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Cerebrovascular disease
Original research
Prior antiplatelet therapy and haematoma expansion after primary intracerebral haemorrhage: an individual patient-level analysis of CLEAR III, MISTIE III and VISTA-ICH
  1. Santosh Murthy1,
  2. David J Roh2,
  3. Abhinaba Chatterjee1,
  4. Nichol McBee3,
  5. Neal S Parikh1,
  6. Alexander E Merkler1,
  7. Babak B Navi1,
  8. Guido J Falcone4,
  9. Kevin N Sheth4,
  10. Issam Awad5,
  11. Daniel Hanley6,
  12. Hooman Kamel1,
  13. Wendy C Ziai7
  14. CLEAR III, MISTIE III and VISTA-ICH Collaborators
  1. 1 Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurolgy, Weill Cornell Medicine, New York, NY, USA
  2. 2 Neurology, Columbia University Irving Medical Center, New York, New York, USA
  3. 3 Neurology, Johns Hopkins University, Baltimore, Maryland, USA
  4. 4 Division of Neurocritical Care and Emergency Neurology, Yale University School of Medicine, New Haven, Connecticut, USA
  5. 5 Neurosurgery, University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA
  6. 6 Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, Maryland, USA
  7. 7 Departments of Neurology, Neurosurgery, and Anesthesiology Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  1. Correspondence to Dr Santosh Murthy, Department of Neurology, Weill Cornell Medicine, New York, New York 10065, USA; sam9200{at}med.cornell.edu

Abstract

Objective To evaluate the relationship between prior antiplatelet therapy (APT) and outcomes after primary intracerebral haemorrhage (ICH), and assess if it varies by haematoma location.

Methods We pooled individual patient data from the Virtual International Stroke Trials Archive-ICH trials dataset, Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase III trial. The exposure was APT preceding ICH diagnosis. The primary outcome was haematoma expansion at 72 hours. Secondary outcomes were admission haematoma volume, all-cause mortality, death or major disability (modified Rankin Scale (mRS) score ≥4) and shift in mRS distribution. Mixed-effects models were used to assess the relationship between APT and outcomes. Secondary analyses were stratified by ICH location and study cohort.

Results Among 1420 patients with ICH, there were 782 (55.1%) lobar and 596 (42.0%) deep haemorrhages. APT was reported in 284 (20.0%) patients. In adjusted regression models, prior APT was not associated with haematoma expansion (OR, 0.97; 95% CI 0.60 to 1.57), major disability or death (OR, 1.05; 95% CI 0.61 to 1.63), all-cause mortality (OR, 0.89; 95% CI 0.47 to 1.85), admission haematoma volume (beta, −0.17; SE, 0.09; p=0.07) and shift in mRS (p=0.43). In secondary analyses, APT was associated with admission haematoma volume in lobar ICH (beta, 0.25; SE, 0.12; p=0.03), but there was no relationship with other ICH outcomes when stratified by haematoma location or study cohort.

Conclusions In a large heterogeneous cohort of patients with ICH, prior APT was not associated with haematoma expansion or functional outcomes after ICH, regardless of haematoma location. APT was associated with admission haematoma volumes in lobar ICH.

https://doi.org/10.1136/jnnp-2020-323458

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    Introduction

    Intracerebral haemorrhage (ICH) is a devastating disease with high mortality.1 Antiplatelet therapy (APT) is believed to contribute to ICH mortality by promoting increased bleeding resulting from platelet inhibition.2 About 20%–30% of patients with ICH are on APT, mostly due to prevalent cardiovascular disease.3 Previous studies assessing the effect of APT on ICH outcomes have yielded conflicting results. For instance, the secondary analysis of the Cerebral Hemorrhage and NXY-059 Treatment trial showed no relationship between APT and haematoma expansion or mortality,4 while a meta-analysis of observational studies found higher mortality with APT.3 A cohort study from the Get-with-the-Guidelines registry showed that dual APT (but not single APT) was associated with increased odds of in-hospital death after ICH.5

