Clinical Study
Use of Erythropoiesis-Stimulating Agents in the Treatment of Anemia in Patients With Systolic Heart Failure
Journal of Cardiovascular Pharmacology and Therapeutics 2015, Vol. 20(1) 59-65 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414541841 cpt.sagepub.com
Desirae E. Lindquist, PharmD1, Jennifer L. Cruz, PharmD, BCPS2, and Jamie N. Brown, PharmD, BCPS, BCACP3
Abstract Objective: To determine the efficacy and safety of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with systolic heart failure. Data Sources: A search of MEDLINE (1946-January 2014) and EMBASE (1947-January 2014) was conducted using the search terms erythropoietin and systolic heart failure. In addition, bibliographies of relevant articles were reviewed for additional citations. Study Selection and Data Extraction: All English language randomized controlled trials evaluating clinical outcomes or adverse events when using ESAs in the setting of systolic heart failure were included. Data Synthesis: A total of 9 studies were reviewed. All studies examining hematological parameters found a statistically significant increase in hemoglobin levels with active treatment versus placebo. Of the 7 trials evaluating exercise tolerance or capacity, only 4 demonstrated statistically significant improvement in these measures in patients receiving ESAs, whereas the remainder showed no clinical benefit. Four studies examined quality-of-life measures. Although numerical improvements were observed in most trials, statistical significance was reached in only 2 trials. A nonsignificant trend for decreased mortality in patients treated with darbepoetin with a similar adverse event profile compared to placebo was shown in one study; however, the largest trial to date showed no benefit in all-cause mortality or heart failure-related hospitalizations with the use of ESAs. Additionally, a statistically significant increase in the number of cerebrovascular events and thrombotic events was found. Conclusion: There is inconclusive evidence to suggest that the use of ESAs in treating anemia in patients with heart failure is beneficial. Although ESAs demonstrated a clear ability for increasing hemoglobin levels, the data regarding clinical outcomes such as exercise parameters, quality of life, and hospitalizations are conflicting. In addition, a mortality benefit has not been shown; therefore, the potential for improved symptomatology must be weighed against the potential for adverse events. Keywords heart failure, anemia, erythropoietin, darbepoetin, quality of life, disease management
Background Patients with concomitant anemia and heart failure have a significantly increased risk of mortality.1 Unfortunately, the prevalence of anemia in patients with heart failure is difficult to establish due to varying definitions of anemia used. The World Health Organization defines anemia as a hemoglobin value less than 13 g/dL in men and less than 12 g/dL in women, while the National Kidney Foundation defines anemia as less than 12 g/dL in both men and postmenopausal women.2 This lack of consensus in the definition of anemia makes isolating the true number of patients with anemia difficult. The exact pathophysiology of anemia in heart failure is unknown. It is most likely multifactorial and involves both natural disease progression and effects from the standard of care medications these patients are receiving.2 Patients who have left ventricular dysfunction usually develop decreased cardiac output, leading to decreased renal perfusion. In normal physiology,
decreased renal perfusion causes the renin–angiotensin–aldosterone system to become activated, leading to salt and water retention and increases in cardiac output. In patients with heart failure, extra fluid can cause hemodilution leading to anemia. Another proposed mechanism for this type of anemia is due to
1
Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA 2 Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC, USA 3 Pharmacy Service, Durham VA Medical Center, Durham, NC, USA Manuscript submitted: March 26, 2014; accepted: June 5, 2014. Corresponding Author: Jennifer L. Cruz, Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, 508 Fulton Street (119), Durham, NC 27705, USA. Email: [email protected]
Downloaded from cpt.sagepub.com at PURDUE UNIV LIBRARY TSS on June 2, 2015
60
Journal of Cardiovascular Pharmacology and Therapeutics 20(1)
adverse effects of the medications used in the treatment of heart failure.2 According to the American College of Cardiology Foundation/American Heart Association 2013 heart failure guidelines, patients diagnosed with systolic heart failure should be placed on an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).3 These drug classes have shown morbidity and mortality benefits in patients with heart failure.2,4,5 In a healthy patient, angiotensin II increases erythropoietin (EPO) secretion by decreasing renal blood flow due to the vasoconstrictor effect of angiotensin II. When an ACEi or ARB is used, this action is prevented. Other proposed causes of anemia in patients with heart failure include proinflammatory cytokines and concomitant chronic kidney disease.2 Therapies that have been evaluated for the treatment of heart failure include blood transfusions, iron therapy, and erythropoiesis-stimulating agents (ESAs).2 Erythropoiesisstimulating agents have shown benefits in multiple types of anemia, including anemia due to chronic kidney disease, chemotherapy treatment, and zidovudine use in human immunodeficiency virus infection; however, they are not currently approved for anemia due to heart failure.6 Known side effects of ESAs are hypertension, iron deficiency, and increased risk of venous thromboembolism, stroke, and death.6,7 The objective of this literature review was to determine the efficacy and safety of ESAs for the treatment of anemia in patients with systolic heart failure.
