Once-Monthly Administration of Darbepoetin Alfa for the Treatment of Patients with Chronic Heart Failure and Anemia: A Pharmacokinetic and Pharmacodynamic Investigation : Journal of Cardiovascular Pharmacology

Journal Logo

Original Article

Once-Monthly Administration of Darbepoetin Alfa for the Treatment of Patients with Chronic Heart Failure and Anemia

A Pharmacokinetic and Pharmacodynamic Investigation

Cleland, John G. F MD*; Sullivan, John T MBChB, FRACP, FACP; Ball, Stephen MD; Horowitz, John D MBBS, PhD§; Agoram, Balaji PhD; Rosser, Dylan BSc; Yates, Wayne MBA; Tin, Lwin MBChB*; Fuentealba, Paulina MD; Burton, Paul B. J MBBS, PhD, FACC

Author Information
Journal of Cardiovascular Pharmacology 46(2):p 155-161, August 2005. | DOI: 10.1097/01.fjc.0000167013.77092.c4
  • Free

Abstract

Anemia has emerged as a potential target for therapy in patients with chronic heart failure (CHF), to improve symptoms, exercise capacity, and possibly prognosis. Anemia in CHF patients is common and is associated with increased morbidity.1-4 More importantly, anemia has been described as a powerful independent predictor of the risk of death and hospitalization in patients with CHF caused by left ventricular systolic and diastolic dysfunction.1,5-10 However, few data currently exist on the treatment of anemia associated with CHF. Most patients with CHF do not appear to have deficiencies of classic hematinic factors.11,12 A few interventional studies have explored the possibility of using erythropoiesis-stimulating proteins (ESPs) for the treatment of anemia in patients with severe CHF.4,13,14 In preliminary studies, treatment with ESPs increased the mean hemoglobin concentration, improved cardiac and renal function,4,14 New York Heart Association (NYHA) functional class,4,14 as well as exercise capacity13 and resulted in a reduced need for hospitalizations and diuretics.4,14 Hence, ESPs may provide an effective therapy for patients with CHF and anemia.

Darbepoetin alfa (Aranesp®), which stimulates erythropoiesis in a manner similar to endogenous erythropoietin, has 2 more N-linked carbohydrate sites than the primary sequence of recombinant human erythropoietin,15 resulting in an approximately 3-fold longer serum half-life and greater in vivo biologic activity, allowing for extended dosing intervals compared with recombinant human erythropoietin.16 Darbepoetin alfa is currently approved for the treatment of anemia secondary to chronic renal failure17,18 and anemia associated with chemotherapy treatment of nonmyeloid malignancies in adults.19 Several studies have shown that darbepoetin alfa effectively and safely maintains hemoglobin levels in these patient populations at dosing intervals of once every 4 weeks20 compared with more frequently administered recombinant human erythropoietin. This extended dosing schedule of darbepoetin alfa significantly improves convenience for both patients and health care providers while effectively and safely maintaining hemoglobin levels and potentially reducing costs.

The 2 studies in healthy subjects and patients with symptomatic CHF and anemia (defined as hemoglobin of ≤12.5 g/dL) reported here are the first to evaluate the pharmacokinetic (PK) profile of darbepoetin alfa; its effect on the hemoglobin concentration (pharmacodynamics) using a range of doses; and to establish subcutaneous (SC) absorption and absolute bioavailability of darbepoetin alfa, which could be altered in patients with CHF because of altered cutaneous blood flow. The results from these studies will inform the assessment of darbepoetin alfa as a treatment option for patients with CHF and anemia using a once-monthly dosing schedule.

METHODS

The institutional review board or the locally appointed ethics committee for each participating study center approved the protocol, and all study participants gave written informed consent.

Study Design

Two phase 1, double-blinded, randomized, placebo-controlled studies with sequentially enrolling cohorts were conducted between December 2002 and February 2004. Figure 1 summarizes the treatment schemata for both studies.

