Transfusion Thresholds: How Low Can We Go?

Transcription

1 Transfusion Thresholds: How Low Can We Go? Jeffrey L. Carson, M.D. Richard C. Reynolds Professor of Medicine Chief, Division of General Internal Medicine Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey, USA

2 Presentation Outline Framework for transfusion decision Side effects of blood Quality of product Effect of anemia on mortality and morbidity Effect of blood transfusion on mortality and morbidity Clinical trials FOCUS Observational data Summary

3 Case 1 68 year old male with COPD is admitted to hospital with increasing dyspnea. He is hypoxic and has large infiltrate on chest xray. The patient is transferred to MICU, intubated and treated with antibiotics. Over the next 3 days Hgb falls from 11 to 8.5 g/dl. He appears to be euvolemic and BP is stable. Transfuse?

4 What Hemoglobin Concentration Transfuse? 11 g/dl 10 g/dl 9 g/dl 8 g/dl 7 g/dl 6 g/dl

5 Case 2 80 year old women 2 days postop for hip fracture repair PMH- hypertension, DM, history of MI three years ago Symptoms- tired and weak Exam ok Hgb 8.5 g/dl Transfuse?

6 What Hemoglobin Concentration Transfuse? 11 g/dl 10 g/dl 9 g/dl 8 g/dl 7 g/dl 6 g/dl

7 Case 3 66 year old male presents with chest pain to ER and ECG shows anterior wall MI Patient taken to cardiac catherization lab and stent inserted in LAD Admission Hgb Following day Hgb 9.2 Large hematoma in groin. Vitals normal Transfuse?

8 Case 3 continued Next day Hgb 8.1 g/dl Vitals normal. No chest pain or dyspnea Transfuse?

9 Case 4 72 year old patient admitted with ischemic foot undergoes fem-pop bypass PMH - MI 3 years ago, DM x 10 years, smoked 30 pack years. Denies angina Preop Hgb Creatinine 2.5 Postop feels little weak Hgb is 9.0 Transfuse?

10 What Hemoglobin Concentration Transfuse? 11 g/dl 10 g/dl 9 g/dl 8 g/dl 7 g/dl 6 g/dl

11 Transfuse vs No Transfuse Benefit Risks Mortality Blood Side Effects Morbidity Risks from Anemia Functional Recovery

12 Side Effects of Allogeneic Transfusion

13 1 in 100 million 1 in 10 million 1 in 1 million 1 in 100,000 1 in 10,000 1 in in in 10 1 in 1 Adverse effects of transfusion Modified from Dzik WH 2003

14 1 in 100 million 1 in 10 million 1 in 1 million 1 in 100,000 1 in 10,000 1 in in in 10 1 in 1 HIV HCV HBV Fatal Hemolysis Fever Adverse effects of transfusion Modified from Dzik WH 2003

15 1 in 100 million 1 in 10 million 1 in 1 million 1 in 100,000 1 in 10,000 1 in in in 10 1 in 1 HIV HCV HBV TRALI TACO Life threatening reaction Fatal Hemolysis Fever Adverse effects of transfusion Modified from Dzik WH 2003

16 Transfusion-Related Acute Lung Injury (TRALI) Acute lung injury with bilateral infiltrates Absence circulatory overload Within 6 hours (usually 2 hours) of receipt of plasma-containing blood or components Chills, fever, dyspnea, cyanosis, and hypotension or hypertension RBC s, FFP, platelets, granulocytes

17 Transfusion Associated Circulatory Overload (TACO) Volume overload from transfusion Frequency reported varies; about 1:100 Common, clinically important, but treatable in most cases

18 1 in 100 million 1 in 10 million 1 in 1 million 1 in 100,000 1 in 10,000 1 in in in 10 1 in 1 HIV HCV HBV TRALI TACO Life threatening reaction Fatal Hemolysis Fever Motor vehicle fatalities Airplane fatalities Firearm homicide Death from medical error Lightning fatalities Fall fatalities Adverse effects of transfusion contrasted with other risks Modified from Dzik WH 2003

