (EPO) and oral iron on the anemia and on cardiac and renal functional parameters.
                Forty consecutive subjects with moderate to severe CHF and anemia (hemoglobin [Hb] <11 g/dL) were studied. They were randomized to receive, in a double-blind fashion, either (a) (group A, the treatment group, 20 patients) s.c. beta-EPO for 3 months twice weekly, in addition to daily oral iron, or (b) (group B, the placebo group, 20 patients) normal saline in s.c. injections and daily oral iron. Two patients in group B were eventually excluded because of a fall of Hb <8 g/dL requiring transfusion, leaving 18 patients in group B. After the 3-months study, the group A patients were maintained on the same treatment for an additional 9 months, whereas in Group B, the placebo and oral iron were stopped.
                In group A, after a mean of 3.5 +/- 0.8 months of treatment, there was a significant increase in Hb from 10.4 +/- 0.6 to 12.4 +/- 0.8 g/dL (P < .01); a significant improvement in New York Heart Association functional class from 3.5 +/- 0.6 to 2.8 +/- 0.5 (P < .05); a longer endurance time on exercise testing, from 5.8 +/- 2.2 to 7.8 +/- 2.5 minutes (P < .01); a greater distance walked on exercise testing, from 278 +/- 55 to 356 +/- 88 meters (P < .01); a significant increase in the peak oxygen consumption (VO2) from 12.8 +/- 2.8 to 15.1 +/- 2.8 mL/kg per minute (<.05); and the VO2 at the anaerobic threshold, from 9.2 +/- 2.0 to 13.2 +/- 3.6 mL/kg minute (P < .01). There was also a significant fall in plasma B-type natriuretic peptide levels from 568 +/- 320 to 271 +/- 120 pg/mL (P < .01), a significant reduction in serum creatinine (P < .01), and an increase in estimated creatinine clearance (P < .05). In group B, there were no significant changes in any of the above parameters over the study period. At the end of the 1-year study, the Hb was still higher in group A than group B, and the rate of hospital admissions/patients over the year averaged 0.8 +/- 0.2 in group A and 1.7 +/- 0.8 in group B (P < .01).
                In anemic CHF patients, correction of anemia with EPO and oral iron leads to improvement in New York Heart Association status, measured exercise endurance, oxygen use during exercise, renal function and plasma B-type natriuretic peptide levels and reduces the need for hospitalization. Anemia is a frequent condition in chronic heart failure (CHF) that affects adversely long-term cardiac outcomes. We sought to investigate the effects of recombinant human erythropoietin analogue darbepoetin alpha on left (LV) and right ventricular (RV) function and neurohormonal activation in patients with CHF and anemia.
                Thirty-two CHF patients (New York Heart Association class II-III, LV ejection fraction [EF] <40%, hemoglobin level <12.5 g/dL, serum creatinine level <2.5 mg/dL) were randomized (2:1) to receive either a 3-month darbepoetin alpha regimen at 1.5 microg/kg every 20 days plus oral iron (n = 21) or placebo plus oral iron (n = 11). Echocardiographic indices of LV systolic and diastolic function and RV function, plasma B-type natriuretic peptide (BNP) and 6-minute walked distance were assessed at baseline and posttreatment.
                Regarding LV function, only treatment with darbepoetin alpha caused a significant improvement in LVEF (F = 22.001, P < .001), end-systolic wall stress (F = 4.934, P = .034), mitral annulus systolic displacement (F = 6.710, P < .015), isovolumic relaxation time (F = 4.909, P = .035), and E/e ratio (F = 7.833, P = .009). The RV systolic pressure (F = 7.715, P = .009) as well as tricuspid annulus systolic displacement and RVEF (F = 9.264, P = .005) were significantly improved only in the darbepoetin alpha group. Darbepoetin alpha had also alpha beneficial effect on New York Heart Association class (F = 14.586, P = .001), plasma BNP (F = 14.781, P = .001), and 6-minute walk test (F = 19.926, P < .001), whereas these parameters did not significantly change in the placebo-treated patients.
                Darbepoetin alpha improves both LV and RV performance and exercise capacity and counteracts neurohormonal activation in CHF patients with anemia. The drug effects on LV diastolic function, RV function, and LV end-systolic wall stress, in particular, are novel findings, with a potential important contribution to patients' symptomatic improvement. Substantial evidence suggests that anemia is an independent risk factor for worse outcomes in patients with heart failure (HF). The Study of Anemia in Heart Failure Trial (STAMINA-HeFT) is the largest multicenter, randomized, double-blind, placebo-controlled trial to date evaluating the effect of treating anemia in HF.
                Patients (N=319) with symptomatic HF, left ventricular ejection fraction < or = 40%, and hemoglobin > or = 9.0 g/dL and < or = 12.5 g/dL were randomized (double-blind) to placebo (N=157) or darbepoetin alfa (N=162) subcutaneously every 2 weeks for 1 year (target hemoglobin, 14.0+/-1.0 g/dL). The primary end point was change from baseline to week 27 in treadmill exercise time. Secondary end points were change from baseline in New York Heart Association class and quality of life at week 27. An additional prespecified efficacy analysis included the time to death by any cause or first HF-related hospitalization by 1 year. At baseline, the median (interquartile range) hemoglobin was 11.4 (10.9, 12.0) g/dL. At week 27, darbepoetin alfa treatment increased median (interquartile range) hemoglobin by 1.8 (1.1, 2.5) g/dL (placebo, 0.3 [-0.2, 1.0] g/dL; P<0.001). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14.0+/-1.0 g/dL during the study and experienced a hemoglobin increase of > or = 1.0 g/dL from baseline. By intent-to-treat analysis, darbepoetin alfa treatment did not significantly improve exercise duration, New York Heart Association class, or quality of life score compared with placebo. A nonsignificant trend was observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated patients compared with placebo (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10). Occurrences of adverse events were similar in both treatment groups.
