Desmopressin use for minimising perioperative blood transfusion

Michael J Desborough; Kathryn Oakland; Charlotte Brierley; Sean Bennett; Carolyn Doree; Marialena Trivella; Sally Hopewell; Simon J Stanworth; Lise J Estcourt

doi:10.1002/14651858.CD001884.pub3

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Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

Funnel plot of comparison: desmopressin vs placebo: total red cell volume transfused. CI: confidence interval; MD: mean difference; SE: standard error.

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Figure 4

Funnel plot of comparison: desmopressin vs placebo: number of participants receiving a red cell transfusion. CI: confidence interval; RR: relative risk.

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Figure 5

Funnel plot of comparison: desmopressin vs placebo: total blood loss. CI: confidence interval; MD: mean difference; SE: standard error.

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Analysis 1.1

Comparison 1 Desmopressin vs placebo, Outcome 1 Red cell volume transfused (intraoperatively).

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Analysis 1.2

Comparison 1 Desmopressin vs placebo, Outcome 2 Red cell volume transfused (total).

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Analysis 1.3

Comparison 1 Desmopressin vs placebo, Outcome 3 Red cell volume transfused (children only, total).

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Analysis 1.4

Comparison 1 Desmopressin vs placebo, Outcome 4 Number of participants receiving a red cell transfusion (intraoperatively).

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Analysis 1.5

Comparison 1 Desmopressin vs placebo, Outcome 5 Number of participants receiving a red cell transfusion (total).

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Analysis 1.6

Comparison 1 Desmopressin vs placebo, Outcome 6 Blood loss (intraoperative).

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Analysis 1.7

Comparison 1 Desmopressin vs placebo, Outcome 7 Blood loss (total).

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Analysis 1.8

Comparison 1 Desmopressin vs placebo, Outcome 8 Blood loss (children only, total).

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Analysis 1.9

Comparison 1 Desmopressin vs placebo, Outcome 9 Number of participants with any bleeding (intraoperatively).

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Analysis 1.10

Comparison 1 Desmopressin vs placebo, Outcome 10 Number of participants with any bleeding (total).

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Analysis 1.11

Comparison 1 Desmopressin vs placebo, Outcome 11 Reoperation due to bleeding.

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Analysis 1.12

Comparison 1 Desmopressin vs placebo, Outcome 12 All‐cause mortality.

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Analysis 1.13

Comparison 1 Desmopressin vs placebo, Outcome 13 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism).

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Analysis 1.14

Comparison 1 Desmopressin vs placebo, Outcome 14 Myocardial infarction.

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Analysis 1.15

Comparison 1 Desmopressin vs placebo, Outcome 15 Stroke.

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Analysis 1.16

Comparison 1 Desmopressin vs placebo, Outcome 16 Venous thromboembolism.

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Analysis 1.17

Comparison 1 Desmopressin vs placebo, Outcome 17 Clinically important hypotension.

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Analysis 2.1

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 1 Red cell volume transfused (total).

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Analysis 2.2

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 2 Number of participants receiving a red cell transfusion (intraoperatively).

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Analysis 2.3

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 3 Number of participants receiving a red cell transfusion (total).

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Analysis 2.4

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 4 Blood loss (total).

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Analysis 2.5

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 5 Reoperation due to bleeding.

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Analysis 2.6

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 6 All‐cause mortality.

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Analysis 2.7

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 7 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism).

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Analysis 2.8

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 8 Myocardial infarction.

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Analysis 2.9

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 9 Stroke.

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Analysis 2.10

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 10 Venous thromboembolism.

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Analysis 2.11

Comparison 2 Desmopressin vs placebo (platelet dysfunction), Outcome 11 Clinically important hypotension.

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Analysis 3.1

Comparison 3 Desmopressin vs tranexamic acid, Outcome 1 Red cell volume transfused (total).

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Analysis 3.2

Comparison 3 Desmopressin vs tranexamic acid, Outcome 2 Number of participants receiving a red cell transfusion (total).

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Analysis 3.3

Comparison 3 Desmopressin vs tranexamic acid, Outcome 3 Blood loss (total).

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Analysis 3.4

Comparison 3 Desmopressin vs tranexamic acid, Outcome 4 Reoperation due to bleeding.

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Analysis 3.5

Comparison 3 Desmopressin vs tranexamic acid, Outcome 5 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism).

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Analysis 3.6

Comparison 3 Desmopressin vs tranexamic acid, Outcome 6 Myocardial infarction.

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Analysis 3.7

Comparison 3 Desmopressin vs tranexamic acid, Outcome 7 Stroke.

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Analysis 3.8

Comparison 3 Desmopressin vs tranexamic acid, Outcome 8 Venous thromboembolism.

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Analysis 4.1

Comparison 4 Desmopressin vs aprotinin, Outcome 1 Number of participants receiving a red cell transfusion (total).

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Analysis 4.2

Comparison 4 Desmopressin vs aprotinin, Outcome 2 Reoperation due to bleeding.

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Analysis 4.3

Comparison 4 Desmopressin vs aprotinin, Outcome 3 All‐cause mortality.

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Analysis 4.4

Comparison 4 Desmopressin vs aprotinin, Outcome 4 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism).

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Analysis 4.5

Comparison 4 Desmopressin vs aprotinin, Outcome 5 Myocardial infarction.

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Analysis 4.6

Comparison 4 Desmopressin vs aprotinin, Outcome 6 Stroke.

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Analysis 4.7

Comparison 4 Desmopressin vs aprotinin, Outcome 7 Venous thromboembolism.

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Analysis 4.8

Comparison 4 Desmopressin vs aprotinin, Outcome 8 Clinically significant hypotension.

