In light of an aging population with increased cardiovascular comorbidity, the use of oral anticoagulation (OAC) is steadily expanding. A variety of pharmacological alternatives to vitamin K ...antagonists (VKA) have emerged over recent years (direct oral anticoagulants, DOAC, i.e., dabigatran, rivaroxaban, apixaban, and edoxaban) which show a reduced risk for the occurrence of intracerebral hemorrhage (ICH). Yet, in the event of ICH under OAC (OAC-ICH), hematoma characteristics are similarly severe and clinical outcomes likewise substantially limited in both patients with VKA- and DOAC-ICH, which is why optimal acute hemostatic treatment in all OAC-ICH needs to be guaranteed. Currently, International Guidelines for the hemostatic management of patients with OAC-ICH are updated as several relevant large-sized observational studies and recent trials have established treatment approaches for both VKA- and DOAC-ICH. While the management of VKA-ICH is mainly based on the immediate reversal of elevated levels of international normalized ratio using prothrombin complex concentrates, hemostatic management of DOAC-associated ICH is challenging requiring specific antidotes, notably idarucizumab and andexanet alfa. This review will provide an overview of the latest studies and trials on hemostatic reversal agents and timing and summarizes the effects on hemorrhage progression and clinical outcomes in patients with OAC-ICH.
OBJECTIVETo evaluate the association of perihemorrhagic edema (PHE) evolution and peak edema extent with day 90 functional outcome in patients with intracerebral hemorrhage (ICH) and identify ...pathophysiologic factors influencing edema evolution.
METHODSThis retrospective cohort study included patients with spontaneous supratentorial ICH between January 2006 and January 2014. ICH and PHE volumes were studied using a validated semiautomatic volumetric algorithm. Multivariable logistic regression and propensity score matching (PSM) accounting for age, ICH volume, and location were used for assessing measures associated with functional outcome and PHE evolution. Clinical outcome on day 90 was assessed using the modified Rankin Scale (0–3 = favorable, 4–6 = poor).
RESULTSA total of 292 patients were included. Median age was 70 years (interquartile range IQR 62–78), median ICH volume on admission 17.7 mL (IQR 7.9–40.2). Besides established factors for functional outcome, i.e., ICH volume and location, age, intraventricular hemorrhage, and NIH Stroke Scale score on admission, multivariable logistic regression revealed peak PHE volume (odds ratio OR 0.984 95% confidence interval (CI) 0.973–0.994) as an independent predictor of day 90 outcome. Peak PHE volume was independently associated with initial PHE increase up to day 3 (OR 1.060 95% CI 1.018–1.103) and neutrophil to lymphocyte ratio on day 6 (OR 1.236 95% CI 1.034–1.477; PSM cohort, n = 124). Initial PHE increase (PSM cohort, n = 224) was independently related to hematoma expansion (OR 3.647 95% CI 1.533–8.679) and fever burden on days 2–3 (OR 1.456 95% CI 1.103–1.920).
CONCLUSIONOur findings suggest that peak PHE volume represents an independent predictor of functional outcome after ICH. Inflammatory processes and hematoma expansion seem to be involved in PHE evolution and may represent important treatment targets.
BACKGROUND AND PURPOSE—This study determined the influence of concomitant antiplatelet therapy (APT) on hematoma characteristics and outcome in primary spontaneous intracerebral hemorrhage (ICH), ...vitamin K antagonist (VKA)- and non–VKA oral anticoagulant-associated ICH.
METHODS—Data of retrospective cohort studies and a prospective single-center study were pooled. Functional outcome, mortality, and radiological characteristics were defined as primary and secondary outcomes. Propensity score matching and logistic regression analyses were performed to determine the association between single or dual APT and hematoma volume.
