Risk predictors to limit neuronal loss after intracerebral haemorrhage
Authors: M Edip Gurol
Journal: The Lancet Neurology (2018)

The brain tries to compensate for injury through reorganisation of functional networks, but neuronal tissue is irreplaceable once lost and therefore functional recovery is usually incomplete. Studies to prevent neuronal loss in chronic progressive diseases such as Alzheimer's disease and in acute conditions such as stroke are ongoing. However, ischaemic and haemorrhagic strokes present an extra layer of complexity because the injury can quickly grow in the acute phase, commonly resulting in death or severe disability through increased intracranial pressure, herniation, and other consequences of the mass effect. In ischaemic stroke, widespread adoption of non-invasive imaging methods that can detect occlusions—which are a significant risk factor for growth of the infarcted tissue—and advances in endovascular recanalisation techniques can now benefit patients presenting within 24 h of symptom onset. Intracerebral haemorrhage is less common than ischaemic stroke, but it is the most deadly or disabling neurological emergency, with mortality rates exceeding 40% in the acute phase and as few as 12% of affected patients able to live independently in the first year after haemorrhage.1van Asch CJ Luitse MJ Rinkel GJ van der Tweel I Algra A Klijn CJ Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis.Lancet Neurol. 2010; 9: 167-176Summary Full Text Full Text PDF PubMed Scopus (1677) Google Scholar Clinicians have investigated surgery for haematoma evacuation and haemostatic therapies to stop the bleeding in intracerebral haemorrhage early after onset to limit the extent of the brain damage in the acute phase, but these trials have so far been unsuccessful.2Mayer 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 (980) Google Scholar, 3Mendelow AD Gregson BA Fernandes HM et al.Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial.Lancet. 2005; 365: 387-397Summary Full Text Full Text PDF PubMed Scopus (1037) Google Scholar Given these results, more data are needed to understand the potential contributors to haematoma growth to identify better treatment targets and enrol the populations most likely to benefit in future studies. In The Lancet Neurology, Rustam Al-Shahi Salman and colleagues' systematic review and meta-analysis4Al-Shahi Salman R Frantzias J Lee RJ et al.Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.Lancet Neurol. 2018; (published online Aug 14.)http://dx.doi.org/10.1016/S1474-4422(18)30253-9Summary Full Text Full Text PDF Scopus (165) Google Scholar on absolute risk and predictors for acute intracerebral haemorrhage growth is a timely initiative that aims to address these pressing needs. Al-Shahi Salman and colleagues analysed individual patient data from 36 cohorts comprising 5435 patients who had acute intracerebral haemorrhage. This large sample size allowed the authors to build good-quality multivariable models that included many relevant clinical variables. In these models, time from symptom onset to baseline imaging, intracerebral haemorrhage volume on baseline imaging, antiplatelet use, and anticoagulant use were independent predictors of haematoma growth. The addition of CT angiography spot sign mildly increased the ability of the model to predict risk of growth, as measured by an increase in the C-index of 0·05 (95% CI 0·03–0·07). Despite a small fraction of the enrolled cohort (351 [6%] patients) taking anticoagulant therapy, its use emerged as the most important modifiable predictor of haematoma growth (odds ratio [OR] 3·48, 95% CI 1·96–6·16). This finding explains why fatality risk in anticoagulant-related intracerebral haemorrhage is twice that of non-anticoagulant-related haemorrhage.5Gurol ME Nonpharmacological management of atrial fibrillation in patients at high intracranial hemorrhage risk.Stroke. 2018; 49: 247-254Crossref PubMed Scopus (16) Google Scholar, 6Rosand J Eckman MH Knudsen KA Singer DE Greenberg SM The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.Arch intern Med. 2004; 164: 880-884Crossref PubMed Scopus (507) Google Scholar Minimising the time on anticoagulation and using potential alternatives such as left atrial appendage closure for nonvalvular atrial fibrillation might be considered in patients at high risk of intracerebral haemorrhage.5Gurol ME Nonpharmacological management of atrial fibrillation in patients at high intracranial hemorrhage risk.Stroke. 2018; 49: 247-254Crossref PubMed Scopus (16) Google Scholar Imaging markers of high risk of intracerebral haemorrhage have been identified that can support decision making in these situations. The presence of cerebral microbleeds, for instance, almost quadruples the risk of intracerebral haemorrhage in people with atrial fibrillation who take anticoagulants.7Wilson D Ambler G Shakeshaft C et al.Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study.Lancet Neurol. 2018; 17: 539-547Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar Overall, such studies and meta-analyses of their data clarify the association between anticoagulants and brain bleeds—ie, that oral anticoagulants increase the risk of intracerebral haemorrhage especially in patients at higher baseline risk and they promote the growth of the haematoma, thereby worsening patient outcomes.4Al-Shahi Salman R Frantzias J Lee RJ et al.Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.Lancet Neurol. 2018; (published online Aug 14.)http://dx.doi.org/10.1016/S1474-4422(18)30253-9Summary Full Text Full Text PDF Scopus (165) Google Scholar, 5Gurol ME Nonpharmacological management of atrial fibrillation in patients at high intracranial hemorrhage risk.Stroke. 2018; 49: 247-254Crossref PubMed Scopus (16) Google Scholar, 6Rosand J Eckman MH Knudsen KA Singer DE Greenberg SM The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.Arch intern Med. 2004; 164: 880-884Crossref PubMed Scopus (507) Google Scholar, 7Wilson D Ambler G Shakeshaft C et al.Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study.Lancet Neurol. 2018; 17: 539-547Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 8Flibotte JJ Hagan N O'Donnell J Greenberg SM Rosand J Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage.Neurology. 2004; 63: 1059-1064Crossref PubMed Scopus (508) Google Scholar, 9Hart RG Sharma M Mundl H et al.Rivaroxaban for stroke prevention after embolic stroke of undetermined source.N Engl J Med. 2018; 378: 2191-2201Crossref PubMed Scopus (521) Google Scholar In Al-Shahi Salman and colleagues' study,4Al-Shahi Salman R Frantzias J Lee RJ et al.Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.Lancet Neurol. 2018; (published online Aug 14.)http://dx.doi.org/10.1016/S1474-4422(18)30253-9Summary Full Text Full Text PDF Scopus (165) Google Scholar antiplatelet use was also associated with a modest increase in risk of haematoma growth (1·68, 95% CI 1·06–2·66; p=0·026), which emphasises the importance of using antiplatelets only when needed. Past history of ischaemic stroke and intracerebral haemorrhage were not included as covariates because of insufficient data, so some degree of residual confounding is possible as many of these patients with high risk of ischaemia and haemorrhage were probably kept on antiplatelets. Shorter time from symptom onset to imaging (OR 0·50, 0·36–0·70; p<0·0001) and larger baseline intracerebral haemorrhage volume (7·18, 4·46–11·60; p<0·0001) were other factors that predicted haematoma growth. Although it is well known that haematoma growth occurs early after haemorrhage in many patients, the identification of 0·5-3·0 h as the timeframe for highest risk of growth in patients not taking anticoagulants is an important addition to the scientific literature. This hyperacute period is when a haemostatic therapy could possibly have a significant effect on haematoma growth and, hence, on clinical outcomes. However, it is important to remember that more than 80% of patients in the current analysis had repeat imaging within 48 h of onset of intracerebral haemorrhage, so it is possible that further haematoma growth might occur later in some patients. Supporting this view, previous studies8Flibotte JJ Hagan N O'Donnell J Greenberg SM Rosand J Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage.Neurology. 2004; 63: 1059-1064Crossref PubMed Scopus (508) Google Scholar including multiple CT scans have shown that anticoagulant-related intracerebral haemorrhage can grow even after the first 24 h. Notably, haemorrhage growth peaked at around 75 mL of baseline volume. However, even if the heightened growth risk of haematomas greater than 20–30 mL can be considered as an opportunity to treat large bleeds, it should be remembered that large baseline intracerebral haemorrhage also means severe tissue damage which might limit potential clinical benefit from haemostatic therapies. Overall, acute treatment for patients with intracerebral haemorrhage continues to represent a conundrum for clinicians. Candidate therapies have non-trivial side-effects—ie, thrombotic events with haemostatic treatments and procedural risks with evacuation-based therapies—and none have yet proven to be beneficial. Hopefully, analyses such as the ones by Al-Shahi Salman and colleagues will provide better targets for intervention and help to identify the ideal populations to be studied in future clinical trials. Additional research of the mechanisms of intracerebral haemorrhage will probably be needed before achieving positive therapeutic trials similar to those that reversed the therapeutic nihilism for patients with ischaemic stroke. I report grants from the US National Institutes of Health (number NS083711). Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient dataIn this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. Full-Text PDF Open Access