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Spontaneous intracerebral hemorrhage (ICH) can be devastating, particularly if hematoma expansion (HE) occurs. Tranexamic acid (TA), an antifibrinolytic drug, significantly reduced mortality in bleeding patients after trauma in the large CRASH-2 trial. The CRASH-2 ICH substudy found that TA nonsignificantly reduced mortality and dependency in traumatic ICH. The aim of this study was to assess the feasibility of performing a randomized controlled trial of tranexamic acid in spontaneous ICH, ahead of a definitive study.
Methods
We performed a single-center, prospective, randomized (2:1), double-blind, placebo-controlled blinded endpoint trial of TA (intravenous 1 g bolus, 1 g infusion/8 h) in acute (<24 hours) spontaneous ICH. The primary objective was to test the feasibility of recruiting to the trial. Other objectives included tolerability (adverse events) and the effect of TA on HE and death and dependency.
Results
The trial was feasible, with 24 patients enrolled (TA, n = 16; placebo, n = 8) between March 2011 and March 2012, and acceptable—only 3 patients declined to participate. All patients received the correct randomized treatment; 1 patient in the TA group did not complete the infusion because of neurologic deterioration. There were no significant differences in secondary outcomes including adverse events, HE, death, and dependency. One patient in the TA group had a deep vein thrombosis .
Conclusions
This, the first randomized controlled trial of TA in ICH, found that the protocol could be delivered on schedule (2 patients/mo) and was feasible. Larger studies are needed to assess safety and efficacy of TA in ICH.
Spontaneous intracerebral hemorrhage (ICH) is a common cause of death and disability worldwide. Outcome after ICH is closely related to both hematoma size and hematoma expansion (HE), which is associated with a bad outcome (death and disability).
Extravasation of arterial blood can be visualized as a white “spot” using contrast-enhanced computed tomography (CT) and/or CT angiography (CTA); the presence of spot-positive hematoma predicts HE and a poor outcome.
Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion.
PREDICT/Sunnybrook ICH CTA Study Group Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study.
Early surgery versus initial conservative treatment in patients with spontaneour supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial.
STICH II Investigators Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial.
trials. Acute blood pressure lowering appears to be safe and may improve outcome in ICH although this was not conclusively demonstrated in the INTERACT studies.
This study focuses on a hemostatic approach to ICH.
Hemostatic drug therapies have been tested in spontaneous ICH, with recombinant factor VIIa (FVIIa) being the most widely studied agent. Although phase II study of FVIIa appeared promising,
Tranexamic acid is a licensed antifibrinolytic drug that can be administered intravenously or orally and is used to reduce bleeding in several conditions including menorrhagia and during cardiac surgery.
In a recent megatrial (CRASH-2) in 20,000 patients with major bleeding after trauma, tranexamic acid (TA) significantly reduced mortality, with no increase in vascular occlusive events.
CRASH-2 Trial Collaborators Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
The CRASH-2 Collaborators The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.
However, patients in CRASH-2 were younger and had less comorbidities than those with spontaneous ICH. In another randomized controlled trial in traumatic ICH, TA nonsignificantly reduced death and death or dependency, without increased thromboembolic events.
Tranexamic acid has been tested in aneurysmal subarachnoid hemorrhage, where it reduced the risk of rebleeding at the expense of increased risk of cerebral ischemia.
Yvo Roos GR, Vermeulen M, Algra A, et al. Antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage: a major update of a cochrane review stroke. 2003;34:2308–2309.
However, administration was prolonged, conferring prolonged exposure to risk of ischemic events. A trial of immediate short-term (72 hours) TA treatment showed a trend to improved outcome,
Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study.
The aim of the present study was to test the feasibility of performing a randomized controlled trial of TA in ICH and assess initial safety, ahead of a definitive study.
Methods
We performed a prospective, randomized, placebo-controlled, blinded end point single-center phase IIa trial of TA in patients with acute spontaneous ICH. The study was approved by Cambridgeshire 2 Research Ethics Committee (November 1, 2010, ref: 10/H0308/80), had a Medicines and Healthcare Products Regulatory Agency Clinical Trial Authorization (03057/0044/0010001, October 4, 2010), was registered with a trial number (ISRCTN 50867461), and performed according to the Declaration of Helsinki and Good Clinical Practice.
