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National Clinical Guideline Centre (UK). Blood Transfusion. London: National Institute for Health and Care Excellence (NICE); 2015 Nov. (NICE Guideline, No. 24.)
Fresh frozen plasma (FFP) is either produced from whole blood or obtained by apheresis and rapidly frozen after production to maintain the activity of labile coagulation factors. FFP can be stored at minus 25°C or below for up to 36 months with rapid thawing at 37°C when needed. After thawing, FFP should be transfused as soon as possible but if delay is unavoidable, it can be stored for up to 4 hours at 22±2°C or 24 hours if stored at 4±2°C. In the UK, FFP is sourced, as far as possible, from male donors in order to minimize the risk of passive transfer of donor white cell antibodies that can cause transfusion-related acute lung injury (TRALI).
In the UK, FFP for use in patients born on or after 01/01/1996 is sourced from countries with a low risk of vCJD and is pathogen inactivated, either single donor methylene blue treated (provided by NHSBT) or pooled solvent detergent treated (commercially available ‘Octaplas’).
Audits show that a large proportion of the FFP used in the UK is possibly inappropriate, exposing patients to unnecessary risks.
14.1. Review question: What is the clinical- and cost-effectiveness of transfusions of fresh frozen plasma (FFP) to treat and prevent bleeding?
For full details see review protocol in Appendix C.
Table 111PICO characteristics of review questions
| Population |
|
|---|---|
| Intervention(s) |
|
| Comparison(s) |
|
| Outcomes | Critical outcomes:
|
| Study design |
|
14.2. Review question: What is the clinical- and cost-effectiveness of different target levels of post-transfusion haemostasis tests with the use of fresh frozen plasma (FFP) for prophylactic transfusions?
For full details see review protocol in Appendix C.
Table 112PICO characteristics of review question
| Population |
|
|---|---|
| Intervention(s) | FFP transfusion to achieve the following target INR levels will be compared to one another:
|
| Comparison(s) |
|
| Outcomes | Critical outcomes:
|
| Study design |
|
14.3. Clinical evidence
We have combined the questions for FFP thresholds and FFP targets in one review. We searched for systematic reviews, randomised controlled trials and observational studies addressing the two clinical questions: effectiveness of transfusions of FFP to treat and prevent bleeding and effectiveness of different target levels of post-transfusion haemostasis tests with the use of FFP for prophylactic transfusions.
Four studies, three RCTs193,226,305 comparing FFP with no FFP and one multicentre prospective cohort study (2 papers) comparing different INR ranges were included in the review.291,321 This review includes 3 comparisons: Therapeutic FFP vs. No FFP (Noddeland 2002); Prophylactic FFP vs. No FFP (Matsumoto 2007, Trimble 2007); FFP transfusion at different INR ranges (Walsh 2010).
One Cochrane review 152 was included in the review; this review aimed to determine whether the use of a restrictive versus a liberal plasma transfusion threshold affected mortality or morbidity in critically ill patients, and also to assess the clinical effects of different plasma transfusion thresholds in critically ill patients. However, no RCTs were identified or included in the Cochrane review that evaluated plasma transfusion strategies according to predetermined coagulation test thresholds.
One large cohort study91 comparing therapeutic FFP transfusion with no FFP transfusion was considered for inclusion. The study aimed to assess the relationship between therapeutic transfusion of FFP and 30 day mortality in cardiac surgery patients suffering from excessive bleeding.
These are summarised in Table 113 below.
Table 113
Summary of studies included in the review.
The table includes references Octaplas and Uniplas which are specific preparations of FFP.
The data for the review could not be pooled due to variation in the study designs, populations groups and comparisons across the studies. The results have been presented per study, but quality assessment was done per outcome as in GRADE applying the criteria of assessment of risk of bias, indirectness and imprecision. Evidence from the included studies is summarised in the modified GRADE clinical evidence profile below (Table 114). The data for some of the outcomes was not reported in an analysable format, for example, no confidence intervals were reported for the change in INR. However, the GDG felt that it was useful to still present the raw data and a modified GRADE approach was undertaken to assess the quality of the evidence in the absence of being able to assess imprecision. See also the study selection flow chart in Appendix E, study evidence tables in Appendix H, forest plots in Appendix K, and excluded studies list in Appendix P.