19 Summary-Side Effects Risks of blood from known problems is very low and comparable to everyday risks Risk of HIV and Hepatitis C about 1:2 million TRALI is important serious side effect but TACO much more common Human error (wrong unit of blood to wrong patient) preventable cause of serious adverse effects of blood

20 Quality of RBC Product

21 Fresh Stored

22 Mean Levels of 2,3 DPG after Transfusion Heaton A, Br J Haematol 1989

23 Duration of Red-Cell Storage and Complications after Cardiac Surgery Patients undergoing cardiac surgery who received blood 6002 patients undergoing cardiac surgery Compared complication rate those who received blood stored for 14 days or less had lower rates of complications and death than those who received blood stored Koch et al. N Engl J Med 2008

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25 ONLINE FIRST Effect of Fresh Red Blood Cell Transfusions on Clinical Outcomes in Premature, Very Low-Birth-Weight Infants The ARIPI Randomized Trial Dean A. Fergusson, MHA, PhD Paul Hébert, MD, MHSc(Epid) Debora L. Hogan, BScN, BA, MScN Louise LeBel, BScN Nicole Rouvinez-Bouali, MD John A. Smyth, LRCPSI Koravangattu Sankaran, MBBS Alan Tinmouth, MD, MSc(Clin Epi) Morris A. Blajchman, MD Lajos Kovacs, MD Christian Lachance, MD Shoo Lee, MBBS, PhD C. Robin Walker, MB,ChB Brian Hutton, PhD Robin Ducharme, HBSc Katelyn Balchin, MSc Tim Ramsay, PhD Jason C. Ford, MD Ashok Kakadekar, MD Kuppuchipalayam Ramesh, MD Stan Shapiro, PhD ALTHOUGH RED BLOOD CELL (RBC) transfusions are used routinely in acutely ill patients, including those in neonatal intensive care units, the clinical consequences of the prolonged stor- Context Even though red blood cells (RBCs) are lifesaving in neonatal intensive care, transfusing older RBCs may result in higher rates of organ dysfunction, nosocomial infection, and length of hospital stay. Objective To determine if RBCs stored for 7 days or less compared with usual standards decreased rates of major nosocomial infection and organ dysfunction in neonatal intensive care unit patients requiring at least 1 RBC transfusion. Design, Setting, and Participants Double-blind, randomized controlled trial in 377 premature infants with birth weights less than 1250 g admitted to 6 Canadian tertiary neonatal intensive care units between May 2006 and June Intervention Patients were randomly assigned to receive transfusion of RBCs stored 7daysorless(n=188)vsstandard-issueRBCsinaccordancewithstandardbloodbank practice (n=189). Main Outcome Measures The primary outcome was a composite measure of major neonatal morbidities, including necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, and intraventricular hemorrhage, as well as death. The primary outcome was measured within the entire period of neonatal intensive care unit stay up to 90 days after randomization. The rate of nosocomial infection was a secondary outcome. Results The mean age of transfused blood was 5.1 (SD, 2.0) days in the fresh RBC group and 14.6 (SD, 8.3) days in the standard group. Among neonates in the fresh RBC group, 99 (52.7%) had the primary outcome compared with 100 (52.9%) in the standard RBC group (relative risk, 1.00; 95% CI, ). The rate of clinically suspected infection in the fresh RBC group was 77.7% (n=146) compared with 77.2% (n=146) in the standard RBC group (relative risk, 1.01; 95% CI, ), and the rate of positive cultures was 67.5% (n=127) in the fresh RBC group compared with 64.0% (n=121) in the standard RBC group (relative risk, 1.06; 95% CI, ). Conclusion In this trial, the use of fresh RBCs compared with standard blood bank practice did not improve outcomes in premature, very low-birth-weight infants requiring a transfusion. Trial Registration clinicaltrials.gov Identifier: NCT ; Current Controlled Trials Identifier: ISRCTN JAMA. 2012;308(14):doi: /2012.jama

26 Age or red blood cell in premature infants (ARIPI) study Double-blind multicenter RCT in 377 patients Premature infants < 1250 g birth weight requiring one or more RBC transfusions Blood stored 7 days- Mean 5.1 days Blood stored for standard time - Mean 14.6 days Primary composite outcome: mortality, retinopathy, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage.

