The Journal of Informed Pharmacotherapy 2003;13:200.
Reviewer: Sean Gorman
Reviewer’s e-mail address: firstname.lastname@example.org
Reviewer's profession/specialty: Pharmacotherapeutic Specialist - Critical Care
Corwin HL, Gettinger A, Pearl RG, Fink MP, Levy MM, Shapiro MJ, et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002; 288:2827-35. PubMed Citation
This was a prospective, randomized, double-blind, placebo-controlled trial conducted at 65 intensive care units in the United States between December 1998 and June 2001. The investigators aimed to determine if weekly administration of recombinant human erythropoietin (rHuEPO) to critically ill intensive care unit (ICU) patients would reduce the exposure to allogeneic red blood cells (RBC).
All patients admitted to either a medical, surgical, or a medical/surgical ICU who remained in the ICU for a minimum of 2 days were evaluated for study eligibility prior to ICU day 3. Inclusion criteria included stay in the ICU for a minimum of 3 days; a minimum age of 18 years; hematocrit (HCT) less than 38%; and informed consent. Patients were excluded if they had renal failure requiring 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; or expected ICU discharge within 48 hours of ICU day 2.
Enrolled patients were randomized to receive rHuEPO 40,000 units or a placebo administered by subcutaneous injection on ICU day 3 and continued once weekly (maximum of 4 doses) for those patients remaining in the unit. The study drug was withheld if the HCT was 38% prior to the scheduled administration.
All patients were to be followed for 28 days following randomization. Patients also received a minimum daily dose of 150 mg elemental iron via the enteral route beginning on ICU day 3 unless they were unable to tolerate enteral feeding. Parenteral iron was given to patients demonstrating an inadequate response to oral iron. The following RBC transfusion guidelines were established for the purposes of the study: no RBC transfusion if hemoglobin (Hgb) > 90 g/L or Hct > 27% unless there was a specific clinical indication (i.e. active bleeding, ischemia, or other); RBC transfusion for Hgb < 90 g/L or Hct < 27% was left to the physician's discretion. Thus, the ultimate decision for RBC transfusion was made by the intensive care physician.
The primary outcome was transfusion independence. This was assessed by comparing the percentage of patients in each treatment group who received any RBC transfusion between study days 1 and 28. Prospectively identified secondary outcomes were the cumulative RBC units transfused per patient through study day 28; the cumulative mortality through study day 28; the change in Hgb from baseline; and the time to first transfusion or death.
This study was designed by the principal investigators (Drs. H. Corwin and Gettinger) with input from the data coordinating center (CareStat Inc. in collaboration with the Boston University School of Public Health) and was reviewed by the study sponsor, Ortho Biotech Products LP, manufacturer and study supplier of rHuEPO. Drs. H. Corwin, Gettinger, and Pearl have received honoraria from Ortho Biotech. Drs. H. Corwin and Gettinger have received research funding from Ortho Biotech. Drs. H Corwin, Gettinger, Fink, Levy, Shapiro, and Pearl have been paid consultants to Ortho Biotech. Drs. Colton and M. Corwin are partners in CareStat Inc.
1. Was assignment of patients randomized?
Yes. Randomization was stratified by site and entailed the use of computer-generated random numbers.
Yes. During a 30-month period, 33,685 patients were screened, and 1,302 (3.9%) were enrolled. A study flow chart was provided that accounted for all patients screened and enrolled in the trial. Of the 1,302 patients randomized, 31 (2.4%) discontinued treatment (2.9% rHuEPO vs. 1.8% placebo) and 36 (2.8%) were lost to follow-up after hospital discharge (2.6% rHuEPO vs. 2.9% placebo). Analysis was conducted as per the intention-to-treat principle.
1. How large was the treatment effect?
Three hundred and twenty-eight of the 650 (50.5%) patients in the rHuEPO group received at least one RBC transfusion during the 28-day follow up period, as compared to 394/652 (60.4%) patients in the placebo group [p < 0.001;ARR = 9.9% (95%CI 4.5% - 15.3% (my calculations)); OR, 0.67 (95%CI 0.54 - 0.83), NNT 11 (95% CI 7 - 22) (my calculations)). For this analysis, patients who had not received a transfusion by the time they were withdrawn from the study or lost to follow-up were assumed to have received no RBC transfusions.