    Given the conflicting data on the association between APT and ICH outcomes, the current American Heart Association and European Stroke Organisation guidelines equivocate regarding the routine use of platelet transfusions after ICH.6 7 In a randomised clinical trial, platelet transfusion was shown to increase the risk of death or dependence among patients with supratentorial ICH on APT.8 These results suggest that alternative therapeutic strategies need to be explored if APT truly predisposes to ICH expansion or poor outcomes. Furthermore, ICH is increasingly recognised as a heterogeneous disease, with growing recognition that lobar and deep haemorrhages are biologically independent entities.9 Prior studies on APT preceding ICH have included all ICH subtypes, and it is unknown if APT has a differential effect on outcomes based on ICH location or presence of intraventricular haemorrhage (IVH). We therefore sought to assess the relationship between APT and ICH outcomes in a large, international cohort of patients with small and large ICH, as well as large IVH.

    Methods

    Study design and eligibility criteria

    We performed a secondary analysis of patients with ICH pooled from three data sources: the Virtual International Stroke Trials Archive-ICH (VISTA-ICH)10; the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial11 and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase III (MISTIE III) trial.12 The Weill Cornell Medicine institutional review board approved the de-identified retrospective analysis of previously collected patient data using these three cohorts.

    The VISTA-ICH collaboration comprises pooled data from international clinical trials in ICH.12 The VISTA cohort used in this study comprised patients: (1) in the placebo arms and/or in the intervention arms of neutral non-surgical trials; (2) presenting with CT proven ICH within 24 hours of symptom onset and (3) with baseline clinical, radiological and laboratory data. CLEAR III was a multicentre, randomised, double-blinded, placebo-controlled trial conducted to determine if pragmatically employed external ventricular drain (EVD) plus intraventricular alteplase improved outcomes by removing IVH, in comparison to EVD plus saline. MISTIE III was a randomised, controlled, open-label, blinded endpoint trial that found image guided, minimally invasive surgery followed by gentle thrombolytic irrigation of the catheterised ICH clot to decrease mortality, but was neutral on the primary endpoint of improved functional outcome in patients with moderate to large ICH, compared with standard medical management.12 For this analysis, we only included the medical arm of the trial. Additionally, we excluded patients with primary IVH based on baseline CT, and those on prior anticoagulant therapy in all three datasets.

    Measurements

    Covariates of interest included age, sex, race and cerebrovascular risk factors. All patients had admission Glasgow Coma Scale (GCS) scores. Non-contrast CT scans were obtained on admission and at 72 hours for this study. Haematoma volume was calculated using semi-automated planimetry, and read centrally within each specific trial by the trial neuroradiologist. Lobar ICH was defined as selective involvement of cerebral cortex, underlying white matter or both.13 Deep ICH was defined as selective involvement of thalami, basal ganglia or both. Involvement of the brainstem or cerebellum was considered infratentorial ICH.

    Exposures and outcomes

    The study exposure was APT prior to the onset of ICH. APT was ascertained based on review of medication history at the time of admission. Since these were patients enrolled in clinical trials, the participating site investigators performed a detailed medication reconciliation to obtain relevant medication history. The VISTA-ICH dataset provided outcomes at 3 months, while outcomes were assessed at 6 months in the CLEAR III and MISTIE III trials. In the analysis using pooled data from all three cohorts, the study primary outcome was haematoma expansion over 72 hours. Secondary outcomes were admission haematoma volume, all-cause mortality, death or major disability, defined as modified Rankin Scale (mRS) scores of 4–6 and shift in mRS distribution. Haematoma expansion was defined as an increase in the baseline haematoma volume by either 33% or >6 mL on the interval CT scan performed at 72 hours.14 Additionally, in the CLEAR III cohort, we assessed IVH expansion as an outcome, since this cohort included predominantly small ICH with large IVH and had robust estimation of IVH volumes at different time points. An interval increases in IVH volume by ≥5 mL on the pre-randomisation neuroimaging scans was considered IVH expansion.15