F1-5
FIGURE 1:
Study design. In study 262 (crossover design), the first injection of darbepoetin alfa (DA) was followed by a second injection via the alternate route of administration after a 28-day washout period. All study participants completed on day 71. In study 198, patients with chronic heart failure (CHF) received a single injection of darbepoetin alfa on study days 1 and 29; healthy subjects (HS) received only 1 injection on day 1. Patients with CHF completed on day 71, healthy subjects on day 43. Adverse events were collected throughout the study; pharmacokinetic (PK) data through 17 days after the first dose (study 198) or 18 days after each dose administration (study 262); hemoglobin (Hgb) through 28 days after each dose. SC, subcutaneous; IV, intravenous.

Study 262 was a 2-sequence, 2-period crossover study. Patients with symptomatic CHF and hemoglobin ≤12.5 g/dL (n = 9) and healthy subjects (n = 6) similar in age and matched in sex were randomized, in a 2:1 ratio, to receive 0.75 μg/kg of darbepoetin alfa (Amgen Inc, Thousand Oaks, CA) or placebo on study days 1 and 29. Study participants received the first injection by either SC or intravenous (IV) administration (randomized in a 1:1 ratio) and the second injection by the alternate route of administration (either IV or SC). The study objectives were measurement of the relative bioavailability (F) of SC-administered darbepoetin alfa and the change in the hemoglobin concentration.

Study 198 had a sequential group design. Patients with symptomatic CHF (n = 24) and hemoglobin ≤12.5 g/dL, and age- and sex-matched healthy subjects (n = 24) were randomized in a 3:1 ratio within each of three treatment groups (n = 8 per group) to receive either 2.0, 3.0, or 5.0 μg/kg of darbepoetin alfa or placebo SC on study days 1 and 29 (patients with CHF) or on study day 1 only (healthy subjects), respectively. The study objective was to determine the PK parameters of darbepoetin alfa after administration of the first dose: area under the serum concentration-time curve from time 0 to infinity (AUC0-), the apparent clearance (CL/F), the peak serum concentration (Cmax), the observed time of peak serum concentration (Tmax), and the half-life (t½); and to determine the change in the hemoglobin concentration.

The safety profile for study participants who received at least 1 dose of darbepoetin alfa or placebo was evaluated for adverse events, including clinically significant changes in electrocardiograms, vital signs, laboratory tests, and the presence of antierythropoietin antibodies. In both studies, CHF patients continued to receive appropriate concomitant therapy.

Study Population

Eligible patients with CHF were at least 18 years of age and had symptomatic CHF; had a left ventricular ejection fraction (LVEF) of ≤45%; had received optimized heart failure therapy for at least 3 months before the start of the study; and had a hemoglobin concentration of ≤12.5 g/dL. Healthy subjects were age-matched (within 5 years of age) and sex-matched to enrolled CHF patients. Study 262 had difficulties enrolling elderly healthy subjects and therefore only matched 6 of the 9 CHF patients. Study participants had adequate iron stores (transferrin saturation [TSat] ≥15%) and normal levels of ferritin, folate, and serum vitamin B12. Important exclusion criteria included the presence of peripheral edema above the midcalf; exacerbation of CHF within 3 months of screening; organ transplantation; mitral or aortic valve disease or left ventricular outflow obstruction requiring surgery; uncontrolled hypertension (diastolic blood pressure ≥100 mm Hg); current malignancy; chemotherapy or radiation therapy within 3 months of screening; systemic hematologic disease or a history of autoimmune hemolysis; patients who had received dialysis, were contraindicated for iron therapy, had been exposed to an erythropoiesis-stimulating therapy (recombinant human erythropoietin or androgens) within 12 weeks before study day −1 (CHF patients) or within 90 days of randomization (healthy subjects); had undergone surgery within 12 months of screening, or had a hemoglobin >15.0 g/dL (healthy subjects only).

