Stefan T. Gerner

Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage

IMPORTANCE Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01829581.

Anemia is an independent prognostic factor in intracerebral hemorrhage: an observational cohort study

IntroductionTo date only two studies have evaluated anemia status in acute intracerebral hemorrhage (ICH) reporting that on admission anemia (OAA) was associated with larger hematoma volume, and lower hemoglobin levels during hospital stay, which related to poorer outcome. The question remains whether anemia influences outcome through related volume-effects or itself has an independent impact?MethodsThis single-center investigation included 435 consecutive patients with spontaneous ICH admitted to the Department of Neurology over five years. Functional short- and long-term outcome (3 months and 1 year) were analyzed for anemia status. Multivariate logistic and graphical regression analyses were calculated for associations of anemia and to determine independent effects on functional outcome. It was decided to perform a separate analysis for patients with ICH-volume <30cm3 (minor-volume-ICH).ResultsOverall short-term-outcome was worse in anemic patients (mRS[4-6] OAA = 93.3% vs. non-OAA = 61.2%, P < 0.01), and there was a further shift towards an increased long-term mortality (P = 0.02). The probability of unfavorable long-term-outcome (mRS[4-6]) in OAA was elevated 7-fold (OR:7.5; P < 0.01). Receiver operating characteristics curve (ROC) analysis revealed a positive but poor association of ICH-volume and anemia (AUC = 0.67) suggesting volume-undriven outcome-effects of anemia (AUC = 0.75). Multivariate regression analyses revealed that anemia, besides established parameters, has the strongest relation to unfavorable outcome (OR:3.0; P < 0.01). This is even more pronounced in minor-volume-ICH (OR:5.6; P < 0.01).ConclusionsAnemia seems to be a previously unrecognized significant predictor of unfavorable functional outcome with independent effects beyond its association with larger hemorrhage volumes. The recognition of anemia and its treatment may possibly influence outcome after ICH and as such prospective interventional studies are warranted.

Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia

Background: Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated. Methods: This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35°C), prolonged (7 ± 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome. Results: Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH-treated patients 66.7 vs. 33.3% of non-TH (p = 0.06). Conclusion: Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact.

Neutrophil-to-Lymphocyte Ratio Is an Independent Predictor for In-Hospital Mortality in Spontaneous Intracerebral Hemorrhage

Background and Purpose: 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). Methods: 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. Results: 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). Conclusions: 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.

Efficacy and safety of combined intraventricular fibrinolysis with lumbar drainage for prevention of permanent shunt dependency after intracerebral hemorrhage with severe ventricular involvement: A randomized trial and individual patient data meta‐analysis

Intraventricular hemorrhage (IVH) is a negative prognostic factor in intracerebral hemorrhage (ICH) and is associated with permanent shunt dependency in a substantial proportion of patients post‐ICH. IVH treatment by intraventricular fibrinolysis (IVF) was recently linked to reduced mortality rates in the CLEAR III study and IVF represents a safe and effective strategy to hasten clot resolution that may reduce shunt rates. Additionally, promising results from observational studies reported reductions in shunt dependency for a combined treatment approach of IVF plus lumbar drains (LDs). The present randomized, controlled trial investigated efficacy and safety of a combined strategy—IVF plus LD versus IVF alone—on shunt dependency in patients with ICH and severe IVH.

Lymphocytopenia Is an Independent Predictor of Unfavorable Functional Outcome in Spontaneous Intracerebral Hemorrhage

