Efficacy Of Recombinant Human Erythropoietin In Critically Ill Patients
Efficacy Of Recombinant Human Erythropoietin In Critically Ill Patients
Context: Anemia is common in the critically ill and results in a large number of red blood cell transfusions. Recent data have shown that red blood cell transfusions in critically ill patients can be decreased with recombinant human erythropoietin (rHuEPO) therapy during their intensive care unit stay.
Objective: To assess the efficacy of rHuEPO therapy in decreasing the occurrence of red blood cell transfusions in patients admitted to a long-term acute care facility (LTAC).
Design: A prospective, randomized, double-blind, placebo-controlled, multiple-center trial.
Setting: Two long-term acute care facilities.
Patients: A total of 86 patients who met eligibility criteria were enrolled in the study with 42 randomized to rHuEPO and 44 to placebo.
Interventions: Study drug (rHuEPO 40,000 units) or a placebo was administered by subcutaneous injection before day 7 of long-term acute care facility admission and continued weekly for up to 12 doses.
Main Outcome Measures: The primary efficacy end point was cumulative red blood cell units transfused. Secondary efficacy end points were the percent of patients receiving any red blood cell transfusion; the percent of patients alive and transfusion independent; cumulative mortality; and change in hematologic variables from baseline. Logistic regression was used to adjust the odds ratio for red blood cell transfusion. All end points were assessed at both study day 42 and study day 84.
Results: The baseline hemoglobin level was higher in the rHuEPO group (9.9 ± 1.15 g/dL vs. 9.3 ± 1.41 g/dL, p = .02) as was the pretransfusion hemoglobin level (8.0 ± 0.5 g/dL vs. 7.5 ± 0.8 g/dL, p = .04). At day 84, patients receiving rHuEPO received fewer red blood cell transfusions (median units per patient 0 vs. 2, p = .05), and the ratio of red blood cell transfusion rates per day alive was 0.61 with 95% confidence interval of 0.2, 1.01, indicating a 39% relative reduction in transfusion burden for the rHuEPO group compared with placebo. There was also a trend at day 84 toward a reduction in the total units of red blood cells transfused in the rHuEPO group (113 units of placebo vs. 73 units of rHuEPO). Patients receiving rHuEPO were also less likely to be transfused (64% placebo vs. 41% rHuEPO, p = .05; adjusted odds ratio 0.47, 95% confidence interval 0.19, 1.16). Most of the transfusion benefit of rHuEPO occurred by study day 42. Increase in hemoglobin from baseline to final was greater in the rHuEPO group (1.0 ± 2 g/dL vs. 0.4 ± 1.7 g/dL, p < .001). Mortality rate (19% rHuEPO, 29.5% placebo, p = .17; relative risk, 0.55, 95% confidence interval 0.21-1.43) and serious adverse clinical events (38 % rHuEPO, 32% placebo, p = .65) were not significantly different between the two groups.
Conclusions: In patients admitted to a long-term acute care facility, administration of weekly rHuEPO results in a significant reduction in exposure to allogeneic red blood cell transfusion during the initial 42 days of rHuEPO therapy, with little additional benefit achieved with therapy to 84 days. Despite receiving fewer red blood cell transfusions, patients treated with rHuEPO achieve a higher hemoglobin level.
The effects of critical illness may persist well after resolution of the acute critical illness as well as after discharge from the intensive care unit (ICU). This chronically critically ill population, many of whom require prolonged mechanical ventilation, is a population that has significant associated morbidity and cost. Therefore, the chronically critically ill constitute an increasingly large and important population of patients. During the last decade, long-term acute care hospitals (LTAC) have been developed to provide care for patients with ongoing complex problems following hospitalization for a critical illness, such as long-term weaning from mechanically ventilation.
Although considerable data are available regarding red blood cell (RBC) transfusion practice in the ICU, few data are available on transfusion practice in critically ill patients after they leave the ICU. There are, however, some suggestions that at least some of these more chronic patients have ongoing RBC transfusion requirements after leaving the ICU. Recent studies have observed that 13% of patients followed for 30 days after ICU admission receive RBC transfusions after leaving the ICU. These patients, 40% of whom are transfused only following ICU discharge, on average receive almost 3 RBC units after leaving the ICU.
Transfusion practice in the critically ill has been under considerable scrutiny during the last decade. Recent studies have raised the concern that immunomodulation related to allogeneic blood transfusion is associated with an increase in infections in the critically ill. Concerns have also been raised regarding possible increases in morbidity associated with the age of RBCs transfused. Adding to the controversy about risk/benefit ratio for RBC transfusion are recent data showing that an aggressive RBC transfusion strategy may decrease the likelihood of survival in selected subpopulations of critically ill adults. In the critically ill, RBC transfusion appears to be independently associated with increases in morbidity and mortality. Accordingly, limiting exposure to allogeneic RBC transfusions would be advantageous in the critically ill population, either acute or chronic.
Recently, in a large, randomized, placebo-controlled trial of critically ill patients admitted to the ICU, administration of a weekly dose of 40,000 units of recombinant human erythropoietin (rHuEPO) for up to four doses resulted in a 20% reduction in the total number of RBC units transfused. The current study was designed to assess the efficacy of rHuEPO in reducing the exposure to allogeneic RBCs in chronically critically ill patients admitted to an LTAC. The objectives were to determine whether administration of rHuEPO to patients admitted to an LTAC would decrease the occurrence of any RBC transfusion as well as decrease the cumulative number of RBC units transfused.
