• Key messages
We do not yet know what the best drugs are to reduce bleeding and blood transfusions during vascular surgery.
• What is vascular surgery?
Vascular surgery is when a surgeon operates on blood vessels, to repair leaks and areas of weakness, or to clear blockages. This review focused on the types of vascular surgery that are more likely to lead to severe bleeding.
• 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.
• What did we want to find out?
We wanted to find out which drug treatments help reduce bleeding and the need for blood transfusion. We also wanted to find out if these treatments increase the risk of side effects, such as blood clots.
• What did we do?
We searched electronic libraries for reports of the most reliable studies (called randomised controlled trials) of drugs to prevent bleeding after surgery on blood vessels.
• What did we find?
We found seven trials of drugs injected before surgery to try to reduce the amount of bleeding. We found 15 trials of dressings or glues with drugs in them. These are used to stop bleeding during surgery and are left inside after the operation. We did not find enough information to be sure which drugs are best for reducing bleeding and transfusions during vascular surgery. Often, the people having surgery were not followed up for very long once they left the operating theatre, so we could not find out whether they needed a blood transfusion afterwards.
One trial, of 9535 people having surgery, tested a drug called tranexamic acid injected before surgery. This included 1399 people who had surgery on their blood vessels, but it did not report much information for this group on its own. The one outcome it did report on, specifically for vascular surgery, was whether there was an increased risk of developing a blood clot if tranexamic acid is given. We found that there may be no difference in the risk of developing a blood clot between tranexamic acid and a placebo.
• What are the limitations of the evidence?
Most of the trials we found were small, with fewer than 100 people included. This is not enough to be sure if any of these treatments might help people. We need to have trials with many hundreds or even thousands of people included to find out if these drugs helped them recover from surgery.
Most of the trials we found did not collect information about blood transfusions after surgery. We think this might be for a few different reasons. Surgeons may transfer the care of patients they have operated on to the care of other healthcare professionals if they require prolonged postoperative care, e.g. physicians. It is more complicated to do a study if they need to work with other healthcare professionals to find out what happened afterwards.
Also, most of the trials were run by the companies that make the treatments. It is cheaper and easier for them to only look at what happens during surgery, especially if people will accept their product without any information about what happens after surgery.
• How up to date is this evidence?
We found all the published trials on this topic up to 31 March 2022. We also found all the trials which have started or are going to be starting soon. The good news is that there is one very large trial on drugs to prevent bleeding in surgery that is already in progress. It is testing tranexamic acid injected before surgery. It plans to recruit 8320 people undergoing a range of surgeries, including surgery on blood vessels, and will report the number of people needing blood transfusions. This will be an important result when the trial is completed, and we hope it will inspire other surgeons to do trials of this sort in future.
Because of a lack of data, we are uncertain whether any systemic or topical treatments used to reduce bleeding due to major vascular surgery have an effect on: all-cause mortality up to 30 days; risk of requiring a repeat procedure or operation due to bleeding; number of red cells transfused per participant up to 30 days or the number of participants requiring an allogeneic blood transfusion up to 30 days.
There may be no effect of tranexamic acid on the risk of thromboembolic events up to 30 days, this is important as there has been concern that this risk may be increased.
Trials with sample size targets of thousands of participants and clinically relevant outcomes are needed, and we look forward to seeing the results of the ongoing trials in the future.
Vascular surgery may be followed by internal bleeding due to inadequate surgical haemostasis, abnormal clotting, or surgical complications. Bleeding ranges from minor, with no transfusion requirement, to massive, requiring multiple blood product transfusions. There are a number of drugs, given systemically or applied locally, which may reduce the need for blood transfusion.
To assess the effectiveness and safety of anti-fibrinolytic and haemostatic drugs and agents in reducing bleeding and the need for blood transfusion in people undergoing major vascular surgery or vascular procedures with a risk of moderate or severe (> 500 mL) blood loss.
