Transcript Efficacy and Safety of Epoietin Alfa in Critically Ill

Efficacy and Safety of
Epoietin Alfa in Critically Ill Patients
NEJM 2007, 357: 965-976
TMR Journal Club October 10, 2007
Katerina Pavenski, MD FRCPC
TM Resident, McMaster University
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Background
• Anemia in critically ill patients is common
– 95% of patients admitted to ICU have Hgb
below normal by day 3
– 42-50% of patients admitted to ICU will
require RBC transfusion
– 85% of patients admitted to ICU for >13
days will require RBC transfusion
Zarychanski et al. CMAJ 2007
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Background
• Etiology is multi-factorial
– Hemodilution
– Increased blood loss (bleeding, blood
draws)
– Shortened red blood cell survival
– Impaired production
• Nutritional deficiencies
• Anemia of critical illness: decreased Epo
production, blunted response to Epo,
functional iron deficiency (upregulation of
hepcidin, trapping of iron in macrophages, etc.)
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Background
• Corwin et al Crit Care Med 1999, 27:2346-50
– RCT, designed as superiority study (sample size
not achieved because of poor accrual)
– Setting: multidisciplinary ICU at 3 academic
institutions
– Study population: 80 patients per study group;
excluded patients with recent thromboembolic
disease (w/i 6 mos. of enrollment)
– Outcomes:
• Cumulative blood transfusion requirement from day 1
• Transfusion independence between Day 8 and 42
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Background
• Corwin et al Crit Care Med 1999, 27:2346-50
– Intervention:
• Epo @ 300 U/kg OR placebo sc qd for 5 days and then
alternate days until Hct>38%
• Iron supplementation (same as in 2007 study)
• RBC transfusion at discretion of attending physician; no
transfusion protocol
– Results
• Significantly less RBCs transfused in epo vs. placebo
group (p<0.002)
• Final Hct concentration better in epo vs. placebo group
(p<0.01)
• No significant differences in mortality or adverse events
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Background
• Corwin et al, JAMA 2002, 288: 2827-35
– RCT, superiority with planned sample size of 1300 (90%
power to detect absolute treatment difference of 10% vis-àvis primary outcome)
– Setting: medical, surgical or medico-surgical ICU at 65 US
centres
– Study population: 650 patients in Epo group and 652 in
placebo group; did not exclude patients with
thromboembolic events
– Outcomes:
• Transfusion independence (% patients in each treatment
group who received any RBC between study days 1 and 28)
• Cumulative RBC transfused per patient through day 28
• Change in Hgb from baseline
• Time to first transfusion or death
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Background
• Corwin et al, JAMA 2002, 288: 2827-35
– Intervention
• Epo 40,000 U OR placebo sc on day 3 and then weekly for
three doses (4th dose if in ICU on day 21)
• Iron supplementation (same as in 2007 study)
• RBC transfusion at discretion of treating physician; no
transfusion if Hgb >9.0 g/dL or Hct >27%
– Results
• Patients on Epo were less likely to undergo transfusion (60.4%
vs. 50.5%, p<0.001, OR 0.67, 95% CI 0.54-0.83)
• Reduction in the total # of RBCs transfused in Epo group and
reduction in RBCs transfused per day alive
• Increase in Hgb from baseline was greater in Epo group
• Mortality and severe adverse events were not significantly
different
• Post-hoc analysis: with Epo treatment, difference in MR in
patient subgroups
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Study Design
• Design:
– Multi-centre, randomized, double-blind,
placebo-controlled trial
• Hypothesis
– Superiority with required sample size 1300
patients (power 80% to detect an absolute
difference of 8% in the primary endpoint)
– Blinded review led to increase in sample
size to 1460
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Study Design
• Randomization between 48 and 96
hours after admission and stratified
according to site and subgroup
• Randomization via computer-generated
random numbers and concealed
• Intention-to-treat analysis
• Planned follow-up 140 days
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Statistical Analysis
• Percentage of patients receiving RBC transfusion
– Cochran-Mantel-Haenszel test
– Stratified according to admission group
– 2 scenarios considered
• Numbers of RBC transfused
– Wilcoxon-Mann-Whitney test
– Transfusion rate – number of units that were transfused for
a given patient divided by the total number of days the
patient was alive
• Mortality
– Kaplan-Meier method
– Evaluated at days 29 and 140
– Cox regression model to evaluate interaction between study
group and admission group
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Study Population
• Inclusion criteria
– Patients admitted to the participating ICUs and remaining in that
ICU for 2 days; 18 years old or older; Hgb<12 g/dL; provided
written informed consent
• Exclusion Criteria
– Expected discharge from ICU w/i 48 hrs after the second day in
the ICU; acute ischemic heart disease; stay more than 48 hours in
the ICU of a transferring hospital; presence of LVAD; history of
pulmonary embolus, DVT, ischemic stroke, other arterial or
venous thrombotic event or a chronic hypercoagulable
disorder; dialysis for any indication; uncontrolled hypertension
after adequate antihypertensive therapy; new onset seizures within
past 3 mos. Or seizures not controlled by medication; third degree
burns on >20% BSA; pregnancy or lactation; diagnosis of acute,
clinically significant GI bleeding on admission; transfusion at the
time of planned enrollment; treatment with epoietin alfa within past
30 days; inability or unwillingness to receive blood products;
participation in another study; hypersensitivity to epoietin alfa or
any of its components
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Study Population
• Setting
– Medical, surgical and medico-surgical ICU
at 115 centers
• Accrual
– December 2003 to June 2006
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Study Design - Intervention
• Epoietin alfa 40,000 U OR placebo sc on
days 1, 8, and 15
– Withhold study drug if hemoglobin >12g/dL on
days 8 and 15
• Elemental iron 150 mg po/NG starting on day
1 (or when first able to tolerate feeds)
– Replace with parenteral iron if response
inadequate (TS<20%, serum ferritin <100ng/ml)
• RBC transfusion on discretion of a treating
physician
– Target Hgb 7-9 g/dL
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Study Design - Outcomes
• Primary
– Percentage of patients receiving RBC
transfusion between days 1 and 29
• Secondary
– # RBC transfused between days 1 and 42
– Mortality at days 29 and 140
– Change in hemoglobin concentration from
baseline at day 29
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Results: Study Flow
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Results: Table 1
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Results – Table 2
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Results
• Hemoglobin concentration
– At day 29, Hgb concentration from
baseline was greater in epoietin arm vs.
