Therapy Efficacy of Recombinant Human Erythropoietin in Critically Ill Patients: A Randomized Controlled Trial
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Summary
Posted By:	Celia Bradford
E-Mail:	celiabradford@telstra.com
Posted Date:	4/2/03
Title:	Efficacy of Recombinant Human Erythropoietin in Critically Ill Patients: A Randomized Controlled Trial
Authors:	Corwin HL, Gettinger A, Pearl RG, Fink MP et al
Reference:	JAMA 2002 Dec 11;288(22):2827-35
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	CONTEXT: Anemia is common in critically ill patients and results in a large number of red blood cell (RBC) transfusions. Recent data have raised the concern that RBC transfusions may be associated with worse clinical outcomes in some patients. OBJECTIVE: To assess the efficacy in critically ill patients of a weekly dosing schedule of recombinant human erythropoietin (rHuEPO) to decrease the occurrence of RBC transfusion. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter trial conducted between December 1998 and June 2001. SETTING: A medical, surgical, or a medical/surgical intensive care unit (ICU) in each of 65 participating institutions in the United States. PATIENTS: A total of 1302 patients who had been in the ICU for 2 days and were expected to be in the ICU at least 2 more days and who met eligibility criteria were enrolled in the study; 650 patients were randomized to rHuEPO and 652 to placebo. INTERVENTION: Study drug (40 000 units of rHuEPO) or placebo was administered by subcutaneous injection on ICU day 3 and continued weekly for patients who remained in the hospital, for a total of 3 doses. Patients in the ICU on study day 21 received a fourth dose. MAIN OUTCOME MEASURES: The primary efficacy end point was transfusion independence, assessed by comparing the percentage of patients in each treatment group who received any RBC transfusion between study days 1 and 28. Secondary efficacy end points identified prospectively included cumulative RBC units transfused per patient through study day 28; cumulative mortality through study day 28; change in hemoglobin from baseline; and time to first transfusion or death. RESULTS: Patients receiving rHuEPO were less likely to undergo transfusion (60.4% placebo vs 50.5% rHuEPO; P<.001; odds ratio, 0.67; 95% confidence interval [CI], 0.54-0.83). There was a 19% reduction in the total units of RBCs transfused in the rHuEPO group (1963 units for placebo vs 1590 units for rHuEPO) and reduction in RBC units transfused per day alive (ratio of transfusion rates, 0.81; 95% CI, 0.79-0.83; P =.04). Increase in hemoglobin from baseline to study end was greater in the rHuEPO group (mean [SD], 1.32 [2] g/dL vs 0.94 [1.9] g/dL; P<.001). Mortality (14% for rHuEPO and 15% for placebo) and adverse clinical events were not significantly different. CONCLUSIONS: In critically ill patients, weekly administration of 40 000 units of rHuEPO reduces allogeneic RBC transfusion and increases hemoglobin. Further study is needed to determine whether this reduction in RBC transfusion results in improved clinical outcomes.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes; 650 to therapy arm (rHuEPO) and 652 to placebo arm. Randomization was stratified by site and entailed use of computer-generated random numbers. Randomization was administered by the data coordinating centre.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes, reporting of loss to follow-up was complete; The treatment group had 17 lost to follow-up, while the placebo group lost 19 to follow-up
2b. Were patients analyzed in the groups to which they were randomized?
	Yes. However, only 54 % of the patients in the treatment arm received all the intended doses of rHuEPO.
3. Were patients, health workers, and study personnel blind to treatment?
	Yes. There was adequate blinding, with the study drug and placebo identical in appearance.
4. Were the groups similar at the start of the trial?
	The 2 groups were generally comparable. The baseline serum iron in the treatment arm was significantly higher than the placebo group. Differences in primary haematologic disease were taken into account by multivariate analysis.
5. Aside from the experimental intervention, were the groups treated equally?
	Yes. All patients received iron.
What are the Results?
1. How large was the treatment effect?
	Primary Outcome Measure compared percentage of patients in each treatment group who received any RBC transfusion between Days 1-28. 60.4% of the placebo group and 50.5% of the treatment group received a transfusion, p<0.001. Secondary Outcome Measures compared cumulative RBC units transfused to 28 days. In the placebo group 1963 units were transfused and in the rHuEPO group 1590 units were transfused, (median units per subject, 1 vs. 2, p<0.001). When comparing cumulative mortality there were no statistical significant differences between the 2 groups (rHuEPO 14% and placebo group 15%). The change in haemoglobin from baseline; rHuEPO saw an increase by 1.32g/dl and in the placebo group by 0.94g/dL which was a statistically different result, p<0.001.
2. How precise was the estimate of the treatment effect?
	After adjusting for baseline characteristics the percentage receiving transfusion had an odds ratio of 0.65 (CI 0.51-0.83). The number of transfusions received had an odds ratio of 0.81 (CI 0.79-0.83). The difference in mortality at 28 days was not statistically different.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	The intensive care units were mixed medical and surgical units with a baseline average APACHE II score of 19.6 and 19.7. However, these units had a liberal transfusion policy with the mean pretransfusion haemogloben bein 8.57g/dL for the placebo group and 8.53g/dL for the treatment group. Our aims at RNSH would be to limit transfusion to patients with haemoglobins less than 7g/dL (See Evidence-based Recommendation regarding restrictive transfusion). Similaly, 21% of patients in each group underwent transfusion at a haemoglobin level greater than 9g/dL - something we would try to avoid unless a specific clinical indication, eg acute ischemic heart disease.
2. Were all clinically important outcomes considered?
	No; One major concern with blood transfusion is spread of blood borne infection. This outcome was not measured at 28 days. The study was not sufficiently powered to detect rare adverse affects of rHuEPO such as red cell aplasia. It is also important to note that costs and patient preferences (desire to avoid transfusions) were not reported.
3. Are the likely treatment benefits worth the potential harms and costs?
	Under the current practice of restrictive transfusion, it is unclear if this treatment is worth the harm and costs. The cost of the rHuEPO is large and would present a substantial financial strain. The morbidity associated with this therapy is not clearly defined in this study. The external validity is questionable as the centres involved have a liberal transfusion policy with 21% of patients in each group undergoing transfusion at a haemoglobin greater than 9 g/dL.
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