Subjects
Adult patients with acute (<24 hours after ictus) spontaneous ICH were identified and enrolled from the stroke service at Nottingham University Hospital NHS Trust. The principal exclusion criteria included secondary ICH (anticoagulation, known vascular malformations), previous venous thromboembolic disease (VTE), recent (<12 months) ischemic events (ischemic stroke [IS], myocardial infarction, peripheral artery disease [PAD]), renal impairment (estimated glomerular filtration rate <50 mmol), and pregnancy or breast feeding.
Full written informed consent was obtained from patients before randomization, or proxy consent was taken from a relative/carer if the patient lacked capacity because of being obtunded, confused, or dysphasic.
Intervention
Patients were randomized to receive either intravenous TA (Cyklokapron; Phamacia Limited, Kent, UK) administered as a 1-g loading dose infusion for 10 minutes followed by a 1-g infusion for a period of 8 hours or matching placebo (.9% saline) administered by identical regime. This regime has been used in other studies
CRASH-2 Trial Collaborators Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
Computerized randomization was performed 2:1 (TA:placebo) with minimization on age, sex, baseline severity (National Institutes of Health Stroke Scale [NIHSS]), and time from stroke onset.
Outcomes
The primary outcome was trial feasibility (surrogate for trial acceptability:number of patients screened who are eligible for enrollment and who gave informed consent).
Secondary outcomes included tolerability (adverse events occurring during or after administration of TA) and safety (clinical information on ischemic events [IS, transient ischemic attack, acute coronary syndrome, PAD] and VTE were also recorded). The Data Safety Monitoring Committee reviewed unblinded safety data after 6, 12, and 18 patients have been recruited and followed for 7 days.
Clinical measures: impairment (NIHSS) at day 7 (or discharge from hospital) and day 90 (end of follow-up); dependency (modified Rankin Scale shift), disability (Barthel Index), quality of life (EuroQoL), mood (Short Zung Depression Scale score), and cognition (telephone MMSE) at day 90.
Radiological measures: percentage hematoma volume change on brain imaging day 1 to day 2 and HE (defined as greater than 6-mL absolute increase in hematoma volume
). All image analyses were performed blinded to clinical status and treatment allocation. CT scan data were exported from the Nottingham University Hospitals Picture Archiving and Communication System in DICOM format to an offline image analysis workstation. The data were converted to analyze format before volumetric analysis using 3DSlicer software.
Fedorov A, Beichel R, Kalpathy-Cramer J, et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging.30:1323–1341.
by a single investigator (Y.K.) in all cases. In a subset of 8 cases, the ICH volume on the baseline and follow-up scans (hence 16 scans) was measured by a second experienced observer (R.A.D.) allowing interobserver variability measurement for ICH volumes and for the calculated change in ICH volume between the 2 scans. Additionally, difference in ICH volume measurement between the 2 readers was calculated as a type A intraclass correlation using an absolute agreement definition.
Statistical Methods
Data were analyzed using Fisher exact test, t test, and Mann–Whitney U test, as appropriate. All analyses were performed using SPSS (Apple Mac, version 11; SPSS Inc., Chicago, IL). Analysis was by intention-to-treat; significance was taken at P less than .05. As this was a feasibility study, no formal sample size calculation was performed.
Results
Of 107 patients who were screened between March 2011 and April 2012, 24 were enrolled (Fig 1). The commonest reason for non-enrollment was inability to randomize within 24 hours of onset because of unknown time of onset. Other reasons included need for immediate neurosurgery (10) and deep coma (6). Of eligible patients, 3 declined to consent.
Figure 1Consort flow diagram. Abbreviations: ADR, adverse drug reaction; MMSE, Mini-Mental State Examination; RCT, randomized controlled trial; VAS, visual analog scale; ZDS, zung depression scale.
The baseline characteristics were matched for age, sex, systolic blood pressure, and baseline stroke severity (Table 1); patients randomized to TA had a trend to larger hematoma volumes, earlier randomization, and were more likely to have had previous stroke and be on antiplatelet therapy.
