A US Multicenter, Retrospective, Observational Study ofErythropoiesis-Stimulating Agent Utilization in Anemic,Critically III Patients Admitted to the Intensive Care Unit
Gretchen M. Brophy, PharmD1; Valerie Sheehan, PharmD2; MarcJ. Shapiro, MD3;Lawrence Lottenberg, MD4; Debra Scarlata, MS5; and Paul Audhya, MD,5* for theASSESS Study Group and Amgen Inc.t
1Departments ofPharmacy and Neurosurgery, Virginia Commonwealth University, Richmond, Virginia;2McKesson Medication Management, Palmdale, California; 3Department ofSurgery, State University ofNew York-Stony Brook, Stony Brook, New York; 4Division ofAcute Care Surgery, Department ofSurgery,University ofFlorida College ofMedicine, Gainesville, Florida; and 5North American Medical Affairs,Amgen Inc., Thousand Oaks, California
ABSTRACTBackground: Anemia is a common comorbid con
dition among patients admitted to the intensive careunit (ICU). Darbepoietin alfa and epoetin alfa areerythropoiesis-stimulating agents (ESAs) used to manage anemia in the ICU, although neither drug has anindication in critically ill patients.
Objective: This study describes ESA practice patterns in anemic, critically ill patients admitted to theICU.
Methods: A total of 19 hospitals participated inthis US multicenter, retrospective, observational studyof adult patients not receiving chronic hemodialysiswho were admitted to the ICU for ~24 hours betweenFebruary 2005 and September 2005 and who received~1 dose of darbepoietin aHa or epoetin aHa. Data onESA doses, dosing frequencies, hemoglobin levels, andred blood cell (RBC) transfusions were abstractedfrom electronic medical records.
Results: A total of 438 patients were included inthe analysis, of whom 201 (46%) were treated withdarbepoietin alfa and 237 (54%) were treated withepoetin aHa. In the respective groups, similar proportions were male (121/201 [60%] and 126/237 [53%])and white (146/195 [75%] and 140/184 [76%]);age was also similar (mean [SD], 62 [19] and 60[18] years). The mean (SD) dose during the first weekof ICU stay was 96.5 (40.5) rg with darbepoietin alfaand 33,439 (23,508) U with epoetin alfa. The mostcommonly prescribed dosing frequency with darbepoietin aHa was once weekly (88.1 % of all prescribeddoses), with a mean (SD) number of injections of 1.8
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(1.75). With epoetin alfa, the most common dosingfrequencies were 3 times weekly (35.9%), I-time dosing (28.5%), and once weekly (24.0%), with a mean(SD) number of injections of 2.9 (4.2). In both groups,the duration of therapy was :c:;1 week in ~50% of patients, and the mean change in hemoglobin concentration was 0.8 g/dL. Overall, 47% (darbepoietin aHa)and 44% (epoetin alfa) of patients were RBC transfusion independent (ie, did not require a transfusionduring their ICU or hospital stay) after receiving thefirst ESA dose.
Key words: anemia, critical care, darbepoietin aHa,epoetin aHa, hemoglobin, transfusion.
*Current affiliation: Abbott Laboratories, Abbott Park, IllinoIs.t Members of the ASSESS Study Group are listed In the
Acknowledgments.
This work was presented In part at the Midyear Clinical Meeting ofthe American Society of Health-System Pharmacists, Las Vegas,Nevada, December 3-8, 2005; at the 35th Annual Congress of theSociety for Critical Care Medicine, San FrancIsco, Callfornla,January6-11, 2006; and at the American College of Clinical PharmacyAnnual Meeting, St. LOUIS, MISSOUri, October 26-29,2006.
Accepted for publicatIOn October 28,2008dOl:1 0.1 016/J.cIInthera.2008.12.0240149-2918/$32.00
INTRODUCTIONIn critically ill patients admitted to the intensive careunit (ICU), anemia is a common comorbid conditionthat develops relatively early and typically persiststhroughout the ICU and subsequent hospital stay.l,2The consequences of anemia in this patient population include multiple red blood cell (RBC) transfusions, longer hospital lengths of stay (LOSs), morbidity, and mortality. 1,2 Among the numerous factors thatmay contribute to anemia in critically ill patients arethe following: diagnostic blood sampling,2,3 acute andoccult blood loss, nutritional deficiencies,4 inadequateerythropoietin production, and a blunted erythropoietin response. 5,6 The relative importance of each anemia risk factor is patient specific.
