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Efficacy and Safety of Epoietin Alfa in Critically Ill Patients NEJM 2007, 357: 965-976

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. 1. Background. Anemia in critically ill patients is common

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Efficacy and Safety of Epoietin Alfa in Critically Ill Patients NEJM 2007, 357: 965-976

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  1. Efficacy and Safety of Epoietin Alfa in Critically Ill PatientsNEJM 2007, 357: 965-976 TMR Journal Club October 10, 2007 Katerina Pavenski, MD FRCPC TM Resident, McMaster University 1

  2. 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

  3. 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.) 3

  4. 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 4

  5. 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 5

  6. 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-à-vis 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 6

  7. 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 7

  8. 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 8

  9. 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 9

  10. 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 10

  11. 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 11

  12. Study Population • Setting • Medical, surgical and medico-surgical ICU at 115 centers • Accrual • December 2003 to June 2006 12

  13. 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 13

  14. 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 14

  15. Results: Study Flow 15

  16. Results: Table 1 16

  17. Results – Table 2 17

  18. 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 18

  19. Results: Figure 2 19

  20. 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 20

  21. Results: Table 3 21

  22. 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 22

  23. Adverse Events: Table 4 23

  24. 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) 24

  25. Author’s Recommendations Corwin CMAJ 2007 25

  26. 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 26

  27. 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

  28. 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

  29. 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 29

  30. 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?

  31. 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%) 31

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