Table 114
Modified GRADE profile: FFP transfusion versus No FFP transfusion.
Table 115
Modified GRADE profile: Therapeutic FFP transfusion versus No FFP transfusion (cohort study).
14.4. Economic evidence
Published literature
No relevant economic evaluations were identified.
One economic evaluation relating to the FFP threshold review question was identified but was excluded due to a combination of limited applicability and methodological limitations.269 This is summarised in Appendix Q, with reasons for exclusion given.
See also the economic article selection flow chart in Appendix F.
Unit costs
Relevant unit costs are provided in Appendix N to aid consideration of cost-effectiveness.
14.5. Evidence statements
Clinical
Prophylactic FFP transfusion versus No prophylactic FFP transfusion
One RCT compared prophylactic FFP transfusion with no prophylactic FFP transfusion. The evidence showed that chest drainage at first 24 hours (cc) in adults and children was found to be lower in the prophylactic FFP group compared with no prophylactic FFP, but there was some uncertainty
The evidence ranged from moderate to very low quality.
No evidence was identified for the critical outcomes such as all-cause mortality at 30 days, infections, quality of life and serious adverse events, and important outcomes such as number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital.
Therapeutic FFP transfusion versus No therapeutic FFP transfusion
One RCT and one cohort study compared therapeutic FFP versus no therapeutic FFP. The evidence suggested that fewer numbers of units (RBC) transfused in patients receiving therapeutic FFP transfusion. The evidence showed that blood loss was higher in patients receiving therapeutic FFP transfusion compared with no therapeutic FFP transfusion, but there was considerable uncertainty
There was no important difference in effects between the groups for the following outcomes number of patients needing RBC transfusion, activated partial thromboplastin time (APTT) (seconds) (before and after surgery) and activated clotting time (ACTT) (seconds) (before and after surgery).
The evidence ranged from moderate to very low quality.
No evidence was identified for the critical outcomes such as all-cause mortality at 30 days, bleeding, infections, quality of life and serious adverse events; and important outcomes such as length of stay in hospital.
FFP transfusion at different INR ranges- Admissions with INR greater than 1.5 versus admissions with normal INR test
One cohort study compared FFP transfusion for patients with admissions with INR greater than 1.5 versus patients with admissions with normal INR test. The evidence showed that mortality (all-cause at 30 days) and length of hospital stay was higher in patients with admissions with INR greater than 1.5; this difference was considered to be clinically important. The evidence showed that the median reductions in INR were greater when the pre- FFP transfusion values were higher (median change -0.1, -0.4, -1.0 and -2.5 for pre-transfusion INRs in the ranges 1 to less than 1.5, 1.6 to 2.5, 2.6 to 3.5 and more than 3.5, respectively); this difference was considered to be clinically important.
The evidence was of very low quality.
No evidence was identified for the critical outcomes such bleeding, infection, quality of life and serious adverse events , and important outcomes such as number of patients needing RBC transfusions and the number of units of RBC transfused.
Economic
No relevant economic evaluations were identified.
