Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage.
Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage.
This is a multicenter, prospective, randomized, open-label trial with blinded endpoint
 (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by
 computed tomography (CT) within 24 hours after the onset of headache, will be randomly
 assigned to the treatment group or the control group. Patients in the treatment group will
 receive standard treatment with the addition of a bolus of TXA (1 g intravenously)
 immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the
 start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients
 in the control group will receive standard treatment without TXA. The primary outcome measure
 is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale
 (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for
 treatment allocation.
Approximately 50% of all patients with a subarachnoid hemorrhage (SAH) die due to the
 hemorrhage or subsequent complications. There are several major causes for this course, such
 as in-hospital rebleed in 21.5% which most frequently occurs within the first 6 hours after
 the primary hemorrhage ("ultra-early rebleed"). A major part of the patients with a rebleed
 die during hospital admission and when they survive, they develop more severe cognitive
 dysfunctions. Reducing the rebleeds by ultra-early administration of tranexamic acid (TXA)
 could be a major factor in improving the functional outcome after SAH.

 To evaluate whether SAH patients treated by state-of-the-art SAH management with additional
 ultra-early and short term TXA administration have a significantly higher percentage of
 favourable outcome after six months (score 0-3 on the Modified Rankin Scale) compared to the
 group treated by up-to-date SAH management without additional TXA.

 To evaluate whether: 1) TXA reduces in-hospital rebleeds and case fatalities; 2) TXA causes
 more ischemic stroke 3) TXA causes more complications (such as thromboembolic events,
 hydrocephalus, extracranial thrombosis or hemorrhagic complications) during treatment,
 admission and follow-up; 4) there is a difference in causes of poor outcome between groups;
 5) there is a difference in discharge locations between groups; 6) there is an association
 between the time between hemorrhage and TXA administration and outcome; 7) TXA increases
 (micro)infarctions after endovascular treatment; 8) TXA reduces health-care costs between
 discharge and six months after hemorrhage; 9) TXA improves quality of life at six months
 after hemorrhage; 10) there are differences in rebleed rates and outcome between genders or
 groups with different WFNS scores at admission.

 Multicenter, prospective, randomized, open label treatment with blind endpoint assessment.

 Adult patients (18 years and older) included within 24 hours after SAH. Group one: standard
 treatment with additional administration of 1 g TXA intravenously in ten minutes, immediately
 after the diagnosis SAH, succeeded by continuous infusion of 1 g per 8 hours until a maximum
 of 24 hours. Group two: standard treatment with no TXA administration. Both groups undergo a
 standardized and validated interview at discharge and six months after hemorrhage to assess
 the modified Rankin Scale score, and both groups receive a questionnaire to evaluate
 health-care costs and quality of life.

 Primary: modified Rankin Scale score after six months, dichotomized into favourable and
 unfavourable outcome. Secondary: rebleed and case fatality rate, complications during the
 first six months after hemorrhage, (micro)infarctions at MR imaging after endovascular
 treatment, health-care costs from discharge until six months, quality of life at six months
 and differences in rebleed rates and outcome between genders or WFNS score at admission.

 Nature and extent of the burden and risks associated with participation, benefit and group
 relatedness: Subjects are randomly allocated to ultra-early TXA therapy or standard
 treatment. Complications are minor and the expected benefit is large compared with separate
 studies done with antifibrinolytic medications. In these studies, the safety of the use of
 these medications in this study population is confirmed. In this patient group there are
 adequate, disoriented and comatose patients on admission, so a part of the studied patients
 are incapacitated when undergoing the study. To extrapolate the conclusions of this study to
 clinical protocols it is necessary to include patients with a SAH in all different severity
 grades. Weighing carefully the benefits versus the burden and risks, it is assumed that
 patients will benefit from ultra-early TXA administration with minimal burden during therapy.
Inclusion Criteria:

 -  Admission to one of the study centers or their referring hospitals

 -  CT-confirmed SAH with most recent ictus less than 24 hours ago Definition:
 subarachnoid hemorrhage is a bleeding pattern on computed tomography with hyperdensity
 in the basal cisterns and/or Sylvian or interhemipheric fissures or a intraparenchymal
 hyperdensity consistent with a hematoma from an anterior, a pericallosal, a posterior
 or a middle cerebral artery aneurysm.

 Exclusion Criteria:

 -  No proficiency of the Dutch or English language

 -  No loss of consciousness after the hemorrhage with WFNS grade 1 or 2 on admission in
 combination with a perimesencephalic hemorrhage Definition: on CT examination presence
 of hyperdensities exclusively in the basal cisterns maximal extending to the proximal
 part of the Sylvian fissure or posterior part of the interhemispheric fissure, without
 evidence for intracerebral or intraventricular haemorrhage (except slight
 sedimentation)

 -  Bleeding pattern on CT compatible with a traumatic SAH

 -  Treatment for deep vein thrombosis or pulmonary embolism

 -  History of a blood coagulation disorder (a hypercoagulability disorder)

 -  Pregnancy checked with a pregnancy test in women in their childbearing period

 -  History of severe renal (serum creatinin >150 mmol/L)

 -  History of severe liver failure (AST > 150 U/l or ALT > 150 U/l or AF > 150 U/l or
 γ-GT > 150 U/l)

 -  Imminent death within 24 hours