Controversies in Transfusion Medicine

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1 Controversies in Transfusion Medicine Jeffrey L. Carson, M.D. Richard C. Reynolds Professor of Medicine Chief, Division of General Internal Medicine Robert Wood Johnson Medical School New Brunswick, New Jersey, USA Presentation Outline Transfusion reactions Overview TRALI RBC transfusion triggers Critically ill Cardiovascular disease Presentation Outline Use of erythropoietin in hospital Indications Adverse effects Target hemoglobin concentration Indications for platelets and FFP Undergoing procedures (surgery, lines, paracentesis, thoracentesis) 1

2 The Transfusion Decision Transfusion vs No Transfusion Benefit Risks Mortality Blood Side Effects Morbidity Anemia Functional Recovery Risk of Transfusion Risks from Blood Transfusion 2

3 Transfusion-Related Acute Lung Injury (TRALI) Acute lung injury characterized by chills, fever, a nonproductive cough, dyspnea, cyanosis, and hypo tension or hypertension within 1 2 h of transfusion Bilateral infiltrates Absence of left atrial hypertension (i.e., circulatory overload) Within 6 hours of receipt of plasma-containing blood and blood components. Typically within 2 hours Packed cells, fresh frozen plasma, platelet concentrates, granulocytes, and, rarely, intravenous immunoglobulin and cryoprecipitate Incidence unclear: estimated 1:5000 Proposed Causes of TRALI Anti-leukocyte antibodies and the concentration of bioactive lipid factors in the donor product Association between infusion of plasma from female donors The United Kingdom blood system recently eliminated female donors from the production of high plasma volume products (FFP) RBC Transfusion 3

4 Anemia in Animals Group Normal CAD Event ST segment changes Lactate production Ventricular function Death ST segment changes Hgb g/dl < 5 < 3 < 3 < Effect of Anemia and CVD on Surgical Mortality and Morbidity Retrospective cohort study of patients who refuse blood transfusion for religious reasons Outcome-30-day mortality or morbidity CVD - patient with history of MI, angina, CHF, or PVD 1,958 patients age 18 or older Carson JL, et al. Lancet 1996;348: Preoperative Hgb and Mortality Preoperative Hgb N % Dead 95% CI Carson Lancet

5 Preop Hgb by Cardiovascular Disease Interaction P=0.03 Conclusions-Risk of Anemia Mortality rises as preoperative hemoglobin falls A postoperative hemoglobin below 5-6 g/dl was associated with very high mortality Animal and human data suggest that patients with CVD may be less tolerant of anemia than patients without CVD Efficacy of Transfusion: Systematic Review Clinical Trials 5

6 All Cause 30 Day Mortality Transfusion in Critical Care Clinical trial in consecutive ICU patients with Hgb < 9.0 g/dl and euvolemia Restrictive: blood given when Hgb < 7.0 g/dl and maintained between 7-9 g/dl Liberal: blood given when Hgb < 10 g/dl and maintained between g/dl Primary outcome 30 day mortality Hebert et al N Engl J Med 1999 Outcomes TRICC Trial Outcome Restrictive N=418 Liberal N=420 Difference (95% CI) 30 d death 18.7% 23.3% 4.7% ( ) 6

7 Morbidity Outcomes in TRICC Restrictive N (%) Liberal N (%) P Value MI 3 (0.7) 12 (2.9) 0.02 Pulmonary Edema 22 (5.3) 45 (10.7) 0.01 ARDS 32 (7.7) 48 (11.4) 0.06 Summary-Clinical Trial Data There is only one adequately powered clinical trial in the world literature evaluating transfusion thresholds Study suggests 7 g/dl is as safe 10g/dL threshold in ICU patients Subanalysis in patients with ischemic heart disease found non significant lower mortality in patients transfused > 10 g/dl. Effect of Transfusion: Systematic Review Observational Studies 7

8 Surgical Blood Transfusion Determine effect of transfusion on mortality, morbidity by comparison with similar patients not receiving transfusion 9,958 patients with hip fracture Age 60 or older Outcomes: Mortality and Morbidity Carson, et al. JAMA 1998;279: Effect of Postoperative Transfusion on 30 Day Mortality Stratum Overall > 10 N Adjusted Odds Ratio (95% CI) 0.96 ( ) 0.91( ) CVD-No CVD-Yes ( ) 1.01 ( ) 1.19 ( ) 1.07 ( ) Transfusion and MI Cohort study in 78,974 Medicare patients 65 years of age or older Mortality at 30 days compared in patients transfused vs not transfused Stratified by admission Hct level Adjusted for co-morbidity Many exclusions Wu et al. N Engl J Med 2001;345:

9 Impact of Transfusion on 30 Day Mortality Admission Hematocrit % % % % % % % Adjusted OR (95% CI) 0.22 ( ) 0.48 ( ) 0.60 ( ) 0.69 ( ) 1.13 ( ) 1.38 ( ) 1.46 ( ) Transfusion in Acute Coronary Syndrome Combined results from 3 large clinical trials of patients with acute coronary syndrome Examined the association in patients with bleeding and nadir Hgb. Primary outcome was 30-day all cause mortality and secondary outcome 30-day all cause mortality or MI. Rao et al. JAMA

10 Association with Transfusion and ACS Nadir Hematocrit 35% 30% 25% 20% Adjusted Odds Ratio of 30- Day Death (95% CI) 291 (10-827) 169 (7-3798) 1.13 ( ) 1.59 ( ) Summary-Observational Studies Results from observational studies are inconsistent Several studies suggest that higher Hgb levels are needed in patients with CVD Unclear if results of observational studies are valid 10