RBC transfusions have frequently been used to treatanemia associated with critical illness. Observationaldata have suggested that >50% of patients admitted tothe ICU receive an RBC transfusion at least once duringtheir stay. 3Among patients who remain in the ICU for>7 days, the proportion of RBC-transfused patients hasbeen reported to be as high as 85%.3 RBC transfusionsin critically ill patients have been associated with a longerICU LOS and an increased mortality rate,I,2,7 promptinga reevaluation of RBC transfusion practices in ICUs.l,2
Randomized controlled trials (RCTs) have reportedthe efficacy of erythropoiesis-stimulating agents (ESAs)in critically ill patients. 8- 10 In 2002, Corwin et a19 reported that weekly administration of epoetin alfa40,000 U was associated with a 20% reduction inRBC transfusions and an increase in hemoglobin concentrations. A small retrospective study in 72 criticallyill patients reported similar rates of transfusion independence and increases in hemoglobin levels in patients receiving epoetin alfa and darbepoietin alfa. ll
However, in a larger RCT in 1460 patients, Corwin etal lO reported that administration of epoetin alfa wasnot associated with decreased RBC transfusions despite the statistically significant increase in hemoglobin concentrations. Additionally, the proportion ofpatients who experienced thrombotic events was significantly greater with epoetin alfa than placebo. lO
Post hoc analyses reported that the risk for thrombotic events was significantly increased in patientswho did not receive heparin at baseline (P = 0.008),but not among patients who did receive heparin atbaseline. 10 Nonetheless, a systematic literature searchof the National Library of Medicine database revealedlimited information on ESA utilization patterns among
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critically ill patients, especially regarding the use ofdarbepoietin aHa and epoetin alfa in the ICU setting.
Both darbepoietin alfa and epoetin alfa stimulateerythropoiesis by the same physiologic mechanism asendogenous erythropoietin. 12,13 However, darbepoietinalfa is a longer-acting ESA with increased in vivo biologicactivity compared with recombinant human erythropoietin,12 thus allowing less frequent administration. 13
In the present report, we describe results fromASSESS (Study to Evaluate Erythropoiesis StimulatingProtein Use and Clinical Outcomes in HospitalizedPatients), a multicenter, retrospective, observationalcohort study. The purpose of this report was to describe dose-utilization patterns of darbepoietin alfaand epoetin alfa for the treatment of anemia in critically ill patients admitted to the ICU.
MATERIALS AND METHODSStudy Design
This was a multicenter, retrospective cohort studyin US patients admitted to the ICU for ~24 hours between February 2005 and September 2005 and whoreceived ~1 dose of darbepoietin alfa or epoetin aHa.Study protocol approval was obtained from the localinstitutional review board at each participating institution. Data were abstracted from electronic medicalrecords by Omnicare Inc. (King of Prussia, Pennsylvania), an independent clinical research organization, infull compliance with the standard medical record review techniques mandated by the generally acceptedCode of Federal Regulations for clinical trials in theUnited States. To achieve a balance between sites using darbepoietin aHa and epoetin alfa, each site completed a survey on inpatient ESA utilization over theprevious 12 months. For each study site, data wereabstracted only for the most commonly used ESA.
Data CollectionPatients' records were identified based on the eligi
bility of patients within each facility. Eligibility criteriawere as follows: age ~18 years; medical or surgicalICU admission for ~24 hours; receipt of darbepoietinalfa or epoetin aHa, but not both, during the hospitalstay; and ~2 hemoglobin measurements obtained onseparate days during hospitalization, with 1 measurement before and 1 after the first ESA administration.
To focus the analysis on the treatment of anemiaprimarily associated with critical illness, data were notincluded from patients whose medical records docu-
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mented an oncology indication. Data from patientswho required acute hemodialysis during the ICU staybut who had not previously required hemodialysiswere included in the analysis.