Study Procedures

Blood samples for measurement of darbepoetin alfa concentrations were obtained before dosing and at regular intervals after dosing until study day 18 (408 hours). Blood samples for measuring the hemoglobin concentration were collected on study day −1, before dosing on day 1 (the average of which was defined as the baseline value), and at regular intervals through 28 days after each dose. Estimated creatinine clearance was calculated using the Cockroft-Gault equation.21 Adverse events were collected throughout the study.

Pharmacokinetic Analysis

We used the Quantikine in vitro diagnostic enzyme-linked immunosorbent assay (ELISA) for the measurement of serum concentrations of darbepoetin alfa (R&D Systems, Minneapolis, MN). The standard curve for the assay ranged from 5.0 ng/mL to 0.125 ng/mL; the lower limit of quantification was 0.14 ng/mL. The assay has been validated22 with demonstrated recovery of spike experiments, parallelism, accuracy, interassay precision (coefficient of variation for darbepoetin alfa ranged from 1% to 4%), and stability. The PK analysis was based on estimations using standard noncompartmental methods from individual serum concentration profiles measured predose (day 1) through 17 days (408 hrs) after administration of the first dose of darbepoetin alfa. Actual sampling times were used for all calculations. Because of the cross-reactivity of endogenous erythropoietin in the darbepoetin alfa assay, baseline-corrected darbepoetin alfa concentrations were used. These were calculated for each subject by subtracting the prestudy endogenous erythropoietin concentration as assessed in the assay, from the postdose darbepoetin alfa concentration. Serum concentrations below the detection limit of the assay were considered zero for all analyses.

Statistical Analysis

Descriptive statistics were used because of the small number of study participants in each treatment group. Key continuous variables were summarized using means and standard deviations. Medians and ranges were used for selected variables. Discrete variables were summarized using frequency counts and percentages.

RESULTS

Baseline Characteristics of Study Cohort

The studies enrolled 33 anemic patients with CHF (9 in study 262; 24 in study 198) and 30 healthy subjects (6 in study 262; 24 in study 198). All study participants were white, and baseline demographics including hemoglobin concentration were similar among treatment groups with anemic CHF patients and healthy subjects, respectively (Table 1). Hematinic values of the study participants were within the normal ranges (ferritin, 18-300 μg/L; folate, 4-22 nmol/L; vitamin B12, 150-750 pmol/L; TSat ≥ 15%). Patients with CHF across dose groups were predominantly in NYHA functional class III or IV (n = 21; 64%); all others were in NYHA functional class II. Twenty-seven (82%) of the CHF patients had a LVEF ≤40%. The primary cause of CHF was ischemic heart disease. At baseline, patients with CHF had a higher mean (±SD) concentration of serum creatinine (158 ± 40 μmol/L) and a lower mean (±SD) estimated creatinine clearance (46 ± 26 mL/min) than healthy subjects (91 ± 16 μmol/L and 66 ± 23 mL/min, respectively).