14.6. Recommendations and link to evidence
| Recommendations |
|
|---|---|
| Relative values of different outcomes | The GDG considered all-cause mortality at 30 days, bleeding (occurrence of bleeding in non-bleeding patients and cessation of bleeding in bleeding patients; bleeding defined as WHO grade 2 and above), infections (including pneumonia, surgical site infection, UTI and septicaemia/bacteraemia), quality of life and serious adverse events as the critical outcomes for decision making. Other important outcomes included the number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital. |
| Trade off between clinical benefits and harms | There was evidence from one RCT comparing therapeutic FFP transfusion with no FFP transfusion, which showed that there were fewer units of RBC transfused in the group with no FFP transfusion when compared with the groups receiving FFP transfusion. The evidence also suggested that blood loss was higher in patients receiving therapeutic FFP transfusion compared with no therapeutic FFP transfusion; but there was considerable uncertainty. There was no evidence of difference in effect between the groups receiving FFP transfusion and no FFP transfusion for important outcomes such as activated clotting time (ACT), activated partial thromboplastin time (APTT) and number of patients needing RBC transfusion. There was also evidence from one of two large multicentre prospective cohort studies (Walsh 2010, Stanworth 2011, Doussau 2014). 321, 291, 91 The study, Walsh 2010, compared the effect of FFP transfusion at different INR ranges and the independent association of mortality with INR levels. The study reported lower mortality at 30 days in patients who were admitted to the hospital with INR less than 1.5 as compared with patients who were admitted with INR greater than 1.5. The median reductions in INR were greater when the pre-FFP transfusion INR values were higher. There was no evidence of difference in effects between the patients admitted with INR greater than 1.5 and INR less than 1.5 for length of hospital stay. The study, Doussau 2014, compared therapeutic FFP transfusion with no FFP transfusion to assess 30 day mortality in cardiac surgery patients suffering from excessive bleeding. The study showed that there was higher mortality and adverse events in the group receiving therapeutic FFP transfusion compared to the group receiving no FFP transfusion. However, the study reported a number of other factors which were found to be significantly associated with 30 day mortality in the univariate analysis. After fitting a model adjusted for all potential confounders, no association was found between FFP transfusion and 30 day mortality. There was no evidence available for the outcomes quality of life, infections, serious adverse events and adverse events related to the transfusion and length of hospital stay. The GDG recommended that FFP should be considered for situations where a patient has clinically significant bleeding and abnormal coagulation test results. In this case, the benefits of potentially reducing bleeding are likely to outweigh the risks of serious adverse events. Major haemorrhage is outside the scope of this guideline. There was no specific evidence available for the use of FFP in the paediatric population. The GDG agreed that the same recommendations should apply for children as for adults. |
| Economic considerations | No relevant economic evaluations comparing different thresholds or targets for FFP transfusion were identified. The costs of FFP and Octaplas® transfusion were considered by the GDG. Clinical FFP (UK sourced) costs £28 per unit in England and North Wales and Octaplas® costs £53 per 200 ml bag. For patients born on or after 1st January 1996 FFP is sourced from countries with a low risk of vCJD. Either Octaplas® or methylene blue FFP (MBFFP), both pathogen inactivated, are used for these recipients. The cost of MBFFP (non-UK sourced) is £177 per unit in England and North Wales.219 It was noted that these costs do not include all costs associated with a transfusion such as staff time, disposables, storage, wastage and laboratory tests. As part of the health economic model developed in this guideline, the additional cost associated with transfusion was estimated to be £70 per first unit transfused. Of note this estimate does not include costs associated with hospital stay or with the management of transfusion-related complications. Furthermore, these costs do not include consideration of the additional laboratory and clinical workload of taking or testing additional samples. For bleeding patients with abnormal coagulation tests the GDG considered that the cost of transfusing FFP was likely to be offset by avoiding the negative costly outcomes that could result from not transfusing these patients. The negative outcomes potentially include further bleeding leading to lengthier and more complex (and more costly) hospitalisation (for example, ICU) and mortality. The GDG agreed that the same recommendations should apply for children as for adults. |