Abstract and Introduction
Abstract
Context: Anemia is common in the critically ill and results in a large number of red blood cell transfusions. Recent data have shown that red blood cell transfusions in critically ill patients can be decreased with recombinant human erythropoietin (rHuEPO) therapy during their intensive care unit stay.
Objective: To assess the efficacy of rHuEPO therapy in decreasing the occurrence of red blood cell transfusions in patients admitted to a long-term acute care facility (LTAC).
Design: A prospective, randomized, double-blind, placebo-controlled, multiple-center trial.
Setting: Two long-term acute care facilities.
Patients: A total of 86 patients who met eligibility criteria were enrolled in the study with 42 randomized to rHuEPO and 44 to placebo.
Interventions: Study drug (rHuEPO 40,000 units) or a placebo was administered by subcutaneous injection before day 7 of long-term acute care facility admission and continued weekly for up to 12 doses.
Main Outcome Measures: The primary efficacy end point was cumulative red blood cell units transfused. Secondary efficacy end points were the percent of patients receiving any red blood cell transfusion; the percent of patients alive and transfusion independent; cumulative mortality; and change in hematologic variables from baseline. Logistic regression was used to adjust the odds ratio for red blood cell transfusion. All end points were assessed at both study day 42 and study day 84.
Results: The baseline hemoglobin level was higher in the rHuEPO group (9.9 ± 1.15 g/dL vs. 9.3 ± 1.41 g/dL, p = .02) as was the pretransfusion hemoglobin level (8.0 ± 0.5 g/dL vs. 7.5 ± 0.8 g/dL, p = .04). At day 84, patients receiving rHuEPO received fewer red blood cell transfusions (median units per patient 0 vs. 2, p = .05), and the ratio of red blood cell transfusion rates per day alive was 0.61 with 95% confidence interval of 0.2, 1.01, indicating a 39% relative reduction in transfusion burden for the rHuEPO group compared with placebo. There was also a trend at day 84 toward a reduction in the total units of red blood cells transfused in the rHuEPO group (113 units of placebo vs. 73 units of rHuEPO). Patients receiving rHuEPO were also less likely to be transfused (64% placebo vs. 41% rHuEPO, p = .05; adjusted odds ratio 0.47, 95% confidence interval 0.19, 1.16). Most of the transfusion benefit of rHuEPO occurred by study day 42. Increase in hemoglobin from baseline to final was greater in the rHuEPO group (1.0 ± 2 g/dL vs. 0.4 ± 1.7 g/dL, p < .001). Mortality rate (19% rHuEPO, 29.5% placebo, p = .17; relative risk, 0.55, 95% confidence interval 0.21-1.43) and serious adverse clinical events (38 % rHuEPO, 32% placebo, p = .65) were not significantly different between the two groups.
Conclusions: In patients admitted to a long-term acute care facility, administration of weekly rHuEPO results in a significant reduction in exposure to allogeneic red blood cell transfusion during the initial 42 days of rHuEPO therapy, with little additional benefit achieved with therapy to 84 days. Despite receiving fewer red blood cell transfusions, patients treated with rHuEPO achieve a higher hemoglobin level.
Introduction
The effects of critical illness may persist well after resolution of the acute critical illness as well as after discharge from the intensive care unit (ICU). This chronically critically ill population, many of whom require prolonged mechanical ventilation, is a population that has significant associated morbidity and cost. Therefore, the chronically critically ill constitute an increasingly large and important population of patients. During the last decade, long-term acute care hospitals (LTAC) have been developed to provide care for patients with ongoing complex problems following hospitalization for a critical illness, such as long-term weaning from mechanically ventilation.
Although considerable data are available regarding red blood cell (RBC) transfusion practice in the ICU, few data are available on transfusion practice in critically ill patients after they leave the ICU. There are, however, some suggestions that at least some of these more chronic patients have ongoing RBC transfusion requirements after leaving the ICU. Recent studies have observed that 13% of patients followed for 30 days after ICU admission receive RBC transfusions after leaving the ICU. These patients, 40% of whom are transfused only following ICU discharge, on average receive almost 3 RBC units after leaving the ICU.
Transfusion practice in the critically ill has been under considerable scrutiny during the last decade. Recent studies have raised the concern that immunomodulation related to allogeneic blood transfusion is associated with an increase in infections in the critically ill. Concerns have also been raised regarding possible increases in morbidity associated with the age of RBCs transfused. Adding to the controversy about risk/benefit ratio for RBC transfusion are recent data showing that an aggressive RBC transfusion strategy may decrease the likelihood of survival in selected subpopulations of critically ill adults. In the critically ill, RBC transfusion appears to be independently associated with increases in morbidity and mortality. Accordingly, limiting exposure to allogeneic RBC transfusions would be advantageous in the critically ill population, either acute or chronic.
Recently, in a large, randomized, placebo-controlled trial of critically ill patients admitted to the ICU, administration of a weekly dose of 40,000 units of recombinant human erythropoietin (rHuEPO) for up to four doses resulted in a 20% reduction in the total number of RBC units transfused. The current study was designed to assess the efficacy of rHuEPO in reducing the exposure to allogeneic RBCs in chronically critically ill patients admitted to an LTAC. The objectives were to determine whether administration of rHuEPO to patients admitted to an LTAC would decrease the occurrence of any RBC transfusion as well as decrease the cumulative number of RBC units transfused.