T1-5
TABLE 1:
Baseline Demographics of Study Population

Pharmacokinetic Results

Figure 2 shows the mean concentrations of darbepoetin alfa after SC and IV administered doses of 0.75 μg/kg, and SC doses of 2.0, 3.0, and 5.0 μg/kg in healthy subjects and anemic patients with CHF. The PK parameters obtained from these serum concentration-time profiles are summarized in Table 2. The decline in the serum concentration of darbepoetin alfa after IV administration was biphasic-a rapid distribution phase followed by a longer elimination phase; in contrast, only 1 phase could be detected after SC dosing (Fig. 2A). After SC administration of 0.75 μg/kg of darbepoetin alfa in CHF patients and in healthy subjects, a mean (±SD) of 29 (±11)% and 37 (±8)% of the dose was systemically available, respectively (range 12% to 43% and 27% to 45%, respectively). The mean (±SD) half-life of darbepoetin alfa in patients with CHF was 58 (±25) hours and 18 (±6) hours after SC and IV administration of 0.75 μg/kg of darbepoetin alfa, respectively (Table 2). In patients with CHF, mean (±SD) peak serum darbepoetin alfa concentrations of 0.9 (±0.4), 3.1 (±2.0), 6.3 (±1.7), and 19.4 (±14.0) ng/mL after SC doses of 0.75, 2.0, 3.0, and 5.0 μg/kg, respectively, were observed 48, 61, 40, and 48 hours, respectively, after dosing (Table 2). At the highest dose (5.0 μg/kg), concentrations of darbepoetin alfa were close to the lower limit of detection 408 hours (17 days) after dosing. In the evaluated dose range, the mean (±SD) AUC0- in CHF patients increased from 123 (±37) to 1889 (±955) h·ng/mL, approximately a 15-fold increase for a 6.7-fold increase in dose. Within the dose range from 0.75 to 3.0 μg/kg the mean (±SD) AUC0- increased 5.5-fold for a 4-fold increase in dose. In contrast, the mean (±SD) AUC0- for healthy subjects increased from 145 (±50) to 1262 (±269) h·ng/mL, approximately an 8.7-fold increase for a 6.7-fold increase in dose. It should be noted that the intersubject variability (as measured by SD) was higher at the 5.0 μg/kg dose compared with lower doses (Table 2).

T2-5
TABLE 2:
Pharmacokinetic Results
F2-5
FIGURE 2:
Serum concentration-time profiles of darbepoetin alfa. Mean (±SD) serum concentration-time profiles of darbepoetin alfa in patients with chronic heart failure (CHF) and in healthy subjects receiving darbepoetin alfa at a dose of 0.75 μg/kg either subcutaneously (SC) or intravenously (IV) (A), 0.75 μg/kg SC (B), 2.0 μg/kg SC (C), 3.0 μg/kg SC (D), or 5.0 μg/kg SC (E).

As illustrated in Figure 2, the PK profile of darbepoetin alfa after SC and IV administration in patients with CHF and in healthy control subjects was qualitatively and quantitatively similar at the evaluated doses. Mean AUC0- in CHF patients and in healthy subjects at doses of 2.0, 3.0, and 5.0 μg/kg differed by less than 33% (Table 2).

Effect of Darbepoetin Alfa on the Hemoglobin Concentration

Darbepoetin alfa administered as single monthly doses of 0.75 μg/kg via SC and IV routes did not appreciably alter hemoglobin after 4 weeks on either study day 29 or 57 (SC and IV data combined; Fig. 3). However, 3 out of 6 anemic CHF patients showed increases from baseline in hemoglobin of 1.1, 0.6, and 0.5 g/dL, respectively, at 4 weeks after the second dose of 0.75 μg/kg (SC/IV) was given on study day 29 (Fig. 3).

F3-5
FIGURE 3:
Change in hemoglobin from baseline in patients with CHF. Individual absolute changes in the hemoglobin (Hgb) concentration (g/dL) from baseline (BL) to study day 29 and study day 57 in patients with chronic heart failure receiving placebo or 0.75, 2.0, 3.0, or 5.0 μg/kg of darbepoetin alfa subcutaneously.

In contrast, at higher doses, darbepoetin alfa increased the hemoglobin concentration at 4 weeks after the first dose in patients with CHF and anemia compared with placebo. Four weeks (study day 29) after receiving darbepoetin alfa as a single SC dose of 2.0, 3.0, or 5.0 μg/kg, anemic patients with CHF showed a mean (±SD) increase from baseline in hemoglobin of 1.6 (±0.9), 0.9 (±0.6), and 1.3 (±1.1) g/dL, respectively, compared with a drop of 0.1 (±0.2) g/dL in those who received placebo. Likewise, 4 weeks (study day 57) after the second dose anemic CHF patients experienced a mean (±SD) increase from baseline in the hemoglobin concentration of 2.3 (±0.6), 1.4 (±1.0), and 2.4 (±1.9) g/dL, respectively, compared with a decrease of 0.4 (±0.2) g/dL in those receiving placebo. Four weeks after the second SC dose of darbepoetin alfa, hemoglobin had risen by ≥2.0 g/dL in 4 of 6 patients receiving 2.0 μg/kg, 2 of 6 receiving 3.0 μg/kg, and 4 of 5 patients receiving 5.0 μg/kg SC of darbepoetin alfa.

