Methods of Antifibrinolytics Administration and their Side Effects

In Reply: Continuous administration of tranexamic acid (6–16 g/day) has been reported to reduce the frequency of rebleeding after aneurysmal subarachnoid hemorrhage (SAH), but to increase the risk of delayed cerebral ischemia owing to vasospasm (11–13, 20). Antifibrinolytics therapy is not used for SAH nowadays because overall outcome does not improve (11, 13). In our study for intracerebral hemorrhage (ICH), the total dose of tranexamic acid, which was 2 g (17), is far smaller than those for SAH. To obtain hemostasis of ICH at the beginning of the treatment, an initial loading of sufficient amount of tranexamic acid makes the clot firm. Once the clot is stabilized, strict control of blood pressure maintains the hemostasis. Then, we did not use tranexamic acid continuously. In all of the case reports on side effects of antifibrinolytics referred by Dr. Fodstad, a large amount of antifibrinolytics was administered continuously (1–6, 8, 9, 14, 19). The side effects were observed during continuous administration of epsilon-amino caproic acid (23–36 g/day) or tranexamic acid (3–6 g/day). Myopathy was induced by continuous administration of antifibrinolytics for 4 weeks or longer (1, 2, 8, 9, 19). Cerebral infarct not related to vasospasm after SAH occurred during continuous medication with antifibrinolytics for 1 year or longer (4, 14). Reduction or disappearance of cerebral aneurysms was observed during continuous administration of antifibrinolytics for 3 weeks or longer (5). On the other hand, in two case reports renal failure was induced in the early phase of treatment with continuous administration of epsilon-amino caproic acid when the patients were in a serious condition with hypotension (3, 6). Thromboembolic complication rates related to continuous administration of tranexamic acid have not been reported so high. Vermeulen et al. (20) reported their randomized control study on SAH using continuous administration of tranexamic acid (6 g/day) for 1 week or longer. In their study deep-vein thrombosis was evident in 21 of 241 patients at 3 months, and there was no difference in incidence between the study groups. Roos et al. (12) reported randomized study on SAH using continuous administration of tranexamic acid (6 g/day) for up to 3 weeks. A serious adverse drug reaction observed in their study was pulmonary embolism, and it was found in only four of 229 patients. On the other hand, a relative small amount of tranexamic acid was administered continuously in two studies on SAH. In one study, tranexamic acid (1.5 g/day) was given for 5 to 25 days (18), and, in another, 5 g/day for up to 3 days (7). In these studies, there were no indications of increased risk of either cerebral ischemia owing to vasospasm or thromboembolic complications that could be linked to tranexamic acid treatment. In our study, 2 g of tranexamic acid was administered for only one time, and, to our knowledge, no serious adverse effect has been reported with this dose of tranexamic acid. Tranexamic acid has been used for about 40 years, and approximately 1,240,000 g of tranexamic acid was supplied in 2004. According to the attached document of tranexamic acid, a limited number of clinical cases of renal dysfunction, cerebral ischemia, cardiac ischemia, and venous thrombosis were reported as serious side effects, and these side effects should be carefully checked during treatment with tranexamic acid. However, these side effects could be regarded as rare, considering the large amount of tranexamic acid consumption. The half-life of 1g of intravenously administered tranexamic acid was 1.9 hours, and 94.8% of it was excreted into urine within 2 days (16). The thromboembolic complications in the rapid administration of antifibrinolytics (RAF) group of our study occurred 4 to 45 days after administration of tranexamic acid (17), while the tranexamic acid was already excreted. However, the possibility cannot be eliminated that tranexamic acid became a trigger to proceed the thromboembolic complications. Table 1 shows thromboembolic complications in the prolonged infusion of antifibrinolytics (PAF) group and the RAF group of our study. The PAF group was used as a control in this study, because PAF has been used in many Japanese hospitals. Thromboembolic complications in the RAF group were described (17). In the PAF group, either a history or presence of renal dysfunction was present in eight patients at admission, and, in one of them, renal function was worsening. Newly developed renal dysfunction after admission was observed in two patients. These renal dysfunctions improved after conservative treatment. A history of ischemic heart disease was found in two patients in the PAF group. None of them showed a recurrence during their hospital treatment. Two patients without history of ischemic heart disease experienced angina pectoris and one patient, who died 50 days after admission, sustained acute myocardial infarction. Five patients in the PAF group had a history of cerebral infarction. None of them sustained cerebral infarction. Newly developed cerebral infarction was observed in one patient. In the PAF group, these complications also seem to have no relationship with the administration of tranexamic acid, because of the interval (3-50 d) between the administration and the occurrence of the symptoms. No significant difference was observed in occurrence of thromoboembolic complications between the PAF group (11.1%) and the RAF group (5.4%) (P = 0.19, χ2 analysis). During and after the treatment with tranexamic acid, adverse effects should be carefully monitored. When a patient has a history of renal dysfunction, dose reduction of tranexamic acid and/or mild blood pressure control might be better to preserve renal function. In all patients treated with this method, careful check of urine volume and renal function should be recommended.TABLE 1: Complications in patients treated with prolonged infusion of antifibrinolytics and rapid administration of antifibrinolyticsClinical Outcome Table 2 shows modified Rankin Scale (mRS) at 1 month after the onset or at discharge. In patients with good outcome (mRS = 0, 1, or 2), no significant difference was observed between the PAF group (19.1%) and the RAF group (26.9%) (P = 0.26, Χ2analysis). On the other hand, more patients had serious outcome (mRS = 5, dead) significantly in the PAF group (36.5%) than those in the RAF group (21.5%) (P = 0.04, χ2analysis). Table 3 shows mRS in patients with hematoma enlargement. In patients without hematoma enlargement, no significant difference was observed in serious outcome (mRS = 5, dead) between the PAF group (34.6%) and the RAF group (20.2%) (P = 0.06, χ2 analysis). Considering the small number of hematoma enlargement in both groups, we cannot conclude that clinical outcome improved in the RAF group by reduction of hematoma enlargement in this study. On the other hand, in all of the patients with hematoma enlargement in this study, consciousness level, and/or severity of paresis became worse in the day after admission than those at admission. Furthermore, no patients with hematoma enlargement showed good outcome (mRS = 0, 1, or 2). Therefore, we considered that hematoma enlargement resulted in worsening of clinical state.TABLE 2: Clinical outcome in patients treated with prolonged infusion of antifibrinolytics and rapid administration of antifibrinolyticsTABLE 3: Clinical outcome in patients with hematoma enlargementWho is the winner? The authors are not related to the drug company, and did not receive any assistance from the drug company. Tranexamic acid costs about $3.00 for 2 g in Japan. Therefore, the drug company is not considered the winner. We think that the winners are the patients without hematoma enlargement treated with this low-cost method. The prolonged infusion of tranexamic acid has been used for ICH in many Japanese hospitals because tranexamic acid is regarded as a relatively safe drug. ICH occurred more frequently in Japan compared with the United States and Europe (15). More than one-fifth of stroke patients treated in our cerebrovascular center experience ICH. ICH is the least treatable form of stroke and is associated with higher morbidity and greater disability than ischemic stroke or SAH (15). Intervention with hemostatic therapy might improve a patient’s disability after ICH by arresting ongoing bleeding and minimizing increases in the volume of the hematoma (10). A well-designed, randomized, control study is needed to confirm our results, and to determine the appropriate dose of tranexamic acid. Side effects, including renal dysfunction, should be carefully monitored during and after the treatment. Takatoshi Sorimachi Tokyo, Japan