Sites were selected for participation based on theirexperience with administration of either darbepoietin aHa or epoetin alfa in the inpatient setting for~12 months. Categorization and selection of sites wasbased on the observation that sites usually stockedand administered only one of the available ESAs atany time. Data were abstracted in a sequential reversechronologic manner, starting with the most recentadmission date. Collected data included the followingparameters: baseline demographic and clinical characteristics, hospital and ICU LOSs, prescribed dosingfrequency and administration of ESA therapy, admission and pretransfusion hemoglobin levels (closestmeasurement within a 24-hour period before transfusion) if available, baseline and last available hemoglobin levels during hospitalization, RBC transfusioncharacteristics, and vital status on discharge. Theeualztation period was defined as the date from hospital admission to the date of hospital discharge ordeath. The baseline hemoglobin concentration wasdefined as the first measurement obtained after thefirst ESA administration in the ICU.
Study End PointsThe primary end point of the present study was the
mean ESA dose administered during the evaluationperiod. Secondary end points were the mean change inhemoglobin concentration from baseline through thelast available measurement (ie, the final hemoglobinminus the baseline hemoglobin), mean hospital andICU LOSs during the evaluation period, and the percentage of patients who did not receive RBC transfusions after the first administration of ESA.
Statistical AnalysisDescriptive statistics were used for analysis of the
data. For continuous variables, these included 2-sided95% CIs, mean (SD), median (interquartile range[IQR]), and sample size. For categoric variables, weused frequencies and percentages. ESA treatment duration was calculated as last administration date minus first administration date, plus 1. The median(95% CI) time to RBC transfusion and time to firstESA administration were estimated using KaplanMeier methods. Regression analysis and analysis of
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variance were used in exploratory analyses of thechange in hemoglobin concentration. Data from allpatients (living or dead) were analyzed and presented.Because hemoglobin concentrations and ESA administration patterns in surviving patients and patients whodied in the hospital might have differed and caused abias in the results, a sensitivity analysis was performedby removing deceased patients from the analysis andassessing the changes in the results.
RESULTSStudy Sites
A total of 19 hospitals participated in the ASSESSstudy. Of these, darbepoietin alfa was predominantlyprescribed in 9 (6 academic [67%] and 3 community[33 %] hospitals); epoetin alfa, in 10 (5 academic [50%]and 5 community [50%] hospitals). Six sites (67%) inwhich darbepoietin aHa was prescribed and 5 (50%) inwhich epoetin alfa was prescribed had ~50 ICU beds.The numbers of admissions in ICUs in which darbepoietin aHa and epoetin alfa were prescribed ranged from26 to 100 and 58 to 100, respectively; data were abstracted from all of the patients admitted to the sites.
Decisional aids, in the form of anemia-managementprotocols for the implementation of ESAs, were available in most of the ICUs. In short, 11 hospitals (58%)(darbepoietin aHa, 6 [67%]; epoetin alfa, 5 [50%]) hadguidelines for ESA use for critically ill patients, whichwere separate from those for hospital inpatients.
Most (7/9 [78%]) of the sites in which darbepoietinalfa was prescribed were Level I trauma centers, compared with 2/10 (20%) of the epoetin aHa sites. Most(7/10 [70%]) sites in which epoetin aHa was prescribed, but none of the sites in which darbepoietinalfa was prescribed, were Level II trauma centers. Onesite that prescribed darbepoietin alfa was a Level IIIcenter. Two hospitals (darbepoietin alfa, 1; epoetinalfa, 1) did not have trauma-level designations.