We searched: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL, and Transfusion Evidence Library. We also searched the WHO ICTRP and ClinicalTrials.gov trial registries for ongoing and unpublished trials. Searches used a combination of MeSH and free text terms from database inception to 31 March 2022, without restriction on language or publication status.
We included randomised controlled trials (RCTs) in adults of drug treatments to reduce bleeding due to major vascular surgery or vascular procedures with a risk of moderate or severe blood loss, which used placebo, usual care or another drug regimen as control.
We used standard Cochrane methods. Our primary outcomes were units of red cells transfused and all-cause mortality. Our secondary outcomes included risk of receiving an allogeneic blood product, risk of reoperation or repeat procedure due to bleeding, risk of a thromboembolic event, risk of a serious adverse event and length of hospital stay. We used GRADE to assess certainty of evidence.
We included 22 RCTs with 3393 participants analysed, of which one RCT with 69 participants was reported only in abstract form, with no usable data. Seven RCTs evaluated systemic drug treatments (three aprotinin, two desmopressin, two tranexamic acid) and 15 RCTs evaluated topical drug treatments (drug-containing bioabsorbable dressings or glues), including fibrin, thrombin, collagen, gelatin, synthetic sealants and one investigational new agent. Most trials were conducted in high-income countries and the majority of the trials only included participants undergoing elective surgery. We also identified two ongoing RCTs.
We were unable to perform the planned network meta-analysis due to the sparse reporting of outcomes relevant to this review.
Systemic drug treatments
We identified seven trials of three systemic drugs: aprotinin, desmopressin and tranexamic acid, all with placebo controls. The trials of aprotinin and desmopressin were small with very low-certainty evidence for all of our outcomes. Tranexamic acid versus placebo was the systemic drug comparison with the largest number of participants (2 trials; 1460 participants), both at low risk of bias. The largest of these included a total of 9535 individuals undergoing a number of different higher risk surgeries and reported limited information on the vascular subgroup (1399 participants).
Neither trial reported the number of units of red cells transfused per participant up to 30 days. Three outcomes were associated with very low-certainty evidence due to the very wide confidence intervals (CIs) resulting from small study sizes and low number of events. These were: all-cause mortality up to 30 days; number of participants requiring an allogeneic blood transfusion up to 30 days; and risk of requiring a repeat procedure or operation due to bleeding.
Tranexamic acid may have no effect on the risk of thromboembolic events up to 30 days (risk ratio (RR) 1.10, 95% CI 0.88 to 1.36; 1 trial, 1360 participants; low-certainty evidence due to imprecision).
There is one large ongoing trial (8320 participants) comparing tranexamic acid versus placebo in people undergoing non-cardiac surgery who are at high risk of requiring a red cell transfusion. This aims to complete recruitment in April 2023. This trial has primary outcomes of proportion of participants transfused with red blood cells and incidence of venous thromboembolism (DVT or PE).
Topical drug treatments
Most trials of topical drug treatments were at high risk of bias due to their open-label design (compared with usual care, or liquids were compared with sponges). All of the trials were small, most were very small, and few reported clinically relevant outcomes in the postoperative period. Fibrin sealant versus usual care was the topical drug comparison with the largest number of participants (5 trials, 784 participants).
The five trials that compared fibrin sealant with usual care were all at high risk of bias, due to the open-label trial design with no measures put in place to minimise reporting bias. All of the trials were funded by pharmaceutical companies.
None of the five trials reported the number of red cells transfused per participant up to 30 days or the number of participants requiring an allogeneic blood transfusion up to 30 days.
The other three outcomes were associated with very low-certainty evidence with wide confidence intervals due to small sample sizes and the low number of events, these were: all-cause mortality up to 30 days; risk of requiring a repeat procedure due to bleeding; and risk of thromboembolic disease up to 30 days.
We identified one large trial (500 participants) comparing fibrin sealant versus usual care in participants undergoing abdominal aortic aneurysm repair, which has not yet started recruitment. This trial lists death due to arterial disease and reintervention rates as primary outcomes.