RESULTS—A total of 3580 patients with ICH were screened, of whom 3545 with information on APT were analyzed. Three hundred forty-six (32.4%) patients in primary spontaneous ICH, 260 (11.4%) in VKA-ICH, and 30 (16.0%) in non–VKA oral anticoagulant-associated ICH were on APT, and these patients had more severe comorbidities. After propensity score matching VKA-ICH patients on APT presented with less favorable functional outcome (modified Rankin Scale score, 0–3; APT, 48/202 23.8% versus no APT, 187/587 31.9%; P=0.030) and higher mortality (APT, 103/202 51.0% versus no APT, 237/587 40.4%; P=0.009), whereas no significant differences were present in primary spontaneous ICH and non–VKA oral anticoagulant-associated ICH. In VKA-ICH, hematoma volume was significantly larger in patients with APT (21.9 7.4–61.4 versus 15.7 5.7–44.5 mL; P=0.005). Multivariable regression analysis revealed an association of APT and larger ICH volumes (odds ratio, 1.80 1.20–2.70; P=0.005), which was more pronounced in dual APT and supratherapeutically anticoagulated patients.
CONCLUSIONS—APT does not affect ICH characteristics and outcome in primary spontaneous ICH patients; however, it is associated with larger ICH volume and worse functional outcome in VKA-ICH, presumably by additive antihemostatic effects. Combination of anticoagulation and APT should, therefore, be diligently evaluated and restricted to the shortest possible time frame.
OBJECTIVE:As common prognostication models in intracerebral hemorrhage (ICH) are developed variably including patients with early (<24 hours) care limitations (ECL), we investigated its interaction ...with prognostication in maximally treated patients and sought to provide a new unbiased severity assessment tool.
METHODS:This observational cohort study analyzed consecutive ICH patients (n = 583) from a prospective registry over 5 years. We characterized the influence of ECL on overall outcome by propensity score matching and on conventional prognostication using receiver operating characteristic analyses. We established the max-ICH score based on independent predictors of 12-month functional outcome in maximally treated patients and compared it to existing models.
RESULTS:Prevalence of ECL was 19.2% (n = 112/583) and all of these patients died. Yet propensity score matching displayed that 50.7% (n = 35/69) theoretically could have survived, with 18.8% (n = 13/69) possibly reaching favorable outcome (modified Rankin Scale score 0–3). Conventional prognostication seemed to be confounded by ECL, documented by a decreased predictive validity (area under the curve AUC 0.67, confidence interval CI 0.61–0.73 vs AUC 0.80, CI 0.76–0.83; p < 0.01), overestimating poor outcome (mortality by 44.8%, unfavorable outcome by 10.1%) in maximally treated patients. In these patients, the novel max-ICH score (0–10) integrates strength-adjusted predictors, i.e., NIH Stroke Scale score, age, intraventricular hemorrhage, anticoagulation, and ICH volume (lobar and nonlobar), demonstrating improved predictive accuracy for functional outcome (12 monthsAUC 0.81, CI 0.77–0.85; p < 0.01). The max-ICH score may more accurately delineate potentials of aggressive care, showing favorable outcome in 45.4% (n = 214/471) and a long-term mortality rate of only 30.1% (n = 142/471).
CONCLUSIONS:Care limitations significantly influenced the validity of common prognostication models resulting in overestimation of poor outcome. The max-ICH score demonstrated increased predictive validity with minimized confounding by care limitations, making it a useful tool for severity assessment in ICH patients.
Objective
To investigate parameters associated with hematoma enlargement in non–vitamin K antagonist oral anticoagulant (NOAC)‐related intracerebral hemorrhage (ICH).
Methods
This retrospective ...cohort study includes individual patient data for 190 patients with NOAC‐associated ICH over a 5‐year period (2011–2015) at 19 departments of neurology across Germany. Primary outcome was the association of prothrombin complex concentrate (PCC) administration with hematoma enlargement. Subanalyses were calculated for blood pressure management and its association with the primary outcome. Secondary outcomes include associations with in‐hospital mortality and functional outcome at 3 months assessed using the modified Rankin Scale.