Patient CharacteristicsA total of 438 patients were included in the analy
sis: 201 patients (46%) treated with darbepoietin aHaand 237 patients (54%) treated with epoetin alfa.During their hospital or ICU stay, most patients ineach ESA group (68% and 71 %, respectively) underwent a surgical procedure (including bedside procedures) or had surgery based on procedure codes of theInternational Classification of Diseases_. Ninth Reuision. 14 The characteristics associated with hospitaliza-
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tion for patients in both ESA groups are summarizedin Table I. The groups that received darbepoietin alfaand epoetin alfa were similar with respect to the mostfrequent medical conditions, discharge status, mortality rates, demographic characteristics, and baselinelaboratory measurements. However, patients who received darbepoietin alfa were more likely to have>2 comorbid conditions, to be treated in the ICU onadmission, and to have a lower hemoglobin level atbaseline (Table I). Because there were differences inthe characteristics of hospitals that prescribed darbepoietin alfa versus epoetin alfa, particularly with regard to trauma-center level designation, end point results for each cohort are presented separately.
Estimated glomerular filtration rate (eGFR; mLimin/I. 73 m2 ) was calculated using a modified Modification of Diet in Renal Disease equation. Levels ofeGFR of <15, 15-29,30-59,60-89, and >90 mLimin/1.73 m2 were recorded. For darbepoietin alfa sites (n =
190), the numbers of patients with these levels were asfollows: 20 (10.5%), 37 (19.5%), 42 (22.1%), 39(20.5%), and 52 (27.4%), respectively. For epoetin alfasites (n = 179), the following numbers of patients fellinto each eGFR group: 20 (11.2%), 34 (19.0%), 38(21.2%), 39 (21.8%), and 48 (26.8%), respectively.Information needed to calculate the eGFR was unavailable for 11 and 58 patients, respectively, from the sitesthat prescribed darbepoietin alfa and epoetin alfa.
The mean (SD) darbepoietin alfa dose during thefirst week of ICU stay was 96.5 (40.5) rg. Sixty-fivepercent of patients (130/201) were administered dosesbetween 100 and <150 rg during the first week ofadministration (Figure). Most patients received thefirst dose in the ICU and during their first ICU admission while being hospitalized (Table II). Most (177/201[88 %]) patients received :c:;1 dose of darbepoietin alfasc. Of all prescribed darbepoietin alfa doses, 88.1 %were once-weekly dosing frequencies, with a mean(SD) dose of 91.1 (35.2) rg; the denominators for thenumber of prescribed doses were 236 and 354 fordarbepoietin alfa and epoetin alfa, respectively. Nearlyhalf (97/201 [48%]) of the patients received darbepoietin alfa for only 1 administration. The remainingpatients received multiple administrations, and ofthese, only 4% received darbepoietin alfa for 1 week,21 % for 2 weeks, 10% for 3 weeks, and 17% for
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~4 weeks. The mean (SD) number of injections was 1.8(1.75). Iron supplements were given to 48% (96/201)of the patients. The median (95% CI) time from ICUadmission to first dose was 7.0 days (6.0-8.0 days).
Change in Hemoglobin ConcentrationHemoglobin measurements on admission to the
hospital were ordered for 43 patients (21 %) who received darbepoietin alfa. In this subset, the mean (SD)hemoglobin concentration was 10.6 (3.0) g/dL on admission. For the overall darbepoietin alfa group (n =
201), hemoglobin was 9.1 (1.2) g/dL before the firstESA administration (baseline). The last mean (SD)hemoglobin measurement was 9.9 (1.3) g/dL, yieldinga mean (SD) change from baseline to the last observedvalue of 0.8 (1.5) g/dL. The median (IQR) number ofdays for the observed hemoglobin change, from before darbepoietin alfa administration to the last measurement after darbepoietin alfa administration, was10.0 (5.0-19.0). The change in hemoglobin concentration was not associated with LOS, dose, or route ofadministration (IV vs SC) (data not shown).
Length ofStayFor patients who received darbepoietin alfa, the
mean (SD) hospital and ICU LOSs were 27.9 (20.8) daysand 22.1 (18.5) days, respectively. The median (IQR)LOSs were 21 days (13-36 days) and 16 days (1029 days), respectively.
