Rapid Administration of Antifibrinolytics and Strict Blood Pressure Control for Intracerebral Hemorrhage
To the Editor:
In a retrospective study, the administration of antifibrinolytics and strict blood pressure control was reported to prevent hematoma growth in patients with spontaneous intracerebral hemorrhage (37). A combination of tranexamic acid and nicardipine was given intravenously to 156 patients. One group received a prolonged infusion of 1 g tranexamic acid over a period of 6 hours and the second group was given a rapid infusion of 2 g tranexamic acid over a period of 10 minutes. Hematoma growth was observed in 17.5 % of the 63 patients in the first group and in 4.3 % of 93 patients in the second group.
The most commonly used synthetic antifibrinolytics are epsilon-aminocaproic acid (EACA), tranexamic acid (AMCA) and para-aminobenzoic acid (PAMBA). On a molar basis AMCA is four to 10 times more potent than EACA and twice as strong as PAMBA (2, 26, 29, 31, 34). These antifibrinolytics have been shown to cross the blood-cerebrospinal fluid (CSF) barrier to reduce or inhibit the increased fibrinolytic activity of blood or CSF after aneurysmal subarachnoid hemorrhage (SAH) and to prolong and solidify experimental thrombosis (12, 15, 16, 30, 35). The therapeutic plasma concentration of synthetic antifibrinolytic drugs has been estimated to be more than 130 mg/L for EACA and more than 10 mg/L for AMCA, which requires an intravenous dosage of 24–36 g of EACA and 3–6 g of AMCA/ 24 hours (3, 14, 28). It is known that antifibrinolytic agents possess sympathomimetic properties and may, theoretically, induce vasoconstriction, possibly by acting via the adrenergic nerve terminals and thus deplete the stored catecholamines (1, 17, 24, 27, 32, 33). There have been several reports of thrombotic episodes, glomerular microthrombi, myopathy, myoglobinuria and cardiovascular complications following administration of antifibrinolytic drugs 4–8, 13, 18, 19, 20, 22, 23, 25, 36, 38, 40). Randomized controlled studies using antifibrinolytics in patients with SAH have shown increased delayed cerebral ischemic complications (9–11, 14, 15, 39). Some authors have suggested the use of antifibrinolytics in combination with calcium channel blockers (nicardipine, nimodipine) in the hope of reducing rebleeds as well as delayed cerebral ischemic complications in SAH (21). However, today the prime rationale for the use of antifibrinolytic drugs in SAH has disappeared (14).
In the present study, no serious adverse effects were noted (37). The occurrence of renal dysfunction in three patients and fatal myocardial infarction in two patients were considered to have no relationship with the administration of tranexamic acid. In my opinion, the authors have no basis for this assumption, and they have refrained from documenting the pharmacokinetics, toxicology, and important side effects of the drug. They simply refer to an “attached document” from the drug manufacturer stating that up to 2.5 g of tranexamic acid can be safely administered in a single dose and, therefore, settled for an arbitrary dose of 2 g. Patients who required surgery or who had a bad prognosis were not included, whereas 20 patients with history of renal disease, angina pectoris, and myocardial infarction were included. There is no mention of clinical outcomes in the report, and the only thing we learn from the study is that there was less hematoma growth. Who is the winner here, the patient or the drug company?
With regard to the potential serious side effects of tranexamic acid as documented in the literature, the therapeutic regimen for intracerebral hemorrhage described in this limited study should be disregarded until a carefully designed randomized controlled clinical trial has been conducted.
New York, New York
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