Results
The study population for analysis of primary and secondary outcomes consisted of 146 NOAC‐ICH patients with available follow‐up imaging. Hematoma enlargement occurred in 49/146 (33.6%) patients with NOAC‐related ICH. Parameters associated with hematoma enlargement were blood pressure ≥ 160mmHg within 4 hours and—in the case of factor Xa inhibitor ICH—anti‐Xa levels on admission. PCC administration prior to follow‐up imaging was not significantly associated with a reduced rate of hematoma enlargement either in overall NOAC‐related ICH or in patients with factor Xa inhibitor intake (NOAC: risk ratio RR = 1.150, 95% confidence interval CI = 0.632–2.090; factor Xa inhibitor: RR = 1.057, 95% CI = 0.565–1.977), regardless of PCC dosage given or time interval until imaging or treatment. Systolic blood pressure levels < 160mmHg within 4 hours after admission were significantly associated with a reduction in the proportion of patients with hematoma enlargement (RR = 0.598, 95% CI = 0.365–0.978). PCC administration had no effect on mortality and functional outcome either at discharge or at 3 months.
Interpretation
In contrast to blood pressure control, PCC administration was not associated with a reduced rate of hematoma enlargement in NOAC‐related ICH. Our findings support the need of further investigations exploring new hemostatic reversal strategies for patients with factor Xa inhibitor–related ICH. Ann Neurol 2018;83:186–196
Objective
Outcome prognostication unbiased by early care limitations (ECL) is essential for guiding treatment in patients presenting with intracerebral hemorrhage (ICH). The aim of this study was to ...determine whether the max‐ICH (maximally treated ICH) Score provides improved and clinically useful prognostic estimation of functional long‐term outcomes after ICH.
Methods
This multicenter validation study compared the prognostication of the max‐ICH Score versus the ICH Score regarding diagnostic accuracy (discrimination and calibration) and clinical utility using decision curve analysis. We performed a joint investigation of individual participant data of consecutive spontaneous ICH patients (n = 4,677) from 2 retrospective German‐wide studies (RETRACE I + II; anticoagulation‐associated ICH only) conducted at 22 participating centers, one German prospective single‐center study (UKER‐ICH; nonanticoagulation‐associated ICH only), and 1 US‐based prospective longitudinal single‐center study (MGH; both anticoagulation‐ and nonanticoagulation‐associated ICH), treated between January 2006 and December 2015.
Results
Of 4,677 included ICH patients, 1,017 (21.7%) were affected by ECL (German cohort: 15.6% 440 of 2,377; MGH: 31.0% 577 of 1,283). Validation of long‐term functional outcome prognostication by the max‐ICH Score provided good and superior discrimination in patients without ECL compared with the ICH Score (area under the receiver operating curve AUROC, German cohort: 0.81 0.78–0.83 vs 0.74 0.72–0.77, p < 0.01; MGH: 0.85 0.81–0.89 vs 0.78 0.74–0.82, p < 0.01), and for the entire cohort (AUROC, German cohort: 0.84 0.82–0.86 vs 0.80 0.77–0.82, p < 0.01; MGH: 0.83 0.81–0.85 vs 0.77 0.75–0.79, p < 0.01). Both scores showed no evidence of poor calibration. The clinical utility investigated by decision curve analysis showed, at high threshold probabilities (0.8, aiming to avoid false‐positive poor outcome attribution), that the max‐ICH Score provided a clinical net benefit compared with the ICH Score (14.1 vs 2.1 net predicted poor outcomes per 100 patients).
Interpretation
The max‐ICH Score provides valid and improved prognostication of functional outcome after ICH. The associated clinical net benefit in minimizing false poor outcome attribution might potentially prevent unwarranted care limitations in patients with ICH. ANN NEUROL 2021;89:474–484
Intraventricular hemorrhage (IVH) is a verified independent prognostic parameter in patients with intracerebral hemorrhage (ICH). However, the impact of the extent of IVH on clinical outcomes is ...unestablished.
We analyzed 1,112 consecutive primary ICH patients of the UKER-ICH cohort (NCT03183167) and hypothesized that there is no difference in outcome between patients without IVH and patients with minor IVH not leading to obstructive hydrocephalus. Propensity score matching and multivariable analyses were performed to account for imbalances in baseline characteristics. Primary outcome was defined as functional outcome 3 months after ICH -assessed using the modified Rankin Scale (mRS) dichotomized into favorable (mRS = 0-3) and unfavorable outcome (mRS = 4-6). Secondary outcomes included mortality at 3 months and a Graeb score-based threshold analysis for association of the extent of IVH with unfavorable clinical outcome.