11 FOCUS To compare the effect of symptomatic transfusion to 10 g/dl threshold transfusion on functional recovery, mortality, and morbidity 2,000 hip fracture patients Cardiovascular disease or risk factors CAD, CHF, PVD, Stroke or DM, hypertension, tobacco use, hyperlipidemia Outcomes include functional recovery, MI, mortality, and other morbidities Transfusion Recommendations Pending additional clinical trials, the best data suggests that a restrictive transfusion trigger (7 g/dl) should be used The appropriate transfusion threshold in patients with cardiovascular disease is unknown Careful assessment of the need for transfusion in each patient should be made Erythropoiesis Stimulating Agents: Indications and Safety Considerations 11

12 FDA Approved Indications Chronic renal insufficiency Cancer HIV Surgery ICU- Not approved Safety New Black Box Warning [Aranesp /EPOGEN/PROCRIT] and other ESAs increased the risk for death and for serious cardiovascular events when dosed to achieve a target a hemoglobin of greater than 12 g/dl 12

13 Phrommintikul Lancet 2007 Meta-analysis of RCT evaluating EPO Targeted different Hgb levels Anemia caused by chronic kidney disease Studies needed to include at least 100 patients and include follow-up for 12 weeks Excluded 24 trials with less 100 patients Mortality Phrommintikul Lancet 2007 Myocardial Infarction 13

14 AV Access Thrombosis Preliminary Overall Conclusions: Chronic Kidney Disease There appears to be a small increase risk of death or cardiovascular outcomes in patients treated with epo with underlying chronic renal disease Meta-analysis should include all studies The risk was primarily identified in studies where Hgb were above 12 g/dl Quality of life measures were inconsistently found to be improved in patients with higher Hgb The current evidence suggests that the risk of maintaining Hgb > 12 /g/dl outweighs potential benefit Risk of TVE by Baseline Hgb in Cancer Trials Outcome Transfusion Mortality TVE Hypertension Relative Risk (95% CI) 0.64 ( ) 1.08 ( ) 1.67 ( ) 1.24 ( ) N 6,510 8,167 1,712 2,263 Bohlius Cochrane Reviews

15 Risk of TVE by Baseline Hgb in Cancer Trials Baseline Hgb Hazard Ratio (95% CI) N < ( ) 0.98 ( ) 3,765 1,712 >12 Bohlius Cochrane Reviews ( ) 1,696 Epo in Head and Neck Cancer RCT in advanced squamous cell Ca of oral cavity, oropharynx, hypopharynx or larynx Hgb < 12 in women and 13 in men Epo given to target of 14 g/dl in women and 15 g/dl in men Primary outcome locoregional progression-free survival Henke, Lancet 2003 Effect of Epoetin B Locoregional progression-free survival Locoregional progression Survival Relative Risk (95% CI) 1.62 ( ) 1.69 ( ) 1.39 ( ) P value

16 Possible Mechanism Tumor cells have epo receptors Breast, prostate, colon, ovary, uterine, cervical, gliobstoma, head and neck squamous cell Henke JCO linked prognosis with presence of receptors in head and neck Positive receptors: Epo increased recurrence 2.07 (95% CI, ) Negative receptors: Epo not influence recurrence 0.94 (95% CI, ) Preliminary Conclusions: Cancer Most but not all recent studies report that epo may worsen mortality in cancer patients Findings come from trials that sought normal Hgb or > 12 g/dl Study Overview RCT administered epoetin alfa or placebo to 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit No difference in blood transfusions between groups Corwin HL et al. N Engl J Med 2007;357:

17 Mortality at Day 29 and Day 140 in the Intention-to-Treat Population Serious Adverse Events Conclusion The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events 17

18 Platelets and Plasma Platelet Trigger Platelet Count 10,000 20,000 50, ,000 Clinical Characteristics Stable Febrile, septic, other risk factors for bleeding Surgery CNS procedures Fresh Frozen Plasma Insufficient data to conclude that abnormal coagulation tests predict bleeding RCT s badly needed Plasma probably not indicated if INR 1.5 or less Hemostasis can be achieved when the activity of coagulation factors is at least 25-30%, and fibrinogen is at least 75 to 100 mg/dl Dose of FFP of approximately 10 to 15 ml/kg. 3-5 units Watch for volume overload 18

19 Controversies in Transfusion Medicine Jeffrey L. Carson, M.D. Richard C. Reynolds Professor of Medicine Chief, Division of General Internal Medicine UMDNJ-Robert Wood Johnson Medical School New Brunswick, New Jersey Safety of allogeneic blood Effect of Anemia on Mortality and Morbidity Indications for allogeneic blood transfusion Erythropoietin stimulating agents Platelets and Plasma Outline Red Blood Cell References Klein HG, Spahn DR, Carson JL Red Cell Transfusion in Clinical Practice. Lancet 2007;370: Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout R, Noveck H, Strom BL. Effect of anemia and cardiovascular disease on surgical mortality and morbidity. Lancet. 1996;348: Carson JL, Duff A, Berlin JA, Lawrence VA, Poses RM, Huber EC, O=Hara DA, Noveck H, Strom BL. Influence of perioperative blood transfusion on postoperative mortality. JAMA. 1998;279: Wu WC., Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345: Rao SV, Jollis JG, Harrington RA et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA. 2004;292(13): Hebert PC, Wells G, Blajchman MA, et al. A multicenter randomized controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340: Corwin HL, Carson JL. Blood transfusion--when is more really less? N Engl J Med 2007;356: Erythropoietin Stimulating Agents Bohlius J, Wilson J, Seidenfeld J, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2006;3: CD Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007;357:

20 Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362: Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 2007;369: Platelets and Plaama Stroncek DF, Rebulla P. Platelet transfusions. Lancet 2007; 370: Strauss RG. Pretransfusion trigger platelet counts and dose for prophylactic platelet transfusions. Curr Opin Hematol 2005;12: Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005;45: