[Table, Recommendations and link to evidence]. - Blood Transfusion

Recommendations	8. Do not routinely use cell salvage without tranexamic acid.
Relative values of different outcomes	The GDG agreed that the number of patients transfused, number of units transfused and mortality were critical outcomes for decision making. Other outcomes which were considered to be important in the decision making process were length of stay in hospital, quality of life and adverse events (infection, thrombotic complications).
Trade off between clinical benefits and harms	There was evidence of effectiveness for some of the critical outcomes for the use of ICS alone in the high and moderate risk groups in adult surgical patients. Although there was some evidence of clinical effectiveness of ICS and PCS alone and in combination with one another in comparison with standard treatment from the pairwise meta-analysis with respect to number of patients transfused and number of units of allogeneic blood transfused, TXA was more effective than cell salvage in the moderate risk group and the combination of ICS and TXA was more effective than cell salvage in the high risk group when reviewed in the network meta-analysis. Although the results of the network meta-analyses showed that PCS was ranked as the best treatment for number of patients transfused and length of stay, and ranked above TXA for number of units transfused in the high risk group, the GDG highlighted that PCS may have limited use, for example, when blood is lost in chest drains in cardiac surgical patients, which is in a minority of cases. They acknowledged that in current practice it may not be considered an appropriate intervention for all high risk surgeries on its own, particularly in patients who have extensive bleeding post-operatively and therefore may require reoperation to stem the bleeding (rather than PCS). The GDG noted that this was unlike ICS, which could be used across all high risk surgeries. The GDG noted that further research was therefore required in this specific group to establish the effectiveness of PCS in high risk surgeries and made a recommendation for further research in this area (see section 6.6.1). No evidence was identified for the comparison of ICS or PCS alone with standard treatment in children. There was very low quality evidence which suggested that the combination of ICS with TXA may result in fewer patients transfused and a lesser volume of total blood transfused in comparison with the use of ICS alone. All evidence was from studies in children who were at high risk of blood loss. No evidence was identified for children who were at moderate or low risk of blood loss. Based on this, and the new economic model, the GDG decided to not recommend the routine use of cell salvage alone in both adults and children. The combination of cell salvage with TXA was more likely to be cost-effective than cell salvage alone and was recommended by the GDG (see recommendation 9 below). However, it is acknowledged there are paediatric patient groups, such as some paediatric cardiac surgery patients, in whom cell salvage may be used and TXA may be considered inappropriate (please see ‘Other considerations’).
Economic considerations	No economic evaluations were identified comparing all relevant interventions, that is TXA or cell salvage, alone or in combination. Two economic evaluations comparing ICS+PCS with no cell savage in cardiac and or orthopaedic surgical adult patients were identified. The first was a cost-utility analysis by Davies 2006⁷⁸ which found that cell salvage (ICS or PCS) was dominant compared to no cell salvage. This analysis was assessed as partially applicable with minor limitations. The second by Klein 2008¹⁶⁹ was a cost-consequence analysis based on a single RCT which found that ICS+PCS was more costly and more effective at reducing the number of units transfused than no cell salvage. This analysis was assessed as partially applicable with potentially serious limitations. Finally a cost-utility analysis by Samnaliev 2013²⁶⁶ comparing ICS with no cell salvage in orthopaedic and cardiac surgical paediatric patient found that ICS was dominant compared to no cell salvage. This analysis was assessed as partially applicable with potentially serious limitations. Note, the effectiveness data used in the analysis was from a non-randomised trial and therefore not reported in the clinical evidence. No economic evaluations were identified for the use of PCS alone in paediatric surgical patients. The evidence from the new economic model conducted indicated that PCS alone in the high and moderate risk of bleeding subgroups was not a cost-effective option in adult surgical patients. PCS was the most cost saving intervention in the high risk group; this was due primarily to the large reduction in hospital length of stay. When the mortality effect of TXA was removed, PCS had the highest QALYs which were attributable to the reduced length of stay. Furthermore, when the QALY difference between PCS and TXA was reduced, as seen insensitivity analyses where mortality and quality of life were adjusted to reflect MI and stroke populations, the length of stay savings were a key driver in establishing the most cost-effective option. The length of stay data for this comparator was based on one RCT with a high baseline length of stay. The GDG had concerns about the applicability of this evidence and therefore sensitivity analyses adjusting for this length of stay and excluding length of stay were undertaken. These resulted in TXA remaining the most cost-effective option. In the high risk group, ICS alone was also not a cost-effective intervention for reducing allogeneic transfusions in adult surgical patients. In the moderate risk group, there were no data identified in the clinical review for ICS in relation to the volume of allogeneic blood transfused. As a result, we were unable to include ICS alone in the analysis without making assumptions for this outcome. We were unable to establish from our analysis whether or not using ICS alone in this group would be a cost-effective intervention. The GDG felt that the new economic analysis conducted for this guideline superseded the published studies which were based on older clinical evidence⁷⁸ and in the case of two analyses¹⁶⁹^,²⁶⁶ on single trials and do not include all relevant treatment options. Furthermore for the two studies that found that cell salvage was dominant to usual care, the cost of cell salvage used in their analyses was less than the cost used in our analysis⁷⁸^,²⁶⁶ and were not considered by the GDG to be reflective of the current NHS context. The GDG extrapolated the findings of the new economic model in adults to children. However, as noted above in the trade-off between clinical benefits and harms, special consideration should be given for some paediatric patient groups (please see other considerations).
Quality of evidence	This recommendation was based on low to very low quality evidence from the pair wise meta-analysis and the network meta-analysis and the results of our economic model.
Other considerations	The GDG discussed the advantages of using cell salvage. One particular advantage highlighted was that, with the use of cell salvage, allogeneic blood transfusion can be avoided, minimising all complications of transfusion including red cell alloimmunisation, that is, developing red cell antibodies causing difficulties in identifying compatible blood for future transfusions if needed. Although the GDG recommended against routinely offering cell salvage alone in adults and children, it was noted that special consideration should be given for its use in paediatric cardiac surgery patients. The GDG acknowledged that cell salvage is widely used during paediatric cardiac surgery to reduce exposure to allogeneic blood whereas TXA may not always be used in the same clinical situations due to uncertainty about the optimal dose and possible side effects.

Recommendations

8.: Do not routinely use cell salvage without tranexamic acid.

Relative values of different outcomes

The GDG agreed that the number of patients transfused, number of units transfused and mortality were critical outcomes for decision making. Other outcomes which were considered to be important in the decision making process were length of stay in hospital, quality of life and adverse events (infection, thrombotic complications).

Trade off between clinical benefits and harms

There was evidence of effectiveness for some of the critical outcomes for the use of ICS alone in the high and moderate risk groups in adult surgical patients. Although there was some evidence of clinical effectiveness of ICS and PCS alone and in combination with one another in comparison with standard treatment from the pairwise meta-analysis with respect to number of patients transfused and number of units of allogeneic blood transfused, TXA was more effective than cell salvage in the moderate risk group and the combination of ICS and TXA was more effective than cell salvage in the high risk group when reviewed in the network meta-analysis.

Although the results of the network meta-analyses showed that PCS was ranked as the best treatment for number of patients transfused and length of stay, and ranked above TXA for number of units transfused in the high risk group, the GDG highlighted that PCS may have limited use, for example, when blood is lost in chest drains in cardiac surgical patients, which is in a minority of cases. They acknowledged that in current practice it may not be considered an appropriate intervention for all high risk surgeries on its own, particularly in patients who have extensive bleeding post-operatively and therefore may require reoperation to stem the bleeding (rather than PCS). The GDG noted that this was unlike ICS, which could be used across all high risk surgeries. The GDG noted that further research was therefore required in this specific group to establish the effectiveness of PCS in high risk surgeries and made a recommendation for further research in this area (see section 6.6.1).

No evidence was identified for the comparison of ICS or PCS alone with standard treatment in children. There was very low quality evidence which suggested that the combination of ICS with TXA may result in fewer patients transfused and a lesser volume of total blood transfused in comparison with the use of ICS alone. All evidence was from studies in children who were at high risk of blood loss. No evidence was identified for children who were at moderate or low risk of blood loss.

Based on this, and the new economic model, the GDG decided to not recommend the routine use of cell salvage alone in both adults and children. The combination of cell salvage with TXA was more likely to be cost-effective than cell salvage alone and was recommended by the GDG (see recommendation 9 below). However, it is acknowledged there are paediatric patient groups, such as some paediatric cardiac surgery patients, in whom cell salvage may be used and TXA may be considered inappropriate (please see ‘Other considerations’).

Economic considerations

No economic evaluations were identified comparing all relevant interventions, that is TXA or cell salvage, alone or in combination. Two economic evaluations comparing ICS+PCS with no cell savage in cardiac and or orthopaedic surgical adult patients were identified. The first was a cost-utility analysis by Davies 2006⁷⁸ which found that cell salvage (ICS or PCS) was dominant compared to no cell salvage. This analysis was assessed as partially applicable with minor limitations. The second by Klein 2008¹⁶⁹ was a cost-consequence analysis based on a single RCT which found that ICS+PCS was more costly and more effective at reducing the number of units transfused than no cell salvage. This analysis was assessed as partially applicable with potentially serious limitations.

Finally a cost-utility analysis by Samnaliev 2013²⁶⁶ comparing ICS with no cell salvage in orthopaedic and cardiac surgical paediatric patient found that ICS was dominant compared to no cell salvage. This analysis was assessed as partially applicable with potentially serious limitations. Note, the effectiveness data used in the analysis was from a non-randomised trial and therefore not reported in the clinical evidence. No economic evaluations were identified for the use of PCS alone in paediatric surgical patients.

The evidence from the new economic model conducted indicated that PCS alone in the high and moderate risk of bleeding subgroups was not a cost-effective option in adult surgical patients. PCS was the most cost saving intervention in the high risk group; this was due primarily to the large reduction in hospital length of stay. When the mortality effect of TXA was removed, PCS had the highest QALYs which were attributable to the reduced length of stay. Furthermore, when the QALY difference between PCS and TXA was reduced, as seen insensitivity analyses where mortality and quality of life were adjusted to reflect MI and stroke populations, the length of stay savings were a key driver in establishing the most cost-effective option. The length of stay data for this comparator was based on one RCT with a high baseline length of stay. The GDG had concerns about the applicability of this evidence and therefore sensitivity analyses adjusting for this length of stay and excluding length of stay were undertaken. These resulted in TXA remaining the most cost-effective option.

In the high risk group, ICS alone was also not a cost-effective intervention for reducing allogeneic transfusions in adult surgical patients. In the moderate risk group, there were no data identified in the clinical review for ICS in relation to the volume of allogeneic blood transfused. As a result, we were unable to include ICS alone in the analysis without making assumptions for this outcome. We were unable to establish from our analysis whether or not using ICS alone in this group would be a cost-effective intervention.

The GDG felt that the new economic analysis conducted for this guideline superseded the published studies which were based on older clinical evidence⁷⁸ and in the case of two analyses¹⁶⁹^,²⁶⁶ on single trials and do not include all relevant treatment options. Furthermore for the two studies that found that cell salvage was dominant to usual care, the cost of cell salvage used in their analyses was less than the cost used in our analysis⁷⁸^,²⁶⁶ and were not considered by the GDG to be reflective of the current NHS context.

The GDG extrapolated the findings of the new economic model in adults to children. However, as noted above in the trade-off between clinical benefits and harms, special consideration should be given for some paediatric patient groups (please see other considerations).

Quality of evidence

This recommendation was based on low to very low quality evidence from the pair wise meta-analysis and the network meta-analysis and the results of our economic model.

Other considerations

The GDG discussed the advantages of using cell salvage. One particular advantage highlighted was that, with the use of cell salvage, allogeneic blood transfusion can be avoided, minimising all complications of transfusion including red cell alloimmunisation, that is, developing red cell antibodies causing difficulties in identifying compatible blood for future transfusions if needed.

Although the GDG recommended against routinely offering cell salvage alone in adults and children, it was noted that special consideration should be given for its use in paediatric cardiac surgery patients. The GDG acknowledged that cell salvage is widely used during paediatric cardiac surgery to reduce exposure to allogeneic blood whereas TXA may not always be used in the same clinical situations due to uncertainty about the optimal dose and possible side effects.

From: 6, Alternatives to blood transfusion for patients having surgery: Cell salvage and tranexamic acid

Blood Transfusion.

NICE Guideline, No. 24.

National Clinical Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2015 Nov.

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