Among the 461 out of 1,112 (41.5%) ICH patients with IVH, 191 out of 461 (41.4%) showed IVH without obstructive hydrocephalus and no requirement of external ventricular drain (EVD) placement. After adjusting for baseline imbalances we found no difference in functional outcome at 3 months between patients without IVH (No-IVH) and patients with IVH not requiring EVD (IVH-w/o-EVD): mRS 0-3: No-IVH 64/161 (39.8%) vs. IVH-w/o-EVD 53/170 (31.2%); p = 0.103. However, there was a trend toward a higher mortality in IVH-w/o-EVD patients (mRS 6: No IVH 40/161 24.8% vs. IVH-w/o-EVD 57/170 33.5%; p = 0.083). Multivariable analysis revealed that a Graeb score >2 was independently associated with unfavorable outcome (mRS 4-6: OR 3.16 1.54-6.48; p = 0.002), and higher mortality (mRS 6: OR 2.57 1.40-4.74; p = 0.002) in IVH patients.
Small amounts of intraventricular blood (Graeb score ≤2) not leading to obstructive hydrocephalus are not associated with unfavorable outcome or death after ICH. Thus, IVH per se should not be considered a binary variable in outcome prediction for ICH patients.
OBJECTIVETo determine the influence of intracerebral hemorrhage (ICH) location and volume and hematoma surface on perihemorrhagic edema evolution.
METHODSPatients with ICH of the prospective ...Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage (UKER-ICH) cohort study (NCT03183167) between 2010 and 2013 were analyzed. Hematoma and edema volume during hospital stay were volumetrically assessed, and time course of edema evolution and peak edema correlated to hematoma volume, location, and surface to verify the strength of the parameters on edema evolution.
RESULTSOverall, 300 patients with supratentorial ICH were analyzed. Peak edema showed a high correlation with hematoma surface (R = 0.864, p < 0.001) rather than with hematoma volumes, regardless of hematoma location. Smaller hematomas with a higher ratio of hematoma surface to volume showed exponentially higher relative edema (R = 0.755, p < 0.001). Multivariable logistic regression analysis revealed a cutoff ICH volume of 30 mL, beyond which an increase of total mass lesion volume (combined volume of hematoma and edema) was not associated with worse functional outcome. Specifically, peak edema was associated with worse functional outcome in ICH <30 mL (odds ratio OR 2.63, 95% confidence interval CI 1.68–4.12, p < 0.001), contrary to ICH ≥30 mL (OR 1.20, 95% CI 0.88–1.63, p = 0.247). There were no significant differences between patients with lobar and those with deep ICH after adjustment for hematoma volumes.
CONCLUSIONSPeak perihemorrhagic edema, although influencing mortality, is not associated with worse functional outcomes in ICH volumes >30 mL. Although hematoma volume correlates with peak edema extent, hematoma surface is the major parameter for edema evolution. The effect of edema on functional outcome is therefore more pronounced in smaller and irregularly shaped hematomas, and these patients may particularly benefit from edema-modifying therapies.
Stroke-associated immunosuppression and inflammation are increasingly recognized as factors that trigger infections and thus, potentially influence the outcome after stroke. Several studies ...demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes in patients with ischemic stroke. However, little is known about the impact of NLR on short-term mortality in intracerebral hemorrhage (ICH).
This observational study included 855 consecutive ICH-patients. Patient demographics, clinical, laboratory, and in-hospital measures as well as neuroradiological data were retrieved from institutional databases. Functional 3-months-outcome was assessed and categorized as favorable (modified Rankin Scale mRS 0-3) and unfavorable (mRS 4-6). We (i) studied the natural course of NLR in ICH, (ii) analyzed parameters associated with NLR on admission (NLROA), and (iii) evaluated the clinical impact of NLR on mortality and functional outcome.
