8.6.5 Antifibrinolytic agents

Plasmin production and excessive activation of fibrinolysis are characteristic of ECC and postoperative inflammatory syndrome. Three antifibrinolytic substances are used to counteract this effect: aprotinin (Trasylol^® ), tranexamic acid (ATX) (Tranex^® , Anvitoff^® , Exacyl^® , Cyclokapron^® ) and ε-amino-caproic acid (AEAC) (Amicar^® ). ATX and AEAC bind to plasminogen lysine and block plasmin activation and hence fibrinolysis. Aprotinin is a non-specific protease inhibitor, which directly blocks plasmin. Clinically, these substances reduce overall blood loss by 30-50% and redo procedures for bleeding by 60% [4,17].

Aprotinin

Aprotinin, which is extracted from bovine lung, was isolated in 1930. It is an inhibitor of serum proteases, kallikrein, protein C and trypsin. In this respect, it was used in the treatment of acute pancreatitis during the 1960s. It has anti-inflammatory effects, but also inhibits NO synthesis. In 1987, Royston described a significant decrease in bleeding after cardiac surgery (286 ml versus 1509 ml) under high-dose (6 million IU) aprotinin prophylaxis [28]. Similar results were subsequently found with doses of only 2 million IU [3]. There is evidence that aprotinin significantly decreases blood loss, particularly in high-risk bleeding situations such as reoperations and patients on antiplatelet therapy [4,6,29]. Aprotinin also reduces the intensity of the systemic inflammatory response and the production of C1, TNF and kallikrein [18]. It reduces the incidence of neurological sequelae by about half (OR 0.5-0.65) in some studies [6,29], but not all [4]. However, aprotinin is responsible for anaphylactic reactions in 0.1-3% of patients. Risk and intensity of reaction is increased if exposure occurs within the previous 6-12 months, which calls for great vigilance when resuming surgery within one year of a first ECC operation [2].

Aprotinin inhibits vasodilation of glomerular afferent arterioles. This preglomerular vasoconstriction may be in addition to the postglomerular efferent arteriolar vasodilation induced by ACE inhibitors: it further reduces glomerular perfusion and renal excretory function in ACE inhibited patients. A clinical study demonstrated a significant association between the combination of aprotinin and ACE inhibitors and renal failure after cardiac surgery (incidence 3.5%) [15]; the incidence of creatinine elevation > 200m mol/L is 11.8% in the combination of aprotinin + ACE inhibitors compared to 5% in patients without aprotinin (OR 2.9). An increase in renal dysfunction rate with aprotinin has been found in several studies, particularly at higher doses [4,6,14].

A few years ago, three observational studies, involving 898, 4,374 and 3,876 patients respectively and using a propensity score to compare  groups, confused the widespread practice of administering aprotinin preventively to the majority of cardiac surgery patients. The first study compared the effects of aprotinin (6 million IU) with those of tranexamic acid (50-100 mg/kg) [14]. The efficacy of the two substances in terms of bleeding and transfusions was identical, but renal complications were more frequent with aprotinin (24% versus 17%, p = 0.01); this association was strengthened in patients with pre-operative renal dysfunction. The second study demonstrated that use of aprotinin (dose ≥ 2 million IU) is associated with an increased risk of renal failure, infarction and stroke compared with tranexamic acid,ε -amino-caproic acid or placebo [21]. Aprotinin increases rate of renal failure (5.5% versus 1.8%), stroke (4.5% versus 1.6%), cardiac events (20.4% versus 13.2%), and mortality (2.8% versus 1.3%). These effects are dose-dependent. None of these complications were increased in other groups. The decrease in bleeding was not significant (753 ml versus 827 ml with placebo and 676 ml with tranexamic acid). The third study repeated the observations of the second but with a 5-year follow-up; mortality of patients who received aprotinin (20.8%) was significantly higher than that of the control group (12.7%) (hazard ratio 1.48), while mortality of patients who received tranexamic acid ore ε-amino-caproic acid was unchanged [20]. The latter two studies have been heavily criticised for selection bias and various methodological problems and are in contradiction with major meta-analyses published at the same time [1]. In all three studies, the dose of aprotinin used was 2-4 million units.

In February 2006, the FDA recommended limiting the use of aprotinin to situations where the benefit of reduced bleeding is essential to medical treatment and outweighs the potential risks of toxicity. Until autumn 2007, the debate could be summarised as follows [13].

• Antifibrinolytics are mainly indicated in situations of high bleeding risk;
• Antifibrinolytics reduce the rate of bleeding by about 30-50%;
• Aprotinin is the most effective agent, but not markedly so; it has an allergic reaction rate of 0.1-2%;
• Aprotinin increases the incidence of renal complications in patients with preoperative renal dysfunction and in patients on ACE inhibitors;
• Aprotinin appears to reduce the incidence of neurological complications;
• Aprotinin is possibly suspected of increasing mortality and rate of cardiac complications;
• Aprotinin is at least five times more expensive than other antifibrinolytics.

