Key messages
• We do not yet know the best medicines to reduce bleeding and blood transfusions during surgery for trauma of the pelvis, hip, or long bones (thigh-bones).
• Some studies are still underway; when they have completed we will hopefully be able to make better conclusions.
Background
Fractures of the pelvis, hips and long bones can result in significant bleeding, with further blood loss if surgery is required to fix the fracture. A long bone is a bone that has a shaft and two ends, and is longer than it is wide. This includes bones of the upper and lower leg, arms, and collarbone. Fractures and subsequent surgery bring a risk of blood transfusion and anaemia. Anaemia is when the number of red blood cells or the haemoglobin concentration within them is lower than normal. Haemoglobin carries oxygen round the body - low haemoglobin levels cause symptoms such as fatigue, weakness, dizziness and shortness of breath.
Why is it important to reduce blood transfusions during vascular surgery?
If people bleed a lot during or after this type of surgery they may need blood transfusions to replace the blood they have lost. It is better to avoid receiving a blood transfusion, if possible, because blood transfusions can cause harm. This is especially important when health services have limited blood supplies. Medicines may reduce the need for a blood transfusion and its associated complications, improve patient outcomes, and decrease healthcare costs. Examples of such medicines are tranexamic acid and recombinant factor VIIa. However, they may cause unwanted effects, such as blood clots.
What did we want to find out?
We wanted to discover if there are any medicines that help to reduce blood loss during surgery to fix fractures in the pelvis, hip, or long bones in adults. We also wanted to find out which of the effective medicines was the most effective. Reducing blood loss reduces the risk of anaemia and requiring a blood transfusion. It can also reduce the risk of requiring another operation to stop the bleeding or to remove a large collection of blood (haematoma) due to previous bleeding.
What did we do?
We searched for studies that investigated using medicines to prevent blood loss in this kind of surgery.
What did we find?
We found 13 studies with 929 people, published between 2005 and 2022. Most studies assessed the effectiveness and safety of tranexamic acid, whether used intravenously (injected into a vein), locally (topically - directly onto the site of the injury), or a combination of the two. Only one study looked at recombinant factor VIIa. Both medicines help the blood to clot.
Main results
Intravenous tranexamic acid
Intravenous tranexamic acid may reduce the need for blood transfusion slightly, and it may result in little to no difference in the risk of death from any cause and the number of people who experience a heart attack, or stroke.
We are uncertain if intravenous tranexamic acid has any impact on the risk of blood clots that form in the veins of the leg (deep vein thrombosis (DVT)), or lungs (pulmonary embolism), or suspected serious reactions to the medicine. There was no evidence to show whether it affected the need for reoperation due to bleeding, or the number of people who had an immediate reaction to blood transfusion.
Topical tranexamic acid
We are uncertain if topical tranexamic acid affects the need for blood transfusion, deaths from any cause, or the number of people who experience a heart attack, stroke, or DVT. There was no evidence to show whether it affected the need for reoperation for bleeding, or the number of people with pulmonary embolism, severe reactions to blood transfusion, or suspected serious reactions to the medicine.
Recombinant factor VIIa
We are uncertain if recombinant factor VIIa has any impact on the need for blood transfusion, the need for reoperation for bleeding, the risk of DVT, pulmonary embolism, or suspected serious reaction to the medicine. There was no evidence to assess whether it impacted deaths from any cause, the risk of heart attack, stroke, or immediate reaction to the medicine.
What are the limitations of the evidence?
We have little confidence in the evidence for some outcomes, and are not confident about the evidence for others. This is because it is possible that people in the studies were aware of which treatment they were getting, also, the studies were small, and did not all provide data about everything in which we were interested.
Ongoing studies and future updates
Twenty-seven studies with a planned total of 4177 participants are currently ongoing. These should be completed and published within the next few years. Once they publish their data, we can update our analyses and probably provide stronger answers than we can now.
How up to date is this evidence
The evidence is current to 7 April 2022.
We cannot draw conclusions from the current evidence due to lack of data. Most published studies included in our analyses assessed the use of tranexamic acid (compared to placebo, or using different routes of administration).
We identified 27 prospectively registered ongoing RCTs (total target recruitment of 4177 participants by end of 2023). The ongoing trials create six new comparisons: tranexamic acid (tablet + injection) versus placebo; intravenous tranexamic acid versus oral tranexamic acid; topical tranexamic acid versus oral tranexamic acid; different intravenous tranexamic acid dosing regimes; topical tranexamic acid versus topical fibrin glue; and fibrinogen (injection) versus placebo.
