Key messages
• Tranexamic acid may be an effective medicine to help blood to clot during hip or knee replacement surgery, which reduces bleeding and the need for a blood transfusion (replacing lost blood with donated blood).
• A high dose of this medicine and administering it in more than one way (for example, as a tablet and injected into the joint at the end of surgery) appears to work best.
• Tranexamic acid is potentially as effective when given as a tablet as when injected into a vein.
• There is little to no evidence to indicate that higher doses of tranexamic acid increase the risk of blood clots in the leg or other harms.
Background
Why is it important to stop bleeding during hip or knee surgery?
Controlling bleeding during surgery reduces the likelihood of the person developing anaemia and requiring a blood transfusion, which carries the risk of complications. Anaemia occurs when the number of red blood cells (haemoglobin) available to carry oxygen is lower than normal. This causes symptoms such as fatigue, weakness, dizziness, shortness of breath and, in severe cases, can be life-threatening. Preventing blood loss during surgery improves patient outcomes, decreases healthcare costs and preserves the limited supplies of donated blood.
Is there a medication that helps control bleeding?
Many research studies have investigated whether certain medication, such as tranexamic acid, can help minimise blood loss during surgery. Most of the studies test different doses of medications, different methods of administration and different times of use, either before, during or after an operation.
What did we want to find out?
We wanted to find out whether medication can reduce blood loss and the need for blood transfusions in people having hip or knee replacement surgery. We also wanted to know the most effective way of giving this medication to patients.
What did we do?
We searched for studies comparing different medications that could help reduce bleeding in adults undergoing planned hip or knee replacement surgery. We also searched for studies comparing medication with a placebo. A placebo is a 'dummy' medication that looks or tastes identical to the medication being tested.
What did we find?
We found 102 studies. Twelve studies did not report the number of included participants; in the other 90 studies, there were 8418 included participants. On average, people were between 50 and 77 years of age and 64% were women. The smallest study included 16 people and the largest involved 300. Studies took place around the globe, with the highest number in Europe and Asia. Of those studies that reported a source of funding, seven were fully funded and five partly funded by pharmaceutical (medication) companies. All studies investigated medications that helped the blood to clot. However, most studies assessed the effectiveness and safety of tranexamic acid administered intravenously (injected into a vein), orally (swallowing a tablet or liquid), injected into the joint during surgery, or with a combination of these methods.
Main results
Our review of the studies showed the following:
• Tranexamic acid was the most effective at controlling bleeding compared to other medications.
• Adults who underwent hip or knee replacement surgery required fewer blood transfusions if they were given tranexamic acid.
• Tranexamic acid given in higher doses using multiple methods of administration, such as orally and injected into the joint during surgery, may be more likely to prevent bleeding.
• Taking tranexamic acid orally is probably as effective at preventing a blood transfusion as injecting the medication into a vein.
We were unable to decide on the optimal dose, which combination of methods are best to administer tranexamic acid and when it is most beneficial to use it (before, during and after surgery). We did not find evidence to suggest that higher doses of tranexamic acid increase the risk of developing a blood clot, or any other harms.
What are the limitations of the evidence?
We are not able to definitively draw conclusions based on the trials included within this review. 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
Thirty studies with a planned total of 3776 participants are currently ongoing. These studies should be completed and published within the next few years. Once the authors publish their data, we may update our analyses and provide stronger answers than we can at present.
How up-to-date is this evidence?
The evidence is current to 18 October 2022.
We found that of all the interventions studied, TXA is probably the most effective intervention for preventing bleeding in people undergoing hip or knee replacement surgery. Aprotinin and EACA may not be as effective as TXA at preventing the need for allogeneic blood transfusion. We were not able to draw strong conclusions on the optimal dose, route and timing of administration of TXA. We found that TXA given at higher doses tended to rank higher in the treatment hierarchy, and we also found that it may be more beneficial to use a mixed route of administration (oral and intra-articular, oral and intravenous, or intravenous and intra-articular). Oral administration may be as effective as intravenous administration of TXA. We found little to no evidence of harm associated with higher doses of tranexamic acid in the risk of DVT. However, we are not able to definitively draw these conclusions based on the trials included within this review.
Hip and knee replacement surgery is a well-established means of improving quality of life, but is associated with a significant risk of bleeding. One-third of people are estimated to be anaemic before hip or knee replacement surgery; coupled with the blood lost during surgery, up to 90% of individuals are anaemic postoperatively. As a result, people undergoing orthopaedic surgery receive 3.9% of all packed red blood cell transfusions in the UK. Bleeding and the need for allogeneic blood transfusions has been shown to increase the risk of surgical site infection and mortality, and is associated with an increased duration of hospital stay and costs associated with surgery.
Reducing blood loss during surgery may reduce the risk of allogeneic blood transfusion, reduce costs and improve outcomes following surgery. Several pharmacological interventions are available and currently employed as part of routine clinical care.
To determine the relative efficacy of pharmacological interventions for preventing blood loss in elective primary or revision hip or knee replacement, and to identify optimal administration of interventions regarding timing, dose and route, using network meta-analysis (NMA) methodology.
We searched the following databases for randomised controlled trials (RCTs) and systematic reviews, from inception to 18 October 2022: CENTRAL (the Cochrane Library), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library (Evidentia), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP).
We included RCTs of people undergoing elective hip or knee surgery only.
We excluded non-elective or emergency procedures, and studies published since 2010 that had not been prospectively registered (Cochrane Injuries policy). There were no restrictions on gender, ethnicity or age (adults only). We excluded studies that used standard of care as the comparator.
Eligible interventions included: antifibrinolytics (tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid (EACA)), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants and non-fibrin sealants.
We performed the review according to standard Cochrane methodology. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using CINeMA. We presented direct (pairwise) results using RevMan Web and performed the NMA using BUGSnet.
We were interested in the following primary outcomes: need for allogenic blood transfusion (up to 30 days) and all-cause mortality (deaths occurring up to 30 days after the operation), and the following secondary outcomes: mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), length of hospital stay and adverse events related to the intervention received.
We included a total of 102 studies. Twelve studies did not report the number of included participants; the other 90 studies included 8418 participants. Trials included more women (64%) than men (36%).
In the NMA for allogeneic blood transfusion, we included 47 studies (4398 participants). Most studies examined TXA (58 arms, 56%). We found that TXA, given intra-articularly and orally at a total dose of greater than 3 g pre-incision, intraoperatively and postoperatively, ranked the highest, with an anticipated absolute effect of 147 fewer blood transfusions per 1000 people (150 fewer to 104 fewer) (53% chance of ranking 1st) within the NMA (risk ratio (RR) 0.02, 95% credible interval (CrI) 0 to 0.31; moderate-certainty evidence). This was followed by TXA given orally at a total dose of 3 g pre-incision and postoperatively (RR 0.06, 95% CrI 0.00 to 1.34; low-certainty evidence) and TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively (RR 0.10, 95% CrI 0.02 to 0.55; low-certainty evidence).
Aprotinin (RR 0.59, 95% CrI 0.36 to 0.96; low-certainty evidence), topical fibrin (RR 0.86, CrI 0.25 to 2.93; very low-certainty evidence) and EACA (RR 0.60, 95% CrI 0.29 to 1.27; very low-certainty evidence) were not shown to be as effective compared with TXA at reducing the risk of blood transfusion.
We were unable to perform an NMA for our primary outcome all-cause mortality within 30 days of surgery due to the large number of studies with zero events, or because the outcome was not reported.
In the NMA for deep vein thrombosis (DVT), we included 19 studies (2395 participants). Most studies examined TXA (27 arms, 64%). No studies assessed desmopressin, EACA or topical fibrin. We found that TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively ranked the highest, with an anticipated absolute effect of 67 fewer DVTs per 1000 people (67 fewer to 34 more) (26% chance of ranking first) within the NMA (RR 0.16, 95% CrI 0.02 to 1.43; low-certainty evidence). This was followed by TXA given intravenously and intra-articularly at a total dose of 2 g pre-incision and intraoperatively (RR 0.21, 95% CrI 0.00 to 9.12; low-certainty evidence) and TXA given intravenously and intra-articularly, total dose greater than 3 g pre-incision, intraoperatively and postoperatively (RR 0.13, 95% CrI 0.01 to 3.11; low-certainty evidence). Aprotinin was not shown to be as effective compared with TXA (RR 0.67, 95% CrI 0.28 to 1.62; very low-certainty evidence).
We were unable to perform an NMA for our secondary outcomes pulmonary embolism, myocardial infarction and CVA (stroke) within 30 days, mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), or length of hospital stay, due to the large number of studies with zero events, or because the outcome was not reported by enough studies to build a network.
There are 30 ongoing trials planning to recruit 3776 participants, the majority examining TXA (26 trials).