27 Fergusson et al. ARIPI Trial. JAMA 2012

28 On-going Trials on RBC Storage Time RECESS RCT double-blind in 1612 patients Cardiac surgery patients Age < 10 days vs 21+ Multiple Organ Dysfunction Score (MODS), mortality, and morbidity ABLE < 8 days vs usual storage ICU patients Mortality INFORM Freshest compatible unit in inventory available Oldest ABO compatible RBC unit in inventory In-hospital mortality

29 Quality of RBC Product Unclear if age of blood is important. Requires further testing in clinical trials

30 Risk of Anemia

31 Anemia in Animals Group Event Hgb (g/dl) Normal ST segment changes < 5 Lactate production < 3 Ventricular function < 3 Death < 3 CAD ST segment changes 7-10

32 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:

33 Preop Hgb and Mortality Preop Hgb N % Dead 95% CI Carson JL, et al. Lancet 1996;348:

34 Preop Hgb by Cardiovascular Disease Interaction P= CVD- No CVD-Yes Adjusted Odds Ratio Preoperative Hemoglobin g/dl

35 Postop Hgb Level and Mortality in Patients with Hgb < 8 g/dl Postop Hgb N(300) % 30 day Mortality % 30 day Mortality Morbidity Carson JL, et al. Transfusion 2002

36 Conclusions-Risk of Anemia Mortality and morbidity rises as preoperative and postoperative hemoglobin falls Animal and human data suggest that patients with CVD may be less tolerant of anemia than patients without CVD

37 Efficacy of Transfusion Clinical Trials

38 Exposure to Blood Transfusion Carson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews 2012 Updated

39 The New England Journal of Medicine Copyright, 1999, by the Massachusetts Medical Society VOLUME 340 F EBRUARY 11, 1999 NUMBER 6 A MULTICENTER, RANDOMIZED, CONTROLLED CLINICAL TRIAL OF TRANSFUSION REQUIREMENTS IN CRITICAL CARE PAUL C. HÉBERT, M.D., GEORGE WELLS, PH.D., MORRIS A. BLAJCHMAN, M.D., JOHN MARSHALL, M.D., CLAUDIO MARTIN, M.D., GIUSEPPE PAGLIARELLO, M.D., MARTIN TWEEDDALE, M.D., PH.D., IRWIN SCHWEITZER, M.SC., ELIZABETH YETISIR, M.SC., AND THE TRANSFUSION REQUIREMENTS IN CRITICAL CARE INVESTIGATORS FOR THE CANADIAN CRITICAL CARE TRIALS GROUP* R