Literature Search A search of MEDLINE (1946-January 2014) and EMBASE (1947-January 2014) was conducted using the medical subject heading terms erythropoietin and systolic heart failure. The search was limited to articles written in English that were randomized controlled trials whose patient population was treated for anemia with ESAs. Trials were required to include either clinical outcomes such as exercise capacity, hospitalization for heart failure, or mortality or provide information on adverse events when using ESAs. Bibliographies of relevant articles were reviewed for additional citations. A total of 9 studies met inclusion criteria. The reviewed articles are discussed based on their contributions to either efficacy or safety. A summary of the trials is listed in Table 1.8-16
Literature Review Silverberg et al conducted a randomized controlled trial to evaluate the effect of correcting mild anemia in patients with severe congestive heart failure (CHF).8 This single-center trial enrolled 32 patients with New York Heart Association (NYHA) class III to IV disease. Patients were randomized in a consecutive fashion into the active (n ¼ 16) or control group (n ¼ 16). Erythropoietin (EPO) was administered for active treatment at an initial dose of 4000 units/wk and titrated to maintain a hemoglobin of 12.5 g/%. In addition, intravenous iron was administered to this group at a dose of 200 mg every 2 weeks until serum ferritin reached 400 mg/L, %Fe saturation
was 40%, or the hemoglobin target was met. Patients were followed for a mean 8.2 + 2.7 months. The groups were well matched at baseline in terms of CHF medications, ejection fraction, renal function, and hemoglobin values. A statistically significant improvement from baseline in NYHA classification was demonstrated in the active group compared to the control group (3.8 + 0.4 to 2.2 + 0.7 vs 3.5 + 0.7 to 3.9 + 0.3, P < .0001). During the follow-up period, 4 deaths occurred in the control group compared to 0 in the active group. Other positive findings of this study were an improvement in ejection fraction, a reduction in CHF-related hospitalization days, and a lower furosemide dose requirement in the patients treated with EPO. The limitations of this study included a small sample size, as well as a lack of blinding and use of a placebo control. Additionally, this study excluded patients with less severe CHF (NYHA class II) and had a narrow entry criteria for hemoglobin values (10-11.5 g/dL). Mancini et al conducted a small, single-blind, randomized, and placebo-controlled trial to investigate the effect of EPO therapy on exercise capacity in patients with chronic heart failure after a 3-month trial period.9 Patients were randomized in a 2:1 ratio to 5000 units of EPO dosed 3 times a week (increased to 10 000 units after 4 weeks if hemoglobin increase was below 1 g/dL) or placebo (0.9% saline) dosed once a week. A total of 26 patients were randomized and 23 completed the study. There was a statistically significant change in hemoglobin levels in response to active treatment (11+ 0.6 to 14.3+ 1.2 g/dL, P < .0001), while the hemoglobin in the placebo group remained unchanged (10.9 + 1.1 to 11.5 + 1.3 g/dL). Peak oxygen consumption (VO2) increased significantly from 11 + 0.8 to 12.7 + 2.8 mL/kg min in the treatment group (P < .05) while it decreased from 10.0 + 1.9 to 9.5 + 1.6 in the placebo group. A positive linear correlation was observed between the change in peak VO2 and plasma hemoglobin levels. For the 6-minute walk test, distance for the placebo group at baseline and end of study was 929 + 356 and 1052 + 403 ft, respectively (nonsignificant), while the EPO group increased significantly from 1187 + 279 to 1328 + 254 ft (P < .05). For quality-of-life outcomes, the placebo group’s Minnesota Living with Heart Failure Questionnaire (MLHFQ) score increased by approximately 10 points (56-66), which signifies a poorer quality of life. In contrast, the average score for the EPO group decreased by 9 points (46-37), indicating an improvement (P < .04). This trial was limited by its small sample size and lack of investigator blinding, although the risk of bias was likely minimal since the outcomes measured were objective in nature. Palazzuoli et al conducted a randomized, double-blind, and single-center study examining the impact of anemia treatment on exercise tolerance and other clinical markers in patients with heart failure.10 Forty patients with hemoglobin values
Use of Erythropoiesis-Stimulating Agents in the Treatment of Anemia in Patients With Systolic Heart Failure
Journal of Cardiovascular Pharmacology and Therapeutics 2015, Vol. 20(1) 59-65 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414541841 cpt.sagepub.com
Desirae E. Lindquist, PharmD1, Jennifer L. Cruz, PharmD, BCPS2, and Jamie N. Brown, PharmD, BCPS, BCACP3