Safety

Darbepoetin alfa was well tolerated by all study participants in all treatment groups. The majority of nonserious adverse events in those receiving darbepoetin alfa were gastrointestinal disorders (41% [n = 19 out of 46] versus placebo, 35% [n = 6 out of 17]); injection site bruising or infusion site reactions (9% [n = 4] versus placebo, 29% [n = 5]); breathing abnormalities (9% [n = 4] versus placebo, 0% [n = 0]); headache (17% [n = 8] versus placebo, 18% [n = 3]).

While receiving darbepoetin alfa, 1 healthy subject had an episode of hypertension, and 3 anemic patients with CHF receiving 2.0, 3.0, and 5.0 μg/kg of darbepoetin alfa, respectively, experienced exacerbation of heart failure. No CHF patients or healthy subjects receiving darbepoetin alfa or placebo developed deep vein thrombosis, pulmonary emboli, cerebrovascular disorder, myocardial infarction, or seizure. Serious adverse events (n = 5) included severe chest infection (1 patient with CHF receiving placebo); mild worsening of CHF, infective exacerbation of chronic obstructive pulmonary disease, or upper abdominal pain (2 patients with CHF receiving 2.0 μg/kg of darbepoetin alfa). One patient with CHF receiving 5.0 μg/kg of darbepoetin alfa developed acute renal failure and had to be removed from the study. One patient with CHF died suddenly while receiving placebo. No serious adverse events were considered related to darbepoetin alfa. No study participant tested positive for antierythropoietin antibodies after exposure to darbepoetin alfa. No other clinically relevant changes were observed, eg, ECG and laboratory measurements (data not shown).

There was no difference in baseline and end-of-study data for plasma B-type natriuretic peptide, LVEF, or NYHA functional class (data not shown). However, the studies were not designed to assess changes from baseline in these measurements.

DISCUSSION

These are the first randomized, double-blind, placebo-controlled studies of darbepoetin alfa treatment in patients with CHF and anemia (hemoglobin ≤12.5 g/dL) to be reported. Darbepoetin alfa, administered at doses of 2.0, 3.0, or 5.0 μg/kg once monthly, produced a sustained increased in the hemoglobin concentration in patients with CHF and anemia. Although 2 doses of 0.75 μg/kg of darbepoetin alfa given 1 month apart did not increase hemoglobin, it is possible that further doses might have done so. The study also demonstrates that the PK profile and absolute bioavailability of darbepoetin alfa are similar in patients with CHF and in healthy subjects and that darbepoetin alfa administered on 2 consecutive months was generally well tolerated. The data presented here provide support and justification for proceeding to additional, long-term clinical trials to establish the safety and efficacy of darbepoetin alfa for the treatment of patients with CHF and anemia using a monthly dosing regimen.

A review of published clinical trials, mainly in patients with left ventricular systolic dysfunction, suggests that approximately 25% of CHF patients have a hemoglobin concentration <12.5 g/dL.1-10 Data collected prospectively in the STAMINA registry (Study of Anemia in a Heart Failure Population) suggest that 33% of CHF outpatients treated at community or specialty heart failure clinics have anemia.23 Similar data have been reported from other surveys.24 The prevalence of anemia may be higher in patients with CHF hospitalized for worsening heart failure,7 and anemia rarely shows spontaneous resolution in this setting.6

A number of post-hoc analyses of data from large clinical trials and population-based patient cohorts have established that anemia is an independent risk factor for increased mortality and morbidity in patients with CHF.1-10 Anemia may merely be associated with a worse outcome because it is a marker of a sick patient. Alternatively, anemia may provoke adverse left ventricular remodeling,5 leading to a worse outcome.

