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Study flow diagram for study selection
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Figure 1

Study flow diagram for study selection

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 1 All‐cause mortality‐at 31 to 100 days.
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Analysis 1.1

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 1 All‐cause mortality‐at 31 to 100 days.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 2 Mortality due to chemotherapy.
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Analysis 1.2

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 2 Mortality due to chemotherapy.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 3 Number of participants with any bleeding.
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Analysis 1.3

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 3 Number of participants with any bleeding.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 4 Number of participants with clinically significant bleeding.
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Analysis 1.4

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 4 Number of participants with clinically significant bleeding.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 5 Severe or life‐threatening bleeding events.
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Analysis 1.5

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 5 Severe or life‐threatening bleeding events.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 6 Number of participants with serious infection episodes.
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Analysis 1.6

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 6 Number of participants with serious infection episodes.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 7 Number of participants with VOD.
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Analysis 1.7

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 7 Number of participants with VOD.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 8 Number of participants with RBC transfusion from study entry.
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Analysis 1.8

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 8 Number of participants with RBC transfusion from study entry.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 9 Number of participants with RBC Transfusion after reaching Hb >80 g/L for restrictive & Hb > 120 g/L for liberal.
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Analysis 1.9

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 9 Number of participants with RBC Transfusion after reaching Hb >80 g/L for restrictive & Hb > 120 g/L for liberal.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 10 Mean number of RBC (units) transfusions per participant during the entire study period.
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Analysis 1.10

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 10 Mean number of RBC (units) transfusions per participant during the entire study period.

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 11 Number of participants with PLT transfusions from the study entry.
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Analysis 1.11

Comparison 1 Restrictive versus liberal red blood cell transfusion RCTs, Outcome 11 Number of participants with PLT transfusions from the study entry.

Restrictive compared with liberal for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support

Patient or population: people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support
Setting: Hospitals, haematology centres
Intervention: Restrictive
Comparison: Liberal red blood cell transfusion RCTs

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with liberal red blood cell transfusion RCTs

Risk with Restrictive

All‐cause mortality at 31 to 100 days

Study population

61 per 1000

15 per 1000

(1 to 163)

RR 0.25

(0.02 to 2.69)

95

(2 RCTs)

⊕⊕⊝⊝

LOW1

Quality of life

Liberal group: median 4.5 (IQR: 3.6 to 5)

Restrictive: median 4.8 (IQR: 4 to 5.2)a

89

(1 RCT)

⊕⊕⊝⊝

VERY LOW2,3,4

Number of participants with any bleeding

Study population

639 per 1,000

595 per 1000
(467 to 754)

RR 0.93
(0.73 to 1.18)

149
(2 RCTs)

⊕⊕⊝⊝
LOW2,3

Number of participants with clinically significant bleeding

Study population

443 per 1,000

456 per 1000
(332 to 633)

RR 1.03
(0.75 to 1.43)

149
(2 RCTs)

⊕⊕⊝⊝
LOW2,3

Serious infections

Study population

400 per 1,000

492 per 1000

(296 to 816)

RR 1.23
(0.74 to 2.04)

89

(1 RCT)

⊕⊝⊝⊝

VERY LOW2,3,4

Length of hospital admission (days)

Liberal: median 36 days (IQR: 29.2 to 44)

Restrictive: median: 35.5 days (IQR: 31.2 to 43.8)

89

(1 RCT)

⊕⊕⊝⊝

LOW2,3

Hospital readmission rate ‐ not reported

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1The level of evidence was downgraded by 2 due to imprecision.
2The level of evidence was downgraded by 1 due to imprecision.
3 The level of evidence was downgraded by 1 due to indirectness, the studies only included adults.
4The level of evidence was downgraded by 1 due to risk of bias (unblinded study).

aThis is a ten‐point scale with a score of zero indicating no fatigue and a score of ten indicating the worst possible fatigue. The median fatigue scare was similar for both groups; P = 0.53.