Abstract Objective: To determine the efficacy and safety of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with systolic heart failure. Data Sources: A search of MEDLINE (1946-January 2014) and EMBASE (1947-January 2014) was conducted using the search terms erythropoietin and systolic heart failure. In addition, bibliographies of relevant articles were reviewed for additional citations. Study Selection and Data Extraction: All English language randomized controlled trials evaluating clinical outcomes or adverse events when using ESAs in the setting of systolic heart failure were included. Data Synthesis: A total of 9 studies were reviewed. All studies examining hematological parameters found a statistically significant increase in hemoglobin levels with active treatment versus placebo. Of the 7 trials evaluating exercise tolerance or capacity, only 4 demonstrated statistically significant improvement in these measures in patients receiving ESAs, whereas the remainder showed no clinical benefit. Four studies examined quality-of-life measures. Although numerical improvements were observed in most trials, statistical significance was reached in only 2 trials. A nonsignificant trend for decreased mortality in patients treated with darbepoetin with a similar adverse event profile compared to placebo was shown in one study; however, the largest trial to date showed no benefit in all-cause mortality or heart failure-related hospitalizations with the use of ESAs. Additionally, a statistically significant increase in the number of cerebrovascular events and thrombotic events was found. Conclusion: There is inconclusive evidence to suggest that the use of ESAs in treating anemia in patients with heart failure is beneficial. Although ESAs demonstrated a clear ability for increasing hemoglobin levels, the data regarding clinical outcomes such as exercise parameters, quality of life, and hospitalizations are conflicting. In addition, a mortality benefit has not been shown; therefore, the potential for improved symptomatology must be weighed against the potential for adverse events. Keywords heart failure, anemia, erythropoietin, darbepoetin, quality of life, disease management
Background Patients with concomitant anemia and heart failure have a significantly increased risk of mortality.1 Unfortunately, the prevalence of anemia in patients with heart failure is difficult to establish due to varying definitions of anemia used. The World Health Organization defines anemia as a hemoglobin value less than 13 g/dL in men and less than 12 g/dL in women, while the National Kidney Foundation defines anemia as less than 12 g/dL in both men and postmenopausal women.2 This lack of consensus in the definition of anemia makes isolating the true number of patients with anemia difficult. The exact pathophysiology of anemia in heart failure is unknown. It is most likely multifactorial and involves both natural disease progression and effects from the standard of care medications these patients are receiving.2 Patients who have left ventricular dysfunction usually develop decreased cardiac output, leading to decreased renal perfusion. In normal physiology,
decreased renal perfusion causes the renin–angiotensin–aldosterone system to become activated, leading to salt and water retention and increases in cardiac output. In patients with heart failure, extra fluid can cause hemodilution leading to anemia. Another proposed mechanism for this type of anemia is due to
1
Department of Pharmacy Practice, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA 2 Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC, USA 3 Pharmacy Service, Durham VA Medical Center, Durham, NC, USA Manuscript submitted: March 26, 2014; accepted: June 5, 2014. Corresponding Author: Jennifer L. Cruz, Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, 508 Fulton Street (119), Durham, NC 27705, USA. Email: [email protected]
Downloaded from cpt.sagepub.com at PURDUE UNIV LIBRARY TSS on June 2, 2015
60
Journal of Cardiovascular Pharmacology and Therapeutics 20(1)
adverse effects of the medications used in the treatment of heart failure.2 According to the American College of Cardiology Foundation/American Heart Association 2013 heart failure guidelines, patients diagnosed with systolic heart failure should be placed on an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).3 These drug classes have shown morbidity and mortality benefits in patients with heart failure.2,4,5 In a healthy patient, angiotensin II increases erythropoietin (EPO) secretion by decreasing renal blood flow due to the vasoconstrictor effect of angiotensin II. When an ACEi or ARB is used, this action is prevented. Other proposed causes of anemia in patients with heart failure include proinflammatory cytokines and concomitant chronic kidney disease.2 Therapies that have been evaluated for the treatment of heart failure include blood transfusions, iron therapy, and erythropoiesis-stimulating agents (ESAs).2 Erythropoiesisstimulating agents have shown benefits in multiple types of anemia, including anemia due to chronic kidney disease, chemotherapy treatment, and zidovudine use in human immunodeficiency virus infection; however, they are not currently approved for anemia due to heart failure.6 Known side effects of ESAs are hypertension, iron deficiency, and increased risk of venous thromboembolism, stroke, and death.6,7 The objective of this literature review was to determine the efficacy and safety of ESAs for the treatment of anemia in patients with systolic heart failure.
