3.6 Effect of perioperative strategies that minimise blood loss

3.6.9 Administration of antifibrinolytics and desmopressin

The detailed findings of the systematic review for these interventions can be found in Section 3.8.1 of Volume 1b of the technical report.4 Only intravenous administration of these agents was considered in this guideline. Some evidence was identified for other types of administration; this is presented in Section 3.8.1 of Volume 1b of the technical report.4

Aprotinin

The results of a head-to-head RCT comparing aprotinin with the lysine analogues tranexamic acid and ε-aminocaproic acid in patients undergoing high-risk cardiac surgery were published in 2008.211 Due to the higher death rate associated with aprotinin compared with the lysine analogues, this study was terminated early, and a worldwide suspension of the supply of aprotinin injection was announced.

Due to these safety concerns, and the restricted availability of aprotinin, these guidelines make no recommendations on the use of aprotinin. However, the available evidence regarding aprotinin is included here.

The systematic literature search for evidence of the effectiveness and safety of aprotinin was limited to the comparison between aprotinin therapy and no therapy (i.e. no treatment or placebo). The systematic review identified 19 Level I studies, of which a good-quality Cochrane review was chosen to provide the pivotal evidence for intravenous aprotinin in an adult perioperative population,212 and five reviews of fair to good quality to provide supportive evidence.213–217 An additional six recent Level II studies (RCTs) of fair to good quality were identified that compared intravenous aprotinin therapy with no therapy.218–223

Transfusion requirements

Published meta-analyses demonstrated that aprotinin therapy compared with no therapy was highly effective at reducing the incidence and volume of allogeneic blood transfusion, and the volume of total blood loss.212 These findings were consistent across most surgery types and, in particular, the most commonly studied surgery types: cardiac and orthopaedic surgery.

Reoperation for bleeding

Meta-analyses demonstrated that aprotinin therapy, compared with no therapy, significantly reduced the rate of reoperation for bleeding.212

Mortality and morbidity

Overall, the effect of aprotinin on mortality and morbidity is uncertain due to underpowering in the trials comparing aprotinin therapy with no therapy.

EVIDENCE STATEMENTS – aprotinin	Evidence	Consistency	Clinical impact	Generalisability	Applicability
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous aprotinin therapy reduces the incidence of allogeneic blood transfusion compared with no therapy.
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous aprotinin therapy reduces the volume of allogeneic blood transfusion compared with no therapy.
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous aprotinin therapy reduces blood loss compared with no therapy.
In adult patients undergoing cardiac surgery, the effect of intravenous aprotinin therapy on mortality, compared with no therapy, is uncertain.			X
In adult patients undergoing coronary artery bypass surgery, the effect of intravenous aprotinin therapy on coronary artery graft occlusion, compared with no therapy, is uncertain.
In adult patients undergoing cardiac surgery, intravenous aprotinin therapy does not appear to have an effect on the risk of myocardial infarction compared with no therapy.			X
In adult patients undergoing hip replacement surgery, the effect of intravenous aprotinin therapy on the risk of myocardial infarction, compared with no therapy, is uncertain.
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous aprotinin therapy does not appear to affect the risk of postoperative renal failure.
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous aprotinin therapy may impair postoperative renal function compared with no therapy.
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous aprotinin therapy on the risk of stroke, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous aprotinin therapy on the risk of venous thromboembolism, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous aprotinin therapy on quality of life, compared with no therapy, is unknown.	NA	NA	NA	NA	NA
In adult patients undergoing cardiac surgery, intravenous aprotinin therapy reduces the risk of reoperation for bleeding compared with no therapy.
In adult patients undergoing noncardiac surgery, the effect of intravenous aprotinin therapy on reoperation for bleeding, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous aprotinin therapy has no effect on hospital length of stay compared with no therapy.			X

(See Table 2.2)

PRACTICE POINT – aprotinin

PP14	There is evidence for the beneficial effect of intravenous aprotinin on incidence and volume of transfusion, blood loss, and the risk of reoperation for bleeding. However, the drug has been withdrawn due to concerns that it is less safe than alternative therapies. a

^a Websites of the Therapeutic Goods Administration (www.tga.gov.au), MedSafe (www.medsafe.govt.nz) and United States Food and Drug Administration (www.fda.gov)