The median NLROA of the entire cohort was 4.66 and it remained stable during the entire hospital stay. Patients with NLR ≥4.66 showed significant associations with poorer neurological status (National Institute of Health Stroke Scale NIHSS 18 9-32 vs. 10 4-21; p < 0.001), larger hematoma volume on admission (17.6 6.9-47.7 vs. 10.6 3.8-31.7 mL; p = 0.001), and more frequently unfavorable outcome (mRS 4-6 at 3 months: 317/427 74.2% vs. 275/428 64.3%; p = 0.002). Patients with an NLR under the 25th percentile (NLR <2.606) - compared to patients with NLR >2.606 - presented with a better clinical status (NIHSS 12 5-21 vs. 15 6-28; p = 0.005), lower hematoma volumes on admission (10.6 3.6-30.1 vs. 15.1 5.7-42.3 mL; p = 0.004) and showed a better functional outcome (3 months mRS 0-3: 82/214 38.3% vs. 185/641 28.9%; p = 0.009). Patients associated with high NLR (≥8.508 = above 75th-percentile) showed the worst neurological status on admission (NIHSS 21 12-32 vs. 12 5-23; p < 0.001), larger hematoma volumes (21.0 8.6-48.8 vs. 12.2 4.1-34.9 mL; p < 0.001), and higher proportions of unfavorable functional outcome at 3 months (mRS 4-6: 173/214 vs. 418/641; p < 0.001). Further, NLR was linked to more frequently occurring infectious complications (pneumonia 107/214 vs. 240/641; p = 0.001, sepsis: 78/214 vs. 116/641; p < 0.001), and increased c-reactive-protein levels on admission (p < 0.001; R2 = 0.064). Adjusting for the above-mentioned baseline confounders, multivariable logistic analyses revealed independent associations of NLROA with in-hospital mortality (OR 0.967, 95% CI 0.939-0.997; p = 0.029).
NLR represents an independent parameter associated with increased mortality in ICH patients. Stroke physicians should focus intensely on patients with increased NLR, as these patients appear to represent a population at risk for infectious complications and increased short-mortality. Whether these patients with elevated NLR may benefit from a close monitoring and specially designed therapies should be investigated in future studies.
Hematoma expansion (HE) is the most important therapeutic target during acute care of patients with intracerebral hemorrhage (ICH). Imaging biomarkers such as non-contrast CT (NCCT) markers have been ...associated with increasing risk for HE. The aim of the present study was to evaluate the influence of NCCT markers with functional long-term outcome and with HE in patients with deep (basal ganglia and thalamus) ICH who represent an important subgroup of patients at the highest risk for functional deterioration with HE due to the eloquence of the affected brain region.
From our prospective institutional database, all patients maximally treated with deep ICH were included and retrospectively analyzed. NCCT markers were recorded at diagnostic imaging, ICH volume characteristics were volumetrically evaluated, and all patients received follow-up imaging within 0-48 h. We explored associations of NCCT makers with unfavorable functional outcome, defined as modified Rankin scale 4-6, after 12 months and with HE. Bias and confounding were addressed by multivariable regression modeling.
In 322 patients with deep ICH, NCCT markers were distributed as follows: irregular shape: 69.6%, heterogenous density: 55.9%, hypodensities: 52.5%, island sign: 19.3%, black hole sign: 11.5%, and blend sign: 4.7%. Upon multivariable regression analyses, independent associations were documented with the functional outcome for irregular shape (aOR: 2.73, 95%CI: 1.42-5.22,
= 0.002), heterogenous density (aOR: 2.62, 95%CI: 1.40-4.90,
= 0.003) and island sign (aOR: 2.54, 95%CI: 1.05-6.14,
= 0.038), and with HE for heterogenous density (aOR: 5.01, 95%CI: 1.93-13.05,
= 0.001) and hypodensities (aOR: 3.75, 95%CI: 1.63-8.62,
= 0.002).
NCCT markers are frequent in deep ICH patients and provide important clinical implications. Specifically, markers defined by diverging intra-hematomal densities provided associations with a 5-times higher risk for HE and a 2.5-times higher likelihood for unfavorable functional long-term outcome. Hence, these markers allow the identification of patients with deep ICH at high risk for clinical deterioration due to HE.
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