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Summary of findings for the main comparison. DDAVP vs placebo or standard care

Participant or population: participants undergoing surgery Intervention: desmopressin Comparison: placebo or standard care
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with desmopressin
Red cell volume transfused (total)	Adult cardiac surgery: red cell volume transfused in the desmopressin group was 0.52 units less (0.96 fewer to 0.08 fewer units, 14 RCTs, 957 participants)			1454 (23 RCTs)	⊕⊕⊝⊝ LOW^a,b	Data not pooled due to clinical heterogeneity and reported as subgroups
	Orthopaedic surgery: red cell volume transfused in the desmopressin group was 0.02 units less (0.67 less to 0.64 more units, 6 RCTs, 303 participants)
	Vascular surgery: red cell volume transfused in the desmopressin group was 0.06 units more (0.60 less to 0.73 more units, 2 RCTs, 135 participants)
	Hepatic surgery: red cell volume transfused in the desmopressin group was 0.47 units less (1.27 less to 0.33 more units, 1 RCT, 59 participants)
Number of participants receiving a red cell transfusion (total)	450 per 1000	436 per 1000 (400 to 476)	RR 0.96 (0.86 to 1.06)	1806 (25 RCTs)	⊕⊕⊕⊝ MODERATE^a
Blood loss (total)	Cardiac surgery: total blood loss in the desmopressin group was 135.24 mL less (210.8 mL to 59.68 mL less, 22 RCTs, 1358 participants).			1643 (28 RCTs)	⊕⊝⊝⊝ VERY LOW^a,c,d	Data not pooled owing to clinical heterogeneity and reported as subgroups
	Orthopaedic surgery: total blood loss in the desmopressin group was 285.76 mL less (514.99 mL to 56.53 mL less, 5 RCTs, 241 participants)
	Vascular surgery: total blood loss in the desmopressin group was 582 mL less (1264.07 mL less to 100.07 mL more, 1 RCT, 44 participants)
All‐cause mortality	16 per 1000	17 per 1000 (7 to 41)	pOR 1.09 (0.51 to 2.34)	1631 (22 RCTs)	⊕⊕⊝⊝ LOW^a,e
All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism)	34 per 1000	44 per 1000 (28 to 67)	pOR 1.36 (0.85 to 2.16)	1984 (29 RCTs)	⊕⊕⊝⊝ LOW^a,e
Quality of life	Not reported		‐	(No studies)	‐
*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; pOR: Peto odds ratio; RCT: randomised controlled trial; RR: risk 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
^aDowngraded one level due to risk of bias: inadequate reporting of blinding and incomplete outcome data ^bDowngraged one level for inconsistency: I² = 66% ^cDowngraded one level for inconsistency: I² = 73% and sensitivity analysis unable to determine cause of heterogeneity ^dDowngraded one level for suspected publication bias ^eDowngraded one level due to imprecision, as confidence intervals include both clinically important benefit and clinically important harm

Summary of findings for the main comparison. DDAVP vs placebo or standard care

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Summary of findings 2. DDAVP vs placebo or standard care: platelet dysfunction subgroup

Participant or population: participants with platelet dysfunction undergoing surgery Intervention: desmopressin Comparison: placebo or standard care
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with desmopressin	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Red cell volume transfused (total)	Red cell volume transfused was 2.6 units	Red cell volume transfused in the desmopressin group was 0.65 units less (1.16 less to 0.13 less)	‐	388 (6 RCTs)	⊕⊕⊝⊝ LOW^a,b
Number of participants receiving a red cell transfusion (total)	541 per 1000	449 per 1000 (357 to 1000)	RR 0.83 (0.66 to 1.04)	258 (5 RCTs)	⊕⊕⊝⊝ LOW^a,b
Blood loss (total)	Mean total blood loss was 1098 mL	Total blood loss in the desmopressin group was 253.93 mL less (408.01 mL less to 99.85 mL less)	‐	422 (7 RCTs)	⊕⊕⊝⊝ LOW^a,b
All‐cause mortality	14 per 1000	10 per 1000 (2 to 59)	pOR 0.72 (0.12 to 4.22)	422 (7 RCTs)	⊕⊝⊝⊝ VERY LOW^a,c
All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism)	32 per 1000	51 per 1000 (19 to 133)	pOR 1.58 (0.60 to 4.17)	422 (7 RCTs)	⊕⊝⊝⊝ VERY LOW^a,d
Quality of life	Not reported		‐	(No studies)	‐
*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; pOR: Peto odds ratio; RCT: randomised controlled trial; RR: risk 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
^aDowngraded one level for risk of bias ^bDowngraded one level for inconsistency due to variation in baseline level of transfusion and blood loss ^cDowngraded two levels for imprecision, as confidence intervals include clinically important benefit and clinically important harm with low background event rate ^dDowngraded one level for imprecision

Summary of findings 2. DDAVP vs placebo or standard care: platelet dysfunction subgroup

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Summary of findings 3. DDAVP vs tranexamic acid

Participant or population: participants undergoing surgery Intervention: desmopressin Comparison: tranexamic acid
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with tranexamic acid	Risk with desmopressin	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Red cell volume transfused (total)	Mean red cell volume transfused was 0.2 units	Red cell volume transfused in the desmopressin group was 0.6 units more (0.09 more to 1.11 more)	‐	40 (1 RCT)	⊕⊕⊝⊝ LOW^a,b
Number of participants receiving a red cell transfusion (total)	239 per 1000	578 per 1000 (248 to 1000)	RR 2.42 (1.04 to 5.64)	135 (3 RCTs)	⊕⊝⊝⊝ VERY LOW^a,b,c
Blood loss (total)	Mean blood loss was 270 mL	Total blood loss in the desmopressin group was 142.81 mL more (79.78 mL more to 205.84 mL more)	‐	115 (2 RCTs)	⊕⊕⊝⊝ LOW^a,b
All‐cause mortality	Not reported		‐	(No studies)	‐
All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism)	18 per 1000	51 per 1000 (6 to 471)	RR 2.92 (0.32 to 26.83)	115 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^a,d,e
Quality of life	Not reported		‐	(No studies)	‐
*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; RCT: randomised controlled trial; RR: risk 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
^aDowngraded one level for risk of bias ^bDowngraded one level for indirectness because most types of surgery or procedures were not represented by the included trials ^cDowngraded one level for imprecision owing to wide confidence intervals ^dDowngraded two levels for imprecision owing to very wide confidence intervals ^eOutcome not downgraded for indirectness because already downgraded three levels for other reasons

Summary of findings 3. DDAVP vs tranexamic acid

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Summary of findings 4. DDAVP vs aprotinin