40 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 NEJM 1999

41 Outcomes TRICC Trial Outcome Restrictive N=418 Liberal N=420 Difference (95% CI) 30 day death 18.7% 23.3% 4.7% ( )

42 Restrictive Liberal Liberal Restrictive Overall Ischemic Heart Disease

43 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

44 Transfusion Requirements After Cardiac Surgery The TRACS Randomized Controlled Trial Ludhmila A. Hajjar, MD, PhD Jean-Louis Vincent, MD, PhD Filomena R. B. G. Galas, MD, PhD Rosana E. Nakamura, MD Carolina M. P. Silva, MD Marilia H. Santos, MD, PhD Julia Fukushima, MSc Roberto Kalil Filho, MD, PhD Denise B. Sierra, MD Neuza H. Lopes, MD, PhD Thais Mauad, MD, PhD Aretusa C. Roquim, MD Marcia R. Sundin, MD Wanderson C. Leão, MD Juliano P. Almeida, MD Pablo M. Pomerantzeff, MD, PhD Luis O. Dallan, MD, PhD Fabio B. Jatene, MD, PhD Noedir A. G. Stolf, MD, PhD Jose O. C. Auler Jr, MD, PhD CARDIAC SURGERY IS ASSOCIATED with a high rate of allogeneic bloodtransfusion,varyingfrom 40% to 90% in most reports. 1-3 The rationale for perioperative red blood cell(rbc)transfusionisbasedontheobservation that anemia is an independent risk factor for morbidity and mortality after cardiac operations. However, trans- Context Perioperative red blood cell transfusion is commonly used to address anemia, an independent risk factor for morbidity and mortality after cardiac operations; however, evidence regarding optimal blood transfusion practice in patients undergoing cardiac surgery is lacking. Objective To define whether a restrictive perioperative red blood cell transfusion strategy is as safe as a liberal strategy in patients undergoing elective cardiac surgery. Design, Setting, and Patients The Transfusion Requirements After Cardiac Surgery (TRACS) study, a prospective, randomized, controlled clinical noninferiority trial conducted between February 2009 and February 2010 in an intensive care unit at a university hospital cardiac surgery referral center in Brazil. Consecutive adult patients (n=502) who underwent cardiac surgery with cardiopulmonary bypass were eligible; analysis was by intention-to-treat. Intervention Patients were randomly assigned to a liberal strategy of blood transfusion (to maintain a hematocrit 30%) or to a restrictive strategy (hematocrit 24%). Main Outcome Measure Composite end point of 30-day all-cause mortality and severe morbidity (cardiogenic shock, acute respiratory distress syndrome, or acute renal injury requiring dialysis or hemofiltration) occurring during the hospital stay. The noninferiority margin was predefined at 8% (ie, 8% minimal clinically important increase in occurrence of the composite end point). Results Hemoglobin concentrations were maintained at a mean of 10.5 g/dl (95% confidence interval [CI], ) in the liberal-strategy group and 9.1 g/dl (95% CI, ) in the restrictive-strategy group (P.001). A total of 198 of 253 patients (78%) in the liberal-strategy group and 118 of 249 (47%) in the restrictive-strategy group received abloodtransfusion(p.001). Occurrence of the primary end point was similar between groups (10% liberal vs 11% restrictive; between-group difference, 1% [95% CI, 6% to 4%]; P=.85). Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications or death at 30 days (hazard ratio for each additional unit transfused, 1.2 [95% CI, ]; P=.002). Conclusion Among patients undergoing cardiac surgery, the use of a restrictive perioperative transfusion strategy compared with a more liberal strategy resulted in noninferior rates of the combined outcome of 30-day all-cause mortality and severe morbidity. Trial Registration clinicaltrials.gov Identifier: NCT JAMA. 2010;304(14):

45 Transfusion in Cardiac Surgery RCT in 502 CABG or cardiac valve replacement surgery Liberal: transfusion if Hct < 30%, Restrictive: transfusion if Hct < 24% Transfusion from start of surgery to discharge from ICU Primary outcome composite of 30 day mortality, cardiogenic shock, ARDS,or renal failure requiring dialysis Hajjar, L. A. et al. JAMA 2010;304:

46 Transfusion in Cardiac Surgery Liberal Restrictive Composite Primary Death at 30 Days Acute Renal Failure on Dialysis All Non-Significant Cardiogenic Shock ARDS Respiratory Cardiac Infection 0% 10% 20% 30% Hajjar, L. A. et al. JAMA 2010;304:

47 Original Article Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery Jeffrey L. Carson, M.D., Michael L. Terrin, M.D., M.P.H., Helaine Noveck, M.P.H., David W. Sanders, M.D., Bernard R. Chaitman, M.D., George G. Rhoads, M.D., M.P.H., George Nemo, Ph.D., Karen Dragert, R.N., Lauren Beaupre, P.T., Ph.D., Kevin Hildebrand, M.D., William Macaulay, M.D., Courtland Lewis, M.D., Donald Richard Cook, B.M.Sc., M.D., Gwendolyn Dobbin, C.C.R.P., Khwaja J. Zakriya, M.D., Fred S. Apple, Ph.D., Rebecca A. Horney, B.A., Jay Magaziner, Ph.D., M.S.Hyg., for the FOCUS Investigators N Engl J Med Volume 365(26): December 29, 2011

48 FOCUS Methods RCT in hip fracture patients CVD or CVD risk factors Hemoglobin < 10 g/dl Liberal (10 g/dl) vs Restrictive (8 g/dl or symptoms) Transfusion Function, mortality, myocardial infarction, morbidity 2016 patients from 47 centers in US and Canada

49 Clinical Characteristics Total N=2016 Liberal N=1007 Restrictive N=1009 Age (+SD) 81.6 (+8.9) 81.8 (+ 8.8) 81.5 (+9.0) Female 75.7% 75.2% 76.3% Any CVD 62.9% 63.3% 62.6% Coronary artery disease 39.9% 39.9% 39.9% CHF 17.4% 18.3% 16.6% Peripheral vascular disease 10.9% 11.6% 10.1% Stroke or TIA 23.5% 24.7% 22.2% DM 25.2% 25.1% 25.4%

50 Hgb and Transfusions Liberal N=1007 Restrictive N=1009 Hgb Prior to Transfusion 9.2 (SD+0.5) 7.9 (SD+0.6) Transfused Patients 974 (96.7%) 415 (41.0%) Median Units Transfused 2.0 (interquartile range, 1,2) 0 (interquartile range, 0,1) Total Units Transfused 1866 units 652 units

51 Primary Outcome: Not Walking or Dead at 60 days Liberal Restrictive Risk Difference Odds Ratio N=1007 N=1009 (95% CI) (95% CI) 60 days 351 (35.2%) 347 (34.7%) 30 days 459 (46.1%) 481 (48.1%) 0.5% (-3.7% to 4.7%) -2.0% (-7.7 to 3.8)* 1.01 (0.84 to 1.22) 0.92 (0.73 to 1.16)* *99% Confidence Intervals for secondary outcomes

52 Mortality Liberal Restrictive 10% 8% 6% 7.6% 6.6% 4% 5.2% 4.3% 2% 0% 2% 1.4% In-hospital 30 Day 60 Day all p=ns

53 Post Randomization Cardiac Events Elevated troponin Liberal N=1005 Restrictive N= (6.2%) 59 (5.9%) MI 23 (2.3%) 38 (3.8%) In-hospital mortality MI, unstable angina or Death 20 (2.0%) 14 (1.4%) 43 (4.3%) 52 (5.2%) Absolute risk difference (99% CI) 0.3% (-2.4% to 3.1%) -1.5% (-3.5 to 0.5) 0.6% (-0.9% to 2.1%) -0.9% (-3.3 to1.6) Odds Ratio (99% CI) 1.06 (0.65 to 1.71) 0.60 ( ) 1.44 (0.58 to 3.56) 0.82 (0.48 to 1.42)

54 Days from Randomization to Discharge Liberal N=1007 Restrictive N=1009 Mean + SD US - N= Canada- N= p=ns

55 new england The journal medicine of established in 1812 january 3, 2013 vol. 368 no. 1 Transfusion Strategies for Acute Upper Gastrointestinal Bleeding Càndid Villanueva, M.D., Alan Colomo, M.D., Alba Bosch, M.D., Mar Concepción, M.D., Virginia Hernandez-Gea, M.D., Carles Aracil, M.D., Isabel Graupera, M.D., María Poca, M.D., Cristina Alvarez-Urturi, M.D., Jordi Gordillo, M.D., Carlos Guarner-Argente, M.D., Miquel Santaló, M.D., Eduardo Muñiz, M.D., and Carlos Guarner, M.D.