Transfusion CharacteristicsThirty-eight patients (19%) who received darbepoi
etin alfa did not receive RBC transfusions at any timeduring their hospital or ICU stays. Ninety-five patients (47%) were transfusion independent (ie, did notrequire an RBC transfusion) from the first administration of darbepoietin alfa. The RBC transfusion characteristics are summarized in Table III. Kaplan-Meieranalysis showed that the median (95% CI) time to thefirst RBC transfusion after hospital admission was4.0 days (2.0-5.0 days); the median (95% CI) time toRBC transfusion from the first ESA dose was 7.0 days(4.0-17.0 days).
Results from a sensitivity analysis suggested thatdata from patients who had died during the evaluation period did not have an impact on the calculatedparameter estimates for change in hemoglobin concentration, LOS, or RBC transfusion characteristics ineither ESA cohort in this study (data not shown).
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Table I. Baseline demographic, medical, and hospital characteristics among critically illpatients who received darbepoietin alfa or epoetin alfa.
Characteristic
Level of care on admission, no. (%)ICU medicalICU surgicalNon-ICU floor
Baseline laboratory measurementsHemoglobin before first ESA dose
(baseline), gjdL, mean (SO)eGFR, mLjminj1.73 m2 , median (IQR)f
Darbepoietin Alfa(n = 201)
145 (72)25 (12)31 (15)
108 (54)79 (39)63 (31)54 (27)34 (17)
30 (15)22 (11)
40 (20)69 (34)92 (46)
39 (19)
121 (60)
146 (75)34 (17)15 (8)
62 (19)
9.1 (1.2)55 (26-95)
Epoetin Alfa(n = 237)
145 (61)31 (13)61 (26)
145 (61)84 (35)72 (30)57 (24)33 (14)
37 (16)20 (8)
39 (17)115(48)83 (35)
39 (16)
126 (53)
140 (76)24 (13)20 (11)
60 (18)
57 (26-94)
leu ~ intensive care unit; ESA ~ erythropoiesis-stimulating agent; eGFR ~ estimated glomerular filtration rate, calculated uSing a modified M ORO (Modification of Diet In Renal Disease) equation; IQR ~
Interquartile range.*Based on patient Incidence.tFor darbepoletln alfa, n ~ 195; for epoetln alfa, n ~ 184. At some study Sites, information on ethnlclty was not collected.
f For darbepoletln alfa, n ~ 190; for epoetl n alfa, n ~ 179.
During the first week of stay in the ICU, the mean(SD) dose of epoetin aHa was 33,439 (23,508) U.Forty-six percent (110/237) of patients received doses
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between 40,000 and <90,000 U during the first weekof administration in the ICU, and 23% (54/237) received doses between 11,000 and <30,000 U (Figure).As described for patients who received darbepoietinalfa, most of those who received epoetin alfa had the
Figure. Dose distributions of erythropoiesis-stimulating agents (A) darbepoietin alfa and (B) epoetin alfa administered to critically ill patients during the first week of stay in the intensive care unit.
first dose administered in the ICU and during theirfirst ICU visit. Most (217/237 [92%]) patients received ~1 dose of epoetin aHa sc. The most common
dosing frequencies were as follows: 3 times weekly(35.9%), with a mean (SD) dose of 11,345 (7541) U;I-time administration (28.5%), with a mean (SD)
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Table II. Oosing information for darbepoietin alfa and epoetin alfa in critically ill patients.
Received iron supplements, no. (%) 96 (48) 111 (47)IV 16 (8) 37 (16)Oral 82 (41) 89 (38)
leu ~ intensive care unit; ESA ~ erythropoiesis-stimulating agent; IQR ~ Interquartde range; BIW ~ tWice a week; TIW ~
3 times a week; QW ~ every week; Q2W ~ every 2 weeks; QOD ~ every other day.*Administered duration of therapy.t Prescribed dosing frequency.t For darbepoletln alfa and epoetln alfa, the denominators for the number of prescribed doses were 236 and 354,
respectively.
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C.M. Brophy et al.