Participant or population: participants undergoing surgery Intervention: desmopressin Comparison: aprotinin
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with aprotinin	Risk with desmopressin	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Red cell volume transfused (total)	Not reported		‐	(No studies)	‐
Number of participants receiving a red cell transfusion (total)	265 per 1000	639 per 1000 (385 to 1000)	RR 2.41 (1.45 to 4.02)	99 (1 RCT)	⊕⊕⊝⊝ LOW^a,b
Blood loss (total)	Not reported		‐	(No studies)	‐
All‐cause mortality	No deaths in either arm of the trial		Not estimable	53 (1 RCT)	⊕⊝⊝⊝ VERY LOW^a,c,d
All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism)	14 per 1000	13 per 1000 (1 to 206)	pOR 0.98 (0.06 to 15.89)	152 (2 RCTs)	⊕⊝⊝⊝ VERY LOW^a,d,e
Quality of life	Not reported		‐	(No studies)	‐
*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; pOR: Peto odds ratio; RCT: randomised controlled trial; RR: risk 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
^aDowngraded one level for risk of bias ^bDowngraded one level for indirectness because most types of surgery or procedures were not represented by the included trials ^cDowngraded two levels for imprecision (no deaths in either arm) ^dNot downgraded for indirectness because already downgraded three levels for other reasons ^eDowngraded two levels for imprecision (very wide confidence intervals)

Summary of findings 4. DDAVP vs aprotinin

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Table 1. Study characteristics

Trial (country)	Number of participants	Surgery type	Cases	Antiplatelet agents or platelet dysfunction (%)	Anticoagulants (%)	Coagulopathy (%)	Thrombocytopenia (%)	Antifibrinolytics (%)	Transfusion protocol	Timing of blood loss or transfusion assessment (hours)
Aida 1991a (Japan)	9	Cardiac	‐	‐	‐	‐	‐	‐	‐	24
Aida 1991b (Japan)	11	Cardiac	‐	‐	‐	‐	‐	‐	‐	24
Alanay 1999 (Turkey)	40	Orthopaedic	Elective	‐	‐	‐	‐	‐	‐	24
Andersson 1990 (Sweden)	19	Cardiac	Elective	0	0	‐	‐	‐	‐	‐
Ansell 1992 (USA)	83	Cardiac	Elective	‐	‐	‐	‐	DDAVP: 2‐4^a Placebo: 0	‐	24
Bignami 2016 (Italy)	135	Cardiac	Elective	DDAVP: 38^b Placebo: 43^b	‐	DDAVP: 1‐5 Placebo: 1‐5	‐	100^c	Yes	24
Brown 1989 (USA)	39	Cardiac	Elective	DDAVP: 60^b Placebo: 50^b	‐	0	‐	‐	‐	24
Casas 1995 (Spain)	149	Cardiac	Elective	DDAVP: 14^b Placebo: 9‐8^b Aprotinin: 14‐6^b	0	0	‐	DDAVP: 0 Placebo: 0 Aprotinin: 100^d	Yes	24
Chuang 1993 (China)	96	Cardiac	‐	‐	‐	‐	‐	‐	‐	24
Clagett 1995 (USA)	91	Vascular	Elective	0	‐	‐	‐	‐	‐	72
de Prost 1992 (France)	92	Cardiac	‐	100^e	‐	‐	0	DDAVP: 4‐3^d Placebo: 13‐3^d	Yes	24
Despotis 1999 (USA)	101	Cardiac	Elective	DDAVP: 52^b Placebo: 66^b 100^f	DDAVP: 6 Placebo: 0	‐	‐	DDAVP 50^a Placebo 61^a	No	24
Dilthey 1993 (Germany)	39	Cardiac	Elective	100^b	0	0	‐	0	Yes	24
Ellis 2001 (Israel)	30	Orthopaedic	Elective	‐	‐	‐	‐	DDAVP: 0 TXA: 100^c	Yes	72
Flordal 1991 (Sweden)	12	Orthopaedic	Elective	‐	‐	‐	‐	‐	‐	24
Flordal 1992 (Sweden)	50	Orthopaedic	Elective	‐	‐	‐	‐	‐	‐	‐
Frankville 1991 (USA)	40	Cardiac	Elective	0	0	0	0	‐	‐	24
Gratz 1992 (USA)	59	Cardiac	Elective	100^b	‐	‐	0	‐	‐	24
Guay 1992 (Canada)	30	Orthopaedic	Elective	0	0	0	0	‐	Yes	24
Guyuron 1996 (USA)	20	Maxillofacial	Elective	‐	‐	0	‐	‐	‐	24
Hackmann 1989 (Canada)	150	Cardiac	Elective	DDAVP: 21‐6^b Placebo: 14‐5^b	‐	0	0	‐	‐	24
Hajjar 2007 (Brazil)	150	Cardiac	‐	‐	‐	‐	‐	‐	‐	72