                In this study of patients with symptomatic HF and anemia, treatment with darbepoetin alfa was not associated with significant clinical benefits. Darbepoetin alfa treatment was well tolerated and effectively raised hemoglobin. A trend of lower risk of morbidity and mortality was observed. Anaemia is common in chronic heart failure (CHF) and associated with worse outcome. This randomized, double-blind, placebo-controlled study evaluated the effect of two darbepoetin alfa dosing regimens on haemoglobin (Hb) rate of rise and clinical effects in patients with CHF and anaemia.
                Patients with CHF (>or=3 months), left ventricular ejection fraction (LVEF) <or= 40%, and Hb 9.0 to 12.5 g/dL received darbepoetin alfa subcutaneously every 2 weeks for 26 weeks at a starting weight-adjusted dose of 0.75 mcg/kg (n = 56) or a fixed dose of 50 mcg (n = 54), or placebo (n = 55), to gradually achieve and maintain a target Hb of 14.0 +/- 1.0 g/dL. Endpoints included rate of Hb rise per week during titration, safety, and changes in 6 min walk distance, New York Heart Association (NYHA) class, LVEF, and quality of life. Most subjects were NYHA class II-III. Mean (SD) age was 71 (11) years, LVEF was 28 (9), and Hb 11.5 (0.7) g/dL. Rate of Hb rise was equivalent between darbepoetin alfa weight-based (+1.87 +/- 1.36 g/dL) and fixed dosing (+1.64 +/- 0.98 g/dL) groups, vs. + 0.07 +/- 1.08 g/dL in the placebo group. Mean Hb concentrations by week 27 were 13.4 and 13.2 g/dL, in the weight-based and fixed dosing groups, respectively. There were non-significant improvements in the combined darbepoetin alfa group vs. placebo for 6 min walk distance (P = 0.074) and Patient's Global Assessment score (P = 0.057). There was a significant improvement in Kansas City Cardiomyopathy Questionnaire total symptom score (8.2 vs. 1.5 points; P = 0.027) but no change in NYHA class, LVEF, and Minnesota Living With Heart Failure Questionnaire score. Six treatment-unrelated deaths occurred in the 110 darbepoetin alfa treated patients, and none in the 55 placebo treated patients. Other adverse events were similar between groups.
                In this study of patients with CHF and anaemia, treatment with darbepoetin alfa raised Hb using different dosing regimens. Darbepoetin alfa improved some quality of life indices, but its safety requires further exploration. Larger trials are needed to determine the effects on long-term morbidity and mortality. Anemia is a frequent comorbidity in chronic heart failure (CHF) adversely affecting patients' prognosis. Erythropoietin seems to improve exercise capacity in CHF patients. This study investigates the effects of recombinant human erythropoietin analog darbepoetin-alpha on quality of life and emotional stress, evaluated by relevant questionnaires in patients with CHF and anemia.
                Forty-one CHF patients [New York Heart Association class: II-III; left ventricular (LV) ejection fraction (EF)<40%; hemoglobin<12.5 g/dl; serum creatinine<2.5 mg/dl] were randomized (1:1) to receive either 3-month darbepoietin-alpha at 1.5 microg/Kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). Echocardiographic LVEF, questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire, functional and overall, Duke's Activity Status Index) and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory], as well as plasma b-type natriuretic peptide and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed at baseline and posttreatment.
                A significant improvement in LVEF (32+/-6 from 26+/-6%, P<0.001), 6MWT (274+/-97 from 201+/-113 m, P<0.01), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, P<0.001) and plasma b-type natriuretic peptide (517+/-579 from 829+/-858 pg/ml, P=0.002) was observed posttreatment only in darbepoetin-treated group. Kansas City Cardiomyopathy Questionnaire functional (78+/-14 from 57+/-24%, P<0.01) and overall (68+/-20 from 47+/-22, P<0.001), Duke's Activity Status Index (19+/-11 from 14+/-9, P<0.05), Zung SDS (38+/-10 from 47+/-11, P<0.05) and Beck Depression Inventory (11+/-9 from 16+/-10, P<0.05) scores also improved in darbepoetin-treated patients, whereas they remain unchanged in the placebo group except for the Zung SDS which worsened (P<0.05). A significant correlation between drug-induced percent changes in 6MWT and Zung SDS (r=-0.627, P<0.05) was also observed.
                Darbepoetin-alpha improves quality of life and emotional stress in CHF patients with anemia, with a parallel increase in exercise capacity.
Meta-analysis of small RCTs suggests that ESA treatment in patients with symptomatic CHF and mild anaemia (haemoglobin more than 10g/dL) can improve anaemia and exercise tolerance, reduce symptoms and have benefits on clinical outcomes. Confirmation requires well-designed studies with careful attention to dose, haemoglobin treatment target and associated iron therapy.