Tranexamic acid

The systematic literature search for evidence of the effectiveness and safety of tranexamic acid was limited to the comparison between tranexamic acid therapy and no therapy (i.e. no treatment or placebo). Thus, a formal systematic review comparing tranexamic acid with other agents (e.g. aprotinin, ε-aminocaproic acid and desmopressin) was not conducted. The systematic review identified 19 Level I studies, of which one good-quality Cochrane review provided the pivotal evidence for intravenous tranexamic acid in an adult perioperative population,212 and five reviews of fair to good quality provided supportive evidence.213,215-217,224 An additional 13 recent Level II studies (RCTs) of variable quality were identified that compared intravenous tranexamic acid therapy with no therapy.221,225-236

In the pivotal evidence review, the authors note that the dose regimens for tranexamic acid varied significantly between trials. In the cardiac trials, the loading or bolus dose ranged from 2.5 mg/kg to 100mg/kg, while the maintenance dose ranged from 0.25 mg/kg/hour to 4.0 mg/kg/hour delivered over 1–12 hours.212 Similar dosing variations were observed in trials assessing other surgery types. As such, the CRG was unable to recommend an evidence-based dosing regimen. Clinicians are referred to the manufacturer’s product information to determine dosing for the clinical setting.

Transfusion requirements

Meta-analyses conducted in the Henry et al (2007) review showed that tranexamic acid therapy significantly reduces the incidence of allogeneic transfusion in patients undergoing cardiac surgery (by 31%) and major orthopaedic surgery (by 56%).212 In the subgroup of RCTs in which a transfusion protocol was used, tranexamic acid therapy resulted in a significant decrease in the incidence of transfusion compared to no therapy; however, there was no significant difference in studies where no transfusion protocol was used.

Of trials that reported units of allogeneic blood transfused in the overall study population, meta-analysis indicated that tranexamic acid therapy significantly reduced (by an average of 1.12 units) the volume of allogeneic transfusion compared with no therapy.212

Blood loss

Meta-analysis showed that tranexamic acid therapy significantly reduced the total volume of blood loss compared with no therapy.212 For patients undergoing cardiac surgery or orthopaedic surgery, the reduction in total blood loss was approximately 440 mL.

Mortality and morbidity

Overall, the effect of tranexamic acid on mortality and morbidity is uncertain due to underpowering in the trials comparing tranexamic therapy with no therapy. Meta-analyses indicated that treatment with tranexamic acid therapy was not associated with increased mortality or morbidity.212

EVIDENCE STATEMENTS – tranexamic acid	Evidence	Consistency	Clinical impact	Generalisability	Applicability
In adult patients undergoing cardiac surgery and major orthopaedic surgery, intravenous tranexamic acid therapy reduces the incidence of allogeneic blood transfusion compared with no therapy.
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous tranexamic acid therapy may reduce the volume of allogeneic blood transfusion compared with no therapy.
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous tranexamic acid therapy reduces blood loss compared with no therapy.
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous tranexamic acid therapy on mortality, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous tranexamic acid therapy does not appear to have an effect on risk of myocardial infarction compared with no therapy.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous tranexamic acid therapy on risk of stroke, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous tranexamic acid therapy on risk of thrombosis, compared with no therapy, is uncertain.			X
In adult patients undergoing cardiac surgery, the effect of intravenous tranexamic acid therapy on risk of renal failure or dysfunction, compared with no therapy, is uncertain.
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous tranexamic acid therapy on quality of life, compared with no therapy, is unknown.	NA	NA	NA	NA	NA
In adult patients undergoing cardiac surgery, the effect of intravenous tranexamic acid therapy on risk of reoperation for bleeding, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous tranexamic acid therapy does not appear to affect hospital length of stay compared with no therapy.		X	X

(See Table 2.2)

RECOMMENDATIONS – tranexamic acid

R17 Grade A	In adult patients undergoing cardiac surgery, the use of intravenous tranexamic acid is recommended (Grade A).
R18 Grade B	In adult patients undergoing noncardiac surgery, if substantial blood loss (blood loss of a volume great enough to induce anaemia that would require therapy) is anticipated, the use of intravenous tranexamic acid is recommended (Grade B).

Epsilon-aminocaproic acid

The following text should be read while keeping in mind that ε-aminocaproic acid injection is not currently registered in Australia.