    Statistical analysis

    We used the Wilcoxon rank-sum test or Student’s t-test for continuous variables depending on the normality of distribution. Categorical variables were analysed using Pearson’s χ2 test (or Fisher exact test when appropriate). To account for heterogeneity in study populations in our primary analysis, we used mixed-effect multivariable logistic regression to study the relationship between prior APT and ICH outcomes. To study the association between APT and admission haematoma volumes, we used linear mixed-effects models. Admission haematoma volume was log-transformed to minimise skewness. We studied the effect of APT on mRS distribution using mixed-effects ordinal logistic regression. We treated covariates as fixed effects, while the study database was treated as a random effect. Covariates for the models were selected based on bivariate regression with a significance of p<0.1 for the outcome of interest. We identified multicollinearity using a variance inflation factor >4. To assess whether the relationship between APT and ICH outcomes differed by ICH location, we tested interactions between prior APT and haematoma location for each outcome with a prespecified threshold of significance for interaction of p<0.1. We then assessed the relationship between prior APT and outcomes, stratified by haematoma location. In additional prespecified subgroup analyses, we stratified by study database and time from symptom onset to admission CT scan (<3 hours and ≥3 hours). We used traditional multiple logistic regression when the three cohorts were analysed separately. Model building was performed as described above. Statistical analyses were performed using Stata (V.14.0). All analyses were two-tailed, and significance level was determined by p<0.05.

    Results

    Study population

    Among 1842 patients with ICH in the pooled sample, 1420 patients were included in the analysis (figure 1). Prior APT was reported in 284 (20.0%) patients (table 1).

    View this table:
    Table 1

    Clinical characteristics of patients with ICH

    Figure 1
    Figure 1

    Flowchart showing patient selection. CLEAR, Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage; ICH, intracerebral haemorrhage; IVH, intraventricular haemorrhage; MISTIE III, Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation Phase III; VISTA-ICH, Virtual International Stroke Trials Archive-ICH.

    Patients on APT were older, more often men and had more cerebrovascular risk factors such as hypertension, diabetes mellitus, hyperlipidaemia and atrial fibrillation, compared with patients not on APT (table 2). As for ICH characteristics, patients with APT had lower GCS scores, and more often had deep haemorrhages and IVH.

    View this table:
    Table 2

    Patient and clinical characteristics, stratified by antiplatelet use and haematoma location

    Association between prior APT and outcomes

    Haematoma expansion rates were lower among patients with APT compared with those without (15.5% vs 20.7%, p=0.049). In multiple logistic regression models adjusted for age, sex, hypertension, diabetes, GCS, baseline haematoma volume, haematoma location, presence of intraventricular haemorrhage and time to first CT scan from ictus, prior APT was not associated with haematoma expansion (OR, 0.97; 95% CI 0.60 to 1.57) (table 3).

    View this table:
    Table 3

    Multivariable analyses evaluating the relationship between prior antiplatelet use and outcomes, stratified by ICH location

    In the multiple logistic regression models adjusted for the above confounders, prior APT was neither associated with all-cause mortality (OR, 0.89; 95% CI 0.47 to 1.85) nor with the composite of major disability or death (OR, 1.05; 95% CI 0.61 to 1.63) (table 4). In the adjusted ordinal analysis of APT on mRS, we found no shift in mRS distribution (adjusted common OR, 1.1; 95% CI 0.7 to 1.4; p=0.43). We did not find any significant interaction between prior APT and haematoma location for any of the above binary or ordinal outcomes.

    View this table:
    Table 4

    Multivariable analysis assessing the relationship between prior antiplatelet use and outcomes, stratified by study cohort and time to CT scan

    Linear mixed effect models showed no relationship between APT and admission haematoma volumes (beta, −0.17; SE, 0.09; p=0.07) (table 5). However, in this analysis, we excluded haematoma location from the model, given a significant interaction between prior APT and haematoma location (p value for interaction=0.001).

