Efficacy and Safety of EPO for the Critically Ill

Although transfusions are given to 35-45% of patients admitted to the intensive care unit (ICU), the view that red blood cell (RBC) transfusions provide an absolute benefit to the critically ill remains under question. Because patients with anemia of critical illness often suffer impaired RBC production, and an absence of elevated erythropoietin concentrations, epoetin alfa treatment might raise hemoglobin (Hb) concentrations and prevent the need for exposure to allogeneic blood.

The authors of the current study conducted two previous trials in critically ill patients in which epoetin alfa treatment was associated with decreased RBC transfusions and increased Hb concentrations. The following study is a prospective, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of a reduced dose of epoetin alfa (40,000 U) in critically ill patients.

In the period between December 2003 and June 2006, all patients admitted to medical, surgical, or medical–surgical ICUs at 115 medical centers were evaluated for eligibility, which included an Hb less than 12 g/dL. Patients were excluded if they had an expected discharge of less than 48 hours after the second day or if patients satisfied other various exclusion criteria. All patients received a weekly, subcutaneous injection of epoetin alfa or placebo for a total of three doses. Patients also received liquid iron. Transfusion with RBCs was determined by the treating physicians with an Hb target concentration of 7-9 g/dL. Transfusions were not recommended in patients with Hb greater than 9 g/dL or a hematocrit of 27% or greater. Patients were randomized and stratified according to ICU site and three mutually exclusive admission groups (trauma, surgical non-trauma, and medical non-trauma).

Epoetin alfa treatment did not result in a decrease in either the number of patients who received transfusions or the mean (+/-SD) number of transfused units. At day 29, there was a greater increase in Hb concentration in the epoetin alfa group than in the placebo group. There was a trend for lower mortality among the epoetin alfa group at day 29 and day 140. Mortality tended to be lower in trauma patients at day 29 and at day 140. Epoetin alfa was also associated with a significant increase in the incidence of thrombotic events.

Although the use of epoetin alfa did not reduce the incidence of transfusions in critically ill patients, the data from this study suggest that it may reduce mortality in patients with trauma. The incidence of thrombotic events was increased in patients treated with epoetin alfa.

Please reference the source article:
Efficacy and safety of epoetin alfa in critically ill patients. Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ; EPO Critical Care Trials Group. N Engl J Med. 2007 Sep 6;357(10):965-76.

NAAC Expert Commentary:
This well-designed prospective, randomized, placebo controlled study of 1,460 critically ill patients (referred to as EPO III) concluded that treatment of critically ill patients with ESA did not reduce transfusions, a primary end point, in this population. Secondary endpoints were the number of units transfused, mortality and change in hemoglobin level. Patients comprised a mixture of medical, surgical and trauma patients randomized to receive either EPO 40,000 units weekly or placebo. Randomization occurred any where from 48 to 96 hours after admission to the ICU. Although delayed randomization ensured a relatively longer length of stay, the study design prevented the inclusion of data on transfusion activity that took place early in the patient’s admission to the ICU (exclusion criteria only considered transfusion at time of enrollment). The delay in randomization might have also led to better stabilization of patients’ condition, which could reduce the likelihood of transfusion. Patients were randomized to receive either 40,000 units of EPO per week for 3 weeks or placebo.

Of the EPO group, approximately one-third received only 1 dose, while another one-third received only two of the three planned doses. Transfusion was determined by the caring physician, adding a level of subjectivity to this intervention. Despite an increased risk of DVT (which disappeared with proper prophylaxis, a standard of care in ICU today) the EPO group demonstrated an increased survival over the placebo group as well as higher ending hemoglobin. Although the increased survival was present throughout the entire trauma population, it was most pronounced in the younger segment of the trauma population. The primary endpoint was not achieved, but major factors such as stricter transfusion criteria and late randomization could have skewed the results. Both the conclusions of the study and the editorial addressing the study discourage the use of EPO in this population. However, the results of this study are in conflict with these recommendations. Anemia in this population responds to EPO treatment which can improve survival.

Iron-Deficiency Anemia as Presentation of Pouchitis

Patients suffering from ulcerative colitis (UC) have found benefit from the ileal pouch with anal anastomosis (IPAA), a surgical procedure consisting of a colectomy and rectal mucoscectomy with construction of an ileal reservoir. However, long-term complications, most notably pouchitis, are thought to lead to hematologic disorders such as iron-deficiency anemia due to insufficient iron intake and impaired absorption. Although few studies have yielded any conclusive associations between IPAA in UC and iron-deficiency anemia, a recent trial at the University of Puerto Rico evaluated post-IPAA patients to describe the percentage of patients with anemia and the causes of anemia.

In the study, 18 patients (mean age of 34 years; 61% female) with a UC diagnosis who underwent IPAA were evaluated for demographic and past medical data, history of anemia, and symptoms of pouchitis. Anemia was defined according to World Health Organization criteria (hemoglobin (Hb) less than 13.0 g/dL in men and less than 12.0 g/dL in women) with hematocrit levels less than 38% in men and less than 33% in women. Of the 18 patients, ten had anemia (average Hb of 9.9 g/dL; average hematocrit of 30.4%), with 100% of the patients in this group presenting with pouchitis. Also, symptoms of anemia preceded symptoms of pouchitis in 5 of 10 patients. In contrast, only 4 of 8 patients with normal Hb levels presented with pouchitis. Overall, pouchitis was found in 14 of 18 patients (77%).

