Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Shapiro MJ, Corwin MJ, Colton T, for the EPO Critical Care Trials Group . Efficacy of Recombinant Human Erythropoietin in Critically Ill PatientsA Randomized Controlled Trial. JAMA. 2002;288(22):2827-2835. doi:10.1001/jama.288.22.2827
Author Affiliations: Critical Care Medicine (Dr H. Corwin) and Department of Anesthesiology (Dr Gettinger), Dartmouth-Hitchcock Medical Center, Lebanon, NH; Department of Anesthesia, Stanford University Medical Center, Stanford, Calif (Dr Pearl); Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa (Dr Fink); Rhode Island Hospital, Providence (Dr Levy); St Louis University Health Science Center, St Louis, Mo (Dr Shapiro); and Department of Pediatrics, Boston University School of Medicine (Dr M. Corwin), Department of Epidemiology, Boston University School of Public Health (Dr Colton), and CareStat Inc (Drs M. Corwin and Colton), Boston, Mass.
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
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
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  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.
Blood transfusion, an integral part of clinical practice for most of
the last century, has been looked upon as relatively "risk free" and with
obvious clinical benefit.1 A dramatic change
in thinking occurred in the early 1980s, when concerns about transfusion-related
infections, particularly those caused by hepatitis C and the human immunodeficiency
virus (HIV), prompted a reevaluation of the risks of allogeneic transfusion.
Although advances in transfusion medicine have greatly decreased the risk
of viral transmission during blood transfusion, other concerns now drive the
debate over transfusion practice and have led to a reexamination of the approach
to red blood cell (RBC) transfusion.
Critically ill patients typically receive multiple RBC transfusions.2- 4 Recent data from both
the United States and Western Europe demonstrate that between 35% and 50%
of all patients admitted to ICUs today receive on average almost 5 RBC units
during their ICU stay.5,6 However,
the view of RBC transfusion as risk free is no longer tenable. In addition
to well-described transfusion complications, recent studies have raised the
issue of immunosuppression related to allogeneic blood transfusion,1,7- 10 as
well as concerns regarding the age of RBCs transfused.11,12 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 subgroups of critically ill adults.13 Accordingly, limiting exposure to allogeneic RBC
transfusions would be advantageous in critically ill patients.
Production of RBCs by the bone marrow is impaired in critically ill
patients, and this phenomenon contributes to both the development and the
persistence of anemia. Critically ill patients tend to be anemic early in
their ICU course and hemoglobin levels fall during the ICU stay.5,6 The
anemia associated with critical illness is probably fundamentally similar
to the anemia of chronic inflammatory disease.14 A
major feature of the anemia of critical illness is a failure of circulating
erythropoietin concentrations to increase appropriately in response to physiologic
stimuli.15- 19 Thus,
we hypothesized that treatment with pharmacological doses of recombinant human
erythropoietin (rHuEPO) might decrease exposure to allogeneic blood and raise
the hemoglobin level in critically ill patients.
Recently, a small, randomized, placebo-controlled trial of critically
ill patients who received a combination of daily administration of rHuEPO
for 5 days followed by every-other-day administration reported an almost 50%
reduction in the number of RBC transfusions.20 Despite
receiving fewer RBC transfusions, patients receiving rHuEPO had a significantly
greater increase in hematocrit. The efficacy of rHuEPO in this trial has raised
the question whether rHuEPO would also be effective at reducing transfusions
in a larger, more diverse critically ill population. Furthermore, in other
clinical settings a weekly rHuEPO dose of 40 000 units has been shown
to be as effective as more frequent dosing regimens.21- 24 Our
study was designed to assess the efficacy of a weekly dosing schedule of rHuEPO
in reducing the exposure to allogeneic RBCs in a large, diverse group of critically
This study was a prospective, randomized, double-blind, placebo-controlled,
multicenter trial conducted at 65 US medical centers between December 1998
and June 2001 (study group members are listed at the end of this article).
