Early initiation of direct anticoagulation after stroke in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: The safety of early initiation of anticoagulant therapy in patients with ischaemic stroke related to atrial fibrillation (AF) is unknown. We investigated the safety of early initiation of direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs) or no anticoagulation. METHODS: This observational, retrospective, single-centre study included consecutive patients with recent (<4 weeks) ischaemic stroke and AF. The primary outcome was the rate of major (intracranial and extracranial) bleeding in patients on different treatment schemes, i.e. DOACs, VKAs and not anticoagulated. We also investigated the rate of ischaemic cerebrovascular events and mortality. RESULTS: We included 959 consecutive patients with AF and ischaemic stroke followed up for an average of 16.1 days after the index event. A total of 559 out of 959 patients (58.3%) were anticoagulated with either VKAs (n = 259) or DOACs (n = 300). Anticoagulation was started after a mean of 7 ± 9.4 days in the DOAC group and 11.9 ± 19.7 days in the VKA group. Early initiation of any anticoagulant was not associated with an increased risk of any major bleeding [odds ratio (OR), 0.49; 95% confidence intervals (CI), 0.21-1.16] and in particular of intracranial bleeding (OR, 0.47; 95% CI, 0.17-1.29; P = 0.143) compared with no anticoagulation. In contrast to VKAs (OR, 0.78; 95% CI, 0.28-2.13), treatment with DOACs (OR, 0.32; 95% CI, 0.10-0.96) reduced the rate of major bleeding compared with no anticoagulation. Early recurrences of ischaemic stroke did not differ significantly among the three groups. CONCLUSIONS: Starting DOACs within a mean of 7 days after stroke appeared to be safe. Randomized controlled studies are needed to establish the added efficacy of starting anticoagulation early after stroke.

Microbleeds in ischemic vs hemorrhagic strokes on novel oral anticoagulants.

OBJECTIVES: To identify differences in clinical characteristics and severity of cerebral small vessel disease (CSVD) including cerebral microbleeds (CMBs), between patients suffering ischemic stroke (IS) or intracerebral hemorrhage (ICH) while taking novel (non-vitamin K antagonists) oral anticoagulants (NOACs). METHODS: Multicenter, prospective, observational cohort study performed at 38 centers between 2012 and 2015. We compared demographics, comorbidity, and functional status (before and after stroke) between NOAC-IS and NOAC-ICH patients. Extent of white matter lesions (WML), and location and counts of CMBs were analyzed in a subgroup of patients for whom MRI including hemorrhage-sensitive sequences was available. RESULTS: A total of 351 patients were included (290 NOAC-IS, 61 NOAC-ICH). Functional status was worse in NOAC-ICH patients before and after stroke. No significant differences were found for demographic variables and cardiovascular comorbidity. In the subgroup with available MRI (n = 116), the proportion of patients with at least one CMB was higher in NOAC-ICH than in NOAC-IS (15/19 [79%] vs 36/97 [37%], P < .001), as was the absolute number of CMBs (median 5 [IQR 1-24] vs 0 [0-1], P < .001). WML were more extensive in NOAC-ICH than in NOAC-IS patients. Adjusted for WML, logistic regression analysis showed higher odds of NOAC-ICH in patients with CMB than without (OR 5.60 [1.64-19.14], P = .006). CONCLUSIONS: Patients with NOAC-ICH have similar clinical characteristics but a higher prevalent burden of CSVD compared to NOAC-IS. The role of neuroimaging in selection of patients for anticoagulation with NOAC requires further investigation in longitudinal studies.

Preexisting cognitive impairment in intracerebral hemorrhage.

OBJECTIVES: Preexisting cognitive impairment is a predictor of cognitive decline after ischemic stroke, but evidence in intracerebral hemorrhage (ICH) is limited. We aimed to determine the prevalence of premorbid cognitive impairment in patients with ICH. MATERIALS AND METHODS: We included patients with acute ICH. Pre-ICH cognitive impairment was determined based on the results of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) that uses information from close relatives. Patients were assessed as having been cognitively impaired with an IQCODE score of ≥3.44; an IQCODE ≥4.00 indicated pre-ICH dementia. CT and MRI images were reviewed to determine the extent of white matter lesions and to measure the radial width of the temporal horn as marker of brain atrophy. We investigated differences of cardiovascular risk factors and imaging data between patients with and without pre-ICH cognitive impairment using correlation analyses, uni- and multivariable regression models. Functional neurological state was assessed using the modified Rankin Scale (mRS). The mRS was dichotomized at the level of 3, and a premorbid mRS of 0-2 was considered as functional independency. RESULTS: Among the 89 participants, median age was 70 years (interquartile range 58-78) and 52 (58.4%) were male. IQCODE indicated pre-ICH cognitive impairment in 18.0% (16 of 89), and 83.1% were functionally independent before ICH. Cognitive impairment was associated with a premorbid mRS≥3 (chi squared test, P=0.009). In multivariable analysis, prior stroke/transient ischemic attack (OR 18.29, 95%-CI 1.945-172.033, P=.011) and hematoma volume (OR 0.90, 95%-CI 0.812-0.991, P=.033) were independently associated with pre-ICH cognitive impairment. CONCLUSIONS: In conclusion, cognitive impairment frequently precedes ICH. A higher frequency of cerebrovascular events suggests a role of vascular processes in the development of cognitive impairment before ICH.