Literature Search A search of MEDLINE (1946-January 2014) and EMBASE (1947-January 2014) was conducted using the medical subject heading terms erythropoietin and systolic heart failure. The search was limited to articles written in English that were randomized controlled trials whose patient population was treated for anemia with ESAs. Trials were required to include either clinical outcomes such as exercise capacity, hospitalization for heart failure, or mortality or provide information on adverse events when using ESAs. Bibliographies of relevant articles were reviewed for additional citations. A total of 9 studies met inclusion criteria. The reviewed articles are discussed based on their contributions to either efficacy or safety. A summary of the trials is listed in Table 1.8-16
Literature Review Silverberg et al conducted a randomized controlled trial to evaluate the effect of correcting mild anemia in patients with severe congestive heart failure (CHF).8 This single-center trial enrolled 32 patients with New York Heart Association (NYHA) class III to IV disease. Patients were randomized in a consecutive fashion into the active (n ¼ 16) or control group (n ¼ 16). Erythropoietin (EPO) was administered for active treatment at an initial dose of 4000 units/wk and titrated to maintain a hemoglobin of 12.5 g/%. In addition, intravenous iron was administered to this group at a dose of 200 mg every 2 weeks until serum ferritin reached 400 mg/L, %Fe saturation
was 40%, or the hemoglobin target was met. Patients were followed for a mean 8.2 + 2.7 months. The groups were well matched at baseline in terms of CHF medications, ejection fraction, renal function, and hemoglobin values. A statistically significant improvement from baseline in NYHA classification was demonstrated in the active group compared to the control group (3.8 + 0.4 to 2.2 + 0.7 vs 3.5 + 0.7 to 3.9 + 0.3, P < .0001). During the follow-up period, 4 deaths occurred in the control group compared to 0 in the active group. Other positive findings of this study were an improvement in ejection fraction, a reduction in CHF-related hospitalization days, and a lower furosemide dose requirement in the patients treated with EPO. The limitations of this study included a small sample size, as well as a lack of blinding and use of a placebo control. Additionally, this study excluded patients with less severe CHF (NYHA class II) and had a narrow entry criteria for hemoglobin values (10-11.5 g/dL). Mancini et al conducted a small, single-blind, randomized, and placebo-controlled trial to investigate the effect of EPO therapy on exercise capacity in patients with chronic heart failure after a 3-month trial period.9 Patients were randomized in a 2:1 ratio to 5000 units of EPO dosed 3 times a week (increased to 10 000 units after 4 weeks if hemoglobin increase was below 1 g/dL) or placebo (0.9% saline) dosed once a week. A total of 26 patients were randomized and 23 completed the study. There was a statistically significant change in hemoglobin levels in response to active treatment (11+ 0.6 to 14.3+ 1.2 g/dL, P < .0001), while the hemoglobin in the placebo group remained unchanged (10.9 + 1.1 to 11.5 + 1.3 g/dL). Peak oxygen consumption (VO2) increased significantly from 11 + 0.8 to 12.7 + 2.8 mL/kg min in the treatment group (P < .05) while it decreased from 10.0 + 1.9 to 9.5 + 1.6 in the placebo group. A positive linear correlation was observed between the change in peak VO2 and plasma hemoglobin levels. For the 6-minute walk test, distance for the placebo group at baseline and end of study was 929 + 356 and 1052 + 403 ft, respectively (nonsignificant), while the EPO group increased significantly from 1187 + 279 to 1328 + 254 ft (P < .05). For quality-of-life outcomes, the placebo group’s Minnesota Living with Heart Failure Questionnaire (MLHFQ) score increased by approximately 10 points (56-66), which signifies a poorer quality of life. In contrast, the average score for the EPO group decreased by 9 points (46-37), indicating an improvement (P < .04). This trial was limited by its small sample size and lack of investigator blinding, although the risk of bias was likely minimal since the outcomes measured were objective in nature. Palazzuoli et al conducted a randomized, double-blind, and single-center study examining the impact of anemia treatment on exercise tolerance and other clinical markers in patients with heart failure.10 Forty patients with hemoglobin values