Approval of the study was obtained from the institutional review committee
at each participating institution and written informed consent was obtained
from each patient (or surrogate). Each institutional review committee determined
who could qualify as a patient surrogate for the purpose of giving consent
at their institution. The study was monitored for safety by an independent
data and safety monitoring board, which met 11 times during the course of
the study; the stopping rule was a mortality difference of P<.001 (DSMB listed at the end of this article). The study objective
was to determine if administration of rHuEPO to critically ill patients admitted
to the ICU would reduce the occurrence of any RBC transfusion as well as reduce
the cumulative number of RBC units transfused.
The study was designed by the principal investigators with input from
the data coordinating center and was reviewed by the study sponsor. Patient
enrollment was done at each site and supervised by the data coordinating center.
Randomization and data analysis were done by the data coordinating center.
The principal investigators and manuscript committee, with assistance from
the data coordinating center, interpreted the data and were responsible for
the manuscript. The final manuscript was reviewed by the study sponsor. The
manuscript committee determined the final manuscript content and had full
access to all data.
All patients admitted to either a medical, surgical, or a medical/surgical
ICU in each of the 65 participating institutions, who remained in the ICU
for at least 2 days, were evaluated for study eligibility prior to ICU day
3 (study day 1). Inclusion criteria included stay in the ICU for 3 days; age
at least 18 years; hematocrit less than 38%; and provision of signed informed
consent. Exclusion criteria included renal failure with dialysis; uncontrolled
hypertension; new onset or uncontrolled seizures; acute burns; pregnancy or
lactation; acute ischemic heart disease; acute gastrointestinal bleeding;
prior treatment with rHuEPO; participation in another research protocol; and
expected ICU discharge within 48 hours of ICU day 2. Patients who met entry
criteria and who gave informed consent were randomized and entered into the
study on ICU day 3 (study day 1). Randomization was stratified by site and
entailed use of computer-generated random numbers (Figure 1).
Study drug (40 000 units of rHuEPO [Procrit; Ortho Biotech Products,
LP, Bridgewater, NJ]) or a placebo identical in appearance was administered
by subcutaneous injection on ICU day 3 and continued once weekly for patients
who remained in the hospital, for a total of 3 doses (study days 1, 7, and
14). Patients who remained in the ICU on study day 21 received a fourth dose.
Syringes were prepared either in the hospital's pharmacy or in the patient
care area. Study drug was withheld if the hematocrit was 38% prior to the
scheduled administration. All patients were to be followed up for 28 days
following randomization (study day 28).
Patients received oral iron (liquid preparation), at least 150 mg/d
of elemental iron, either orally or via nasogastric tube beginning on study
day 1 (ICU day 3), unless they could not tolerate oral feeding. Parenteral
iron was to be given to patients demonstrating an inadequate response to oral
iron (transferrin saturation <20% and a decrease of serum ferritin to <100
ng/mL [<225 pmol/L]).
The need for RBC transfusion was determined by each patient's physician.
The following transfusion guideline was established for the study: no RBC
transfusion if the hemoglobin level was at least 9 g/dL or the hematocrit
concentration was at least 27%, unless there was a specific clinical indication
(active bleeding, ischemia, or other); RBC transfusion for a hemoglobin level
less than 9 g/dL or a hematocrit concentration less than 27% was at a physician's
discretion. There was no hemoglobin level or hematocrit concentration that
mandated an RBC transfusion. Transfusion indication, pretransfusion hemoglobin
level, and pretransfusion hematocrit concentration were recorded for each
RBC transfusion. In addition, patients were monitored for all adverse events
associated with either drug administration or RBC transfusion.
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 were 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. Additional data recorded included ICU length of stay,
hospital length of stay, and days receiving mechanical ventilation.
Baseline demographic, diagnostic, and laboratory data were obtained
at randomization. Acute Physiology and Chronic Health Evaluation (APACHE)
II scores were based on data obtained within the first 24 hours after ICU
admission. Admitting diagnosis was selected from a list of diagnostic categories;
all that applied were noted. Comorbidities identified from the medical history
included cardiac disease, chronic pulmonary disease, diabetes mellitus, hypertension,
malignancy, peripheral vascular disease, primary hematologic disease, and
Adverse events were assessed daily. Laboratory data were obtained weekly,
within 24 hours prior to the weekly administration of study drug, and at study
completion. Patients discharged from the hospital prior to study day 28 had
final laboratory data obtained within 7 days of study day 28. Mechanical ventilation
was recorded on a daily basis, as was a patient's presence in the ICU.