| Quality of evidence | The quality of evidence from 1 RCT was very low due to the indirectness of the interventions/population, risk of bias arising from a lack of allocation concealment and inadequate blinding. The quality of evidence from the two cohort studies was very low due to the indirectness of the population, and to the risk of bias arising from selection bias related to the design of the observational study. There was no specific evidence available for children. The recommendation was based on the indirect evidence and consensus opinion of the GDG members. |
| Other considerations | The recommendations apply to adults and children requiring FFP transfusions. The GDG noted that the cause of an abnormal coagulation screen should be investigated. The GDG noted that the recommendation may not be applicable to patients with major haemorrhage. For such patients please refer to other appropriate guidance (for example, follow the recommendations in NICE's guideline on Major trauma, currently in development). |
| Recommendations |
|
|---|---|
| Relative values of different outcomes | The GDG considered all-cause mortality at 30 days, bleeding (occurrence of bleeding in non-bleeding patients and cessation of bleeding in bleeding patients; bleeding defined as WHO grade 2 and above), infections (including pneumonia, surgical site infection, UTI and septicaemia/bacteraemia), quality of life and serious adverse events as the critical outcomes for decision making. Other important outcomes included the number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital. |
| Trade off between clinical benefits and harms | No evidence was identified on the effectiveness of FFP transfusions in non-bleeding patients. In patients who have abnormal coagulation test results but are not bleeding and are not having invasive procedures or surgery with a risk of clinically significant bleeding, the GDG considered a more cautious approach and recommended not offering FFP transfusion as there is no evidence of benefit and a risk of complications associated with transfusion, for example, transfusion associated circulatory overload (TACO). There was no specific evidence available for the indications for prophylactic FFP transfusion in the paediatric population. Accordingly, the GDG agreed that the same recommendations should apply for children as for adults in this clinical situation. . |
| Economic considerations | No relevant economic evaluations comparing different thresholds or targets for FFP transfusion were identified. The costs of FFP and Octaplas® transfusion were considered by the GDG. Clinical FFP (UK sourced) costs £28 per unit in England and North Wales and Octaplas® costs £53 per 200 ml bag. For patients born on or after 1st January 1996 FFP is sourced from countries with a low risk of vCJD. Either Octaplas® or methylene blue FFP (MBFFP), both pathogen inactivated, are used for these recipients. The cost of MBFFP (non-UK sourced) is £177 per unit in England and North Wales.219 It was noted that these costs do not include all costs associated with a transfusion such as staff time, disposables, storage, wastage and laboratory tests. As part of the health economic model developed in this guideline, the additional cost associated with transfusion was estimated to be £70 per first unit transfused. Of note this estimate does not include costs associated with hospital stay or with the management of transfusion-related complications. Furthermore, these costs do not include consideration of the additional laboratory and clinical workload of taking or testing additional samples. The GDG considered that the lack of clinical effectiveness and the potential infectious and immunological risks from receiving a transfusion did not justify the additional cost of transfusing fresh frozen plasma in these populations. There was no specific evidence available for the use of prophylactic FFP transfusion in the paediatric population. The GDG agreed that the same recommendations should apply for children as for adults. |
| Quality of evidence | No evidence was identified for the use of FFP for prophylactic transfusions in adults. The recommendations were based on the consensus expert opinion of the GDG members. There was no specific evidence available for children. |
| Other considerations | The recommendation applies to adults and children requiring FFP transfusions. The GDG noted that the cause of an abnormal coagulation screen should be investigated. In patients who require reversal of a vitamin K antagonist, the GDG noted that fresh frozen plasma should not be given. Such patients have reduced levels of factors II, VII, IX and X and correction involves rapid replacement of these factors which is most effectively achieved by the administration of prothrombin complex concentrate (PCC) rather than with FFP. FFP provides a dilute form of the clotting factors and therefore a large volume of plasma needs to be infused rapidly which is impractical. The GDG also noted the BCSH guidelines on oral anticoagulation which state that fresh frozen plasma produces suboptimal anticoagulation reversal and should only be used if prothrombin complex concentrate is not available.161 |
| Recommendations |
|
|---|---|
