Haemostatic treatment for intracerebral haemorrhage
Authors: Joseph P Broderick
Journal: The Lancet (2018)

Spontaneous intracerebral haemorrhage remains the only stroke subtype without a scientifically proven treatment. The baseline factors associated with intracerebral haemorrhage mortality and functional outcomes are volume of intracerebral or intraventricular haematoma, growth of intracerebral haematoma during first hours of onset, age, Glasgow Coma Scale, and infratentorial location.1Hemphill 3rd, JC Bonovich DC Besmertis L Manley GT Johnston SC The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.Stroke. 2001; 32: 891-897Crossref PubMed Google Scholar, 2Davis SM Broderick J Hennerici M et al.Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66: 1175-1181Crossref PubMed Scopus (860) Google Scholar, 3Brott T Broderick J Kothari R et al.Early hemorrhage growth in patients with intracerebral hemorrhage.Stroke. 1997; 28: 1-5Crossref PubMed Scopus (1172) Google Scholar, 4Broderick J Brott T Duldner J Tomsick T Huster G Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality.Stroke. 1993; 24: 987-993Crossref PubMed Scopus (1420) Google Scholar Of these factors, only the growth of intracerebral or intraventricular haematomas and their resulting volumes are biologically modifiable. However, the time course of ongoing bleeding for intracerebral haemorrhage is even shorter than it is for focal brain ischaemia, with the large majority of bleeding completed within 3 h of onset.2Davis SM Broderick J Hennerici M et al.Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66: 1175-1181Crossref PubMed Scopus (860) Google Scholar, 3Brott T Broderick J Kothari R et al.Early hemorrhage growth in patients with intracerebral hemorrhage.Stroke. 1997; 28: 1-5Crossref PubMed Scopus (1172) Google Scholar, 5Mayer SA Brun NC Begtrup K et al.Recombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med. 2005; 352: 777-785Crossref PubMed Scopus (1155) Google Scholar, 6Mayer SA Brun NC Begtrup K et al.Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med. 2008; 358: 2127-2137Crossref PubMed Scopus (978) Google Scholar The TICH-2 trial reported by Nikola Sprigg and colleagues7Sprigg N Flaherty K Appleton JP et al.Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.Lancet. 2018; (published online May 16.)http://dx.doi.org/10.1016/S0140-6736(18)31033-XSummary Full Text Full Text PDF PubMed Scopus (217) Google Scholar in The Lancet is an international, randomised, placebo-controlled trial of adults with intracerebral haemorrhage. 2325 participants (1024 [44%] women, mean age 68·9 years) received 1 g intravenous tranexamic acid bolus followed by an infusion of another 1 g intravenous tranexamic acid over 8 h, or matching placebo, within 8 h of symptom onset. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale (mRS) analysed via ordinal logistic regression, with adjustment for stratification and minimisation criteria. The TICH-2 trial has several major strengths: very broad and generalisable inclusion criteria, a therapeutic agent shown to slow traumatic bleeding with a good safety record, a large sample size for a stroke trial, and a clear statistical design with a modest planned effect size, given the broad inclusion criteria. Unfortunately, TICH-2 found no significant difference in functional status 90 days after intracerebral haemorrhage with tranexamic acid (adjusted odds ratio [aOR] 0·88, 95% CI 0·76–1·03, p=0·11). Additionally, there was no difference between the tranexamic acid and placebo groups in the proportion of participants who were dead or dependent at day 90 (ie, mRS >3; aOR 0·82, 95% CI 0·65–1·03, p=0·08), despite a reduction in early deaths and serious adverse events. Thus, TICH-2 showed the safety of tranexamic acid but not significance for the primary clinical endpoint. Yet the strengths of TICH-2, broad inclusion criteria, and the biological effects of the therapeutic agent under study, are the most likely explanations for the negative trial results. A 1·4 mL decrease in haematoma growth from baseline to 24 h, as detected in the tranexamic acid group compared with the placebo group, is unlikely to change clinical outcomes substantially. In a previous trial of recombinant factor VIIa (rFVIIa), for each 1 mL increase in intracerebral haematoma volume from baseline, patients were 6% more likely to have an increase of one full point on the mRS.2Davis SM Broderick J Hennerici M et al.Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66: 1175-1181Crossref PubMed Scopus (860) Google Scholar One would expect that a therapeutic agent would need to decrease growth by 3–4 mL to provide a detectable clinical benefit without a very large sample size. How much of this limited effect on haematoma growth in TICH-2 was due to the biological effect of tranexamic acid on haemostasis and how much was due to the timing of administration of tranexamic acid in the trial cannot be determined from the published data. In the phase 2B rFVIIa trial, the haemostatic effect of rFVIIa, a procoagulant haemostatic agent, was more evident when treatment was given within 3 h after the onset of symptoms; the absolute increase in volume of intracerebral haemorrhage was 10·7 mL for the placebo group, as compared with 4·4 mL for the rFVIIa-treated patients (p=0·009).5Mayer SA Brun NC Begtrup K et al.Recombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med. 2005; 352: 777-785Crossref PubMed Scopus (1155) Google Scholar There was no effect on haemorrhage growth in patients treated with rFVIIa beyond 3 h from onset.5Mayer SA Brun NC Begtrup K et al.Recombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med. 2005; 352: 777-785Crossref PubMed Scopus (1155) Google Scholar Additional subgroup analyses of haemorrhage growth at 3 h and 2 h after onset in the TICH-2 database could clarify whether tranexamic acid's limited effect on intracerebral haemorrhage growth is related to the strength of its haemostatic effect or the timing of treatment. A limitation of TICH-2 is its inclusion of participants in whom slowing of bleeding has minimal effect on patient outcome. Patients with intracerebral haematoma of a volume of greater than 60 mL uniformly die or are severely disabled.1Hemphill 3rd, JC Bonovich DC Besmertis L Manley GT Johnston SC The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.Stroke. 2001; 32: 891-897Crossref PubMed Google Scholar, 4Broderick J Brott T Duldner J Tomsick T Huster G Volume of intracerebral hemorrhage: a powerful and easy-to-use predictor of 30-day mortality.Stroke. 1993; 24: 987-993Crossref PubMed Scopus (1420) Google Scholar The post-hoc TICH-2 subgroup analysis of baseline intracerebral haemorrhage volume supports this observation. In patients with baseline intracerebral haematoma volumes greater than 60 mL, the point estimate favoured placebo, whereas those with volumes of 30–60 mL had significant benefit associated with tranexamic acid. Similarly, older patients generally have very poor functional outcomes after intracerebral haemorrhage, except for those with much smaller intracerebral haemorrhages, and slowing of bleeding in these patients might have little effect on outcomes.8Mayer SA Davis SM Skolnick BE et al.Can a subset of intracerebral hemorrhage patients benefit from hemostatic therapy with recombinant activated factor VII?.Stroke. 2009; 40: 833-840Crossref PubMed Scopus (131) Google Scholar TICH-2 and previous haemostatic trials for intracerebral haemorrhage provide strong guidance for the design of future trials of intracerebral haemorrhage. First, the chosen agent should have a documented major effect on haematoma growth (3 mL or greater) and be administered within 2–3 h after onset, the time window during which most intracerebral haematoma growth occurs. The Hemorrhagic Stroke Academia Industry (HEADS) Roundtable recently recommended exemption from informed consent or deferred consent to minimise time to treatment in future trials of intracerebral haemorrhage.9The Hemorrhagic Stroke Academia Industry (HEADS) Roundtable ParticipantsUnmet needs and challenges in clinical research of intracerebral hemorrhage.Stroke. 2018; 49: 1299-1307Crossref PubMed Scopus (33) Google Scholar The trials should exclude patients with large intracerebral or intraventricular haematoma volumes—ie, patients who cannot clinically benefit from a further decrease in haemorrhage growth. Exclusion of the very elderly (age ≥80 years or even ≥70 years) might also make detection of any clinical benefit easier. Finally, the subgroup analyses of TICH-2 trial suggest that control of blood pressure in addition to a haemostatic agent might maximise clinical benefit.10Anderson CS Huang Y Wang JG et al.Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial.Lancet Neurol. 2008; 7: 391-399Summary Full Text Full Text PDF PubMed Scopus (647) Google Scholar, 11Anderson CS Heeley E Huang Y et al.Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage.N Engl J Med. 2013; 368: 2355-2365Crossref PubMed Scopus (1058) Google Scholar A previous post-hoc subgroup analysis of the rFVIIa trials provides a potential blueprint for the subgroup of patients most likely to benefit in a haemostatic trial for intracerebral haemorrhage.8Mayer SA Davis SM Skolnick BE et al.Can a subset of intracerebral hemorrhage patients benefit from hemostatic therapy with recombinant activated factor VII?.Stroke. 2009; 40: 833-840Crossref PubMed Scopus (131) Google Scholar Such a trial will require global efforts to recruit sufficient patients in an earlier time window. Whether the pathophysiology of intracerebral haemorrhage can be altered enough to improve clinical outcome remains one of the major questions in the treatment of acute stroke. I declare no competing interests. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trialFunctional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect. Full-Text PDF Open Access