56 Methods Adults with hematemesis or melena Selected exclusions: Massive exsanguinating bleeding Acute coronary syndrome or other cardiovascular disease Hemoglobin level > 12 g/dl

57 Transfusion Protocol and Outcomes Restrictive: 7 g/dl with target 7-9 Liberal: 9 g/dl with target 9-11 In both groups, patients received one unit immediately. Primary outcome: Death at 45 days Secondary outcomes: further bleeding defined as hematemeis, fresh melena with bp <100 or puls

58 Rate of Survival, According to Subgroup. Rate of Survival, According to Subgroup. Villanueva C et al. N Engl J Med 2013;368:11-21

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60 Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease Jeffrey L. Carson, MD, a Maria Mori Brooks, PhD, b J. Dawn Abbott, MD, c Bernard Chaitman, MD, d Sheryl F. Kelsey, PhD, b Darrell J. Triulzi, MD, e Vankeepuram Srinivas, MD, f Mark A. Menegus, MD, f Oscar C. Marroquin, MD, g Sunil V. Rao, MD, h Helaine Noveck, MPH, a Elizabeth Passano, MS, b Regina M. Hardison, MS, b Thomas Smitherman, MD, g Tudor Vagaonescu, MD, i Neil J. Wimmer, MD, j and David O. Williams, MD j New Brunswick, NJ; Pittsburgh, PA; Providence, RI; Saint Louis, MO; New York, NY; Durham, NC; and Boston, MA Funded by National Heart, Lung, Blood Institute American Heart Journal 2013

61 MINT Methods RCT; pilot study in 110 patients ACS (STEMI, NSTEMI, Unstable angina) and Stable coronary artery disease patient undergoing cardiac catherization during the index hospitalization Hemoglobin < 10 g/dl Liberal (10 g/dl) vs Restrictive (8 g/dl or symptoms) Feasibility and clinical outcomes

62 Clinical Endpoints at 30 Days A N=55 B N=54 Absolute risk difference (95% CI) Death/MI/ Revascularization 6 (10.9%) 14 (25.9%) Death 1 (1.8%) 7 (13.0%) MI 5 (9.1%) 7 (13.0%) Revascularization 0 (0.0%) 2 (3.7%) *p=0.054, adjusted for age p= % (0.7 to 29.3)* 11.2%** (1.5 to 20.8) 13.0% (-7.9 to15.6) 3.7% (-1.3 to 8.7) **p=0.032

63 Clinical Endpoints at 30 Days Liberal N=55 Restrictive N=54 Absolute risk difference (95% CI) Death/MI/ Revascularization 6 (10.9%) 14 (25.9%) Death 1 (1.8%) 7 (13.0%) MI 5 (9.1%) 7 (13.0%) Revascularization 0 (0.0%) 2 (3.7%) *p=0.054, adjusted for age p= % (0.7 to 29.3)* 11.2%** (1.5 to 20.8) 13.0% (-7.9 to15.6) 3.7% (-1.3 to 8.7) **p=0.032

64 p=0.032

65 Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion (Review) Carson JL, Carless PA, Hebert PC

66 JAMA CLINICAL EVIDENCE SYNOPSIS CLINICIAN S CORNER Outcomes Using Lower vs Higher Hemoglobin Thresholds for Red Blood Cell Transfusion Clinical Question: Is a lower vs higher hemoglobin threshold best for minimizing both red blood cell use and adverse clinical outcomes when used to trigger red blood cell transfusions in anemic patients in critical care and acute care settings? Bottom Line: Compared with higher hemoglobin thresholds, a hemoglobin threshold of 7 or 8 g/dl is associated with fewer red blood cell units transfused without adverse associations with mortality, cardiac morbidity, functional recovery, or length of hospital stay. Jeffrey L. Carson, MD Paul A. Carless, MMedSc (Clin Epid) Paul C. Hébert, MD, MSc T hemoglobin levels were most commonly maintained at 9.0 to 13.3 g/dl. Alowerhemoglobinthresholdfor transfusion was associated with reduced red blood cell transfusion (mean fusion (mean difference, 1.48 g/dl; 95% CI, 1.92 to 1.03). The relative risk (RR) for 30-day allcause mortality was 0.85 (95% CI, 0.70 to 1.03) (FIGURE). Hospital mortality JAMA 2013

