Transcript Transfusion Strategies for Patients in Pediatric Intensive

Transfusion Strategies for Patients
in Pediatric Intensive Care Units
Lacroix J et al.
NEJM 2007;356:1609-19
Maggie Constantine, MD, FRCPC
Resident, Transfusion Medicine
TMR Journal Club
May 14, 2007
Pediatric ICU RBC Transfusion
Objectives
Background
 Overview of article
 Non-inferiority trial mini-review
 Critical appraisal of article

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Adult ICU RBC Transfusion
TRICC Trial
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Transfusion
Requirements in
Critical Care
 Equivalence trial
 Liberal vs restrictive
transfusion
strategies
 Prospective,
randomized
 Multicenter
 1994 to 1997
 838 patients

Outcomes
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Primary
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All cause mortality at
30 days
Secondary
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All cause mortality at
60 days, in-hospital
mortality rates
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NEJM 1999; 340(6)
Adult ICU RBC Transfusion
TRICC Trial
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NEJM 1999; 340(6)
Adult ICU RBC Transfusion
TRICC Trial - Results

Restrictive strategy
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Average daily Hgb
85 +/- 0.7 g/L
2.6 +/- 4.1 RBC
units per day
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Liberal strategy
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Average daily Hgb
107 +/- 0.7 g/L
5.6 +/- 5.3 RBC
units per day
P=<0.01
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NEJM 1999; 340(6)
Adult ICU RBC Transfusion
TRICC Trial - Results
NEJM 1999; 340(6)
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NEJM 1999; 340(6)
Adult ICU RBC Transfusion
TRICC Trial - Results
P=0.10
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NEJM 1999; 340(6)
Adult ICU RBC Transfusion
TRICC Trial - Results
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NEJM 1999; 340(6)
Adult ICU RBC Transfusion
TRICC Trial - Conclusions
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Results applicable widely
Adhere to transfusion threshold of 70 g/L with a
Hgb range of 70 to 90 g/L
Remember those excluded:
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Active bleeding
Chronic anemia
Imminent death
Pregnancy
Admission after a routine cardiac procedure
RBC not pre-storage LRD
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NEJM 1999; 340(6)
RBC transfusions in critically ill patients
Background – RCTs Liberal vs Restrictive RBC Strategies
Study
Setting
# patients
30-Day Mortality
– Liberal [%(n)]
30-Day Mortality
– Restrictive
[%(n)]
Topley et al., 1956
Trauma
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Blair et al., 1986
GI bleed
50
8.3 (2)
0 (0)
Fortune et al., 1987
Trauma, acute
hemorrhage
25
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
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Adult and Pediatric ICU RBC Transfusion
Surveys

Survey of transfusion practices
Adult Intensivists
Transfusion threshold : 50
to 120 g/L
Important transfusion
triggers
Lactate, low PaO2,
shock, age, ER
surgery, APACHE II
score, chronic anemia,
coronary ischemia
Crit Care Med. 1998 Mar;26(3):482-7.
Pediatr Crit Care Med. 2002 Oct;3(4):335-40.
Pediatric Intensivists
Transfusion threshold : 70
to 130 g/L
Important transfusion
triggers
Lactate, low PaO2,
active GI bleeding,
age, ER surgery, high
pediatric mortality
score
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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
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NEJM 2007; 356(16)
TRIPICU
Study design
Prospective non-inferiority
 19 tertiary-care pediatric ICUs in 4
countries
 Treatment arms – pre-storage LRD
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Restrictive strategy
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Transfusion threshold 70 g/L
Target range 85 to 95 g/L
Liberal strategy
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Transfusion threshold 95 g/L
Target range 110 to 120 g/L
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TRIPICU
Study design
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Inclusion
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Stable, critically ill
children
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Age 3 days to 14
years
At least one Hgb
</= 95 g/L within 7
days after admission
to pediatric ICU
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Exclusion
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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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TRIPICU
Study design
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Block-randomization
Stratification for center and 3 age groups
Follow-up 28 days
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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
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Acute blood loss
Surgical intervention
Severe hypoxemia
Hemodynamically unstable
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TRIPICU
Study design
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Primary outcome
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Proportion of patients who died during 28 days
after randomization, had concurrent MODS or
progression of MODS
Secondary outcome
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Daily PELOD scores, sepsis, transfusion rxns,
resp infections, CRI, AE, LOS and death
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TRIPICU
Study design
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Statistical design
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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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TRIPICU
Results
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TRIPICU
Results
Baseline
characteristics
similar
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TRIPICU
Results
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TRIPICU
Results
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TRIPICU
Results
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TRIPICU
Results
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TRIPICU
Results – Primary outcomes
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TRIPICU
Results – Secondary outcomes
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TRIPICU
Results – Secondary outcomes
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TRIPICU
Authors’ 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 Transfusion
Non-inferiority trials
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Non-inferiority vs. equivalence
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Impossible to prove two treatments have exact
equivalent effects
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Inordinately large numbers needed
Non-inferiority
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Experimental treatment is not worse than an active
control by more than the “equivalence margin”
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Snapinn SM. Curr Control Trials Cardiovasc Med 2000, 1:19-21.
Pediatric ICU RBC Transfusion
Non-inferiority trials
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When might a non-inferiority trial be
performed:
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Applications based upon essential similarity

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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 Transfusion
Non-inferiority trials
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Specifying the non-inferiority margin
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Specify on the basis of a clinical notion of a
minimally important effect
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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
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Historical trials – assumption that effect of active
control is similar in trial
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Snapinn SM. Curr Control Trials Cardiovasc Med 2000, 1:19-21.
Pediatric ICU RBC Transfusion
Non-inferiority trials

Specifying the non-inferiority margin
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Generally based not on full effect of active control
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“fashionable” for non-inferiority margin to be 15%
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Lower bound CI for that effect
The smaller the margin the larger the sample size
Per-protocol and intention-to-treat analyses
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ITT: tends to bias results toward equivalence
Per-protocol: can bias results in either direction
Both support non-inferiority
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Snapinn SM. Curr Control Trials Cardiovasc Med 2000, 1:19-21.
Pediatric ICU RBC Transfusion
Non-inferiority trials
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Potential sources of inferiority in noninferiority trials
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Selection of patient
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Treatment compliance
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Also need to document concommitant nonrandomized
treatments
Outcome measures
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Similar population to patient type in whom efficacy of
active control has been clearly established
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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TRIPICU
Critical 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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TRIPICU
Critical appraisal

Treatment effect?
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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)
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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
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NNT to prevent one red-cell transfusion was 2 (RS
group)
Concerns for this non-inferiority trial
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Suspended protocol
Non-blinding of patients and clinicians
Derivation of non-inferiority margin (historical data not
referenced)
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TRIPICU
Critical appraisal
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Interpretation of conclusion
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“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
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Secondary outcomes showed that the restrictive
strategy was NO WORSE for
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AE
Nosocomial infections
Reactions to RBC
LOS, mechanical ventilation
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TRIPICU
Critical appraisal
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Can the results be applied to my patient
care? Unclear
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Unclear how varied a patient population the
results can be applied to
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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
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Mortality rate exceedingly low
Negative clinical effects resulting from impaired
oxygen delivery – MODS
Negative effects of transfusion
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Transfusion Strategies for Patients
in Pediatric Intensive Care Units
Lacroix J et al.
NEJM 2007;356:1609-19
Maggie Constantine, MD, FRCPC
Resident, Transfusion Medicine
TMR Journal Club
May 14, 2007
Comments? Questions?