Bleeding after Cardiovascular Surgery: A continuing problem

In this issue of Circulation, Lamy and colleagues report the results of a well designed clinical trial comparing topical versus intravenous administration of the antifibrinolytic drug tranexamic acid on bleeding outcomes and seizure incidence after cardiothoraic surgery(1). Excessive blood loss after cardiovascular surgery is associated with increased mortality and complications after the operation. In fact, a return to the operating room for bleeding has been associated with a 12% risk of mortality versus less than 3 % in patients not requiring re-exploration (2). In a study from a large tertiary referral center, a return to the operating room was also associated with an increase in the rate of atrial fibrillation, renal insufficiency, wound infection and other complications. Patients with excessive bleeding had a marked increase in the length of hospital stay contributing to greater cost of treatment. (2). Even excessive bleeding in the absence of re-exploration is associated with increased cost, mortality and complications (3). Thus, bleeding after cardiovascular surgery is a major issue with quality and financial consequences.

There are preoperative predictors of excessive bleeding after cardiovascular and other types of surgery. These include advanced age of the patient, baseline renal insufficiency, liver dysfunction, a prolonged, complex operation, and a preoperative coagulopathy. The use of anti-platelet agents such as clopidogrel and ticagrelor and anti-thrombotic drugs such as eliquis and dabigatran are widespread and certainly associated with excessive bleeding after an elective or emergency operation. The ACC/AHA Revascularization Guidelines recommend that surgeons should delay surgery if possible if patients are taking these drugs (4), but the clinical urgency of operation and pressure from cardiologists, hospital administration and patients themselves often make a delay problematic.

Many drugs have been administered in an attempt to decrease bleeding after cardiovascular surgery. These include tranexamic acid as was examined in the current study (1) and an older drug that works essentially through the same mechanism, epsilon-aminocaproic acid. Both tranexamic acid and epsilon-aminocaproic acid work by inhibiting fibrinolysis, or the dissolution of clot due to being an analog of the amino acid lysine. Plasminogen is released into the systemic circulation after being synthesized in the liver and has several lysine receptor sites involve in the conversion of plasminogen to plasmin. When plasminogen is converted to plasmin, it becomes the active form of the enzyme. Tranexamic acid blocking this conversion of plasminogen to plasmin prevents fibrin clot degradation by plasmin and maintains fibrin's structure and role in clot formation. Epsilon-aminocaproic acid probably has somewhat less antifibrinolytic activity than tranexamic acid, and maybe slightly less effective than tranexamic acid in preventing bleeding, but it is not associated with postoperative seizures after administration and many surgeons still prefer its use.

Many other drugs have been investigated and are often administered to prevent bleeding such as activated factor VII (5), factor XIII (6) and prothrombin complex concentrates. Other agents have been administered to prevent bleeding due to anti-thrombotic drugs such as idarucizumab for dabigatran reversal (7,8) and prothrombin complex and andexanet (9) for other novel oral anticoagulant drugs. There are newly developed devices in development to remove ticagrelor, novel oral anti-coagulants and inflammatory cytokines from the circulation during surgery in an attempt to diminish bleeding (10). Some of these drugs administered to reduce postoperative bleeding, while effective, are associated with risk including thrombotic complications and death. (5,11).

As stated above, the study by Lamy et al in this issue of Circulation, is a well-designed clinical trial that examined the relative effectiveness of topical vs intravenous administration of tranexamic acid, an antifibrinolytic drug that reduces the breakdown of clot. The study was a multicenter, blinded, randomized controlled trial of patients recruited by convenience sampling in academic hospitals undergoing cardiac surgery with cardiopulmonary bypass. The rationale for the study was that tranexamic acid when administered intravenously during cardiovascular surgery has been shown to reduce bleeding. It is widely available, and unlike some of the other drugs mentioned, it is rather inexpensive. However, one downside of the therapy is a small but significant increase in the incidence of seizures. The hypothesis was that patient would benefit with a reduction in bleeding and transfusion with the topic administration of tranexamic acid, but not have the uncommon but noted complication of postoperative seizures associated with the intravenous administration of the agent. Patients receiving intravenous tranexamic acid have an increased incidence of seizures following administration due to the similarity in molecular structure of tranexamic acid compared to γ-aminobutyric acid and glycine, leading to neuronal hyperexcitability (12, 13). Unfortunately, despite the design of the trial, it was largely negative. While the incidence of seizures after surgery was markedly decreased with the topical administration of tranexamic acid, the reduction in bleeding and transfusion was also significantly reduced compared to the intravenous, or standard, administration of the drug. In retrospect, there may have been some weaknesses in the rationale of the study. Bleeding from openings in vessels or transected vessels is less effectively treated with the topical administration of tranexamic acid or other agent compared to its effectiveness when delivered intravascularly, since bleeding starts from within a vessel and moves outward. However, other topical agents are effective when applied external to the bleeding vessel. The topical application of tranexamic acid likely does not have the same effect as the intravenous application. However, other agents such as topical thrombin or surgical sealants such as Bioglue ^™ (Artivion) are applied externally and do provide efficacy in reducing bleed loss, most frequently in aortic surgery. These agents do not work through an antifibrinolytic mechanism, but are effective when applied topically due to providing a mechanical barrier to bleeding or inducing clot formation.

If this trial had been positive, with a marked reduction in bleeding and with an elimination of seizures, this may have changed the way we treat patients during cardiovascular surgery. One often cannot predict the outcome of a trial, only hope for the beneficial hypothesized outcome. Cardiovascular surgery has had a major impact and is a cornerstone on the treatment of patients with cardiovascular disease. Clinical trials such as the one published by Lamy et al need to be conducted so that the quality of surgery continues to improve and complications such as bleeding continue to decrease.