Peri-procedural silent cerebral infarcts after left atrial appendage occlusion.

BACKGROUND AND PURPOSE: To determine the rate of peri-interventional silent brain infarcts after left atrial appendage occlusion (LAAO). METHODS: In this prospective, uncontrolled single-center pilot study, consecutive patients with atrial fibrillation undergoing LAAO between July 2013 and January 2016 were included. The Amplatzer Cardiac Plug, WATCHMAN or Amulet device was used. A neurological examination and cranial magnetic resonance imaging (MRI) were performed within 48 h before and after the procedure. MRI was evaluated for new diffusion-weighted imaging (DWI) hyperintensities, cerebral microbleeds (CMBs) and white-matter lesions (WMLs). RESULTS: Left atrial appendage occlusion was performed in 21 patients (mean age, 73.2 ± 9.5 years). Main reasons for LAAO were previous intracerebral hemorrhage (n = 11) and major systemic bleeding (n = 6). No clinically overt stroke occurred peri-interventionally. After the intervention, one patient had a small cerebellar hyperintensity on DWI (4.8%; 95% confidence interval, 0.0-14.3) that was not present on the MRI 1 day before the procedure. Among 11 patients with available MRI just before LAAO, there were no significant changes in the number of CMBs and the severity of WMLs after LAAO. CONCLUSIONS: This study of peri-interventional MRI in LAAO suggests a low rate of silent peri-procedural infarcts in this elderly population. Confirmation in larger studies is needed.

Prevalence of atrial fibrillation and association of previous antithrombotic treatment in patients with cerebral microbleeds.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are associated with an increased risk of intracerebral hemorrhage. The impact of oral anticoagulation (OAC) on CMBs is not well characterized. Our aim was to assess the prevalence of CMBs in stroke and transient ischaemic attack (TIA) patients with atrial fibrillation (AF) and to analyze the implications of previous treatment with OAC. METHODS: In this retrospective analysis on data from a prospectively recruiting stroke registry, patients with ischaemic stroke or TIA with brain magnetic resonance imaging including susceptibility weighted imaging were consecutively enrolled during a 3-year period. For each patient cardiovascular risk factors, AF history and recent diagnosis of AF, present use of OAC and antiplatelets, the National Institute of Health Stroke Scale and the premorbid modified Rankin Scale score were recorded. Two independent raters identified CMBs according to consensus criteria. CMB location was classified as lobar, deep or in the posterior fossa. RESULTS: In all, 785 patients (mean age 63.9 ± 14.2 years) were included. At least one CMB was detected in 186 (23.7%) patients. CMBs were significantly more frequent in patients with AF (30.5% vs. 22.4%). Patients with previous OAC treatment were more likely to have CMBs (36.7% vs. 22.8%, P = 0.03) and abundant CMBs (n > 10) were more frequent in anticoagulated patients even after adjustment for age. However, age was the only independent factor predicting CMBs (P = 0.001). CONCLUSIONS: Cerebral microbleeds are common in elderly AF patients with acute ischaemic stroke. Previous OAC is associated with a higher number of CMBs predominantly in the lobar location. Establishing a causal relationship requires prospective longitudinal investigation.

Prevalence of renal dysfunction in ischaemic stroke and transient ischaemic attack patients with or without atrial fibrillation.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is associated with a higher risk of stroke and atrial fibrillation (AF). There are limited data on the comorbidity of renal dysfunction and AF in stroke patients. Our aim was to determine the frequency of kidney dysfunction in ischaemic stroke patients with and without AF. METHODS: In a prospectively collected, single center cohort of acute ischaemic stroke and transient ischaemic attack (TIA) patients, glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease equation on admission. Renal function was graded into five categories (cat.): cat. 1, eGRF ≥90 ml/min/1.73 m(2); cat. 2, 60-89; cat. 3, 30-59; cat. 4, 15-29; cat. 5, <15. The diagnosis of AF was based on medical history, a 12-lead electrocardiogram (ECG) and 24-h Holter or continuous ECG monitoring. RESULTS: In total, 2274 patients (1727 stroke, 547 TIA; median age 71.0) were included. Median eGFR was 78.6 ml/min/1.73 m(2) (interquartile range 61/95); 21.1% were in cat. 3, 2.1% in cat. 4, 0.7% in cat. 5. In all, 535 patients (23.5%) suffered from AF; 28.0% of these were in cat. 3, 2.6% and 0.8% in cat. 4 and cat. 5, respectively. In multivariable analysis, age [odds ratio (OR) 1.1], diabetes (OR 1.8), heart failure (OR 1.7) and AF (OR 1.4) were independently associated with kidney dysfunction (eGFR < 60). CONCLUSIONS: Renal dysfunction is far more common in stroke patients than in the general population and more common in AF-related stroke. These findings may have implications for the choice of anticoagulants.