Hedderich 1990 (Canada)	62	Cardiac	Elective	DDAVP: 38‐7^b Placebo: 41.9^b	‐	‐	‐	‐	‐	18 blood loss 48 transfusion
Hemșinli 2012a (Turkey)	20	Cardiac	Emergency	100^b	‐	‐	‐	0	‐	30
Hemșinli 2012b (Turkey)	34	Cardiac	Emergency	100^b	‐	‐	‐	100^c	‐	30
Hemșinli 2012c (Turkey)	28	Cardiac	Emergency	100^b	‐	‐	‐	DDAVP: 0 TXA: 100^c	‐	30
Horrow 1991a (USA)	82	Cardiac	Elective	‐	0	‐	‐	0	Yes	12
Horrow 1991b (USA)	77	Cardiac	Elective	‐	0	‐	‐	100^c	Yes	12
Horrow 1991c (USA)	75	Cardiac	Elective	‐	0	‐	‐	DDAVP: 0 TXA: 100^c	Yes	12
Jin 2015 (China)	102	Cardiac	Elective	‐	0	0	0	100^c	‐	6
Karnezis 1994a (USA)	36	Orthopaedic	Elective	‐	0	‐	‐	‐	Yes	24
Karnezis 1994b (USA)	56	Orthopaedic	Elective	‐	0	‐	‐	‐	Yes	24
Kobrinsky 1987 (USA)	35	Cardiac	Elective	0	‐	‐	‐	‐	‐	34
Kuitunen 1992 (Finland)	30	Cardiac	Elective	0	0	‐	‐	‐	Yes	16
Lazarchick 1995 (USA)	23	Not reported	‐	‐	‐	‐	‐	‐	‐	‐
Lee 2010 (South Korea)	48	Dialysis catheter	Elective	100^g	‐	‐	0	‐	‐	‐
Leino 2010 (Finland)	71	Orthopaedic	Elective	0	0	0	‐	‐	Yes	96
Lethagen 1991 (Sweden)	50	Vascular	Elective	0	0	0	‐	‐	Yes	‐
Letts 1998 (Canada)	30	Orthopaedic	Elective	‐	‐	‐	‐	‐	‐	Intraoperative only
Manno 2011 (Italy)	162	Kidney biopsy	Elective	0	0	‐	‐	‐	‐	72
Marquez 1992 (USA)	65	Cardiac	Elective	0	0	‐	‐	‐	Yes	24
Marczinski 2007 (Netherlands)	28	Orthopaedic/Breast/Abdominal	Elective	0	0	0	0	‐	‐	48
Mongan 1992a (USA)	86	Cardiac	Elective	0	0	‐	‐	‐	Yes	24
Mongan 1992b (USA)	29	Cardiac	Elective	100^h	0	‐	‐	‐	Yes	24
Oliver 2000 (USA)	60	Paediatric cardiac	Elective	DDAVP: 9.7^b Placebo: 3.4^b	DDAVP: 6.5 Placebo: 6.9	‐	‐	‐	No	24
Ozkisacik 2001 (Turkey)	66	Cardiac	Elective	0	‐	0	‐	‐	Yes	24
Pleym 2004 (Norway)	92	Cardiac	Elective	100^b	0	0	0	DDAVP: 6.5^c Placebo: 17.4^c	Yes	16
Reich 1991 (USA)	27	Cardiac	Elective	DDAVP: 28.6^b Placebo: 38.5^b	‐	0	0	‐	‐	24
Reynolds 1993 (USA)	95	Paediatric cardiac	‐	‐	‐	‐	‐	‐	‐	24
Rocha 1988 (Spain)	100	Cardiac	Elective	‐	‐	0	0	‐	‐	72
Rocha 1994 (Spain)	109	Cardiac	Elective	‐	‐	0	0	DDAVP (1): 0 DDAVP (2): 0 Control: 0 Aprotinin: 100^d	‐	72
Salmenpera 1991 (Finland)	30	Cardiac	Elective	0	0	0	‐	‐	Yes	16
Salzman 1986 (USA)	70	Cardiac	Elective	‐	‐	‐	‐	‐	‐	24
Schott 1995 (Sweden)	79	Orthopaedic	Elective	0	0	0	0	‐	Yes	24
Seear 1989 (Canada)	60	Paediatric cardiac	‐	‐	‐	‐	‐	‐	‐	24
Shao 2015 (China)	90	Sinus	Elective	0	0	0	0	‐	‐	Intraoperative only
Sheridan 1994 (Canada)	44	Cardiac	Elective	100^b	0	0	0	‐	‐	24
Spyt 1990 (UK)	98	Cardiac	Elective	DDAVP: 14.3^b Placebo: 10.2^b	0	‐	‐	‐	Yes	˜24
Steinlechner 2011 (Austria)	43	Cardiac	Elective	100^g	0	‐	‐	‐	Yes	24
Temeck 1994 (USA)	83	Cardiac	Elective	‐	‐	‐	‐	DDAVP: 20^a Placebo: 30.2^a	‐	24
Theroux 1997 (USA)	21	Orthopaedic	Elective	0	0	0	0	‐	Yes	24
Wingate 1992a (USA)	23	Plastic	Elective	‐	‐	‐	‐	‐	‐	24
Wingate 1992b (USA)	21	Plastic	Elective	‐	‐	‐	‐	‐	‐	24
Wong 2003 (Hong Kong)	59	Hepatic	Elective	0	0	0	‐	‐	Yes	Intraoperative only
Zohar 2001 (Israel)	40	Orthopaedic	Elective	‐	0	‐	‐	DDAVP: 0 TXA: 100^c	Yes	12
Blank cells indicate that information was not reported in the original papers ^aEpsilon‐aminocaproic acid ^bAntiplatelet agents ^cTranexamic acid ^dAprotinin ^eDefined as bleeding time greater than 10 seconds ^fDefined as hemoSTATUS < 60% ^gDefined as prolonged platelet function analyser‐100 closure time ^hDefined as thromboelastography maximum clot amplitude < 50 mm