There was only a slight difference in the proportion of withdrawals/patients lost to follow-up between groups (5.5% for rHuEPO vs. 4.7% for placebo). An additional analysis was performed whereby patients who were withdrawn from the study or lost to follow-up were assumed to have received RBC transfusions. Under these conditions, the investigators reported that 53.4% of the rHuEPO group were transfused vs. 63.3% of the placebo group [no p value reported; ARR = 9.9%; OR, 0.66 (0.53-0.83), with an NNT of 10 (7 - 23) (my calculations)]. To account for differences in baseline characteristics between groups, the investigators performed a logistic regression analysis to adjust the OR for RBC transfusion. This adjustment revealed similar results [Adjusted OR 0.65; (0.51-0.83)].
The mean number of units of RBC transfused per patient was 2.4 (SD 4.79) for the rHuEPO group vs. 3.0 (SD 5.42) for the placebo group (no p value reported). The median number of units of RBC transfused per patient was 1 (IQR 0-3) for the rHuEPO group versus 2 (IQR 0-4) for the placebo group (p < 0.001). There did not appear to be a meaningful difference in total number of days alive between the two groups (16,247 for rHuEPO vs. 16,235 for placebo).
The investigators report the results of an analysis accounting for time at risk for transfusion. However, this analysis was performed post-hoc and therefore should only be considered hypothesis-generating. The transfusion rate/days alive for the rHuEPO group was 0.098 (SE 0.0074) vs. 0.121 (SE 0.0085). The relative reduction in transfusion rate/days alive was 19%.
The absolute reduction in transfusion rate/days alive was 0.02 (95% CI 0.04 - 0.001); the clinical significance of this reduction is unknown. The effect estimate for the ratio of transfusion rates (rHuEPO/placebo) was 0.81 (95% CI 0.79-0.83); p = 0.04). There was no statistically significant difference between groups for median ICU-free days (18 days rHuEPO group vs. 17 days placebo group; p = 0.25). Also, there was no difference between groups in terms of median ventilator-free days (22 days rHuEPO vs. 20 days placebo; p = 0.27). However, this study was not powered to show a small difference in length of stay outside of the ICU or mechanical ventilation.
The mean increase in Hgb from baseline to final determination was significantly greater for patients who received rHuEPO (13.2 g/L (SD 20) versus 9.4 g/L (SD 19) for placebo; p<0.001). The clinical significance of this small difference is likely negligible.
A Kaplan-Meier plot was constructed to determine whether a difference existed between groups with regards to the composite endpoint of time to first transfusion or death. A difference did exist between the 2 treatment groups in favor of rHuEPO commencing near the end of the first week following randomization (p = 0.001).
There was no difference in 28-day mortality between the 2 groups (14% in rHuEPO vs. 15% in placebo; p = 0.61). Although not stated in the methods as an endpoint, there did not appear to be a significant difference in reported serious adverse events between the groups.
Subgroup analyses for proportions of patients undergoing transfusion and the incidence of mortality were performed based on admitting diagnosis, age, and APACHE II score (ICU severity of illness scale). These subgroups were selected for analysis post-hoc and therefore should be considered hypothesis generating only. The reduction in the percentage of rHuEPO patients undergoing transfusion was consistent across all subgroups analyzed. However, overall mortality varied widely by subgroup, with an increase in mortality with advanced age and higher APACHE II scores (indicating more severe illness). Multivariate analysis demonstrated no treatment or treatment-by-baseline variable interaction with mortality.
2. How precise was the estimate of the treatment effect?
For the primary endpoint of proportion of patients who received any RBC transfusion during the 28-day follow-up, the ARR was 9.9% and the 95% CI was 4.5% to 15.3% (my calculations). The OR was 0.67 (95%CI 0.54 - 0.83) and the NNT was 11 (95% CI 7 - 22) (my calculations)).