67 30-Day Mortality Carson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews Update 2012 Update

68 Myocardial Infarction Carson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews Update 2012 Update

69 Infection Carson JL, Carless P, Hebert PC. Cochrane Database of Systematic Reviews Update 2012 Update

70 Summary-Clinical Trial Data 7,167 patients enrolled in clinical trials evaluating transfusion thresholds Most trials are small and only one (FOCUS) is larger than 1000 patients Results consistently suggest restrictive transfusion approach is safe No adequately powered RCT in acute coronary syndrome

71 Efficacy of Transfusion Observational Studies

72 Meta-analysis of Observational Studies Evaluate efficacy of RBC transfusion 45 observational studies; 272,596 patients In 42 of 45 studies, the risk of transfusion out-weighed the benefit

73 Transfusion and Mortality Marik and Corwin Crit Care Med 2008

74 Association of Blood Transfusion With Increased Mortality in Myocardial Infarction: A Meta-analysis Chatterjee et al. Arch Intern Med. 2012

75 Association of Transfusion and ACS Nadir Hematocrit Adjusted Odds Ratio of 30-Day Death (95% CI) (10-827) (7-3798) ( ) ( ) JAMA. 2004;292:

76 INVITED COMMENTARY Here We Go Again Blood Transfusion Kills Patients? D obloodtransfusionskillmorepatientswithan acute myocardial infarction than anemia? Chatterjee and colleagues 1 would have you believe that they do. We remain unconvinced. In reviewing the study, we first wondered whether the authors asked the right question. As physicians, we believe that profound anemia is life threatening, 2 and as a consequence transfusions in many patients are life saving. Therefore, we expected that more nuanced, clinically relevant questions would be addressed. For instance, we should be asking: What is a safe hemoglobin transfusion trigger in most patients? Or, Which patients experiencing an acute myocardial infarction are at greater risk for transfusions or anemia than others? In a synthesis of the literature focused on the issue of harms, the authors summarized results from 10 studies that included a total of patients. 1 The systematic review identified only one small randomized trial 3 and went on to conduct a meta-analysis of observational studies that compared patients who underwent transfusion with patients who did not undergo transfusion. Chatterjee and colleagues 1 documented that 18.2% of patients transfused died compared with 10.2% of patients not transfused. This represented a weighted absolute risk increase of 12% or a number needed to harm of 8. Clinically important information is missing from this analysis. Perhaps most important, the investigators did not adequately consider the hemoglobin concentration before transfusion. The authors did analyze the study stratified by a pretransfusion hemoglobin concentration of less than 10 g/dl (to convert hemoglobin con- JAMA INTERN MED/ VOL 173 (NO. 2), JAN 28,

77 Summary- Observational Studies Results from observational studies mostly found that transfusion was harmful The effect of transfusion cannot be reliably evaluated in an observational study

78 Annals of Internal Medicine First published March 26, 2012 on annals.org. Clinical Guidelines Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB Jeffrey L. Carson,, MD; Brenda J. Grossman,, MD, MPH; Steven Kleinman, MD; Alan T. Tinmouth,, MD; Marisa B. Marques,, MD; Mark K. Fung,, MD, PhD; John B. Holcomb,, MD; Orieji Illoh,, MD; Lewis J. Kaplan,, MD; Louis M. Katz,, MD; Sunil V. Rao,, MD; John D. Roback,, MD, PhD; Aryeh Shander,, MD; Aaron A.R. Tobian,, MD, PhD; Robert Weinstein, MD; Lisa Grace Swinton McLaughlin,, MD; ; and Benjamin Djulbegovic, MD, PhD, for the Clinical Transfusion Medicine Committee of the AABB* + Author Affiliations