Table 1Baseline characteristics
Active
Placebo
Total
Number of patients
16
8
24
Age, mean
67.9 (13.2)
68.5 (12.9)
68.1 (12.8)
Sex (male %)
10 (62.5)
4 (50)
15 (62.5%)
Systolic blood pressure (mm Hg)
166.6 (19.6)
165.5 (27.5)
166.3 (21.9)
NIHSS (/42)
14.8 (8.9)
15.9 (9.1)
15.1 (8.8)
Glasgow Coma Scale (/15)
12.7 (3.1)
12.8 (2.7)
12.7 (2.9)
History of previous stroke (%)
2 (12.5)
0
2 (8.3%)
History of hyperlipidemia (%)
5 (31.3)
0
5 (20.8%)
History of hypertension (%)
10 (62.5)
5 (62.5)
15 (62.5%)
History of IHD (%)
0
0
0
History of PAD (%)
0
0
0
History of TIA (%)
1 (6.3)
2 (25)
3 (12.5%)
History of AF (%)
1 (6.3)
0
1 (4.2%)
History of diabetes mellitus (%)
2 (12.5)
0
2 (8.3%)
History of previous antiplatelet use (%)
4 (25%)
1 (12.5)
5 (20.1%)
Ethnicity (%)
African
2 (12.5)
0
2 (8.3%)
South Asian
1 (6.3)
0
1 (4.2%)
White British
13 (81.3)
8 (100)
21 (87.5%)
Sinus rhythm on ECG
15 (93.6)
8 (100)
Atrial fibrillation of ECG
1 (6.3)
0
1 (4.2%)
Smoking, current (%)
3 (18.7)
0
3 (12.5%)
Modified Rankin Scale (/6)
.5 (1.0)
.1 (.4)
.4 (.9)
Onset to randomization (h)
11.3 (7.4)
15.2 (9.4)
12.6 (8.1)
Abbreviations: AF, atrial fibrillation; ECG, electrocardiogram; IHD, ischemic heart disease; NIHSS, National Institutes of Health Stroke Scale; PAD, peripheral artery disease; TIA, transient ischemic attack.
All patients received all their bolus injection, and 1 patient in the tranexamic group did not receive their infusion because of rapid deterioration, which initially was thought to be an allergic reaction but was later confirmed as because of HE.
No patients were lost to follow-up; however, cognition, mood, and quality of life data were missing in a number of participants who were unable to answer questions because of communication problems. There were no significant differences in functional outcomes between the groups (Table 2); point estimates variably favored TA or placebo but with no apparent trends.
Table 2Secondary outcomes at day 90
Outcome
Tranexamic acid
Placebo
Total
2P
Modified Rankin Scale (/6)
3.6 (1.9)
3.4 (2.1)
3.5 (1.9)
.82
Barthel Index (/100)
59.2 (39.7)
81.7 (18.1)
66.3 (35.5)
.11
MMSE (/30)
21.3 (.8)
18.6 (4.0)
20.2 (2.8)
.21
Zung Depression Scale (/40)
21.3 (12.6)
18.2 (6.8)
20.1 (10.5)
.63
EuroQoL: HUS
.5 (.5)
.54 (.27)
.51 (.44)
.89
EuroQoL: Visual analogue scale (/100)
76.8 (14.3)
66.3 (17.0)
73.3 (15.3)
.28
Length of stay (d)
19.4 (24.5)
10.8 (14.0)
16.6 (21.7)
.37
Day 90 disposition (%)
Living at home
10 (62.5)
6 (75)
16 (66.7)
.22
In-patient
2 (12.5)
0
2 (8.3)
1.0
Nursing home
1 (6.3)
0
1 (4.2)
1.0
Death
3 (18.8)
2 (25)
5 (20.8)
.72
Abbreviations: HUS, health utility score; MMSE, Mini-Mental State Examination.
Six patients in the TA group and 2 in the control group had SAEs (Table 3). One patient had a deep vein thrombosis 8 days after treatment with TA; there were no other episodes of VTE or arterial thrombosis (IS, transient ischemic attack, acute coronary syndrome, or PAD); 5 patients in the TA group and 2 in the control group had neurologic deterioration (NIHSS score >1).
Basal ganglia hematoma were more common than lobar hematoma in both groups (Table 4). Only 4 patients had CTA before randomization, and none of these were positive for contrast extravasation (ie, all “spot negative”).
Table 4Radiological measures between TA versus placebo
The intraclass correlation coefficients of .997 (95% confidence interval .989-.999, P < .0005) and .953 (95% confidence interval .803-.990, P < .0005) were obtained for absolute ICH volume and for the calculated change in ICH volume. The mean difference in absolute ICH volume measurement between the 2 readers was 1.75 mL (range .01-4.91 mL).
Four patients had radiological HE, 3 in the TA group and 1 in the control group. There was a trend to greater percent HV increase in the control group (9.7%) versus the TA group (5.4%).
Discussion
There is an urgent need for effective treatments for ICH. We have shown here that administration and testing of the prohemostatic agent TA in ICH is feasible. However, the numbers enrolled in this study are too small to draw any conclusions on safety or efficacy, and as expected, no trends were seen for or against TA.