Table 1. Study characteristics

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Table 2. Intervention characteristics

Trial	DDAVP dose(s) (μg/kg)	Timing of dose	Timing summary	Comparator(s)
Preoperative DDAVP
Alanay 1999	0.3	Induction of anaesthesia	Preoperative	Placebo
Flordal 1991	0.3 (× 2)	At start of surgery and again after 6 hours	Preoperative	Placebo
Flordal 1992	0.3 (× 2)	At start of surgery and again after 6 hours	Preoperative	Placebo
Guay 1992	10 μg/m²	At time of first skin incision	Preoperative	Placebo
Guyuron 1996	20 μg	30 minutes preoperatively	Preoperative	Placebo
Kobrinsky 1987	10 μg/m²	Immediately after induction of anaesthesia	Preoperative	Placebo
Lazarchick 1995	0.3	After anaesthetic induction	Preoperative	Placebo
Lee 2010	0.3	Not reported	Preoperative	Placebo
Leino 2010	0.4	At start of surgery	Preoperative	Placebo
Leino 2010	0.4	At start of surgery	Preoperative	DDAVP 0.2 μg/kg
Lethagen 1991	0.3	Immediately before start of operation	Preoperative	Placebo
Letts 1998	10 μg/m²	Immediately after induction of anaesthesia	Preoperative	Placebo
Manno 2011	0.3	1 hour before biopsy	Preoperative	Placebo
Marczinski 2007	15 μg to 45 μg depending on weight	Not reported	Preoperative	Placebo
Schott 1995	0.3 (× 2)	Post induction of anaesthesia and again after 6 hours	Preoperative	Placebo
Shao 2015	0.3	After induction of anaesthesia	Preoperative	Placebo
Steinlechner 2011	0.3	After induction of anaesthesia	Preoperative	Placebo
Theroux 1997	0.3	Not reported	Preoperative	Placebo
Wingate 1992a	0.3	After induction of anaesthesia	Preoperative	Placebo
Wingate 1992b	0.3	After induction of anaesthesia	Preoperative	Placebo
Wong 2003	0.3	After induction of anaesthesia	Preoperative	Placebo
DDAVP administered at end of operation
Aida 1991a	0.3	15 minutes after reversal of heparin	End of operation	Placebo
Aida 1991b	0.3	15 minutes after reversal of heparin	End of operation	Placebo
Andersson 1990	0.3	15 minutes after reversal of heparin	End of operation	Placebo
Ansell 1992	0.3	Immediately after reversal of heparin	End of operation	Placebo
Bignami 2016	0.3	In event of excessive bleeding, after reversal of heparin	End of operation/postoperative	Placebo
Brown 1989	0.3	Immediately after reversal of heparin	End of operation	Placebo
Casas 1995	0.3	Immediately after reversal of heparin	End of operation	Placebo
Casas 1995	0.3	Immediately after reversal of heparin	End of operation	Aprotinin^a
Chuang 1993	0.3	60 minutes after reversal of heparin	End of operation	Placebo
Clagett 1995	20 μg	15 minutes after heparinisation and before aortic cross‐clamp application	End of operation	Placebo
Despotis 1999	0.4	Unclear	End of operation	Placebo
Dilthey 1993	0.3	5 minutes after reversal of heparin	End of operation	Placebo
Ellis 2001	0.3	Before removal of tourniquet	End of operation	Placebo
Ellis 2001	0.3	Before removal of tourniquet	End of operation	Tranexamic acid^b
Frankville 1991	0.3	5 minutes after reversal of heparin	End of operation	Placebo
Gratz 1992	0.3	Immediately after reversal of heparin	End of operation	Placebo
Hackmann 1989	0.3	Immediately after reversal of heparin	End of operation	Placebo
Hajjar 2007	0.3	Immediately after surgery	End of operation	Placebo
Hedderich 1990	0.3	Immediately after reversal of heparin	End of operation	Placebo
Horrow 1991a	0.3	Immediately after reversal of heparin	End of operation	Placebo
Horrow 1991b	0.3	Immediately after reversal of heparin	End of operation	Placebo
Horrow 1991c	0.3	Immediately after reversal of heparin	End of operation	Tranexamic acid^c
Jin 2015	0.3	Before cardiac rewarming	End of operation	Placebo
Karnezis 1994a	0.3	30 minutes before closure of wound	End of operation	Placebo
Karnezis 1994b	0.3	30 minutes before closure of wound	End of operation	Placebo
Marquez 1992	0.3	Immediately after reversal of heparin	End of operation	Placebo
Marquez 1992	0.3	Immediately after reversal of heparin	End of operation	DDAVP 0.3 μg/kg × 2
Mongan 1992a	0.3	After reversal of heparin and before chest closure	End of operation	Placebo
Mongan 1992b	0.3	After reversal of heparin and before chest closure	End of operation	Placebo
Oliver 2000	0.3	10 minutes after reversal of heparin	End of operation	Placebo
Ozkisacik 2001	0.3	After reversal of heparin (timing unclear)	End of operation	Placebo
Pleym 2004	0.3	Immediately after reversal of heparin	End of operation	Placebo
Reich 1991	0.3	15 minutes after reversal of heparin	End of operation	Placebo
Reynolds 1993	0.3	5 minutes after reversal of heparin	End of operation	Placebo
Rocha 1988	0.3	Immediately after reversal of heparin	End of operation	Placebo
Rocha 1994	0.3	Immediately after reversal of heparin	End of operation	Standard care
				Aprotinin^d
				DDAVP 0.3 μg/kg × 2
Salmenpera 1991	0.3	Via pulmonary artery catheter immediately after sternal closure	End of operation	Placebo
Salzman 1986	0.3	Immediately after reversal of heparin	End of operation	Placebo
Seear 1989	0.3	After reversal of heparin (timing unclear)	End of operation	Placebo
Sheridan 1994	10 μg/m²	After reversal of heparin (timing unclear)	End of operation	Placebo
Spyt 1990	0.3	After reversal of heparin (timing unclear)	End of operation	Placebo
Temeck 1994	0.3	After reversal of heparin (timing unclear)	End of operation	Placebo
Zohar 2001	0.3	30 minutes before deflation of tourniquet	End of operation	Tranexamic acid^b
DDAVP administered postoperatively
de Prost 1992	0.3	Between end of operation and 6 hours postoperatively	Postoperative	Placebo
Kuitunen 1992	0.3	Immediately after sternal closure	Postoperative	Placebo
Timing of DDAVP administration unclear
Hemșinli 2012a	0.3	Not reported	Not clear	Standard care
Hemșinli 2012b	0.3	Not reported	Not clear	Standard care
Hemșinli 2012c	0.3	Not reported	Not clear	Tranexamic acid^c
^aAprotinin 2 million KIU in 200 mL preoperatively, 2 million KIU in 200 mL in fluid prime, 500,000 KIU in 50 mL/h from skin incision to skin closure ^bTranexamic acid 15 mg/kg 30 minutes before tourniquet removed over 30 minutes, then 10 mg/kg/h until 12 hours after tourniquet deflated ^cTranexamic acid 10 mg/kg loading dose after induction of anaesthesia and before first skin incision over 30 minutes, then 1 mg/kg/h for 10 hours ^dAprotinin 2 million KIU within 30 minutes after induction of anaesthesia followed by a continuous infusion of 500,000 KIU/h until the patient left the operating room, plus an additional bolus of 2 million KIU aprotinin in the pump prime by replacement of crystalloid solution Abbreviation KIU: kilounits

Table 2. Intervention characteristics

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Table 3. DDAVP vs placebo: intraoperative volume of red cells transfused

Trial	Reason not included in meta‐analysis	DDAVP arm	Placebo arm
Orthopaedic surgery
Leino 2010	Reported as mean (no standard deviation)	0.3 units (n = 23)	0.5 units (n = 24)
Letts 1998	Reported as mean (no standard deviation)	4.6 units (n = 16)	5.0 units (n = 14)
Theroux 1997	Reported as median and range	51.5 (24 to 98.6) mL/kg (n = 10)	48.3 (24.5 to 96) mL/kg (n = 11)