A sample size of 1300 was calculated to provide at least 90% power to
detect an absolute treatment difference of 10% with respect to the primary
efficacy end point, percentage of patients receiving any RBC transfusion.
All patients were followed up for 28 days, unless death occurred earlier.
Analysis of outcomes was on an intent-to-treat basis.
The primary efficacy end point was evaluated using a 2-sided Fisher
exact test. Patients not receiving transfusion at the time of study withdrawal
or lost to follow-up were considered not transfused for this analysis. In
addition, a second analysis was done in which all patients withdrawn or lost
to follow-up were considered transfused.
Secondary analyses were specified in the original study protocol. To
compare the number of RBC units transfused per patient in the 2 study groups,
we used the Mann-Whitney test. Transfusion rate, expressed as RBC units transfused
per day alive while in the study, was determined by dividing the total number
of RBC units transfused for each group by the total number of days alive for
the patients in that group (sum of the number of days alive for each individual
patient in the group, maximum of 28 for a patient surviving to study day 28).
Mechanical ventilation was analyzed as ventilator-free days, defined
as the number of days a patient was alive and did not receive mechanical ventilation
through study day 28. Patients were included whether mechanical ventilation
was initiated on or after study day 1. Patients who were reventilated were
also included. Patients were excluded only if they withdrew from the study,
were lost to follow-up, or had a missing ventilator stop date with a hospital
discharge date prior to study day 28. Reventilation was analyzed only for
those patients who were candidates for reventilation, ie, discontinued initial
mechanical ventilation prior to study day 28 and who did not die on the day
of or the day after discontinuation of mechanical ventilation. Ventilator-free
days were compared using the Mann-Whitney test. Similarly, ICU length of stay
was analyzed as ICU-free days, defined as the number of days a patient was
alive and not in the ICU through study day 28. Patients were excluded only
if they withdrew from the study or were lost to follow-up. Readmission to
the ICU was analyzed only for those patients who were candidates for readmission,
ie, discharged from their initial ICU stay prior to study day 28 and did not
die on their last day in the ICU. Number of ICU-free days was compared using
the Mann-Whitney test.
Several survival analyses of time to event (death, first transfusion,
first transfusion or death, ICU readmission, ventilation, reventilation) were
performed. Kaplan-Meier survival curves for the 2 groups were compared using
the log-rank test.
Logistic regression was performed to adjust the odds ratio (OR) for
RBC transfusion. Covariates entered included age, sex, diagnostic categories,
comorbidities, APACHE II score, baseline hemoglobin, baseline iron, baseline
erythropoietin level, and baseline serum creatinine. Two statistical approaches,
Cox semiparametric modeling assuming proportional hazards and recursive partitioning,
were used to explore the association of mortality with treatment and other
To assess changes in laboratory values from baseline to final value,
analysis of covariance was used with baseline value and number of days between
baseline and final value as covariates.
Results are presented as mean (SD) unless otherwise indicated. All statistical
tests were 2-tailed at the .05 significance level, except for the tests of
treatment-by-covariate interactions, which were at the .10 significance level.
Analyses were conducted with SAS OnlineDoc version 8 (SAS Institute Inc, Cary,
In addition to the main analysis of all patients, several subgroups
of patients were analyzed separately for both percentage of patients undergoing
transfusion and mortality. Although these subgroups were not prospectively
identified, they were identified prior to knowledge of treatment assignment
and prior to the locking of the database and the conduct of the final data
analysis. The DSMB identified 3 mutually exclusive admitting diagnostic categories
for safety monitoring during the study: trauma; surgical, nontrauma; and medical,
nonsurgical, nontrauma. These 3 admitting diagnostic categories were determined
independently of the baseline admitting diagnoses. Four other subgroups identified
were identical to the subgroups studied by Hebert et al13 to
allow for comparison of our findings with theirs: age younger than 55 years;
age 55 years or older; APACHE II score 20 or lower; and APACHE II score higher
Among the 33 685 patients screened on ICU day 2 (Figure 1), more than 70% were ineligible for the study, primarily
because of expected ICU discharge within 24 to 48 hours. Of those eligible,
approximately two thirds were not approached for consent to participate, in
most instances because of inability to identify and contact the appropriate
patient surrogate(s) during the window of time for study enrollment. Of those
patients (or surrogates) asked to consent, 50% agreed.