The systematic literature search for evidence of the effectiveness and safety of ε-aminocaproic acid was limited to the comparison between ε-aminocaproic acid therapy and no therapy (i.e. no treatment or placebo). Thus, a formal systematic review comparing ε-aminocaproic acid with other agents (e.g. aprotinin, tranexamic acid and desmopressin) was not conducted. The systematic review identified 13 Level I studies, of which a good-quality Cochrane review provided the pivotal evidence for intravenous ε-aminocaproic acid in an adult perioperative population,212 and four reviews of fair to good quality provided supportive evidence.213,215 An additional two recent Level II studies (RCTs) of good and fair quality were identified that compared intravenous ε-aminocaproic acid therapy with no therapy.237,238

In the pivotal evidence review, the authors noted that the dose regimens for ε-aminocaproic acid varied significantly between trials.212 The loading dose ranged from 80 mg to 15 g (75–150 mg/kg); and the maintenance dose ranged from 1 g/hour to 2 g/hour (12.5–30 mg/kg/hour), infused over varying time periods.

Transfusion requirements

Meta-analyses conducted in the Henry et al (2007) review showed that intravenous ε-aminocaproic acid significantly reduced the incidence of allogeneic transfusion in patients undergoing cardiac surgery (by 35%) but not orthopaedic surgery or liver surgery; however, this may be due to the smaller amount of evidence available for noncardiac surgery.212 In the subgroup of RCTs in which a transfusion protocol was used, ε-aminocaproic acid therapy resulted in a significant decrease in the incidence of transfusion compared with no therapy; there was no significant difference in the one study where no transfusion protocol was used.

Of trials that reported units of allogeneic blood transfused in the overall study population, meta-analysis indicated that ε-aminocaproic acid therapy significantly reduced (by an average of 1.77 units) the volume of allogeneic transfusion compared with no therapy.212 However, there was no significant difference in trials that reported units of allogeneic blood transfused in those patients that received transfusion.

Blood loss

Meta-analysis showed that ε-aminocaproic acid therapy reduced postoperative blood loss compared with no therapy.212 For patients undergoing cardiac surgery or orthopaedic surgery, the reduction in postoperative blood loss was approximately 196 mL and 276 mL, respectively. In the six trials that reported intraoperative blood loss, there was a reduction in blood loss in favour of ε-aminocaproic acid in patients undergoing cardiac surgery but not orthopaedic surgery.212,237,238

Mortality and morbidity

Overall, the effect of ε-aminocaproic acid on mortality and morbidity is uncertain due to a lack of power in the studies reviewed.

EVIDENCE STATEMENTS – ε-aminocaproic acid	Evidence	Consistency	Clinical impact	Generalisability	Applicability
In adult patients undergoing cardiac surgery, intravenous ε-aminocaproic acid therapy reduces the incidence of allogeneic blood transfusion compared with no therapy.
In adult patients undergoing noncardiac surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on the incidence of allogeneic blood transfusion, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on volume of allogeneic blood transfusion, compared with no therapy, is uncertain.
In adult patients undergoing cardiac surgery, intravenous ε-aminocaproic acid therapy reduces blood loss compared with no therapy.
In adult patients undergoing major orthopaedic surgery, intravenous ε-aminocaproic acid therapy may reduce blood loss compared with no therapy.
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on mortality, compared with no therapy, is uncertain.
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on risk of myocardial infarction, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on risk of stroke, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on risk of venous thromboembolism, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on quality of life, compared with no therapy, is unknown.	NA	NA	NA	NA	NA
In adult patients undergoing cardiac surgery, the effect of intravenous ε-aminocaproic acid therapy on risk of reoperation for bleeding, compared with no therapy, is uncertain.
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous ε-aminocaproic acid therapy on length of hospital stay, compared with no therapy, is uncertain.

(See Table 2.2)

RECOMMENDATION – ε-aminocaproic acid

R19 Grade C	In adult patients undergoing cardiac surgery, the use of intravenous ε-aminocaproic acid is recommended (Grade C).

PRACTICE POINT – ε-aminocaproic acid

PP15	There is evidence for the beneficial effect of intravenous ε-aminocaproic acid on reduction of perioperative blood loss and volume of transfusion (Grade C). However, the drug is not marketed in Australia and New Zealand.

Desmopressin

Desmopressin is registered in Australia for use as an antidiuretic; in diabetes insipidus, mild to moderate haemophilia A, von Willebrand disease (excluding type IIB) in pre-dental or minor surgery; and in cases of excessive bleeding associated with platelet disorders. In relation to minimisation of bleeding and transfusion, the product information for desmopressin states that it is indicated for:

The systematic literature search for evidence of the effectiveness and safety of desmopressin was limited to the comparison between desmopressin therapy and no therapy (i.e. no treatment or placebo). Thus, a formal systematic review comparing desmopressin with other agents (e.g. aprotinin, tranexamic acid and ε-aminocaproic acid) was not conducted. The systematic review identified seven Level I studies, of which one fair-quality review provided the pivotal evidence for intravenous desmopressin in an adult perioperative population;239 and two reviews of good quality provided supportive evidence.214,240 A literature search was conducted to identify recent Level II evidence; no additional RCTs were identified.