Table 3. DDAVP vs placebo: intraoperative volume of red cells transfused

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Table 4. DDAVP vs placebo: total volume of red cells transfused

Trial	Reason not included in meta‐analysis	DDAVP arm	Placebo arm
Adult cardiac surgery
Aida 1991a	Reported as mL/kg (mean ± standard deviation)	8.3 ± 5.6 mL/kg (n = 5)	10.8 ± 6.3 mL/kg (n = 4)
Aida 1991b	Reported as mL/kg (mean ± standard deviation)	10.2 ± 6.4 mL/kg (n = 5)	13.2 ± 6.6 mL/kg (n = 6)
Alanay 1999	Reported as median (interquartile range)	1.7 (2.3) units (n = 18)	0.6 (1.3) units (n = 22)
Bignami 2016	Reported as median (interquartile range)	2 (1 to 4) units (n = 68)	2 (1 to 3) units (n = 67)
Frankville 1991	Reported as mean (no standard deviation)	2.4 units (n = 15)	2 units (n = 15)
Hackmann 1989	Reported as median (90% confidence interval)	2 (1 to 8.5) units (n = 74)	2 (1 to 9.8) units (n = 76)
Kuitunen 1992	Reported as mean (range)	1.3 (0 to 2) units (n = 15)	1.1 (0 to 3) units (n = 15)
Marquez 1992	Reported as median only	2 units (n = 21)	2 units (n = 22)
Mongan 1992a	Reported as mean only	0.86 units (n = 44)	1.79 units n = 42)
Mongan 1992b	Reported as mean only	2.4 units (n = 13)	2.2 units (n = 16)
Rocha 1994	Reported as mL/m² (mean ± standard deviation)	740.4 ± 416.3 mL/m² ^{(n = 25)}	662.8 ± 380.7 mL/m² ^{(n = 28)}
Spyt 1990	Reported as mean only	1.38 units (n = 49)	1.30 units (n = 49)
Orthopaedic surgery
Ellis 2001	Reported as mean only	0.7 units (n = 10)	1.1 units (n = 10)
Theroux 1997	Reported as median and range	64.8 (30.3 to 123.6) mL/kg (n = 10)	64.9 (33.8 to 110) mL/kg (n = 11)
Maxillofacial surgery
Guyuron 1996	Reported as mean (no standard deviation)	0.6 units (n = 10)	0.9 units (n = 10)

Table 4. DDAVP vs placebo: total volume of red cells transfused

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Table 5. DDAVP vs placebo: intraoperative blood loss

Trial	Reason not included in meta‐analysis	DDAVP arm	Placebo arm
Adult cardiac surgery
Hackmann 1989	Reported as median (90% confidence interval)	200 (0 to 1150) mL (n = 74)	200 (0 to 1013) mL (n = 76)
Rocha 1988	Reported as mL/m² body surface area	131 ± 106 mL/m² (n = 50)	193 ± 137 mL/m² (n = 50)
Paediatric cardiac surgery
Oliver 2000	Reported as mL/m²	49.3 ± 43.7 mL/m² (n = 31)	73.6 ± 71.1 mL/m² (n = 29)
Orthopaedic surgery
Leino 2010	Reported as mean (no standard deviation)	1200 mL (n = 23)	1463 mL (n = 24)
Hepatic surgery
Wong 2003	Reported as median (range)	832.5 (350 to 2955) mL (n = 30)	800 mL (250 to 7128) mL (n = 29)
Other surgery
Marczinski 2007	Reported as mean and range	251 (2 to 1330) mL (n = 14)	504 (50 to 2100) mL (n = 14)

Table 5. DDAVP vs placebo: intraoperative blood loss

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Table 6. DDAVP vs placebo: total blood loss

Trial	Reason not included in meta‐analysis	DDAVP arm	Placebo arm
Adult cardiac surgery
Aida 1991a	Reported as mL/kg (mean ± standard deviation)	8.0 ± 1.4 mL/kg (n = 5)	5.9 ± 1.5 mL/kg (n = 4)
Aida 1991b	Reported as mL/kg (mean ± standard deviation)	11.3 ± 10 mL/kg (n = 5)	7.5 ± 4 mL/kg (n = 6)
Alanay 1999	Reported as median (interquartile range)	950 (950) mL (n = 18)	975 (811) mL (n = 22)
Bignami 2016	Reported as median (interquartile range)	575 (422.5 to 770) mL (n = 68)	590 (476.25 to 1013.75) mL (n = 67)
Casas 1995	Reported as mL/m² body surface area (mean ± standard deviation)	400 ± 192 mL/m² (n = 50)	489 ± 361 mL/m² (n = 51)
de Prost 1992	Reported as mL/m² body surface area (mean ± standard deviation)	582 ± 410 mL/m² (n = 44)	465 ± 303 mL/m² (n = 37)
Dilthey 1993	Reported as median (range)	1000 (600 to 1800) mL (n = 19)	1075 (400 to 1740) mL (n = 20)
Hackmann 1989	Reported as median (90% confidence interval)	865 (358 to 2495) mL (n = 74)	783 (300 to 2219) mL (n = 76)
Hajjar 2007	Reported as mL/m² (mean ± standard deviation)	258 ± 106 mL/m² (n = 75)	526 ± 314 mL/m² (n = 75)
Hemșinli 2012a	Reported as mean (no standard deviation)	1430 mL (n = 10)	1767 mL (n = 10)
Hemșinli 2012b	Reported as mean (no standard deviation)	574 mL (n = 16)	535 mL (n = 18)
Marquez 1992	Reported as median only	1157 mL (n = 21)	1180 mL (n = 22)
Rocha 1988	Reported as mL/m² body surface area (mean ± standard deviation)	458 ± 206 mL/m² (n = 50)	536 ± 304 mL/m² (n = 50)
Rocha 1994	Reported as mL/m² body surface area (mean ± standard deviation)	551.8 ± 324.1 mL/m² (n = 28)	438.7 ± 228.1 mL/m² (n = 25)
Salmenpera 1991	Reported as median (range)	1020 (530 to 1155) mL (n = 15)	1100 (425 to 1720) mL (n = 15)
Orthopaedic surgery
Flordal 1991	Reported as mean (no standard deviation)	1320 mL (n = 6)	1380 mL (n = 6)
Theroux 1997	Reported as estimated percentage blood loss: median (range)	147.8% (57% to 428.8%) (n = 10)	111.2% (65% to 239.5%) (n = 11)
Maxillofacial surgery
Guyuron 1996	Reported as mean (range)	675 (380 to 1330) mL (n = 10)	819 (200 to 1600) mL (n = 10)

