Transfusion Strategies for Patients in Pediatric Intensive Care Units Lacroix J et al. NEJM 2007;356:1609-19 Maggie Constantine, MD, FRCPC Resident, 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

2

Pediatric ICU RBC TransfusionObjectives Background Overview of article Non-inferiority trial mini-review Critical appraisal of article

3

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)

4

Adult ICU RBC TransfusionTRICC Trial

NEJM 1999; 340(6)

5

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)

6


NEJM 1999; 340(6)

NEJM 1999; 340(6)

7


P=0.10

NEJM 1999; 340(6)

8


NEJM 1999; 340(6)

9

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)

10

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

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 13 17

11

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.

12

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

13

TRIPICU

NEJM 2007; 356(16)

14

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

15

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

16

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

17

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

18

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

19

TRIPICUResults

20

TRIPICUResults

Baseline characteristics similar

21

TRIPICUResults

22

TRIPICUResults

23

TRIPICUResults

24

TRIPICUResults

25

TRIPICUResults – Primary outcomes

26

TRIPICUResults – Secondary outcomes

27

TRIPICUResults – Secondary outcomes

28

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.”

29

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.

30

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

31

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


32

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


33

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

34

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

35

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)

36

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

37

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?

Documents

Transfusion Strategies for Patients in Pediatric Intensive Care Units Lacroix J et al. NEJM 2007;356:1609-19 Maggie Constantine, MD, FRCPC Resident, Transfusion