Pelvic, hip, and long bone fractures can result in significant bleeding at the time of injury, with further blood loss if they are treated with surgical fixation. People undergoing surgery are therefore at risk of requiring a blood transfusion and may be at risk of peri-operative anaemia. Pharmacological interventions for blood conservation may reduce the risk of requiring an allogeneic blood transfusion and associated complications.
To assess the effectiveness of different pharmacological interventions for reducing blood loss in definitive surgical fixation of the hip, pelvic, and long bones.
We used a predefined search strategy to search CENTRAL, MEDLINE, PubMed, Embase, CINAHL, Transfusion Evidence Library, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) from inception to 7 April 2022, without restrictions on language, year, or publication status.
We handsearched reference lists of included trials to identify further relevant trials. We contacted authors of ongoing trials to acquire any unpublished data.
We included randomised controlled trials (RCTs) of people who underwent trauma (non-elective) surgery for definitive fixation of hip, pelvic, and long bone (pelvis, tibia, femur, humerus, radius, ulna and clavicle) fractures only. There were no restrictions on gender, ethnicity, or age.
We excluded planned (elective) procedures (e.g. scheduled total hip arthroplasty), and studies published since 2010 that had not been prospectively registered.
Eligible interventions included: antifibrinolytics (tranexamic acid, aprotinin, epsilon-aminocaproic acid), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants, and non-fibrin sealants.
Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using GRADE. We did not perform a network meta-analysis due to lack of data.
We included 13 RCTs (929 participants), published between 2005 and 2021. Three trials did not report any of our predefined outcomes and so were not included in quantitative analyses (all were tranexamic acid versus placebo).
We identified three comparisons of interest: intravenous tranexamic acid versus placebo; topical tranexamic acid versus placebo; and recombinant factor VIIa versus placebo. We rated the certainty of evidence as very low to low across all outcomes.
Comparison 1. Intravenous tranexamic acid versus placebo
Intravenous tranexamic acid compared to placebo may reduce the risk of requiring an allogeneic blood transfusion up to 30 days (RR 0.48, 95% CI 0.34 to 0.69; 6 RCTs, 457 participants; low-certainty evidence) and may result in little to no difference in all-cause mortality (Peto odds ratio (Peto OR) 0.38, 95% CI 0.05 to 2.77; 2 RCTs, 147 participants; low-certainty evidence).
It may result in little to no difference in risk of participants experiencing myocardial infarction (risk difference (RD) 0.00, 95% CI −0.03 to 0.03; 2 RCTs, 199 participants; low-certainty evidence), and cerebrovascular accident/stroke (RD 0.00, 95% CI −0.02 to 0.02; 3 RCTs, 324 participants; low-certainty evidence).
We are uncertain if there is a difference between groups for risk of deep vein thrombosis (Peto OR 2.15, 95% CI 0.22 to 21.35; 4 RCTs, 329 participants, very low-certainty evidence), pulmonary embolism (Peto OR 1.08, 95% CI 0.07 to 17.66; 4 RCTs, 329 participants; very low-certainty evidence), and suspected serious drug reactions (RD 0.00, 95% CI −0.03 to 0.03; 2 RCTs, 185 participants; very low-certainty evidence).
No data were available for number of red blood cell units transfused, reoperation, or acute transfusion reaction.
We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures), and upgraded the evidence for transfusion requirement for a large effect.
Comparison 2. Topical tranexamic acid versus placebo
We are uncertain if there is a difference between topical tranexamic acid and placebo for risk of requiring an allogeneic blood transfusion (RR 0.31, 95% CI 0.08 to 1.22; 2 RCTs, 101 participants), all-cause mortality (RD 0.00, 95% CI −0.10 to 0.10; 1 RCT, 36 participants), risk of participants experiencing myocardial infarction (Peto OR 0.15, 95% CI 0.00 to 7.62; 1 RCT, 36 participants), cerebrovascular accident/stroke (RD 0.00, 95% CI −0.06 to 0.06; 1 RCT, 65 participants); and deep vein thrombosis (Peto OR 1.11, 95% CI 0.07 to 17.77; 2 RCTs, 101 participants).
All outcomes reported were very low-certainty evidence.
No data were available for number of red blood cell units transfused, reoperation, incidence of pulmonary embolism, acute transfusion reaction, or suspected serious drug reactions.
We downgraded the certainty of the evidence for imprecision (wide confidence intervals around the estimate and small sample size, particularly for rare events), inconsistency (moderate heterogeneity), and risk of bias (unclear or high risk methods of blinding and allocation concealment in the assessment of subjective measures, and high risk of attrition and reporting biases in one trial).
Comparison 3. Recombinant factor VIIa versus placebo
Only one RCT of 48 participants reported data for recombinant factor VIIa versus placebo, so we have not presented the results here.