    View this table:
    Table 5

    Multivariable analyses evaluating the relationship between prior antiplatelet use and log-transformed admission haematoma volume, stratified by ICH location, study cohort and time to CT scan

    Subgroup analysis

    When stratified by haematoma location, there continued to be no adjusted association between prior APT and dichotomised ICH outcomes (table 3). However, APT was associated with admission haematoma volume in lobar ICH (beta, 0.64; SE, 0.29; p=0.03), but not in deep ICH (beta, −0.04; SE, 0.09; p=0.65; table 4). When the three cohorts were analysed separately, this lack of association persisted (table 5). Data on platelet transfusion were available in the CLEAR III and MISTIE III cohorts, and included as a covariate in the regression analyses. In the CLEAR III cohort, 29 (29%) patients previously on APT received platelet transfusions compared with 9 (2.8%) who were not previously on APT (p<0.001), while in the MISTIE III cohort, platelet transfusions were administered in 19 (25.7%) patients on APT, and in 9 (5.4%) not on APT. Additionally, there was no relationship between APT and IVH expansion in the CLEAR III cohort (OR, 0.8; 95% CI 0.2 to 3.6). There were 525 patients with ICH who had baseline CT scans within 3 hours of symptom onset, while the remaining 895 patients presented after 3 hours. There was no relationship between APT and ICH outcomes, regardless of the time to CT scan from symptom onset.

    Post hoc analysis

    To account for imbalances in baseline characteristics, we performed a 1:1 propensity score matching of patients on APT with those not on APT. Using the treatment effects or ‘teffects psmatch’ function in Stata, matching was performed, on age, sex, race, hypertension, diabetes mellitus, admission ICH volume and presence of IVH. When admission ICH volume was the outcome of interest, patients were matched on baseline characteristics except ICH volume. In the 210 matched pairs, prior APT was not associated with haematoma expansion (beta, −0.03; SE, 0.04; p=0.44), admission ICH volume (beta, −0.08; SE, 0.10; p=0.46), all-cause mortality (beta, 0.04; SE, 0.03; p=0.34) or unfavourable mRS (beta, 0.07; SE, 0.05; p=0.16).

    Discussion

    In this secondary analysis of pooled individual data from clinical trials encompassing the full spectrum of ICH, prior APT was not associated with haematoma expansion or functional outcomes, regardless of haematoma location or the study cohort. Prior APT was an independent predictor of higher admission haematoma volume in lobar ICH but not deep haemorrhages.

    Studies assessing the relationship between APT and admission haematoma volume, and APT and haematoma expansion, have yielded conflicting results. A recent cohort study showed that APT did not influence haematoma characteristics,16 but prior APT was a predictor of haematoma volume in lobar haemorrhage in a large prospective study.17 In this context, our findings from a large, international prospective cohort of patients who had ICH with small and large ICH, and large IVH, offer more evidence to suggest that APT may not be associated with haematoma expansion. Furthermore, APT may influence admission haematoma volume preferentially in lobar ICH, but not in deep ICH, despite APT use being more common in the latter.

    A recent patient-level meta-analysis of over 5000 patients with ICH showed that APT was an independent predictor of early haematoma growth,18 contrary to our findings. The study also showed that the period of rapid haematoma expansion was within the first 3 hours from symptom onset. The meta-analysis included patients on prior anticoagulation, an established independent predictor of haematoma expansion,19 while our study excluded them. Additionally, further stratification by haematoma location was not performed. Most studies including ours had median time to CT scans closer to or beyond the 3-hour time point, and consequently, the period of maximum ICH growth likely occurred prior to the baseline CT scan, and accounted for the lack of association between APT and haematoma expansion. However, we found no difference in outcomes in our subgroup analysis stratified by time to CT scan (<3 hours vs ≥3 hours). We observed no difference in the timing of ascertainment of neuroimaging relative to symptom onset in our study between lobar and deep ICH. From a pathophysiological standpoint, it is possible that biological differences underlying lobar and deep ICH, particularly cerebral amyloid angiopathy, may partly explain the association between APT and baseline haematoma volumes.9

    There is a discrepancy between APT and ICH outcomes in current literature. One possible explanation could be the regimen of APT prior to ICH. A recent analysis of Get-with-the-Guidelines registry data reported that patients with dual APT had increased odds of death, while those on single APT had similar odds compared with patients not on APT.5 However, haematoma characteristics were not available, precluding assessment of haematoma expansion as an outcome; and functional outcomes were assessed at discharge, which might not account for long-term recovery.5 In our study, we did not find an association between prior APT and mortality, although most patients were on a single agent. Given the small number of patients previously on dual APT in our study (n=22), we were unable to reliably evaluate the impact of dual APT on ICH outcomes.