Background and Purpose— Stroke-associated immunosuppression is an increasingly recognized factor triggering infections and thus potentially influencing outcome after stroke. Specifically, lymphocytopenia after intracerebral hemorrhage (ICH) has only been addressed in small-sized retrospective studies of mixed intracranial bleedings. This cohort study investigated the natural course of lymphocytopenia, parameters associated with lymphocytopenia on admission (LOA) and during stay, and evaluated the clinical impact of lymphocytopenia in solely ICH patients. Methods— This observational study included 855 consecutive patients with ICH. Patient demographics, clinical and neuroradiological data as well as laboratory and in-hospital measures were retrieved from institutional prospective databases. Functional 3-month outcome was assessed by mailed questionnaires. Lymphocytopenia was defined as <1.0 (109/L) and was correlated with patient’s characteristics and outcome. Results— Prevalence of LOA was 27.3%. Patients with LOA showed significant associations with poorer neurological status (18 [10–32] versus 13 [5–24]; P<0.001), larger hematoma volume (18.5 [6.2–46.2] versus 12.8 [4.4–37.8]; P=0.006), and unfavorable outcome (74.7% versus 63.3%; P=0.0018). Natural course of lymphocyte count during hospital stay revealed a lymphocyte nadir of 1.1 (0.80–1.53 [109/L]) at day 5. Focusing on patients with day-5-lymphocytopenia, compared with patients with LOA, revealed increased rates of infections (63 [71.6] versus 113 [48.5]; P<0.001) and poorer functional outcome at 3 months (76 [86.4] versus 175 [75.1); P=0.029). Adjusting for baseline confounders, multivariable logistic and receiver operating characteristics analyses documented independent associations of day-5-lymphocytopenia with unfavorable outcome (day-5-lymphocytopenia: odds ratio, 2.017 [95% confidence interval, 1.029–3.955], P=0.041; LOA: odds ratio, 1.391 [0.795–2.432], P=0.248; receiver operating characteristics: day-5-lymphocytopenia: area under the curve=0.673, P<0.0001, Youden’s index=0.290; LOA: area under the curve=0.513, P=0.676, Youden’s index=0.084), whereas receiver operating characteristics analyses revealed no association of age or hematoma volume with day-5-lymphocytopenia (age: area under the curve=0.540, P=0.198, Youden’s index=0.106; volume: area under the curve=0.550, P=0.0898, Youden’s index=0.1224). Conclusions— Lymphocytopenia is frequently present in patients with ICH and may represent an independent parameter associated with unfavorable functional outcome. Developing lymphocytopenia affected outcome even stronger than LOA, a finding that may open up new therapeutic avenues in specific subsets of patients with ICH.

Severity assessment in maximally treated ICH patients: The max-ICH score.

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 months: AUC 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.

Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves

Aims Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time‐window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. Methods and results We pooled individual patient‐data (n = 2504) from a nationwide multicentre cohort‐study (RETRACE, conducted at 22 German centres) and eventually identified MHV‐patients (n = 137) with anticoagulation‐associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no‐TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity‐score matching and multivariable cox‐regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no‐TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no‐TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate‐ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67‐35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA‐timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33‐21.37; P < 0.01). The hazard for the composite—balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10‐5.70; P = 0.03). Conclusion Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing—between least risks for thromboembolic and haemorrhagic complications—provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk. Figure. No Caption available.

Association of prothrombin complex concentrate administration and hematoma enlargement in non–vitamin K antagonist oral anticoagulant–related intracerebral hemorrhage

To investigate parameters associated with hematoma enlargement in non–vitamin K antagonist oral anticoagulant (NOAC)‐related intracerebral hemorrhage (ICH).

Assessing the value of topiramate in refractory status epilepticus.

PURPOSE The aim of this study was to assess factors associated with the use of topiramate (TPM) in refractory status epilepticus (RSE). METHODS We retrospectively reviewed RSE episodes over a 12-year period. Episodes treated with and without TPM were compared in terms of demographics, RSE characteristics, clinical course, and outcome in univariate and multivariate analyses. Subgroups defined by type of RSE were studied separately. Functional outcome was assessed with the modified Rankin Scale. RESULTS Among 71 episodes, 17 (23.9%) were treated with TPM and seizure control was achieved in all of these. The results of unadjusted comparisons suggested a use of TPM in younger and healthier patients who received more perseverant treatment indicated by a higher number of antiepileptic drugs applied. In multivariate analysis adjusting for RSE duration, however, these associations lost significance. Furthermore, TPM was not a predictor of successful RSE termination in neither the overall cohort, nor in the subgroup of complex-partial RSE. CONCLUSION After multivariate adjustment, no significant differences were observed between episodes treated with and without TPM in baseline characteristics, treatment, and outcome. Regarding the latter, this study does therefore not yield evidence for a particular efficacy of TPM in RSE.