Interquartile range: IQR

Figures and Tables -
Summary of findings 2. Summary of findings of NRS

Restrictive compared with liberal for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support

Patient or population: people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support
Setting: Department of haematology
Intervention: Restrictive
Comparison: Liberal red blood cell transfusion NRS

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with liberal red blood cell transfusion RCTs

Risk with Restrictive

All‐cause mortality at 31 to 100 days

Liberal: 1 death (46 participants)

Restrictive: 1 death (38 participants)

84
(1 study)

⊕⊝⊝⊝
VERY LOW1

Mean 31 days follow‐up

Quality of life ‐ not reported

Number of participants with any bleeding ‐ not reported

Number of participants with clinically significant bleeding

Liberal: 8 (46 participants)

Restrictive: 3 (38 participants)

84
(1 study)

⊕⊝⊝⊝
VERY LOW1

The study authors reported that there was no significant difference between the two groups.

Serious infections ‐ not reported

Length of hospital admission ‐ not reported

Hospital readmission rate ‐ not reported

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1The level of evidence was downgraded by 1 due to imprecision.

Figures and Tables -
Summary of findings 2. Summary of findings of NRS
Table 1. Important complications of transfusion and their approximate frequency in the UK extrapolated from data from the Serious Hazards of Transfusion (SHOT) scheme 2014 (Bolton‐Maggs 2014) compared with low income countries (WHO 2015)

Transfusion Risk

Frequency in the UK (units transfused) ( Bolton‐Maggs 2014)

Frequency in low income countries ( WHO 2015 )

ABO incompatible red cell transfusion

3.7 in 1 million (10 cases per 2663488 transfusions)

unknown

Transfusion‐related acute lung injury

0.4 in 1 million (10 cases per 2663488 transfusions)

unknown

Transfusion associated circulatory overload

34.1 in 1 million (91 cases per 2663488 transfusions)

unknown

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Table 1. Important complications of transfusion and their approximate frequency in the UK extrapolated from data from the Serious Hazards of Transfusion (SHOT) scheme 2014 (Bolton‐Maggs 2014) compared with low income countries (WHO 2015)
Table 2. Frequency of infection in donated blood in high and low income countries (WHO 2015)

Transfusion transmitted infection

Frequency in high income countries

Frequency in low income countries

HIV

2 in 100,000 (IQR 0.4 in 100,000 to 20 in 100,000)

850 in 100,000 (IQR 480 in 100,000 to 2000 in 100,000)

HBV

20 in 100,000 (IQR 8 in 100,000 to 24 in 100,000)

3590 in 100,000 (IQR 2010 in 100,000 to 6080 in 100,000)

HCV

20 in 100,000 (IQR 0.4 in 100,000 to 22 in 100,000)

1070 in 100,000 (IQR 630 in 100,000 to 1690 in 100,000)

IQR=interquartile range

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Table 2. Frequency of infection in donated blood in high and low income countries (WHO 2015)
Table 3. Jansen 2004: 'Risk of bias' assessment for observational studies using the Newcastle‐Ottawa Scale (Wells 2013)

Risk of Bias

Assessment

Support for judgement

Selection (one star each, maximum four stars)

2 stars

Representativeness of the exposed cohort

0 stars

This study only included participants with AML as opposed to all patients with haematological malignancies

Selection of the non‐exposed cohort

0 star

Participants in the control were from a second haematology centre, but there was no information to reassure that this cohort was drawn from the same community as exposed cohort

Ascertainment of exposure

1 star

Secondary analyses from HOVON 29, prospective randomised controlled trial

Demonstration that outcome of interest was not present at start of study

1 stars

The primary outcome and other outcomes were defined and were based on events that occurred after the study started

Comparability of cohort on design and analyses (maximum of two stars) Recognition of at least 75% of the main potential confounding factors (2 stars) Recognition of 50% to 75% of the main potential confounding factors (1 star)

0 stars

< 50% of potential cofounders considered and sex, age and AML type were adjusted for in the multiple regression model. There was no discussion on previous severe bleeding, use of anticoagulation, use of radiotherapy in addition to chemotherapy, previous cardiovascular disease, previous alloimmunisation or performance status

Outcome (one star each, maximum of four stars)

2 stars

Assessment of outcome

0 stars

Not described

Was follow‐up long enough for outcomes to occur?