Table 6. DDAVP vs placebo: total blood loss

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Table 7. DDAVP vs tranexamic acid: total volume of red cells transfused

Trial

Reason not included in meta‐analysis

DDAVP arm

Tranexamic acid arm

Orthopaedic surgery

Ellis 2001

Reported as mean only

0.7 units

(n = 10)

0.1 units

(n = 10)

Table 7. DDAVP vs tranexamic acid: total volume of red cells transfused

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Table 8. DDAVP vs tranexamic acid: total blood loss

Trial

Reason not included in meta‐analysis

DDAVP arm

Tranexamic acid arm

Adult cardiac surgery

Hemșinli 2012c

Reported as mean (no standard deviation)

1430 mL

(n = 10)

535 mL

(n = 18)

Table 8. DDAVP vs tranexamic acid: total blood loss

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Table 9. DDAVP vs aprotinin: total volume of red cells transfused

Trial

Reason not included in meta‐analysis

DDAVP arm

Aprotinin arm

Adult cardiac surgery

Rocha 1994

Reported as mL/m² body surface area (mean ± standard deviation)

740.4 ± 416.3 mL/m²

(n = 25)

366.1 ± 331.9 mL/m²

(n = 28)

Table 9. DDAVP vs aprotinin: total volume of red cells transfused

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Table 10. DDAVP vs aprotinin: total blood loss

Trial	Reason not included in meta‐analysis	DDAVP arm	Aprotinin arm
Adult cardiac surgery
Casas 1995	Reported as mL/m² body surface area (mean ± standard deviation)	400 ± 192 mL/m² (n = 50)	195 ± 146 mL/m² (n = 48)
Rocha 1994	Reported as mL/m² body surface area (mean ± standard deviation)	551.8 ± 324.1 mL/m² (n = 25)	358.5 ± 156.3 mL/m² (n = 28)

Table 10. DDAVP vs aprotinin: total blood loss

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Comparison 1. Desmopressin vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Red cell volume transfused (intraoperatively) Show forest plot	7		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 Adult cardiac surgery	1	19	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐1.22, 1.02]
1.2 Paediatric cardiac surgery	1	60	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.87, 1.67]
1.3 Orthopaedic surgery	3	144	Mean Difference (IV, Random, 95% CI)	‐0.50 [‐0.89, ‐0.11]
1.4 Vascular surgery	1	44	Mean Difference (IV, Random, 95% CI)	‐1.20 [‐2.55, 0.15]
1.5 Plastic surgery	1	23	Mean Difference (IV, Random, 95% CI)	‐0.75 [‐1.23, ‐0.27]
2 Red cell volume transfused (total) Show forest plot	23		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 Cardiac surgery	14	957	Mean Difference (IV, Random, 95% CI)	‐0.52 [‐0.96, ‐0.08]
2.2 Orthopaedic surgery	6	303	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.67, 0.64]
2.3 Vascular surgery	2	135	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.60, 0.73]
2.4 Hepatic surgery	1	59	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐1.27, 0.33]
3 Red cell volume transfused (children only, total) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4 Number of participants receiving a red cell transfusion (intraoperatively) Show forest plot	6	349	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.50, 1.09]

4.1 Cardiac surgery	2	115	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.43, 1.10]
4.2 Plastic surgery	2	44	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.45, 1.64]
4.3 Kidney biopsy	1	162	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.4 Other	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Number of participants receiving a red cell transfusion (total) Show forest plot	25	1806	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.06]

5.1 Cardiac surgery	17	1350	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.82, 1.06]
5.2 Orthopaedic surgery	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.45, 1.64]
5.3 Vascular surgery	1	91	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.83, 1.34]
5.4 Paediatric cardiac surgery	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.66, 2.06]
5.5 Plastic surgery	2	44	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.45, 1.64]
5.6 Hepatic surgery	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.15, 2.21]
5.7 Kidney biopsy	1	162	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.8 Maxillofacial surgery	1	20	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.88, 4.54]
6 Blood loss (intraoperative) Show forest plot	11		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Cardiac surgery	2	87	Mean Difference (IV, Random, 95% CI)	‐138.20 [‐623.40, 347.01]
6.2 Orthopaedic surgery	5	224	Mean Difference (IV, Random, 95% CI)	‐118.24 [‐278.43, 41.95]
6.3 Vascular surgery	1	44	Mean Difference (IV, Random, 95% CI)	‐525.0 [‐1177.34, 127.34]
6.4 Sinus surgery	1	90	Mean Difference (IV, Random, 95% CI)	‐28.0 [‐31.70, ‐24.30]
6.5 Plastic surgery	2	44	Mean Difference (IV, Random, 95% CI)	‐146.02 [‐487.86, 195.83]
7 Blood loss (total) Show forest plot	28		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 Adult cardiac surgery	22	1358	Mean Difference (IV, Random, 95% CI)	‐135.24 [‐210.80, ‐59.68]
7.2 Orthopaedic surgery	5	241	Mean Difference (IV, Random, 95% CI)	‐285.76 [‐514.99, ‐56.53]
7.3 Vascular surgery	1	44	Mean Difference (IV, Random, 95% CI)	‐582.0 [‐1264.07, 100.07]
8 Blood loss (children only, total) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.1 Paediatric cardiac surgery	2	155	Mean Difference (IV, Random, 95% CI)	1.11 [‐12.92, 15.15]
9 Number of participants with any bleeding (intraoperatively) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

9.1 Dialysis catheter	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10 Number of participants with any bleeding (total) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

10.1 Kidney biopsy	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
11 Reoperation due to bleeding Show forest plot	23	1783	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.66 [0.40, 1.09]