The study’s results seem to indicate that iron-deficiency anemia may be a clinical presenting sign of pouchitis. In addition, observing Hb and hematocrit levels in patients following IPAA may serve as a surveillance tool for pouchitis. A further strength of this study is that etiology of anemia in females could not be attributed to past history of excessive bleeding or metrorrhagia. However, the study utilized a small sample population, and larger, more comprehensive studies are needed to better determine the use of Hb and hematocrit levels as surveillance tools for pouchitis following IPAA.

Please reference the source article:
Iron-deficiency anemia as presentation of pouchitis. Pastrana RJ, Torres EA, Arroyo JM, Rivera CE, Sanchez CJ, Morales L. Journal of Clinical Gastroenterology. 2007 Jan;41(1):41-4.

NAAC Expert Commentary:
Pouchitis is a common complication of ileal pouch with anal anastomosis (IPAA) which is typically performed for surgical treatment of ulcerative colitis. Although the severity of pouchitis can range from mild to severe, it can be quite debilitating. Clinically overt cases of pouchitis can be diagnosed endoscopically with typical histologic features. Nevertheless, patients may present with very mild symptoms or clinical presentation. If diagnosed accurately and early, the mainstay of therapy remains antibiotic treatment. In a small study of patients with IPAA, Pastrana RJ and colleagues have recently reported a high prevalence of iron deficiency anemia in those with pouchitis. In this study, 55% of the entire cohort had iron deficiency anemia while 77% of the cohort had clinically overt pouchitis. Nevertheless, all patients with pouchitis (100%) had iron deficiency anemia. These findings suggest that iron-deficiency anemia may be an early marker of pouchitis and proposes that close monitoring of hemoglobin levels in patients with IPAA may be warranted.

Blood Conservation in the Critically Ill

Erythropoiesis-stimulating agents (ESAs) have been shown to have a supportive therapy role in patients with anemia of critical illness by reducing the need for blood exposures and red blood cell (RBC) transfusions. Despite these benefits, many recent studies have pointed towards higher mortality rates and adverse cardiovascular events in patients receiving ESA dosing. Currently, no studies have clearly defined how IV iron supplementation can have an effect on patient response to ESAs. However, a recent pilot study has attempted to develop criteria for a standardized approach for the appropriate use of pharmaceutical treatments, specifically epoetin alfa, in critically ill patients with anemia.

In the pilot trial, 87 patients (mean age 67.4 years; 53% female) were investigated in an open-enrollment study at a mixed medical/surgical ICU unit of a Baltimore community hospital from August 2004 through May 2005. Patient eligibility was based on Grade I World Health Organization criteria (hemoglobin less than or equal to 10.5 g/dL), as well as exclusion factors such as renal failure or previous epoetin alfa treatment. Based on previous studies of epoetin alfa dosing, a once weekly dose of 600 units/kg was used as a standard, along with an order option of 100 mg iron sucrose given intravenously for three days. In addition, folic acid, ascorbic acid, and cyancobalamin were also administered at the clinician’s discretion.

After evaluation of the total patient population, a significant pharmacodynamic response (0.8 g/dL increase following five days administration) was demonstrated in patients receiving epoetin alfa. Specifically, overall reticulocyte counts increased by 1.9%, with non-transfusion groups seeing the highest increase (2.4%). On average, 1.9 units of RBC were transfused, with 31% of patients receiving no transfusions. In addition, supplementation of IV iron therapy appeared to enhance the effect of epoetin alfa. Dramatic increases in absolute reticulocyte counts were seen in non-transfusion groups, while the IV iron group had the least RBC units transfused.

It would seem, then, that the recent pilot study was successful in developing a useful, standardized approach in utilizing ESAs with iron supplement therapy. Given the 4 million-unit shortfall of RBC predicted in the U.S. over the next 25 years, this study’s weekly dosing schedule, with optional iron supplementation, seems to be a cost-effective alternative. However, in light of recent blood shortages, as well as Food and Drug Administration warnings on high levels of ESA dosing, further testing needs to be done to determine optimal dosing levels and cost-efficient use of ESAs.

Please reference the source article:
Blood Conservation in the Critically Ill. Thomas J, Martinez A. American Journal of Health-system Pharmacy. 2007 Aug 15;64(16 Suppl 11):S11-8.

NAAC Expert Commentary:
This open label study demonstrates that ESAs are effective in the treatment of anemia in critically ill patients. Moreover, the effect of EPO treatment in this population was enhanced by use of an algorithm for administration of complimentary nutritional treatment with iron and vitamins. Previous randomized placebo controlled trials have demonstrated a reduction in allogeneic transfusion in this population. Although outcome was not demonstrated, a new study released in the New England Journal of Medicine (Corwin HL, et al. N Engl J Med. 2007 Sep 6;357(10):965-76) demonstrated increased hemoglobin response with EPO and improved survival in ICU patients compared to placebo. Allogeneic blood transfusions are associated with increased morbidity and mortality in this population and the availability of another modality is beneficial. Optimal dosing and length of treatment have not been well established in ICU patients.

However, this study attempts to give a weight-based dose rather than the commonly used 40,000 units per week. Weight-based dosing makes more sense for this population, since a 100 kg male receiving 40,000 units per week may be under-dosed, while a 40 kg female may be overdosed with the same 40,000 units. A 600 unit per kg once a week dosing guideline is a sound approach but may result in some wasted product depending on a patient’s weight. This study also demonstrated the importance of supplemental iron. Iron has been shown to improve EPO effect and possibly reduce the dose of EPO. In summary, although these findings were not the product of a randomized controlled study, the use of clinical pathways and algorithms may lead to better clinical outcomes, as demonstrated in this article. The targeted reduction in allogeneic transfusion was achieved, as well as increased hemoglobin level.