1 star

Yes, 31 days from chemotherapy

Adequacy of follow‐up of cohorts

0 star

Reported for all, except unclear for infection, mean Hb during follow‐up, total number of platelet/red blood cell units received

Follow‐up equal between groups for primary and secondary outcomes?

1 star

Follow‐up not significantly different

Additional concerns

None

Overall assessment

4 stars

AML = acute myeloid leukaemia
Hb = haemoglobin

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Table 3. Jansen 2004: 'Risk of bias' assessment for observational studies using the Newcastle‐Ottawa Scale (Wells 2013)
Table 4. Review secondary outcome‐red blood cell transfusion

Study

No. of participants received RBC transfusion during the study period

Mean no. RBC units transfusions/participant during study period

Number of participant‐days with RBC transfusions

Proportion of participant‐days with RBC transfusions

Mean Hb within first +100 days:

Number of RBC units per transfusion

Interval between RBC transfusions

(mean) (days)

RCTs

De Zern 2016

Restrictive:

57/59

Liberal:

30/30

Restrictive:

mean 8.2 (SD 4.2)

Liberal:

mean 11.3 (SD 5.4)

NR

NR

Restrictive:

mean 33.6 (SD 1.4)

Liberal:

mean 33.2 (SD 2.0)

NR

NR

Robitaille 2013

Restrictive:

3/3

Liberal:

3/3

Restrictive:

(mean 1.3 [SD 0.58]; median 1 [range 1 to 2; SE 0.33])

Liberal:

(mean 8.7 [SD 5.5]; median 9 [range 3 to 14; SE 3.2])

NR

NR

Restrictive:

[mean pre transfusion Hb 69 g/L (range 69 g/L to 70 g/L) no SD]

Liberal:

[mean pre transfusion Hb 106 g/L (range 118 g/L to 132 g/L) no SD]

NR

NR

Webert 2008

Restrictive:

26/29

(24/29 from when Hb ≥80 g/L)

Liberal:

29/31

(28/28 from when Hb ≥ 120g/L)

NR

Restrictive:

75 (70/467 days of observation once reached target Hb)

Liberal:

113 g/L (72/410 days of observation once reached target Hb)

Restrictive:

0.151 (0.150 after study Hb threshold reached)

Liberal:

0.233 (0.176 after study Hb threshold reached)

[RR 1.56; 95% CI 1.16 to 2.10]

[RR 1.18: 95% CI 0.90 to 1.54; once study Hb threshold reached]a

NR

NR

NR

NRS

Jansen 2004

NR

Restrictive:

mean 9.6 (SD 3.9); Median 9 (SE 0.6); Range 3 to 21

Liberal:

mean 10.8 (SD 2.9); Median 11.0 (SE 0.4); Range 6 to 21

NR

NR

Restrictive:

Age < 25 Hb 7.5 (n = 3); 25‐50 yrs Hb 8.0 (n = 22); Age 50‐70 years Hb 8.3 (n = 13)

Liberal:

Age < 25 years Hb 8.8 (n = 3); 25‐50 years Hb 9.3 (n = 32); 50‐70 years Hb 9.5 (n = 11)

Restrictive:

Mean 1.3

(SD 0.5); Median

1.0 (SE 0.03); range 1‐4

Liberal:

Mean 1.82 (SD 0.4); Median 2 (SE 0.03); Range 1‐5

Restrictive: 3.1 days

(No SD)

Liberal:

3 days

(No SD)

CI = confidence interval
Hb = haemoglobin
RBC = red blood cell
RR ‐ risk ratio
SD = standard deviation
SE = standard error

Trial HB: Restrictive ≥ 80g/L and Liberal ≥ 120g/L

aData analysed by study authors, reported as relative risks derived from adjusted Cox regression models, allowing for repeated measures.