11.1 Cardiac surgery	19	1483	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.64 [0.38, 1.05]
11.2 Orthopaedic surgery	1	30	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.3 Paediatric cardiac surgery	1	60	Peto Odds Ratio (Peto, Fixed, 95% CI)	6.93 [0.14, 349.88]
11.4 Dialysis catheter insertion	1	48	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.5 Kidney biopsy	1	162	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 All‐cause mortality Show forest plot	22	1631	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.09 [0.51, 2.34]

12.1 Cardiac surgery	16	1239	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.09 [0.48, 2.51]
12.2 Orthopaedic surgery	3	171	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.3 Vascular surgery	1	91	Peto Odds Ratio (Peto, Fixed, 95% CI)	8.50 [0.52, 138.60]
12.4 Paediatric cardiac surgery	2	130	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.13 [0.01, 2.14]
13 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism) Show forest plot	29	1984	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.36 [0.85, 2.16]

13.1 Cardiac surgery	19	1311	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.46 [0.88, 2.42]
13.2 Orthopaedic surgery	6	280	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.21 [0.14, 363.30]
13.3 Vascular surgery	2	141	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.23, 2.60]
13.4 Sinus surgery	1	90	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.5 Kidney biopsy	1	162	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Myocardial infarction Show forest plot	26	1704	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.32 [0.70, 2.46]

14.1 Cardiac surgery	16	1031	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.52 [0.77, 3.00]
14.2 Orthopaedic surgery	6	280	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.3 Vascular surgery	2	141	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.55 [0.11, 2.88]
14.4 Kidney biopsy	1	162	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.5 Sinus surgery	1	90	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Stroke Show forest plot	19	1277	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.95 [0.94, 9.24]

15.1 Cardiac surgery	11	733	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.95 [0.94, 9.24]
15.2 Orthopaedic surgery	5	201	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.3 Vascular surgery	1	91	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.4 Kidney biopsy	1	162	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.5 Sinus surgery	1	90	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Venous thromboembolism Show forest plot	20	1377	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.17, 3.38]

16.1 Cardiac surgery	11	754	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.53 [0.11, 2.62]
16.2 Orthopaedic surgery	6	280	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.21 [0.14, 363.30]
16.3 Vascular surgery	1	91	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.4 Kidney biopsy	1	162	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.5 Sinus surgery	1	90	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Clinically important hypotension Show forest plot	18	1183	Risk Ratio (M‐H, Random, 95% CI)	2.32 [1.37, 3.91]

17.1 Cardiac surgery	13	762	Risk Ratio (M‐H, Random, 95% CI)	2.88 [1.32, 6.30]
17.2 Orthopaedic surgery	2	109	Risk Ratio (M‐H, Random, 95% CI)	2.05 [0.99, 4.24]
17.3 Paediatric cardiac surgery	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.06, 14.27]
17.4 Sinus surgery	1	90	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
17.5 Kidney biopsy	1	162	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Desmopressin vs placebo

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Comparison 2. Desmopressin vs placebo (platelet dysfunction)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Red cell volume transfused (total) Show forest plot	6	388	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.16, ‐0.13]

2 Number of participants receiving a red cell transfusion (intraoperatively) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3 Number of participants receiving a red cell transfusion (total) Show forest plot	5	258	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.66, 1.04]

4 Blood loss (total) Show forest plot	7	422	Mean Difference (IV, Random, 95% CI)	‐253.93 [‐408.01, ‐99.85]

5 Reoperation due to bleeding Show forest plot	6	413	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.39 [0.18, 0.84]

6 All‐cause mortality Show forest plot	7	422	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.72 [0.12, 4.22]

7 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism) Show forest plot	7	422	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.58 [0.60, 4.17]

8 Myocardial infarction Show forest plot	5	277	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.72 [0.60, 12.37]

9 Stroke Show forest plot	3		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

10 Venous thromboembolism Show forest plot	4	248	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.56 [0.06, 5.50]

11 Clinically important hypotension Show forest plot	5	315	Risk Ratio (M‐H, Random, 95% CI)	6.58 [1.18, 36.76]

Comparison 2. Desmopressin vs placebo (platelet dysfunction)

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Comparison 3. Desmopressin vs tranexamic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Red cell volume transfused (total) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

1.1 Orthopaedic surgery	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2 Number of participants receiving a red cell transfusion (total) Show forest plot	3	135	Risk Ratio (M‐H, Random, 95% CI)	2.42 [1.04, 5.64]

2.1 Cardiac surgery	1	75	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.82, 2.59]
2.2 Orthopaedic surgery	2	60	Risk Ratio (M‐H, Random, 95% CI)	4.15 [1.58, 10.90]
3 Blood loss (total) Show forest plot	2	115	Mean Difference (IV, Random, 95% CI)	142.81 [79.78, 205.84]

3.1 Cardiac surgery	1	75	Mean Difference (IV, Random, 95% CI)	115.0 [35.38, 194.62]
3.2 Orthopaedic surgery	1	40	Mean Difference (IV, Random, 95% CI)	180.0 [86.82, 273.18]
4 Reoperation due to bleeding Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

4.1 Cardiac surgery	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.1 Cardiac surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Orthopaedic surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6 Myocardial infarction Show forest plot	2	115	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

6.1 Cardiac surgery	1	75	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 Orthopaedic surgery	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Stroke Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.1 Cardiac surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.2 Orthopaedic surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Venous thromboembolism Show forest plot	2	115	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

8.1 Cardiac surgery	1	75	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8.2 Orthopaedic surgery	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Desmopressin vs tranexamic acid

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Comparison 4. Desmopressin vs aprotinin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants receiving a red cell transfusion (total) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.1 Cardiac surgery	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Reoperation due to bleeding Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

2.1 Cardiac surgery	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 All‐cause mortality Show forest plot	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

3.1 Cardiac surgery	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 All thrombotic events (including myocardial infarction, ischaemic stroke, other arterial thromboembolism, and venous thromboembolism) Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

4.1 Cardiac surgery	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Myocardial infarction Show forest plot	2	152	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

5.1 Cardiac surgery	2	152	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Stroke Show forest plot	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	Totals not selected

6.1 Cardiac surgery	2		Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Venous thromboembolism Show forest plot	2	152	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

7.1 Cardiac surgery	2	152	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Clinically significant hypotension Show forest plot	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

8.1 Cardiac surgery	1	53	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 4. Desmopressin vs aprotinin

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