The causes of anemia associated with CHF are not well understood. Hematinic deficiencies appear uncommon.11,12 An inadequate increase in erythropoietin relative to the severity of the anemia or reduced end-organ response to erythropoietin may be important. Treatments for heart failure including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and carvedilol may reduce hemoglobin, either by causing hemodilution or by reducing hemoglobin production.25 Chronic renal failure and activation of inflammatory cytokines may also be important factors.25

Observational data and single-center studies show that ESPs increase the hemoglobin concentration in patients with CHF and anemia, and accordingly can lead to improvements in exercise capacity, cardiac and renal function, cardiac functional class, quality of life, and a reduction in hospitalizations.4,13,14 The present study was not designed to examine changes in measures of morbidity, but 3 ongoing phase-2 studies are currently investigating the potential benefit of darbepoetin alfa treatment on outcomes in patients with CHF and anemia. These studies combined will randomize approximately 500 anemic CHF patients to either placebo or darbepoetin alfa and determine the need for a larger study to investigate effects on morbidity and mortality.

The PK profile of darbepoetin alfa over a dose range of 0.75 μg/kg to 5.0 μg/kg in CHF patients was similar to that measured in healthy subjects. This shows, for the first time, that changes in metabolism and hemodynamics associated with CHF do not have an important effect on either absorption or systemic distribution of darbepoetin alfa. The data show that the serum concentration of darbepoetin alfa in CHF patients and in healthy subjects was close to the limit of detection within 2 to 3 weeks after administration of darbepoetin alfa. Previous studies have shown that the PK profile of darbepoetin alfa does not change after repeated dosing in patients with chemotherapy-induced anemia (data on file, Amgen) and in patients with chronic renal failure.22 Therefore, accumulation of darbepoetin alfa is unlikely in patients with CHF using a monthly dosing regimen. The absolute bioavailability in patients with CHF, with mean values of 30% to 40%, was similar to healthy subjects and values reported in patients requiring renal dialysis.26

In anemic patients with CHF, exposure (AUC) to darbepoetin alfa in doses ranging from 0.75 to 3.0 μg/kg, which are clinically relevant doses, appeared to scale linearly with dose. Patients receiving a dose of 5.0 μg/kg appeared to have a greater than dose-proportional increase in mean exposure. However, high interpatient variability at the highest dose and the small sample size leave some uncertainty. Healthy subjects appeared to have dose-proportional exposure over the tested range.

Safety and Limitations

Darbepoetin alfa was well tolerated in this study, and no serious adverse event was reported to be study-related by the investigators. One healthy subject developed hypertension, and 3 patients experienced exacerbation of CHF while receiving darbepoetin alfa. ESP-induced hypertension is probably caused by increased vascular resistance, an effect that could also cause an exacerbation of CHF. However, worsening CHF is a common event, and larger clinical trials are needed for a robust safety assessment. One third of patients with CHF in this study had rather mild symptoms of heart failure, and although left ventricular systolic function was definitely impaired, there were few patients with a very low ejection fraction. It is possible that bioavailability, pharmacokinetics, and safety profile would be different in sicker patients, and clinicians must be alert to this possibility.

In conclusion, treatment of patients with CHF and anemia with ESPs might improve symptoms, morbidity, and mortality. Darbepoetin alfa administered once monthly at doses of 2.0 μg/kg or higher produces a sustained increase in hemoglobin concentration in patients with CHF and anemia. The PK profile of darbepoetin alfa in CHF patients is similar to that in healthy subjects, and accumulation after repeated dosing is unlikely. The use of a long-acting ESP, such as darbepoetin alfa, offers the important advantage of less frequent dosing, which will improve convenience for both patients and health care providers and reduce costs. Adequately powered trials are under way to investigate whether darbepoetin alfa improves symptoms and exercise capacity and will determine the need for a morbidity/mortality trial.