In early November 2007, a large Canadian randomised controlled trial (BART: Blood conservation using Antifibrinolytics: Randomized Trial in high-risk cardiac surgery) showed an increase in mortality and cardiovascular complications in the aprotinin group compared to the tranexamic acid and ε-amino-caproic acid groups (RR 1.53) [8]. Although it reduces bleeding more than the other two substances (RR 0.79), aprotinin appears to increase death risk  in massive bleeding. As a result, Bayer withdrew Trasylol^® from the world market on 6 November 2007.

The speed of this withdrawal came as a great surprise, especially as BART study has serious methodological weaknesses and the weight of evidence in the literature favours aprotinin in coronary artery bypass grafting and in patients on antithrombotic drugs [24]. Although European and Canadian health authorities have clearly stated that benefits of aprotinin outweigh its risks in cardiac surgery [7,10], its use has not resumed. However, the substance may return to the market, as the company Nordic™ has bought back the licence and the European Medicines Agency (EMA) has lifted the ban.

Tranexamic acid

In the meantime, most centres have chosen to replace aprotinin with tranexamic acid (ATX). This lysine analogue binds to plasminogen reversibly and inhibits its conversion to plasmin. Tranexamic acid is slightly less effective than aprotinin in reducing blood loss and redo procedures for bleeding, especially when bleeding is severe: transfusions are reduced by 34%, compared with 39% in aprotinin-treated patients [11]. However, ATX does not trigger allergic reactions or postoperative renal dysfunction. In addition, it is less expensive. Dosages described in literature range from 10 to 100 mg/kg total dose; product half-life is 2 hours. It is important to give a first dose before the ECC (10-30 mg/kg), followed by an infusion (1-2 mg/kg/h) or a repeat of the first dose in the ECC (usually 2 mg/kg), and a dose after  ECC [5,31]. The aim is to maintain a plasma concentration of 20 mcg/mL. An infusion can be started postoperatively if necessary. The maximum dose mentioned is 150 mg/kg. There is little evidence that doses above 10 mg/kg and 1 mg/kg/hour increase efficiency [27]. ATX reduces the number of blood transfusions by 46% and risk of major bleeding or tamponade by 50% (4,331 cardiac surgery patients on ATX compared with 7,994 patients on placebo), with no change in thrombotic risk (OR 0.92) [25].

Unfortunately, increasing doses increase risk of postoperative seizures up to 5-7 fold [17,22,25]. In a study of 4,883 patients using a moderate dose (24 mg/kg), risk of seizures is increased by 70% (OR 1.70) in the ATX group compared to control group; these differences are more pronounced in open heart surgery (OR 2.03) than in coronary surgery (OR 1.21) [16]. Risk becomes major when total dose exceeds 50-80 mg/kg. However, the safety of ATX has been demonstrated in the CRASH-2 study: 2 gm within the first 3 hours after trauma with major bleeding did not cause serious side effects, but reduced mortality due to blood loss (RR 0.85) [30]. Although risk is low for hyperfibrinolysis at 10 mg/kg [9],  prothrombotic risk is not absent, especially at higher doses (RR 1.61) [26].

ATX is currently antifibrinolytic first choice. Ideally, the dose should be adapted to bleeding risk: bolus of 10 mg/kg and infusion of 1 mg/kg/h for low-risk cases, total dose of 50 mg/kg for high-risk cases. High doses carry a risk of postoperative convulsion and thrombogenicity [12]. However, there are still grey areas regarding its pharmacology, safety and dosages, which are empirical. Its indiscriminate "one size fits all" administration is not adapted to clinical reality, and its prophylactic use remains open to discussion [19].

Other antifibrinolytic agents

ε -amino-caproic acid is significantly less effective than ATX: the transfusion rate is reduced by 19% compared to 34% for ATX [11]. Dosage is 50 mg/kg bolus followed by infusion o25 mg/kg/hour [27]. In patients on aspirin, antifibrinolytics significantly reduce transfusion rate (OR 0.37) [23].

The financial impact of  antifibrinolytic choice is enormous, aprotinin is an expensive drug: CHF 220 for 1 million IU (US$ 200.00); the equivalent dose of tranexamic acid is CHF 24 (1 gm) (US$ 25.00); AEAC is the cheapest: US$ 5.00. For comparison, a blood bag  costs CHF 235.00 in Switzerland (value February 2012).

 © CHASSOT PG, MARCUCCI Carlo, last update November 2019.

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