    The strengths of our study include a large sample size, well-defined eligibility criteria, pre-established time points for neuroimaging, inclusion of small to large ICH and large IVH and blinded assessment of outcomes. However, our study also has important limitations. First, inclusion of a selective cohort of patients with ICH with rigid screening and monitoring performed in the setting of a trial, limit the generalisability of the results. Second, outcomes were assessed at different time points in the three cohorts, and combining them may have introduced heterogeneity in the study; however, the results remained unchanged when the cohorts were analysed separately. Third, lack of data on the type of APT (ie, aspirin, clopidogrel, etc.) and APT regimen (single vs dual APT) precluded further exploration of these associations with outcomes. Finally, data on platelet transfusion were available in the CLEAR III and MISTIE III cohorts, and was not associated with haematoma expansion or clinical outcomes, similar to the findings of a recent study.16

    Conclusion

    In a large prospective cohort of patients with ICH, we found that prior APT was not associated with haematoma expansion, or functional outcomes, but was associated with admission haematoma volumes in lobar ICH. These findings in conjunction with the results of the PATCH trial question the need for platelet function reversal strategies in medically managed patients with ICH.

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    Footnotes

    • Twitter @san_murthy

    • Contributors SM: study concept, design, acquisition and interpretation of data, drafting of manuscript with critical revisions. SM had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. DJR: critical revision of the manuscript for intellectual content. AC: critical revision of the manuscript for intellectual content. MC: critical revision of the manuscript for intellectual content. NM: critical revision of the manuscript for intellectual content. NSP: critical revision of the manuscript for intellectual content. AEM: critical revision of the manuscript for intellectual content. BBN: critical revision of the manuscript for intellectual content. GJF: critical revision of the manuscript for intellectual content. KNS: critical revision of the manuscript for intellectual content. IA: critical revision of the manuscript for intellectual content. DH: critical revision of the manuscript for intellectual content. HK: critical revision of the manuscript for intellectual content. WCZ: study concept, design, acquisition and analysis of data, drafting of the manuscript including critical revisions for intellectual content and study supervision.

    • Funding The study was funded by the National Institutes of Health grants (K23NS105948) to SBM, and (U01-NS08082 and U01-NS080824) to DH and WCZ.

    • Competing interests BBN is supported by the NIH (K23NS091395) and the Florence Gould Endowment for Discovery in Stroke, serves as a member of the data and safety monitoring board for the PCORI-funded TRAVERSE trial and has received personal fees for medicolegal consulting on stroke. AEM is supported by AHA grant 18CDA34110419 and the Leon Levy Foundation. He has received personal fees for medicolegal consulting on stroke. GJF is supported by the NIH (K76AG059992, R03NS112859), the American Heart Association (18IDDG34280056) and the Yale Pepper Scholar Award (P30AG021342). KNS is supported by the NIH (U24NS107215, U24NS107136, RO1NR018335, and U01NS106513), Novartis, and Bard, and reports grants from Hyperfine, Biogen, and Astrocyte unrelated to this work. DH is supported by the NIH (U01NS080824 and U24TR001609), and reports personal fees from Op2Lysis, personal fees from BrainScope and Neurotrope, and non-financial support from Genentech outside the submitted work. HK is supported by the NIH (U01NS095869 and R01NS097443) and the Michael Goldberg Research Fund; serves as the co-PI for the NIH-funded ARCADIA trial which receives in-kind study drug from the BMS-Pfizer Alliance and in-kind study assays from Roche Diagnostics; serves as a steering committee member of Medtronic’s Stroke AF trial (uncompensated); serves on an endpoint adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim; and has served on an advisory board for Roivant Sciences related to Factor XI inhibition. WCZ receives consulting fees from C.R. Bard, Inc. outside of the area of work commented on here. All remaining authors declare no competing interests.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. Individual de-identified participant data from the VISTA-ICH, CLEAR III and MISTIE III may be obtained by submitting a formal proposal to the respective steering committees. Additionally, data from the CLEAR III and MISTIE III trials may be requested by writing to the National Institute of Neurological Disorders and Stroke clinical trials repository.

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