ACKNOWLEDGMENTS

We are grateful to Margaret Salfi, Nigel Baker, and Liyun Ni for their help in preparing this manuscript.

REFERENCES

1. Horwich TB, Fonarow GC, Hamilton MA, et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:1780-1786.
2. Kalra PR, Bolger AP, Francis DP, et al. Effect of anemia on exercise tolerance in chronic heart failure in men. Am J Cardiol. 2003;91:888-891.
3. Szachniewicz J, Petruk-Kowalczyk J, Majda J, et al. Anaemia is an independent predictor of poor outcome in patients with chronic heart failure. Int J Cardiol. 2003;90:303-308.
4. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoetin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000;35:1737-1744.
5. Anand I, McMurray JJV, Whitmore J, et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004;110:149-154.
6. Sharma R, Francis DP, Pitt B, et al. Haemoglobin predicts survival in patients with chronic heart failure: a substudy of the ELITE II trial. Eur Heart J. 2004;25:1021-1028.
7. Felker GM, Gattis WA, Leimberger JD, et al. Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure. Am J Cardiol. 2003;92:625-628.
8. Kosiborod M, Smith GL, Radford MJ, et al. The prognostic importance of anemia in patients with heart failure. Am J Med. 2003;114:112-119.
9. Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure. J Am Coll Cardiol. 2003;41:1933-1939.
10. Brucks S, Little WC, Chao T, et al. Relation of anemia to diastolic heart failure and the effect on outcome. Am J Cardiol. 2004;93:1055-1057.
11. Witte KKA, Desilva R, Chattopadhyay S, et al. Are hematinic deficiencies the cause of anemia in chronic heart failure? Am Heart J. 2004;147:924-930.
12. Cromie N, Lee C, Struthers AD. Anaemia in chronic heart failure: what is its frequency in the UK and its underlying causes? Heart. 2002;87:377-378.
13. Mancini DM, Katz SD, Lang CC, et al. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003;107:294-299.
14. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001;37:1775-1780.
15. Macdougall IC. Novel erythropoiesis stimulating protein. Semin Nephrol. 2000;20:375-381.
16. Egrie JC, Dwyer E, Browne JK, et al. Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol. 2003;31:290-299.
17. Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int. 2001;60:741-747.
18. Nissenson AR, Swan SK, Lindberg JS, et al. Randomized, controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients. Am J Kidney Dis. 2002;40:110-118.
19. Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002;94:1211-1220.
20. Jadoul M, Vanrenterghem Y, Foret M, et al. Darbepoetin alfa administered once monthly maintains haemoglobin levels in stable dialysis patients. Nephrol Dial Transplant. 2004;19:898-903.
21. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.
22. Allon M, Kleinman K, Walczyk M, et al. Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients undergoing dialysis. Clin Pharmacol Ther. 2002;72:546-555.
23. Wagoner LE, Butler J, Oren R, et al. Anemia is common in patients with heart failure seen in specialty and community cardiology clinics: results from the STAMINA-HFP Registry (Study of Anemia in a Heart Failure Population). J Am Coll Cardiol. 2004;43(Suppl A):217A. [Abstract]
24. Cleland JGF, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme-a survey on the quality of care among patients with heart failure in Europe. Eur Heart J. 2003;24:442-463.
25. Felker GM, Adams KF, Gattis WA, et al. Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol. 2004;44:959-966.
26. Goodkin DA, Gimenez LF, Graber SE, et al. Hematocrit stability following intravenous versus subcutaneous administration of epoetin alfa to dialysis patients: a post hoc analysis. Clin Nephrol. 1999;51:367-372.
Keywords:

anemia; heart failure; hemoglobin; pharmacokinetics; risk factors

© 2005 Lippincott Williams & Wilkins, Inc.