Discussion
In this prespecified secondary analysis of the TICH-2 trial, randomisation to tranexamic acid in the presence of baseline SBP≤170 mmHg was associated with less haematoma expansion and improved clinical outcomes with fewer deaths and SAEs, less death and dependency, and improved quality of life scores compared with placebo. This was despite patients being older, randomised later and having larger baseline haematoma volumes than those with SBP>170 mm Hg. A>15% reduction in SBP from baseline to day 2 was associated with fewer deaths by day 7 and 90 in those randomised to tranexamic acid but not placebo, while a>5% increase in SBP was associated with increased death and SAEs by day 7 overall, and increased SAEs in those randomised to placebo by day 7 and 90. BP lowering treatment by day 2 was more frequently used over the time course of the trial in line with changes in international clinical guidelines. Despite this, 66% of the trial population remained hypertensive on day 2.
Baseline characteristics differed by baseline SBP group; participants with SBP≤170 mm Hg had larger haematomas in lobar locations on average, while participants with SBP>170 mm Hg had deep haematomas on a background of hypertension. This may, in part, reflect the distribution of ICH due to underlying aetiology, that is, lobar haematomas in CAA and deep haematomas secondary to hypertensive arteriolopathy. A multicentre cohort study in China involving 5656 patients with ICH found that admission BP differed by ICH aetiology with patients with CAA having a lower BP and larger haematoma volumes than patients with presumed hypertensive arteriolopathy who had a higher BP and smaller haematoma volumes at baseline.17 Dichotomising ICH location as either lobar or non-lobar may risk over-simplifying the underlying aetiology given that lobar ICH comprises CAA-related ICH, hypertensive arteriolopathy and mixed cerebral small vessel disease.18 Recently, a detailed secondary imaging analysis of TICH-2 demonstrated that in participants with lobar CAA-related ICH, there was an increased risk of haematoma expansion with increasing time from randomisation, while the risk of haematoma expansion was constant irrespective of baseline haematoma volume.19 These effects were not seen in those with non-CAA lobar or non-lobar ICH and may suggest a difference in haematoma dynamics between these ICH groups.19 CAA-related bleeding may originate from leptomeningeal vessels and have more space to expand into (including the subarachnoid space), resulting in prolonged, slower, lower pressure bleeding over several hours.19 This may potentially provide a longer treatment window for haemostatic agents including tranexamic acid to exert their effects. These hypotheses require further testing and should be considered in ongoing and future studies of tranexamic acid in ICH.
Although trials to date have yet to demonstrate a positive effect of haemostatic therapies on clinical outcome in ICH,20 there are several possible explanations for tranexamic acid being associated with improved clinical outcomes in those with baseline SBP≤170 mm Hg. First, a lower baseline SBP is associated with less haematoma expansion than higher baseline SBP,1–3 therefore, any potential treatment effect of tranexamic acid on haematoma expansion may be larger as there is no separate pathological mechanism in the form of elevated BP to overcome. However, in the present analysis, there was no difference in the rate of haematoma expansion between baseline SBP groups: 28.2% in the≤170 mm Hg group vs 25.7% in the >170 mm Hg group, p=0.21. Second, by dichotomising baseline SBP, we may have unintentionally selected a group of participants more likely to benefit from tranexamic acid independent of BP, such as people with moderate-sized lobar haematomas as opposed to smaller deep haematomas. Although sensitivity analyses adjusting for baseline haematoma characteristics did not alter the treatment effect of tranexamic acid, there was a significant interaction between haematoma location and tranexamic acid on the primary outcome in those with baseline SBP≤170 mm Hg suggesting that there may be a differential effect of tranexamic acid depending on haematoma location.
Those participants with a >15% decrease in SBP from baseline to day 2 were less likely to die by days 7 and 90 when randomised to tranexamic acid; a finding not seen in those randomised to placebo. In contrast, a >5% increase in SBP from baseline to day 2 was associated with increased death and SAEs at day 7 overall, and increased SAEs at days 7 and 90 in those randomised to placebo. Therefore, a reduction in BP from baseline to day 2 combined with treatment with tranexamic acid may be beneficial, while an increase in BP in those randomised to placebo may be harmful. These results should be considered preliminary given their observational nature within a randomised controlled trial. However, one plausible explanation for why BP lowering and tranexamic acid may be additive or even synergistic in ICH is by attenuating haematoma expansion and improving clinical outcome.
The strengths of this study include the prespecified nature of the analyses within the context of the largest trial of haemostatic therapies in ICH with almost complete follow-up data. However, there are several limitations. First, we do not have data on what BP lowering medications patients were taking prior to their ICH. Therefore, we were unable to establish any association between the use of pre-ICH antihypertensives and prerandomisation baseline BP. This includes any BP lowering medication given after symptom onset of their ICH but before randomisation, which may have influenced the baseline BP recorded prior to randomisation. Second, there were few BP readings recorded in the trial; two measurements prerandomisation and two measurements on day 2. Therefore, we were unable to assess any effect of BP variability, which has been shown to be a stronger predictor of clinical outcome in acute ICH21 22 and ischaemic stroke23 than absolute BP. Nor could we adjust for early BP change within the first hours after ICH. Instead, we used the change in BP from baseline to day 2 to look for any associations with outcome. These analyses were within randomised treatment groups, are therefore observational, may represent chance and should be considered as hypothesis generating. Third, ICH aetiology was investigator-reported and largely determined by CT imaging. This may have led to less precise characterisation of ICH aetiology, particularly in those with mixed pathology. Last, given this is a subgroup analysis, our findings may represent chance. Although we did not adjust for multiplicity of testing, this subgroup analysis was prespecified in the statistical analysis plan of the main TICH-2 trial (including the SBP cut-point), has biological plausibility, had a positive interaction with treatment on outcome and followed the statistical analysis plan of the main TICH-2 trial.
In summary, this prespecified subgroup analysis of the TICH-2 trial demonstrated that randomisation to tranexamic acid in participants with baseline SBP≤170 mm Hg was associated with less haematoma expansion and improved clinical outcomes across multiple domains both early and late after ICH. Future research should seek to establish which subgroups of patients may benefit from tranexamic acid in acute ICH, including by haemorrhage location, size and underlying aetiology including CAA. Whether BP lowering is additive or synergistic in the presence of tranexamic acid in acute ICH is unclear and future clinical trials may help to provide a clearer treatment paradigm for clinicians.