placebo arm (1.6+/-2.0 g/dL vs. 1.2+/1.8
g/dL, p<0.001)
– At day 29, absolute Hgb concentration
was greater in epoietin arm vs. placebo
arm (11.2+/-1.8 g/dL vs. 10.8+/-1.7 g/dL,
p<0.001)
– By day 42, Hgb concentration was not
statistically different in two groups
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Results: Figure 2
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Results
• At day 29, mortality was significantly lower in
the epoietin group (8.5% vs. 11.4%, p=0.02)
– In trauma group, mortality was also significantly
lower in the epoietin group (3.5% vs. 6.6%,
p=0.04)
• At day 140, mortality was similar in two
groups
– For all patients, 14.2% (epoietin) vs. 16.8%
(placebo), p=0.08
– For trauma group, 6.0% (epoietin) vs. 9.2%
(placebo), p=0.08
• Cox model
– Hazard ratios for mortality in the trauma patients
were significant at day 29 and day 140
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Results: Table 3
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Adverse Events
• At least one adverse event
– 94.4% of patients on placebo, 94.8% of patients
on epoietin
• Serious adverse event
– 43.5% of patients on placebo, 44.0% of patients
on epoietin
– Significantly increased incidence of thrombotic
vascular events in epoietin group (16.5% vs.
11.5%, hazard ratio 1.41, 95% CI 1.06 to 1.86,
p=0.008)
• Most apparent in those who received three doses of
epoietin alfa vs. three doses of placebo
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Adverse Events: Table 4
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Results
• No significant difference between the
epoietin and placebo groups in median
length of ICU stay
• Similar number of ventilator-free days
• Similar median duration of mechanical
ventilation
• At day 140, ventilation has been discontinued
for 96.6% of patients on epoietin and 98.4%
of patients on placebo (p=0.02)
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Author’s Recommendations
Corwin CMAJ 2007
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Critical Appraisal
• Are results valid?
– Patients randomized? Yes
– Randomization concealed? Yes
– Was follow-up sufficiently long and complete?
• 140 days probably enough
• 109 patients (7.5%) lost to follow-up (7.6% in placebo
group, 7.4% in Epo group)
– Patients analyzed in the groups to which they
were randomized? Yes (intention-to-treat)
– Were patients and clinicians blinded? Yes
– Were the groups treated equally, apart from
experimental treatment? Yes
– Were the groups similar at the start of the trial?
Yes
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Critical Appraisal
• Are the valid results of this randomized trial
important?
– Trial was powered for the primary outcome (% of
patients receiving RBC transfusion)
• Conclusion that “epoietin alfa does not reduce the
incidence of red cell transfusion among critically ill
patients” is definitely trustworthy
– Trial was not powered for the composite
secondary outcomes (including mortality)
– Overall mortality was not affected by Epo
– However, pre-planned subgroup analysis showed
mortality benefit in trauma subgroup
Critical Appraisal
• Therefore, the findings of mortality benefit
should be viewed as hypothesis generating
• Potential mortality benefit of Epo
– At day 29, RRR 47%, ARR 3.1%, NNT 30
– At day 140, RRR 35%, ARR 3.2, NNT 31
• Likelihood of help versus harm
– Unable to calculate – unclear how many TE were
in the trauma group
– Trauma patients are inherently pro-thrombotic
(higher baseline risk of TE)
– Real TE rate in this study may be higher than
reported because there was no active
surveillance for TE
Critical Appraisal
• Is apparent difference in treatment efficacy among subgroups
likely?
– Does it make biological and clinical sense? No
• Epo acts as anti-apoptotic agent and may protect cells
from hypoxemia and ischemia
• Presumably this happens in all critical illnesses, so why
would trauma patients have a particular benefit? (stats)
– Is this difference clinically and statistically significant?
• Yes and yes
– Was it hypothesized before the study began?
• Yes
– Was it confirmed in other studies?
• Suggested by previous Corwin’s study
– Was it one of just a few subgroup analyses carried out in
the study? Yes
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Critical Appraisal
• Are these valid results applicable to our
patient?
– Where the study patients similar to my patients?
Yes
– Is the treatment feasible in our setting? Yes
– Were all clinically important outcomes
considered? Yes
– Are the likely treatment benefits worth the
potential harm and costs?
• Unclear
• So where does this leave us?
Instead of Conclusion
• R. Zarychanski et al. CMAJ 2007, 177: 725-734
– Meta-analysis identified 9 relevant RCTs (3326 patients)
• included 3 Corwin’s studies
– Epoietin alfa (compared to placebo or no intervention) had
no statistically significant effect on overall mortality (OR
0.86, 95% CI 0.71-1.05, I2 0%)
– Epo alfa (compared with placebo) significantly reduced
odds of a patient receiving at least 1 transfusion (OR 0.73,
95% CI 0.64-0.84, I2 54.7%)
– Mean number of RBC transfused per patient decreased by
0.41 units in Epo group (95% CI 0.10-0.74, I2 79.2%)
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