A total of 1302 patients were enrolled in the study, with 650 randomized
to receive rHuEPO and 652 to receive placebo. The 2 groups were generally
comparable at enrollment with respect to baseline demographic characteristics
and laboratory values as well as admitting diagnosis and comorbidities (Table 1). There were some statistically
significant differences; however, the magnitudes were not clinically meaningful
and multivariate analysis took these variables into account. The study drug
exposure was as follows: 15% received 1 dose; 31% received 2 doses; 37% received
3 doses; and 17% received 4 doses.
The percentage of patients who received any RBC transfusion during the
28-day follow-up was significantly lower in the rHuEPO group than in the placebo
group (n = 328 [50.5%] vs n = 394 [60.4%]; P<.001;
OR, 0.67; 95% confidence interval [CI], 0.54-0.83). After adjustment for baseline
characteristics, the effect of rHuEPO was essentially unchanged (adjusted
OR, 0.65; 95% CI, 0.51-0.83). The results of an additional analysis in which
all patients withdrawn or lost to follow-up were considered to have had transfusion
were similar to those described above (63.3% placebo vs 53.4% rHuEPO; OR,
0.66; 95% CI, 0.53-0.83).
A Kaplan-Meier plot of the time to first transfusion indicates that
a difference between the 2 treatment groups commenced near the end of the
first week following randomization and increased progressively over the course
of the 28-day follow-up (Figure 2A).
A similar pattern occurred for the composite end point of time to first transfusion
or death (Figure 2B).
The cumulative number of RBC transfusions for each treatment group over
the 28-day follow-up appears in Table 2. The total number of RBC units transfused was 1590 units for rHuEPO
therapy compared with 1963 units for placebo therapy. The cumulative RBC transfusions
were significantly lower in patients receiving rHuEPO compared with placebo
patients. This was initially assessed based on the cumulative RBC units per
subject (median units per subject, 1 vs 2; P<.001).
A second analysis that accounted for time at risk for transfusion demonstrated
a 19% reduction in RBC units transfused per day alive (ratio of transfusion
rates, 0.81; 95% CI, 0.79-0.83; P = .04). Figure 3 displays the cumulative units transfused
by study day. This plot suggests that the treatment groups do not begin to
differ with regard to RBC units transfused until approximately 1 week following
The mean (SD) increase in hemoglobin from baseline to final determination
was significantly greater for patients who received rHuEPO (1.32  g/dL
vs 0.94 [1.9] g/dL for placebo; P<.001). The mean
day the final hemoglobin measurement was obtained was identical for both groups
at study day 23.
Transfusion practices were similar in the 2 treatment groups. The mean
pretransfusion hemoglobin was 8.57 (0.96) g/dL for the placebo group and 8.53
(1.08) g/dL for the rHuEPO group. Among those patients undergoing transfusion,
pretransfusion hemoglobin was similar in the 2 treatment groups for the first
RBC transfusion as well as for all subsequent RBC transfusions. Similarly,
21% of patients in each group underwent transfusion at a hemoglobin level
greater than 9 g/dL or hematocrit greater than 27%.
There was no significant difference in 28-day mortality between the
2 groups (14% in rHuEPO vs 15% in placebo; P = .61, Figure 4). The incidence of severe adverse
events reported was comparable between the 2 treatment groups (Table 3).
Median hospital length of stay (19 days for rHuEPO vs 21 days for placebo; P = .82) and median ICU-free days (18 days for rHuEPO vs
17 days for placebo; P = .25) did not differ between
groups. However, there was a higher, but not statistically significant, ICU
readmission rate in the placebo group compared with the rHuEPO group (13.3%
vs 9.8%, respectively; P = .07).