Figures and Tables -
Table 4. Review secondary outcome‐red blood cell transfusion
Table 5. Review secondary outcomes ‐ platelet and red cell transfusions

Study ID

Number of PLTs transfused per participant

Number of participant‐days with PLT transfusions

Proportion of participant‐days with RBC transfusions

Interval between PLT transfusions (mean & SD)(days)

Number of PLT units per transfusion (mean & SD) (units)

Nmber of PLT transfusion per participant

RCTs

De Zern 2016

NR

NR

NR

NR

NR

Restrictive:

median:9

(IQR: 5.5 to 12.5)

Liberal;

median: 9

(IQR: 7 to 12)

Robitaille 2013

NR

NR

NR

NR

NR

NR

Webert 2008

Restrictive:

26/29 from study entry, 26 from when target Hb reached

Liberal:

27/31 from study entry; 26 from when target Hb reached

Restrictive:

124 from study entry; 122 from Hb 80 g/L to 100 g/L

Liberal:

0.265 from study entry; 0.283 from when Hb > 120 g/L

Restrictive:

0.249 from study entry; 0.261 from when Hb 8‐10

Liberal:

0.265 from study entry; 0.283 from when Hb > 12

[RR 1.06; 95% CI 0.74 to 1.52]

[RR 1.02: 95% CI 0.73 to 1.44; once study Hb threshold reached]a

NR

NR

NR

NRS

Jansen 2004

Restrictive: Mean 7.5 (SD 3.8); median 7 (SE 0.6); range 2 to 18

Liberal:

Mean 8.5 (SD 4.9); median 7 (SE 0.7); range 2 to 30

P > 0.05

NR

NR

Restrictive:

4 days

(No SD)

Liberal:

3.8 days

(No SD)

Restrictive:

Mean 1.1 (SD 0.4); median 1 (SE 0.03); range 1 to 4

Liberal:

Mean 1.2 (SD 0.5); Median 1 (SE 0.03); range 1 to 4

NR

aData analysed by study authors, reported as relative risks derived from Cox regression models.

IQR = Interquartile range

Figures and Tables -
Table 5. Review secondary outcomes ‐ platelet and red cell transfusions
Comparison 1. Restrictive versus liberal red blood cell transfusion RCTs

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality‐at 31 to 100 days Show forest plot

2

95

Risk Ratio (M‐H, Fixed, 95% CI)

0.25 [0.02, 2.69]

2 Mortality due to chemotherapy Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3 Number of participants with any bleeding Show forest plot

2

149

Risk Ratio (M‐H, Fixed, 95% CI)

0.93 [0.73, 1.18]

4 Number of participants with clinically significant bleeding Show forest plot

2

149

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.75, 1.43]

5 Severe or life‐threatening bleeding events Show forest plot

2

149

Risk Ratio (M‐H, Fixed, 95% CI)

1.57 [0.39, 6.30]

6 Number of participants with serious infection episodes Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7 Number of participants with VOD Show forest plot

1

Peto Odds Ratio (Peto, Fixed, 95% CI)

Totals not selected

8 Number of participants with RBC transfusion from study entry Show forest plot

3

155

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.90, 1.05]

9 Number of participants with RBC Transfusion after reaching Hb >80 g/L for restrictive & Hb > 120 g/L for liberal Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10 Mean number of RBC (units) transfusions per participant during the entire study period Show forest plot

2

95

Mean Difference (IV, Fixed, 95% CI)

‐3.58 [‐5.66, ‐1.49]

11 Number of participants with PLT transfusions from the study entry Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 1. Restrictive versus liberal red blood cell transfusion RCTs