79 Key Principles Focus on hemoglobin concentration thresholds and other clinical parameters that might trigger transfusion Hemodynamically stable Based on Cochrane systematic review We limited the systematic review to randomized clinical trials because this study design provides the best unbiased evidence of treatment effect

80 In hospitalized hemodynamically stable patients, at what Hgb should a decision to transfuse RBC be considered? We recommend adhering to a restrictive transfusion strategy. In adult and pediatric ICU patients, transfusion should be considered at Hgb < 7 g/dl. In surgical patients, transfusion should be considered at Hgb < 8 g/dl or for symptoms. Quality of evidence: High Strength of recommendation: Strong

81 In hospitalized hemodynamically stable patients, with pre-existing cardiovascular disease, at what Hgb should a decision to transfuse RBC be considered? We suggest adhering to a restrictive transfusion strategy. Transfusion should be considered at Hgb < 8 g/dl or for symptoms. Quality of evidence: Moderate Strength of recommendation: Weak

82 In hospitalized hemodynamically stable patients, should transfusion be guided by symptoms rather than hemoglobin concentration? We suggest that transfusion decisions should be influenced by symptoms as well as hemoglobin concentration Quality of evidence: Low Strength of recommendation: Weak

83 In hospitalized hemodynamically stable patients, with acute coronary syndrome, at what Hgb should a decision to transfuse RBC be considered? We cannot recommend for or against liberal or restrictive transfusion threshold. Further research is needed to determine optimal RBC transfusion threshold. Quality of evidence: Very low Strength of recommendation: Uncertain

84 Cases

85 Case 1 68 year old male with COPD is admitted to hospital with increasing dyspnea. He is hypoxic and has large infiltrate on chest xray. The patient is transferred to MICU, intubated and treated with antibiotics. Over the next 3 days Hgb falls from 11 to 8.5 g/dl. He appears to be euvolemic and BP is stable. Transfuse?

86 Case 2 80 year old women 2 days postop for hip fracture repair PMH- hypertension, DM, history of MI three years ago Symptoms- tired and weak Exam ok Hgb 8.5 Transfuse?

87 Case 3 66 year old male presents with chest pain to ER and ECG shows anterior wall MI Patient taken to cardiac catherization lab and stent inserted in LAD Admission Hgb Following day Hgb 9.2 Large hematoma in groin. Vitals normal Transfuse?

88 Transfusion Recommendations The best data suggests that a restrictive transfusion trigger should be used The need for transfusion should be carefully assessed for each patient Choose a Hgb to CONSIDER transfusion There is limited trial data and the lowest threshold that has been tested is 7 g/dl

89 Transfusion Recommendations However, don t pull the trigger right away if that magic level is reached Do a quick history and physical examination If the patient is clinically stable, hold off transfusing It is likely that the patient will do fine without blood

90 Case 4 72 year old patient admitted with ischemic foot undergoes fem-pop bypass PMH - MI 3 years ago, DM x 10 years, smoked 30 pack years. Denies angina Preop Hgb Creatinine 2.5 Postop feels little weak Hgb is 9.0 Transfuse?

91 Vascular Surgery No trials in this setting Of the trials that have been performed, the population of patients included in FOCUS seems closest Included patients with CVD or risk factors Older group with frequent co-morbidity Restrictive transfusion defined as 8 g/dl or symptoms Unknown if could use even lower threshold such as 7 g/dl GI bleeding trial excluded patients with cardiovascular disease

92 Your Guidelines My view is that we should base our guidelines on highest quality of evidence Trials, trials, trials We should be cautious in generalizing results since the patients underlying illness and co-morbidity may be very important Other guidelines have different opinion and seem willing to recommend lower thresholds in settings without trials When we don t have high quality evidence, we should conclude we don t know what to recommend, and not be rigid in our recommendations