| Relative values of different outcomes | The GDG considered all-cause mortality at 30 days, bleeding (occurrence of bleeding in non-bleeding patients and cessation of bleeding in bleeding patients; bleeding defined as WHO grade 2 and above), infections (including pneumonia, surgical site infection, UTI and septicaemia/bacteraemia), quality of life and serious adverse events as the critical outcomes for decision making. Other important outcomes included the number of patients needing RBC transfusions, the number of units of RBC transfused, correction of abnormal coagulation tests and length of stay in hospital. |
| Trade off between clinical benefits and harms | There was evidence from two RCTs in adults comparing prophylactic FFP transfusion with no FFP transfusion. There was no evidence of a difference in effect between the groups receiving prophylactic FFP transfusion and no FFP transfusion for critical outcomes such as bleeding. There was no evidence available from the studies for the following outcomes: mortality, quality of life, infections, serious adverse events and adverse events related to the transfusion, length of hospital stay and abnormal coagulation tests. The GDG drew on its knowledge and experience to make this recommendation based on the consensus expert opinion of its members. It agreed that prophylactic FFP transfusion should be considered for patients having surgery or invasive procedures with a risk of clinically significant bleeding and abnormal coagulation test results. However, given the lack of evidence of benefit and the potential risks of transfusion, prophylactic FFP should be reserved for patients at high risk of clinically significant bleeding (including bleeding at critical sites). There was no specific evidence available for the indications for prophylactic FFP transfusion in the paediatric population. The GDG agreed that the same recommendations should apply for children as for adults in the absence of evidence that children with abnormal coagulation tests having invasive procedures or surgery at risk of bleeding should be treated differently with FFP compared to adults. |
| Economic considerations | No relevant economic evaluations comparing different thresholds or targets for FFP transfusion were identified. The costs of FFP and Octaplas® transfusion were considered by the GDG. Clinical FFP (UK sourced) costs £28 per unit in England and North Wales and Octaplas® costs £53 per 200 ml bag. For patients born on or after 1st January 1996 FFP is sourced from countries with a low risk of vCJD. Either Octaplas® or methylene blue FFP (MBFFP), both pathogen inactivated, are used for these recipients. The cost of MBFFP (non-UK sourced) is £177 per unit in England and North Wales.219 It was noted that these costs do not include all costs associated with a transfusion such as staff time, disposables, storage, wastage and laboratory tests. As part of the health economic model developed in this guideline, the additional cost associated with transfusion was estimated to be £70 per first unit transfused. Of note this estimate does not include costs associated with hospital stay or with the management of transfusion-related complications. Furthermore, these costs do not include consideration of the additional laboratory and clinical workload of taking or testing additional samples. For patients having surgery or invasive procedures with a risk of clinically significant bleeding and where there are abnormal coagulation test results, the GDG considered that the cost of transfusing FFP was likely to be offset by avoiding the negative costly outcomes that would result from not transfusing these patients. The negative outcomes potentially include bleeding leading to lengthier and more complex (and more costly) hospitalisation (for example, ICU) and mortality. There was no specific evidence available for the use of prophylactic FFP transfusion in the paediatric population. The GDG agreed that the same recommendations should apply for children as for adults. |
| Quality of evidence | The quality of evidence was very low due to the indirectness of the interventions/population, the risk of bias arising from a lack of allocation concealment and inadequate blinding. The recommendations were based on indirect evidence and the consensus expert opinion of the GDG members. There was no specific evidence available for children. |
| Other considerations | The GDG noted that the risk of bleeding depends on the patient's clinical condition and that of the procedure itself. Surgeons may also attribute a particular level of bleeding risk to certain procedures based on their experience and expertise. The GDG noted that the cause of an abnormal coagulation screen should be investigated. The recommendations apply to adults and children requiring FFP transfusions. |
- Review question: What is the clinical- and cost-effectiveness of transfusions of fresh frozen plasma (FFP) to treat and prevent bleeding?
- Review question: What is the clinical- and cost-effectiveness of different target levels of post-transfusion haemostasis tests with the use of fresh frozen plasma (FFP) for prophylactic transfusions?
- Clinical evidence
- Economic evidence
- Evidence statements
- Recommendations and link to evidence
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