Absorption of tranexamic acid as a prodrug in healthy volunteers.

The absorption of trans-4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid, Cyklokapron) administered as the prodrug trans-4-(aminomethylcyclohexanecarboxylate hydrochloride (Kabi 2161) was investigated in 3 healthy volunteers. Kabi 2161 was given orally in doses of 1, 2, 3 and 3.5 mmol, respectively, and as a reference a clinical dose of 1.5 g tranexamic acid (9.6 mmol) was administered. At 3 mmol of Kabi 2161 the same maximum plasma concentration of tranexamic acid was obtained as with the reference drug but with Kabi 2161 it appeared earlier. The recovery of tranexamic acid in the urine 0-48 h after administration of Kabi 2161 was 84.7, 82.4, 89.4 and 97.5%, resp., of the increasing doses. For the tranexamic acid 37.0% could be recovered. A similar result was seen in the areas under the plasma concentration-time curves normalized for dose. With Kabi 2161, 13.1, 19.6, 14.4 and 14.3 mg.h/l.mmol were found compared to 8.0 mg.h/l.mmol with tranexamic acid. From these results it was concluded that Kabi 2161 markedly increased the bioavailability of tranexamic acid in man.

Antifibrinolytic treatment in subarachnoid hemorrhage.

We enrolled 479 patients with subarachnoid hemorrhage in a multicenter, randomized, double-blind, placebo-controlled trial to determine whether treatment with the antifibrinolytic agent tranexamic acid improves outcome by preventing rebleeding. At three months there was no statistical difference between the outcomes in the tranexamic acid group and the control group. Of the 173 patients who died, 84 had received tranexamic acid and 89 placebo (95 per cent confidence interval for the difference in mortality rate, -6 to 11 per cent). Similarly, when analysis was restricted to patients with an angiographically demonstrated aneurysm, there was no significant difference between the groups. This absence of effect was not due to a lack of antifibrinolytic action, since the rate of rebleeding was reduced from 24 per cent in the control group to 9 per cent in the tranexamic acid-treated group (chi-square = 18.07, P less than 0.001), but resulted from a concurrent increase in the incidence of ischemic complications (15 per cent in the control group and 24 per cent in the tranexamic acid group; chi-square = 8.07, P less than 0.01). We conclude that until some method can be found to minimize ischemic complications, tranexamic acid is of no benefit in patients with subarachnoid hemorrhage.

Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: a consecutive controlled clinical trial.

A randomized controlled clinical trial was carried out to study the effect of tranexamic acid (AMCA, Cyklokapron; AB Kabi, Stockholm, Sweden) in the prevention of early rebleeding after the rupture of an intracranial aneurysm. The incidence of vasospasm, hydrocephalus, cerebral ischemic and thromboembolic complications, morbidity, and mortality was also evaluated. The series comprises 59 patients, 30 treated with tranexamic acid and 29 controls. The treatment was stopped if there was rebleeding, operation, or discharge from the hospital. There were 6 recurrent hemorrhages in 6 patients in the tranexamic acid-treated group and 11 recurrences in 7 patients in the control group. Recurrent hemorrhages occurred later in tranexamic acid-treated patients than in controls. Five patients in each group died from rebleeding. Five additional treated patients and 2 controls died from cerebral ischemic dysfunction. The results suggest that tranexamic acid may protect patients with ruptured aneurysms from rebleeding for 1 or 2 weeks, but that it also may produce cerebral ischemic complications.

Determination of tranexamic acid (AMCA) and fibrin/fibrinogen degradation products in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage.

Six patients with recently ruptured intracranial aneurysms were treated preoperatively with tranexamic acid (AMCA). Two patients received 6 g daily in i.v. infusion, two had 6 g daily by i.v. injection, and two patients were given AMCA 9 g daily by mouth during the first week after bleeding. Serial assays of AMCA and fibrin/fibrinogen degradation products (FDP) in cerebrospinal fluid (CSF) were performed during 6--13 days after the initial subarachnoid haemorrhage (SAH). Judged from the decline in CSF-FDP, an assumed therapeutic level of greater than or equal to 1 mg/l of AMCA in CSF was reached within 24--36 hours after the first dose when the drug was administered intravenously and within 48 hours when the drug was given orally.

Pharmacokinetics and bioavailability of tranexamic acid.

Tranexamic acid 1 g was given intravenously to three healthy volunteers. Plasma concentrations decayed in three monoexponential phases. Most elimination took place during the first eight hours, giving an apparent elimination half-life of approximately two hours. Plasma clearance ranged between 110-116 ml/min. The urinary recovery of tranexamic acid exceeded 95% of the dose. Ten healthy volunteers were given tranexamic acid 2 g orally on an empty stomach, and together with a meal. Food had no influence on the absorption of tranexamic acid, as judged by comparison of the peak plasma concentration, the time required to reach the peak, the AUC from zero to six hours, and the urinary excretion data. The oral bioavailability of tranexamic acid, calculated from 24 h urinary excretion after oral and intravenous administration, was 34% of the dose.

Tranexamic acid in the preoperative management of ruptured intracranial aneurysms.

A randomized, controlled clinical trial was carried out to study the effect of tranexamic acid (AMCA, trans-AMCHA) in prevention of early rebleeding after proven rupture of an intracranial aneurysm. The series comprises 46 patients admitted to the hospital within three days after the first bleeding. Twenty-three were treated with tranexamic acid and 23 were controls. Nine patients in the control group and one in the group treated with tranexamic acid had confirmed rebleeding. The incidence of vasospasm, cerebral ischemia and hydrocephalus as well as mortality and morbidity is discussed.