Table III. Red blood cell transfusion characteristics from the first dose of darbepoietin alfa or epoetin alfa inthe intensive care unit going forward.*
Hemoglobin within 24 hours beforefirst transfusion, g/dL, mean (SO)f 7.9 (0.9) 8.2 (1.2)
Time to first transfusion, days,median (95% CI) 7.0 (4.0-17.0) 7.0 (5.0-9.0)
No. of units transfused per patient, median (IQR) 3.6 (2.0-5.8) 3.0 (1.9-5.0)
Total no. of units transfused 550 568
Total no. of days of exposure since first ESA 3505 4004
IQR ~ Interquartde range; ESA ~ erythropoiesis-stimulating agent.* Defmed as the period between the first ESA dose and the date of discharge or death.t Calculated from the population that received transfusions.t For darbepoletm alfa, n ~ 95; for epoetm alfa, n ~ 114.
dose of 21,347 (14,632) U; and once-weekly administration (24.0%), with a mean (SD) dose of 33,482(12,405) U (Table II). The denominators for the number of prescribed doses were 236 and 354 for darbepoietin aHa and epoetin alfa, respectively. Almost onethird (73/237 [31 %]) of the patients were administered epoetin alfa only 1 time. The remaining patientsreceived multiple administrations, and, of these, 20%received epoetin alfa for 1 week; 24%, for 2 weeks;11 %, for 3 weeks; and 14%, for ~4 weeks. The mean(SD) number of injections was 2.9 (4.2). Forty-sevenpercent (111/237) of the patients received iron supplements. The median (95% CI) time from ICU admission to first epoetin aHa administration was 5.0 days(4.0-5.0 days).
Change in Hemoglobin ConcentrationFew patients receiving epoetin alfa had hemoglobin
measurements on hospital admission (n = 65). Themean (SD) hemoglobin concentration on admission ofthis subset was 11.3 (2.5) g/dL, compared with 9.6(1.5) g/dL for the overall epoetin aHa group (n = 237)before the first ESA administration (baseline). At lastmeasurement, the mean (SD) hemoglobin concentration was 10.4 (1.4) g/dL. The mean (SD) change in he-
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moglobin from baseline to the last observed value was0.8 (2.0) g/dL. The median (IQR) number of days forthe observed hemoglobin change from before epoetinalfa administration to the last measurement after epoetin alfa administration was 10.0 (5.0-17.0). Change inhemoglobin was not associated with LOS, dose, orroute of administration (IV vs SC) (data not shown).
Length ofStayIn patients who received epoetin alfa, the mean
(SD) hospital and ICU LOSs were 25.1 (23.2) and 17.2(17.3) days, respectively. The median (IQR) LOSswere 17 days (11-30 days) and 12 days (6-23 days),respectively.
Transfusion CharacteristicsIn the epoetin aHa cohort, 65 patients (27.4 %)
never received RBC transfusions during their hospitalor ICU stay, and 105 patients (44.3%) were transfusion independent from the first ESA administration(Table III). The median (95% CI) time to first RBCtransfusion after hospital admission was 6.0 days(4.0-9.0 days), and the median (95% CI) time to RBCtransfusion from the first ESA dose was 7.0 days(5.0-9.0 days).
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DISCUSSIONAlthough neither epoetin alfa nor darbepoietin alfahas an indication in critically ill patients, this studydescribes the 2005 practice patterns in the use of thesedrugs in patients admitted to the ICU in 19 sitesacross the United States.