Median ventilator-free days did not differ between the 2 groups (22
days for rHuEPO vs 20 days for placebo; P = .27).
There were also no statistically significant differences between the 2 treatment
groups in either reventilation rate (16.6% for rHuEPO vs 20.5% for placebo; P = .17) or new-onset ventilation (20.8% for rHuEPO vs
24.4% for placebo; P = .38).
The subgroups analyzed were admitting diagnosis (trauma; surgical, nontrauma;
and medical, nonsurgical, nontrauma); age younger than 55 years; age 55 years
or older; APACHE II score 20 or lower; and APACHE II score higher than 20.
The percentage of patients undergoing transfusion and the OR for RBC
transfusion for the entire group and for each subgroup are shown in Table 4. The reduction in the percentage
of rHuEPO patients undergoing transfusion was consistent across all the subgroups
analyzed, as well as for the range of baseline hemoglobin levels (Table 4).
Mortality in each subgroup for patients receiving rHuEPO and patients
receiving placebo is shown in Table 5.
Overall mortality varied widely by subgroup, with the expected increase in
mortality with older age and higher APACHE II scores. There was also considerable
variation in mortality across the subgroups by treatment group. However, multivariate
analysis using Cox semiparametric and recursive partitioning approaches demonstrated
no treatment or treatment-by-baseline variable interaction with mortality.
In a previous randomized, placebo-controlled trial conducted in 160
patients, a combination of daily administration of rHuEPO (300 U/kg) followed
by administration every other day resulted in an almost 50% reduction in total
RBC transfusions.20 There was also a trend
toward an increase in the percentage of patients receiving no RBC transfusions
(transfusion independence) with rHuEPO therapy. Our study, in a much larger
and more diverse group of critically ill patients, expands the findings of
the prior trial. A weekly dosing schedule of 40 000 units of rHuEPO significantly
increased the percentage of patients achieving transfusion independence as
well as reduced the cumulative number of RBCs transfused compared with placebo
patients. The RBC transfusion reduction was consistent across all of the subgroups
examined, although not all comparisons were statistically significant. In
both studies, despite the reduction in the number of RBC transfusions, the
increase in hemoglobin level was significantly greater with rHuEPO therapy.
The reduction in total RBC units transfused and the increase in hemoglobin
level were more modest in this study. This smaller transfusion effect is in
part a consequence of the 2-week shorter follow-up period. If the total RBC
units transfused in the 2 studies are compared at 28 days following randomization,
the reduction in RBC transfusion in the earlier trial20 is
approximately 30%, closer to the 19% reduction seen in this trial. Therefore,
it is possible that a longer follow-up period would have demonstrated a greater
reduction in RBC transfusion than the 19% reduction observed. An additional
contributing factor to the difference in effect size may be the decrease in
total rHuEPO dose received by patients in our trial. In the current study
patients received, on average, half the amount of rHuEPO that was given in
the earlier trial (80 000 units vs 160 000 units).
Transfusion practice varies greatly among physicians and institutions.25 Recently, a transfusion strategy in critically ill
patients to maintain a hemoglobin level between 7 and 9 g/dL has been shown
to be as effective as, and in some subgroups superior to, a transfusion strategy
to maintain a hemoglobin level between 10 and 12 g/dL.13,26 However,
recent reports suggest that the "transfusion trigger" in most ICUs remains
higher than the more conservative transfusion strategy.5,6 Clearly,
transfusion practice could affect our results and the magnitude of any potential
benefit resulting from rHuEPO therapy. In the current study, 60% of the patients
in the placebo group underwent transfusion. This rate of transfusion, as well
as the number of units transfused per patient, was comparable to the transfusion
practice pattern observed in the prior trial as well as the restrictive group
in the TRICC trial.13,20 Similarly,
the pretransfusion hemoglobin level (8.5 g/dL) was identical in both the placebo
and the rHuEPO groups, and importantly, transfusion practice in the current
trial is consistent with recent reports of transfusion practices in ICUs across
the United States6 and Western Europe.5 Therefore, the results of this study reflect the efficacy
of rHuEPO in a setting representative of the predominant transfusion practice
in ICUs today.
