7.2.14 Antifibrinolytic agents

Plasmin production and excessive activation of fibrinolysis are characteristic of ECC and the postoperative inflammatory syndrome. Three antifibrinolytic substances are used to counteract this effect: aprotinin (Trasylol^® ), tranexamic acid (ATX, Anvitoff^® , Exacyl^® , Cyclokapron^® ) ande -amino-caproic acid (AEAC, Amicar^® ). ATX and AEAC bind to plasminogen lysine and block plasmin activation and thus fibrinolysis. Aprotinin is a non-specific protease inhibitor, which directly blocks plasmin. Clinically, these substances reduce overall blood loss by 30% and repeat bleeding surgeries by 60% [4,16].

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 [17]. It reduces the incidence of neurological sequelae by about half (OR 0.5-0.65) in some studies [6,24,29], but not all [4,20]. However, aprotinin is responsible for anaphylactic reactions in 0.1-3% of patients. The risk and intensity of the 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 previous 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 showed a significant association between the combination of aprotinin and ACE inhibitors and renal failure after cardiac surgery (incidence 3.5%) [14]; 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 the rate of renal dysfunction with aprotinin has been found in several studies [6,13,20], particularly at higher doses [4].

About 15 years ago, three 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 tranexamic acid (50-100 mg/kg) [13]. 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 the use of aprotinin (dose ≥ 2 million IU) is associated with an increased risk of renal failure, infarction and stroke compared to tranexamic acid,e -amino-caproic acid or placebo [20]. Aprotinin increases the 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 the 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; the mortality of patients who received aprotinin (20.8%) was significantly higher than that of the control group (12.7%) (hazard ratio 1.48), while the mortality of patients who received tranexamic acid ore -amino-caproic acid was unchanged [19]. The latter two studies have been heavily criticised for their selection bias 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 [12].

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

In early November 2007, a large Canadian study (BART: Blood conservation using Antifibrinolytics: Randomized Trial in high-risk cardiac surgery) showed an increase in mortality and complications in the aprotinin group compared to the tranexamic acid ande -amino-caproic acid groups (relative risk increased up to 40%) [9]. Although it reduces bleeding slightly more than the other two substances, aprotinin increases the risk of death in case of 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 the BART study had serious methodological weaknesses and the weight of evidence in the literature favoured aprotinin in coronary artery ECC and in patients on antithrombotic drugs [23]. Although European and Canadian health authorities have clearly stated that the benefits of aprotinin outweigh its risks in cardiac surgery [8], 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. Its potential use is reserved for adults operated on in ECC who present a high haemorrhagic risk and a low renal risk, and for centres that participate in a European registry collecting all cases. On the other hand, multimodal blood-sparing programmes have reduced bleeding problems to such an extent that the benefit of aprotinin has largely faded in the current context [7].

Tranexamic acid

Since then, most centres have chosen to replace aprotinin with tranexamic acid (Anvitoff^® , Cyclokapron^® ). This lysine analogue binds to plasminogen reversibly and inhibits its conversion to plasmin. Although slightly less effective than aprotinin in reducing blood loss and bleeding recurrences, tranexamic acid (ATX) does not trigger allergic reactions or postoperative renal dysfunction. In addition, it is less expensive [10]. Dosages described in the literature range from 15 to 100 mg/kg total dose. It is important to give a first dose before the ECC (10-50 mg/kg), followed by an infusion (1-15 mg/kg/h) or a repeat of the first dose in the ECC (usually 2 mg/kg), and a dose after the ECC [5,31]. An infusion can be started postoperatively if necessary. The aim is to maintain a plasma concentration of 20 mcg/mL. The maximum dose mentioned is 150 mg/kg/24 hours. Compared to placebo, ATX (total dose 50 mg/kg) reduces the transfusion rate by 30% and the rate of repeat haemostasis by 50% [25].

However, increasing doses increase the risk of postoperative seizures up to 5-7 fold [16,21]. In a study of 4,883 patients using a moderate dose (24 mg/kg), the risk of seizures is increased by 70% (OR 1.70) and mortality by 90% (OR 1.89) in the ATX group compared to the control group; these differences are more pronounced in open heart surgery than in coronary surgery[ 15] . The risk of seizure becomes major when the total dose exceeds 50-80 mg/kg. ATX is also associated with postoperative renal failure, particularly in valve surgery [21]. However, the safety of ATX was demonstrated in the CRASH-2 study: administration of 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 the risk is low for hyperfibrinolysis at 10 mg/kg [9], the prothrombotic risk is not absent, especially at higher doses (RR 1.61) [26].

ATX is currently the antifibrinolytic of first choice. Ideally, the dose should be adapted to the 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 [11]. 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 [18].

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 [10]. The dosage is 50 mg/kg bolus followed by an infusion of 25 mg/kg/hour [27]. In patients on aspirin, antifibrinolytics significantly reduce the transfusion rate (OR 0.37) [22].

The financial impact of the choice of antifibrinolytic is considerable, because aprotinin is an expensive drug: SFr 220 for 1 million IU (US$ 200.00); the equivalent dose of tranexamic acid is SFr 74 (1 gm) (US$ 25.00); AEAC is the cheapest: US$ 5.00. For comparison, a blood bag costs about CHF 800 in Switzerland, including handling and complications (CHF 220 gross).  However, in the best of cases, anifibrinolytics only save an average of 1.4 units of blood.

© CHASSOT PG, GRONCHI F, April 2008, last update December 2019

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