Twenty-four patients were recruited over 2 years (2 patients/mo), the intended rate. All patients bar 1 received the full dose of TA/placebo. With respect to safety, no significant differences between TA and placebo were seen for rates of death, serious adverse events, neurologic deterioration, or VTE. The commonest adverse event was neurologic deterioration, often associated with HE, although in a number of patients, it was associated with a systemic cause, such as aspiration pneumonia or atrial fibrillation. With respect to VTE, a potential complication with TA, 1 patient had a deep vein thrombosis 8 days after treatment with TA; larger numbers are needed to assess safety; however, no increase in VTE was seen in CRASH-2.
CRASH-2 Trial Collaborators Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
We used a definition of HE of greater than 6-mL absolute increase. Five patients had more than 33% increase in hematoma volume, but in only 3 of these, the volume increase was greater than the 3-mL absolute increase. Again, there was no difference between TA and placebo. Patients in the treatment group were more likely (nonsignificant) to have been taking antiplatelet therapy, a risk factor for HE.
PREDICT/Sunnybrook ICH CTA Study Group Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study.
We did not include patients on the basis of CTA; first, CTA is not a standard of care in stroke patients in the United Kingdom (in our study, only 4 patients had a CTA), and second, spot-negative patients can still go on to suffer HE.
There was no increase in cerebral edema, an important finding, as an experimental model of warfarin-induced ICH demonstrated that TA-treated animals had increased cerebral edema. This warrants further investigation in a larger study.
The limitations of this study are 3-fold. First, it was a very small pilot study, designed only to test the feasibility of performing a randomized control trial of TA in ICH. Second, patients were recruited at an average time of 10-15 hours postonset, that is, in the acute rather than hyperacute phase after ICH. The window for recruitment of up to 24 hours was deliberately chosen because this was a feasibility study. Nevertheless, it is likely that any prohemostatic agent will need to be given much earlier if it is to be effective by reducing HE because expansion occurs early after onset.
All the patients who underwent HE were enrolled greater than 4 hours after stroke onset, and 5 of 6 received treatment more than 12 hours after ictus. Patients in the treatment group were enrolled somewhat earlier and had somewhat larger baseline hematoma volumes although both observations were nonsignificant; these findings are not surprising because earlier randomization is expected to be associated with more severe stroke presentations.
The feasibility of recruiting patients to a hyperacute (short time window), multicenter trial was not addressed by this pilot study; however, other studies suggest that this will be feasible.
Third, although we did not confirm that fibrinolysis was inhibited in vitro, the dose regime used for administering TA here has been demonstrated to have antifibrinolytic action in other studies.
In conclusion, we found it was feasible to administer TA in acute ICH. Larger studies, recruiting patients much earlier, are now needed to determine safety and efficacy. A number of such studies are in preparation with 2 studies currently recruiting patients. One such phase III trial, TICH-2,
STOP-AUST: the spot sign and tranexamic acid on preventing ICH growth—AUStralasia trial. 2013. Available at: http://clinicaltrials.gov/show/NCT01702636. Accessed August 8.
phase II trial will assess the effect of TA on hematoma expansion in “spot-positive” patients.
Acknowledgments
We thank the patients who took part in the TICH study and the members of the Data Safety Monitoring Committee: Ashit Shetty (Stroke Physician, Nottingham), P.M.W.B., and C.J.R. N.S. and P.M.W.B. conceived the study and drafted the manuscript, C.J.R. performed statistical input, and Y.K. and R.A.D. performed neuroradiological input and comments on the manuscript. All authors have read and approved the submitted manuscript.
References
Steiner T.
Bosel J.
Options to restrict hematoma expansion after spontaneous intracerebral hemorrhage.
Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion.
Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study.
Early surgery versus initial conservative treatment in patients with spontaneour supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial.
Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial.
Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.
The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.
Yvo Roos GR, Vermeulen M, Algra A, et al. Antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage: a major update of a cochrane review stroke. 2003;34:2308–2309.
Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study.
Fedorov A, Beichel R, Kalpathy-Cramer J, et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging.30:1323–1341.
STOP-AUST: the spot sign and tranexamic acid on preventing ICH growth—AUStralasia trial. 2013. Available at: http://clinicaltrials.gov/show/NCT01702636. Accessed August 8.
Disclosure: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.
Conflict of interest: None.
Funding: TICH was funded by the University of Nottingham early career research and knowledge transfer award, The Stroke Association (start up bursary for N.S.), and the Division of Stroke, University of Nottingham. P.M.W.B. is the Stroke Association Professor of Stroke Medicine.
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