In view of questions that have been raised regarding the safety and
efficacy of RBC transfusions,13 does a reduction
in RBC transfusions with rHuEPO therapy lead to better clinical outcomes?
In the present study there were no significant differences in morbidity or
mortality observed between the 2 groups. Clearly, the current study does not
have the power to identify small differences in clinical outcomes among subgroups.
As in the prior study,20 rHuEPO therapy
did not increase serious clinical events. As with clinical outcomes, even
a study as large as the current one does not have the power to identify less
common adverse events. Recently, the occurrence of pure red-cell aplasia associated
with the presence of antierythropoietin antibodies was reported in a small
number of patients with chronic renal failure treated with rHuEPO administered
subcutaneously.27,28 This phenomenon
was not observed in our trial, although our follow-up time was short.
The individuals studied represent a diverse group of critically ill
patients from multiple ICUs across the United States. The major reason for
ineligibility for the study was early discharge from the ICU. The intent of
the study was to focus on "long-term" ICU patients, those with the highest
transfusion burden.3 The 30% of patients found
eligible for the study is consistent with other reports regarding the number
of patients remaining in the ICU for longer than 1 week.2,5,6 Only
one third of eligible patients were approached for consent, reflecting the
difficulty of performing research in a critically ill patient population.29,30 Regulations governing who can serve
as a surrogate to provide consent for participation in a research study when
patients are unable to consent for themselves are becoming stricter. This
is a particularly important issue for research in the ICU, where patients
often are not able to provide consent for themselves. The difficulty in identifying
and contacting the appropriate surrogate in the relatively short time frame
prior to randomization was responsible for the majority of the instances in
which consent was not requested. There did not appear to be any systematic
exclusion of patients other than for the reasons delineated in the protocol,
but no information about excluded patients was collected to assess whether
the group studied was representative.
The cost of rHuEPO is approximately $400 for each 40 000-unit dose
while the cost of a unit of RBCs is generally in the $300 to $400 range. The
average patient received 2 or 3 doses of rHuEPO ($800-$1200) and avoided approximately
1 unit of RBCs ($300-$400). However, the reduction in the number of RBC units
transfused (19%) may itself be beneficial, independent of any additional clinical
outcome effects. For example, not transfusing "unnecessary" units of RBCs
avoids the morbidity and mortality directly associated with each RBC unit
transfused (ie, transfusion reactions, transfusion-related infection) as well
as the potential for medical errors associated with the transfusion process
itself.31,32 The avoidance of
unnecessary RBC transfusions would also save a resource that is becoming increasingly
scarce. Establishing whether rHuEPO therapy is cost-effective will involve
the consideration of all these factors as well as any additional benefit in
clinical outcome achieved.
Could similar benefit be achieved by changing transfusion practice?
Clearly, as demonstrated by Hebert et al,13 changing
transfusion practice will substantially impact the number of RBC units transfused.
However, even in the restrictive group of the study by Hebert et al, two thirds
of the patients received at least 1 RBC transfusion, a rate of transfusion
similar to that observed in the placebo group in the current study. Therefore,
the potential to reduce transfusion with the use of rHuEPO remains at even
more restrictive transfusion thresholds. Key in identifying critically ill
patients who will be most likely to benefit from rHuEPO is selecting the more
"long-term" critically ill patient (ie, longer than 1 week length of stay),
who represent 25% to 30% of critically ill patients.3,5,6
In conclusion, weekly therapy with 40 000 units of rHuEPO in critically
ill patients results in a significant reduction in their exposure to allogeneic
RBC transfusion. Despite receiving fewer RBC transfusions, patients treated
with rHuEPO achieve a higher hemoglobin level, consistent with the hypothesis
that the anemia of critical illness is an underproduction anemia characterized
in part by a relative erythropoietin deficiency.14,15 No
differences in clinical outcomes were demonstrated between the rHuEPO and
placebo groups. Therefore, while it is clear that rHuEPO treatment reduces
RBC transfusions in critically ill patients, further study is necessary to
establish whether this reduction in RBC transfusions will also result in improved
clinical outcomes for some critically ill patients.