The present study suggests that ESAs are usedamong a heterogeneous group of patients with anemiain the ICU. The dose and dosing frequencies variedacross patients. The most common (88.1 %) startingdose frequency of darbepoietin alfa was once weekly.The starting dose frequency of epoetin alfa was morediverse, with doses of 3 times weekly in 35.9%, onceweekly in 24.0%, and 1-time dosing in 28.5% of patients. The mean total dose of epoetin alfa during thefirst week of ICU stay in our study was 33,439 U.This finding was similar to the labeled indication forchemotherapy-induced anemia (40,000 U) and thedose (40,000 U) used in 2 previous randomized,placebo-controlled trials of epoetin alfa in critically illpatients (1302 and 1460 patients, respectively) admitted to the ICU. 9 ,1O The mean total darbepoietin alfadose (96.5 rg) during the first week of ICU stay in ourstudy was also similar to the labeled indication forchemotherapy-induced anemia 12 and equivalent to thedose used in a large trial of epoetin alfa (40,000 U ofepoetin alfa is equivalent to 100 rg of darbepoietinalfa).12
In the present study, the numbers of darbepoietinalfa and epoetin alfa doses administered (median, 1.0and 2.0, respectively) were lower than in the studyreported by Voils et al,11 a small, single-center, retrospective study of darbepoietin alfa (n = 39) and epoetin alfa (n = 33) use in ICU patients (median numberof doses, 3.5 and 4.0, respectively). These differencesmay be explained by the shorter ICU stay in our studythan in the study by Voils et al (median of 16 and12 days compared with 22 and 25 days for darbepoietin alfa and epoetin alfa, respectively). The recent studyby Corwin et al,1O in which 1460 patients were enrolled,reported single doses of ESA therapy in 28.2% ofpatients and 2 doses in 32.2% of patients randomizedto the epoetin alfa arm of the study. According to thestudy protocol, patients were to receive up to 3 dosesof epoetin alfa (on days 1,8, and 15) depending on theLOS. Thus, single doses are not uncommon in hospitalpractice, even in a protocol-driven trial, as well as inactual clinical practice as reported in our retrospectivestudy.
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Not surprisingly, the usage patterns we observed inthe present study differed significantly from the protocol administration in the studies by Corwin et al.8-10In the present study, the first ESA administration generally occurred late in the course of the ICU stay, at amedian (95% CI) of 7.0 days (6.0-8.0 days) after ICUadmission for darbepoietin alfa and 5.0 days (4.05.0 days) after ICU admission for epoetin alfa. Incontrast, the studies by Corwin et al specified administration of epoetin alfa on ICU day 3, or within 2 to4 days after ICU admission. Similar delays in dosingwere identified in the study by Voils et al,11 which reported the first administration of ESA around day 10of the ICU stay.
In the present study, the patients treated with darbepoietin alfa had lower hemoglobin levels and morecomorbid conditions than the patients treated withepoetin alfa. This finding may be due to the differences between the cohorts in trauma center level designation; darbepoietin alfa-treated patients werelargely from Level I trauma centers, whereas the epoetin alfa-treated patients were largely from Level IItrauma centers. Nonetheless, mean hemoglobin concentrations at baseline in patients from both ESA cohorts were below normal values (ie, <13.0 g/dL formen and <12.0 g/dL for women, according to theWorld Health Organization guideline I5 ), which is consistent with the published literature. 16,17 Data frompatients who had hemoglobin measurements at hospital or ICU admission, at baseline (before the first ESAadministration), and last observed values showed thatthe hemoglobin concentration decreased over time,with an average decrease of >1.0 g/dL between timepoints. A previous study suggested that in critically illpatients without acute blood loss and no history ofhematologic disease or chronic kidney disease, thedecline in hemoglobin concentration is greatest duringthe first 3 days in the ICU and averages ~0.52 (SD0.69) g/dL/d. 18 Hebert et aF reported, however, thata restrictive approach to RBC transfusion, maintaining hemoglobin as low as 7.0 to 9.0 g/dL, may besafe in critically ill patients. This may explain whyapproximately half of the patients who received darbepoietin alfa and epoetin alfa in the present studyreceived the first RBC transfusion at medians (95%CI) of 4.0 days (2.0-5.0 days) and 6.0 days (4.09.0 days) after admission, respectively, despite beinganemic at admission (according to mean hemoglobinconcentration).
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Rates of transfusion independence in ESA-treatedpatients were similar between the 3 studies by Corwinet al (55%,8 50%,9 and 54%10) and the present study(47% and 44 % for darbepoietin aHa and epoetin alfa,respectively). In the 2007 publication by Corwin et aI,the authors noted that the lack of difference in thenumber of transfusions between the epoetin alfagroup and the placebo group (relative risk, 0.95 [95%CI, 0.85-1.06]) may be due to a "conservative shift" intransfusion practices, because the transfusion triggerwas 0.5 g/dL higher in the previous studies. Corwin etal concluded that "epoetin alfa did not reduce the incidence of transfusion among critically ill patients, but itmay reduce mortality in patients with trauma."
