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© SICS EBM Group 2004
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Low dose Epoetin Alfa in critically ill patients; RCT
Lead author: Corwin HL Dartmouth-Hitchcock Medical Centre, Lebanon, NH 03756, USA. howard.l.corwin@hitchcock.org.
Three-part Clinical Question: Patients: All ICU patients. Intervention: Low dose epoetin alfa (40, 000 U) or placebo. Outcomes: Percentage of patients receiving blood transfusions, no of units of red cells transfused, change in Hb from baseline, mortality, adverse events. Search Terms: Erythropoietin, red cell transfusion, critically ill, anaemia, mortality, outcome, randomized controlled trial, EPO Critical Care Trials Group.
The Study: Double-blinded, concealed, randomized trial with
intention-to-treat.
Inclusion criteria: 18+yrs, Hb <12g/dl, written informed consent (patient or surrogate) Exclusion criteria: expected ITU discharge within 48hrs of day 2, acute IHD during ITU admission, stay > 48hrs in the ICU of a transferring hospital, left ventricular assist device, history of PE, DVT, ischaemic stroke, other arterial or venous thrombosis (excluding superficial thrombosis), chronic hypercoagulable disorder, dialysis, uncontrolled hypertension (systolic > 200mmHg or diastolic > 110), new-onset seizures within 3 months, seizures not controlled on medication, pregnancy or lactation, 3rd degree burns ≥ 20%, acute GI bleed, transfusion at time of consideration, treatment with epoetin alfa within last 30 days, unable or unwilling to accept blood products, other study participation, hypersensitivity to epoetin alfa or constituents.
All patients given liquid iron (150mg elemental iron/day) at start of day 1. If no response, converted to parental iron (transferrin saturations <20%, serum ferritin <100ng/ml) Blood transfusion requirement determined upon individual clinical grounds, no set targets. Arbitrary target Hb 7 - 9g/dL or haematocrit ≈ 27%. Control group (N = 727; 727 analysed): As experimental group but with placebo.
The Evidence (All Patients):
The Evidence (Trauma Patients, n= 402 intervention / 391 control):
EBM Comments:
1. Do the methods allow accurate testing of the hypothesis? Yes. Well designed double blinded concealed randomized trial with large patient numbers calculated to achieve statistical power.
2. Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes.
3. Are conclusions valid in light of the results? Perhaps.
(I) The authors were correct in stating that there was no benefit for non-trauma patients. However with regards to trauma patients, the authors concluded “we believe that epoetin alfa could benefit trauma patients remaining in an ICU for more than 48 hours and who have haemoglobin concentrations below 12 g per deciliter and no history of thrombotic disease”. There was a statistically significant mortality benefit at 29 days for trauma patients but in the uncorrected data this was lost by 140 days. Therefore “could” benefit is appropriate. A definite answer for trauma patients can only be derived from a larger study. (II) 60% of the intervention group received only 1 or 2 doses of epoetin alfa. Therefore, the potential overall effect on haemoglobin concentration may not have been demonstrated in this study. This may explain why a reduction in blood transfusion requirements was not shown. (III) Transfusion triggers were higher than presently recommended (TRICC trial, McIntyre et al), especially in the trauma subgroup. Restrictive transfusion in this subgroup was demonstrated to be as safe as liberal.
4. Did results get omitted, and why? No. All patients, including those lost to follow up (control:134,epo:115) are included in denominator.
5. Did they suggest areas of further research? Yes.
(I) The mechanism of action responsible for the effects of epoetin alfa, thought to be non-haematopoietic i.e. anti-apoptotic. Improvement in clinical outcome as represented by decreased mortality and moderate rise in haemoglobin occurred in the absence of a reduction in transfusion requirements as previously found. Is this plausible however in view of the low doses of epoetin alpha administered? (II) Increased thrombotic risk and death.
6. Did they make any recommendations based on the results and were they appropriate? Yes.
a. Epoetin alfa may be beneficial in trauma patients remaining on ICU ≥ 48hrs with a haemoglobin of <12g/dl and no previous history of thrombotic disease (study criteria met). This is only supported by adjusted data at 140 days. In view of this, the cost and complications this is unlikely to become routine practise. b. There is evidence to suggest that epoetin should not be administered before a patient has been in ICU > 48hrs. c. The use of epoetin in non-trauma patients is not supported unless they have an approved indication. d. Concurrent prophylactic heparin should be considered in all patients.
7. Is the study relevant to my clinical practice? Yes. Although when assessing applicability of the study findings to UK practise one must remember that the case mix was, with >50% trauma, was not typical of the UK.
8. What level of evidence does this study represent? 1++
9. What grade of recommendation can I make on this result alone? A
10. What grade of recommendation can I make when this study is considered along with other available evidence? A
11. Should I change my practice because of these results? No. Epoetin is not routinely used in critical care in this clinical setting currently. The exact mechanism of action of Epoetin is unclear and there is not significant evidence to suggest clinical benefit. The risks currently out weight the benefits.
12. Should I audit my current practice because of these results? No. Epoetin alfa is not routinely used in UK ICU’s. Appraised by: Dr Oona Tanner (SHO), Department of Anaesthetics, Stirling Royal Infirmary, Livilands, Stirling, FK8 2AU. 10th October 2007.
©SICS EBMG 2009
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