Transfusion Strategies for Patients in Pediatric Intensive Care Units
Lacroix J et al. NEJM 2007;356:1609-19
Maggie Constantine, MD, FRCPCResident, Transfusion Medicine
TMR Journal ClubMay 14, 2007
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Pediatric ICU RBC TransfusionObjectives Background Overview of article Non-inferiority trial mini-review Critical appraisal of article
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Adult ICU RBC TransfusionTRICC Trial
Transfusion Requirements in Critical Care Equivalence trial Liberal vs restrictive
transfusion strategies
Prospective, randomized
Multicenter 1994 to 1997 838 patients
Outcomes Primary
All cause mortality at 30 days
Secondary All cause mortality at
60 days, in-hospital mortality rates
NEJM 1999; 340(6)
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Adult ICU RBC TransfusionTRICC Trial
NEJM 1999; 340(6)
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Adult ICU RBC TransfusionTRICC Trial - Results
Restrictive strategy Average daily Hgb
85 +/- 0.7 g/L 2.6 +/- 4.1 RBC
units per day
Liberal strategy Average daily Hgb
107 +/- 0.7 g/L 5.6 +/- 5.3 RBC
units per day
P=<0.01
NEJM 1999; 340(6)
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Adult ICU RBC TransfusionTRICC Trial - Results
NEJM 1999; 340(6)
NEJM 1999; 340(6)
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Adult ICU RBC TransfusionTRICC Trial - Results
P=0.10
NEJM 1999; 340(6)
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Adult ICU RBC TransfusionTRICC Trial - Results
NEJM 1999; 340(6)
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Adult ICU RBC TransfusionTRICC Trial - Conclusions
Results applicable widely Adhere to transfusion threshold of 70 g/L with a
Hgb range of 70 to 90 g/L Remember those excluded:
Active bleeding Chronic anemia Imminent death Pregnancy Admission after a routine cardiac procedure
RBC not pre-storage LRD
NEJM 1999; 340(6)
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RBC transfusions in critically ill patientsBackground – RCTs Liberal vs Restrictive RBC StrategiesStudy Setting # patients 30-Day Mortality –
Liberal [%(n)]30-Day Mortality – Restrictive [%(n)]
Topley et al., 1956 Trauma 22
Blair et al., 1986 GI bleed 50 8.3 (2) 0 (0)
Fortune et al., 1987 Trauma, acute hemorrhage
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Johnson et al., 1992 CVS 38
Hebert et al., 1995 ICU 69 25 (9) 24 (8)
Bush et al., 1997 Vascular Surgery 99 8 (4) 8 (4)
Carson et al., 1998 Ortho (hip #) 84 2.4 (1) 2.4 (1)
Hebert et al., 1999 ICU 838 23.3 (98) 18.7 (78)
Bracey et al., 1999 Cardiac Surgery 428 2.7 (6) 1.4 (3)
Lotke et al., 1999 Ortho (knee) 127
Grover et al., 2006 Vascular Surgery 260
McIntyre et al., 2006 Trauma (head) 67 13 17
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Adult and Pediatric ICU RBC TransfusionSurveys
Survey of transfusion practices
Adult IntensivistsTransfusion threshold : 50 to 120 g/L
Important transfusion triggers
Lactate, low PaO2, shock, age, ER surgery, APACHE II score, chronic anemia, coronary ischemia
Pediatric IntensivistsTransfusion threshold : 70 to 130 g/L
Important transfusion triggers
Lactate, low PaO2, active GI bleeding, age, ER surgery, high pediatric mortality score
Crit Care Med. 1998 Mar;26(3):482-7.
Pediatr Crit Care Med. 2002 Oct;3(4):335-40.
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The PINT Study - Journal of Pediatrics Sept
2006;149:301-7 Authors’ conclusions The present findings provide evidence that
transfusion thresholds in ELBW infants can be moved downwards by at least 10g/L without incurring a clinically important increase in the risk of death or major neonatal morbidity
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TRIPICU
NEJM 2007; 356(16)
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TRIPICUStudy design Prospective non-inferiority 19 tertiary-care pediatric ICUs in 4
countries Treatment arms – pre-storage LRD
Restrictive strategy Transfusion threshold 70 g/L Target range 85 to 95 g/L
Liberal strategy Transfusion threshold 95 g/L Target range 110 to 120 g/L
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TRIPICUStudy design Inclusion
Stable, critically ill children
Age 3 days to 14 years
At least one Hgb </= 95 g/L within 7 days after admission to pediatric ICU
Exclusion ICU stay expected to be
<24 hours No approval from
physician <3 days or >14 years of
age Unstable hemodynamically Acute blood loss Weighed <3 kg Cardiovascular problems Never discharged from
NICU Hemolytic anemia Enrolled in another study
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TRIPICUStudy design Block-randomization Stratification for center and 3 age groups Follow-up 28 days
Clinical staff and parents were not blinded Statistician and members of the data and safety MC
were blinded Protocol “temporarily suspended” not = to breach
of adherence to protocol Acute blood loss Surgical intervention Severe hypoxemia Hemodynamically unstable
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TRIPICUStudy design Primary outcome
Proportion of patients who died during 28 days after randomization, had concurrent MODS or progression of MODS
Secondary outcome Daily PELOD scores, sepsis, transfusion rxns,
resp infections, CRI, AE, LOS and death
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TRIPICUStudy design Statistical design
Non-inferiority margin = 10% Need 626 subjects One-sided alpha of 5%; power of 90%
NNT to prevent one red-cell transfusion in RS group
Intention-to-treat and per-protocol analyses
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TRIPICUResults
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TRIPICUResults
Baseline characteristics similar
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TRIPICUResults
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TRIPICUResults
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TRIPICUResults
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TRIPICUResults
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TRIPICUResults – Primary outcomes
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TRIPICUResults – Secondary outcomes
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TRIPICUResults – Secondary outcomes
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TRIPICUAuthors’ Conclusions “…we found that a restrictive transfusion
strategy can safely decrease the rate of exposure to red cells as well as the total number of transfusions in critically ill children, even though suspensions of transfusion strategies were permitted under prespecified conditions.”