The retrospective analysis presented in this paperhad a number of limitations. Given the nonrandomselection of hospital and patient records, statisticalcomparisons between treatment groups were not performed. In addition, because of its descriptive nature,the present study was not designed to include a controlgroup (ie, patients who did not receive ESAs), and thehemoglobin target in each patient was unknown, so itwas not possible to determine the effect of ESA treatment on clinical outcomes. A number of confoundingvariables might have influenced the outcomes, including use of iron, ESA dosing, transfusions, surgeries andprocedures, blood-sample collection in the ICU, hospital trauma-level designation, and region of the country.The number of doses given might have been confounded by the LOS, and the duration of ESA treatment inthe present study was confounded by ICU and hospitalLOSs and survival. In addition, the data collected in2005 might not have reflected current usage patterns.Nonetheless, the present study has value as a description of the common prescription patterns of darbepoietin alfa and epoetin alfa in an ICU setting in this critically ill patient population in 2005.
CONCLUSIONBased on these results, it is apparent that the practicepatterns associated with ESA treatment of critically illpatients admitted to the ICU between February 2005and September 2005 were highly variable.
ACKNOWLEDGM ENTSDr. Brophy has received research funding from AmgenInc. and is a consultant for Amgen Inc. and OrthoBiotech Products, LP, Bridgewater, New Jersey. Dr.Sheehan was a member of the speaker's bureau for
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Amgen Inc. at the time of the study. Dr. Shapiro received clinical research funding for this study fromAmgen Inc. Dr. Lottenberg's spouse is an employee ofAmgen Inc. Ms. Scarlata is an employee of Amgen Inc.Dr. Audhya was an employee of Amgen Inc. at thetime of the study.
This work was performed by the Study to EvaluateErythropoiesis Stimulating Protein Use and ClinicalOutcomes in Hospitalized Patients (ASSESS) StudyGroup and by Amgen Inc. Members of the ASSESSStudy Group included: C. Alaniz, University of Michigan Hospitals, Ann Arbor, Michigan; ]. Benson, LDSHospital, Salt Lake City, Utah; G.M. Brophy, VirginiaCommonwealth University Health System, Richmond,Virginia; M.A. Dannenhoffer, Buffalo General Hospital, Buffalo, New York; K. Greer, Mercy Hospital ofPittsburgh, Pittsburgh, Pennsylvania; L. Lottenberg,University of Florida Health Sciences Center, Gainesville, Florida; D. Matanin, Latrobe Area Hospital,Latrobe, Pennsylvania; R. Mena, Providence St. Joseph Medical Center, Burbank, California; S. Penkova,Northern Medical Center/North Mississippi MedicalCenter, Tupolo, Mississippi; B. Romig, Moses ConeHealth System, Greensboro, North Carolina; T. Rowe,Multicare Health System, Tacoma, Washington; B.Sabol, St. Elizabeth Health Center, Youngstown, Ohio;M.]. Shapiro, Stony Brook University Hospital, StonyBrook, New York; V. Sheehan, Baylor UniversityMedical Center, Dallas, Texas (currently, McKessonHealth Systems, Keller, Texas); C. Solorzano, Montefiore Medical Center, Bronx, New York; K. Tuttle,Providence Medical Research Center, Spokane, Washington; G. Voss, Avera McKennan Hospital and University Health Center, Sioux Falls, South Dakota;B. Walters, Fairview Hospital, Cleveland, Ohio; andL. Wibbenmeyer, University of Iowa Hospitals &Clinics, Iowa City, Iowa.
The authors thank Dikran Toroser, PhD (AmgenInc.), Beate D. Quednau, PhD (Amgen Inc.), DonnaHarrell (Amgen Inc.), and Mandy Suggitt (on behalfof Amgen Inc.) for expert editorial assistance.
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Address correspondence to: Gretchen M. Brophy, PharmD, VirginiaCommonwealth University, Medical College of Virginia Campus, 410North 12th Street, PO Box 980533, Richmond, VA 23298-0533. E-mail:[email protected]