The mean pre-transfusion Hgb (~85 g/L) was similar between the groups in this study. The clinicians in this study used a higher Hgb value for initiating RBC transfusions than that suggested in the previous TRICC trial (70 g/L). (1) This landmark trial was published while the current study was underway and this may partially explain the differences in transfusion practices. Assuming that clinicians have adopted a more restrictive (i.e. lower Hgb value) transfusion threshold since the publication of the TRICC study, the more liberal (i.e. higher Hgb value) transfusion threshold seen in this study may weaken its external validity. However, this is unlikely since this threshold is within the highly variable range observed in practice in the US and Western Europe.(2,3) This study also revealed that 21% of all patients underwent transfusion at Hgb > 90 g/L or Hct > 27%. Transfusion thresholds can widely fluctuate among ICU clinicians and there remains considerable debate surrounding the optimal transfusion threshold. (4)
2. Were all clinically important outcomes considered?
Yes. Exposure to transfused RBC units was documented. Mortality rate was also captured, although it is unclear how exposure to RBC transfusion and rHuEPO would affect this outcome. Any change in Hgb from baseline was also captured and shown to be significantly greater for patients receiving rHuEPO, however the clinical significance of this surrogate endpoint is debatable. All patients were monitored for adverse drug reactions.
Anemia in the critically ill is a common problem that results from a multitude of factors including numerous blood draws, occult gastrointestinal bleeding, and blood loss caused by surgical techniques. (6) The remedy of choice for correcting anemia is RBC transfusion. However, the actual benefits of increasing Hgb through RBC transfusion have not been clearly elucidated and this therapy is not devoid of adverse events. A potential option for treatment of anemia that may spare RBC transfusion in the ICU population is rHuEPO. Endogenous erythropoietin triggers RBC production by bone marrow stimulation, however secretion has been shown to be reduced in patients with inflammatory disorders and sepsis. (6) A previous well-designed study examined the role of prophylactic rHuEPO on the number of RBC transfusions required in a medical-surgical ICU population. (7) The dosing regimen of rHuEPO was 300 U/kg/day for 5 days followed by alternate day dosing for 2-6 weeks. This previous study showed a reduction in number of units of RBC transfusions required, however mortality, length of stay, and adverse effects did not differ between groups.
The transfusion threshold is an arbitrarily determined value below which the deleterious effects of reduced oxygen-carrying capacity are expected. The investigators in this study utilized a transfusion threshold of 85 g/L, which may be a higher Hgb level than would be expected based on the results of the TRICC trial. (1) Also, 21% of patients in each group underwent transfusion at a Hgb > 90 g/L or Hct > 27%, which appears high. This study may have been able to show a similar reduction in RBC transfusions simply by mandating a lower transfusion threshold of 70 g/L.
Approximately 0.5% to 3% of all transfusions result in some adverse events, but the majority of them are minor reactions with no significant consequences. (5) The minor adverse effects associated with RBC transfusions include allergic reactions, febrile nonhemolytic reactions, red blood cell alloimmunization, and leukocyte/platelet alloimmunization. These events are of little clinical consequence in the majority of patients. (8) Rarely, more severe reactions can occur, such as acute hemolytic reactions, delayed hemolytic reactions, transfusion-related acute lung injury, and transmission of infectious agents. (8) Canadian Blood Services performs donor screening and highly sensitive laboratory screening tests on all blood for syphilis, hepatitis B and C, HIV 1 and 2, and Human T-Cell lymphotropic virus I and II. (9) For example, the risk of transmission of HIV and HCV in Canada through blood transfusion between 1987-1996 was estimated to be 1 in 752,000 and 1 in 225,000 donations, respectively. (10) The risk of becoming infected with West Nile Virus, Creutzfeldt-Jakob Disease, and Variant Creutzfeldt-Jakob Disease also appears to be very low. (9) The incidence of transfusion-transmitted bacterial reaction is estimated to be 1 in 500,000 units of red cells. (5) Therefore the risk of becoming infected with any infectious agent is exceedingly low. This study revealed no difference between groups in the incidence of sepsis, pneumonia, or abscess development.
Since there is evidence suggesting an extremely low risk for experiencing clinically meaningful transfusion-related adverse events, the usefulness of transfusion-independence as a primary endpoint is questionable. Is it practical to aim for complete RBC transfusion avoidance in critically ill patients who reside in an ICU for greater than 2 days? What may be of greater importance is the total exposure to RBC transfusions, as the risk of experiencing an adverse event will increase with repeated exposure. While patients receiving rHuEPO did have a statistically significant lower median number of transfusions, it did not appear to differ from a clinical perspective.
The significant cost of rHuEPO, its marginal effect on transfusion avoidance, and its lack of effect on other clinically meaningful outcomes should preclude routine use in the ICU. There are no data to support using rHuEPO to spare RBC transfusions in times of blood supply shortages.
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