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Pediatric ICU RBC TransfusionNon-inferiority trials Non-inferiority vs. equivalence
Impossible to prove two treatments have exact equivalent effects
Inordinately large numbers needed Non-inferiority
Experimental treatment is not worse than an active control by more than the “equivalence margin”
Snapinn SM. Curr Control Trials Cardiovasc Med 2000, 1:19-21.
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Pediatric ICU RBC TransfusionNon-inferiority trials When might a non-inferiority trial be
performed: Applications based upon essential similarity
Modified release products Products with a potential safety benefit over
standard When a direct comparison against an active
comparator would be acceptable No important loss of efficacy compared to the
active comparator would be acceptable Disease areas where use of placebo arm is not
possible
EMEA/CPMP/EWP/2158/99
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Pediatric ICU RBC TransfusionNon-inferiority trials Specifying the non-inferiority margin
Specify on the basis of a clinical notion of a minimally important effect
Clearly subjective Tend to set equivalence margin to be greater than
the effect of active control -> harmful treatments fitting within the definition of non-inferiority
Specify with reference to the effect of the active control in historical placebo-controlled trials
Historical trials – assumption that effect of active control is similar in trial
Snapinn SM. Curr Control Trials Cardiovasc Med 2000, 1:19-21.
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Pediatric ICU RBC TransfusionNon-inferiority trials Specifying the non-inferiority margin
Generally based not on full effect of active control Lower bound CI for that effect
“fashionable” for non-inferiority margin to be 15% The smaller the margin the larger the sample size
Per-protocol and intention-to-treat analyses ITT: tends to bias results toward equivalence Per-protocol: can bias results in either direction Both support non-inferiority
Snapinn SM. Curr Control Trials Cardiovasc Med 2000, 1:19-21.
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Pediatric ICU RBC TransfusionNon-inferiority trials Potential sources of inferiority in non-
inferiority trials Selection of patient
Similar population to patient type in whom efficacy of active control has been clearly established
Treatment compliance Also need to document concommitant
nonrandomized treatments Outcome measures
Consistent well-defined criteria Blinding – could give similar scores to both groups
Appropriate follow-up
Pocock SJ Fundamental & Clin Pharmacol 2003;17:483-490
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TRIPICUCritical appraisal Randomization? YES Were all patients entered into trial
properly accounted for? YES Follow-up complete? NO – protocol
violations Blinding – NOT of patients and clinicians Were groups similar at start of trial? YES Concommitant treatments similar? YES
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TRIPICUCritical appraisal Treatment effect?
Same number of deaths in each arm New or progressive MODS – absolute risk reduction was
0.4% (95% CI, -4.6 to 5.5 with restrictive strategy) Per-protocol analyses: 0.8% (95% CI, -4.3 to 5.9) Upper limit of 95% CI did not exceed non-inferiority margin
of 10% ??? 12% in each group… how was “0.4%” calculated
Cannot calculate RR or RRR NNT to prevent one red-cell transfusion was 2 (RS group)
Concerns for this non-inferiority trial Suspended protocol Non-blinding of patients and clinicians Derivation of non-inferiority margin (historical data not
referenced)
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TRIPICUCritical appraisal Interpretation of conclusion
“we found that while a restrictive transfusion strategy decreases the rate of exposure to red cells, it is NO WORSE than a liberal transfusion in terms of MODS in critically ill children”
? Benefit of decreased red cell exposure Secondary outcomes showed that the restrictive
strategy was NO WORSE for AE Nosocomial infections Reactions to RBC LOS, mechanical ventilation
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TRIPICUCritical appraisal Can the results be applied to my patient
care? Unclear Unclear how varied a patient population the
results can be applied to 4372 excluded for 5399 patients screened Mindful of exclusion criteria Suspended protocol: 12% in RS and 6% in LS group
Clinically important outcomes considered: YES Mortality rate exceedingly low Negative clinical effects resulting from impaired
oxygen delivery – MODS Negative effects of transfusion
Transfusion Strategies for Patients in Pediatric Intensive Care Units
Lacroix J et al. NEJM 2007;356:1609-19
Maggie Constantine, MD, FRCPCResident, Transfusion Medicine
TMR Journal ClubMay 14, 2007
Comments? Questions?