In the pivotal evidence review, the authors noted that the dose of desmopressin varied slightly across the 42 included RCTs, being mostly a single 0.3 μg/kg dose administered over 15–30 minutes during surgical haemostasis.239 In six studies the dose was repeated, and in eight studies it was administered immediately before surgery.

Transfusion requirements

Meta-analyses conducted in the Crescenzi et al (2008) review showed that desmopressin did not significantly reduce the incidence of transfusion of blood products (including red blood cells, FFP and platelets) for cardiac surgery or noncardiac surgery.239 However, meta-analysis of the subgroup of RCTs that assessed desmopressin therapy in patients undergoing primary coronary artery bypass surgery showed a significant reduction in transfusion incidence (by 15%) compared with no therapy, which was not seen in the subgroup of RCTs that assessed desmopressin therapy in patients undergoing complex cardiac surgery.240 Of the RCTs in patients undergoing cardiac surgery that reported the incidence of transfusion with platelets only, desmopressin therapy did not significantly reduce the incidence of transfusion compared with no therapy.239

Desmopressin therapy significantly reduces the volume of transfusion overall; however, in the subgroup of RCTs that assessed desmopressin in patients undergoing cardiac surgery, the effect was not statistically significant.

Blood loss

Meta-analyses of the volume of blood loss showed a statistically significant reduction overall in patients on desmopressin therapy compared with no therapy. This effect was significant in the subgroup of RCTs that assessed desmopressin in patients undergoing cardiac surgery, but not in patients undergoing noncardiac surgery.239

Mortality and morbidity

Overall, the effect of intravenous desmopressin on mortality and morbidity is uncertain due to underpowering of studies. However, desmopressin use resulted in a large and statistically significantly increased risk of post-administration transient hypotension.239,240 The direction and magnitude of the risks of mortality and stroke suggest that desmopressin may be associated with an increased risk for these outcomes.239,240 Although the results of the meta-analyses did not reach statistical significance, this may have been due to a lack of statistical power rather than a lack of risk associated with desmopressin therapy.

EVIDENCE STATEMENTS – desmopressin	Evidence	Consistency	Clinical impact	Generalisability	Applicability
In adult patients undergoing primary coronary artery bypass surgery, intravenous desmopressin therapy reduces the incidence of allogeneic blood transfusion compared with no therapy.			X
In adult patients undergoing complex cardiac surgery, intravenous desmopressin therapy does not reduce the incidence of allogeneic blood transfusion compared with no therapy.			X
In adult patients undergoing cardiac surgery, intravenous desmopressin therapy may reduce the incidence of platelet transfusion compared with no therapy.			X
In adult patients undergoing noncardiac surgery in which substantial blood loss is anticipated, intravenous desmopressin therapy does not appear to reduce the incidence of allogeneic blood transfusion compared with no therapy.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous desmopressin therapy may reduce the volume of transfusion compared with no therapy.
In adult patients undergoing cardiac surgery, intravenous desmopressin therapy reduces blood loss compared with no therapy.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous desmopressin therapy on mortality, compared with no therapy, is uncertain.
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous desmopressin therapy on risk of myocardial infarction, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous desmopressin therapy on risk of stroke, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous desmopressin therapy on risk of thrombosis, compared with no therapy, is uncertain.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, intravenous desmopressin therapy increases the risk of mild and transient hypotension compared with no therapy.			X
In adult patients undergoing surgery in which substantial blood loss is anticipated, the effect of intravenous desmopressin therapy on quality of life, compared with no therapy, is unknown.	NA	NA	NA	NA	NA
In adult patients undergoing cardiac surgery, the effect of intravenous desmopressin therapy on risk of reoperation for bleeding, compared with no therapy, is uncertain.

(See Table 2.2)

PRACTICE POINT – desmopressin

PP16	In adult patients undergoing surgery in which substantial blood loss (blood loss of a volume great enough to induce anaemia that would require therapy) is anticipated, the routine use of desmopressin is not supported, due to uncertainty about the risk of stroke and mortality.