Feasibility of the Montreal Cognitive Assessment in acute stroke patients.

BACKGROUND AND PURPOSE: Cognitive deficits are common following stroke. Cognitive function in the acute stroke setting is a predictive factor for mid-term outcome. The Montreal Cognitive Assessment (MoCA) is a screening tool for cognitive impairment. The feasibility of MoCA in the acute phase of stroke was evaluated and factors predictive of cognitive impairment were determined. METHODS: In this prospective, single-centre, explorative and observational study consecutive patients with ischaemic (IS) or haemorrhagic (ICH) stroke were enrolled between March 2011 and September 2012. The routine work-up for each patient encompassed assessment of cardiovascular risk factors, the National Institutes of Health Stroke Scale (NIHSS) and the pre-morbid modified Rankin Scale (mRS) score. Cognitive performance was measured using the German version of the MoCA within the first days of admission. A MoCA score of <26 was considered to indicate cognitive impairment. RESULTS: Between March 2011 and September 2012 a total of 842 patients with IS (89.0%) and ICH (11.0%) were enrolled in our study. MoCA was feasible in 678/842 patients (80.5%). Factors independently associated with non-feasibility were stroke severity (NIHSS), pre-morbid functional status (mRS), age and lower educational level. Mean MoCA was 21.4 (SD 5.7). A total of 498/678 (73.5%) patients appeared cognitively impaired (<26/30). Independent predictive factors for a lower MoCA score were age, educational level, stroke severity (NIHSS) and pre-morbid functional status (mRS). CONCLUSIONS: In the acute phase of stroke, MoCA is feasible in about 80% of eligible patients. At this stage, MoCA identifies a cognitive impairment in 75% of patients.

Prevalence of atrial fibrillation in intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Oral anticoagulation (OAC) is an effective preventive therapy for ischemic stroke in atrial fibrillation (AF). The management of anticoagulation in AF patients with previous intracerebral hemorrhage (ICH) is challenging. The aim of this study was to determine the prevalence of AF after acute ICH in a consecutive monocenter cohort, and to document the subsequent management with respect to OAC. METHODS: Consecutive patients with spontaneous ICH were prospectively included within 19 months. Diagnosis of AF was based on medical history, 12-lead electrocardiogram (ECG), 24-h and continuous ECG monitoring. CHADS2 scores and patient medication were recorded at admission and after 3 months. Additionally, after 3 months mortality, the management of anticoagulation and a newly detected AF were assessed. RESULTS: In total, 206 ICH patients were eligible for data analysis. After 3 months, AF had been diagnosed in 64/206 ICH patients (31.1%). Mortality after 3 months was higher in patients with AF in univariate analysis (45.3% vs. 31.0%). After adjusting for comorbidities and OAC use, AF did not remain an independent predictor for mortality. In total, 35 patients with AF survived 3 months. Of these, CHADS2 score was 2 (2/3, median, interquartile range (IQR)) and 27/35 patients had an indication for OAC with respect to the CHADS2 score, but only 25.7% had been (re-)started on OAC. No consistent factors for deciding whether to initiate OAC treatment could be identified. CONCLUSIONS: Atrial fibrillation is a frequent comorbidity in patients suffering an ICH. Our findings underline the prevailing uncertainty regarding the anticoagulation management of AF after ICH.

Prolonged low-dose thrombolysis in posterior circulation stroke.

BACKGROUND: We aimed to investigate the feasibility, preliminary safety, and efficacy of prolonged low-dose intravenous thrombolysis in posterior circulation stroke patients with a thrombus lodged in the basilar artery who were ineligible for standard rtPA administration. METHODS: We retrospectively analyzed consecutively collected patients in our stroke database who suffered from a basilar artery thrombosis and were treated with prolonged (>1 h), intravenous, low-dose (≤20 mg) rtPA between 01/2005 and 11/2012. RESULTS: Patients included in this study (n = 14) were 68.5 years (IQR 55.5; 72.75) of age and presented with a median NIHSS of 2 (1; 5.25). Median time from symptom onset to treatment was 63 h (33; 141). A median dose of 5.21 µg/kg h (4.46; 6.25) rtPA was administered over 24 h (min 10; max 48). No patient experienced symptomatic intracerebral hemorrhage, one patient developed a spinal epidural hematoma, and two elderly patients were switched to comfort care and died. In eight patients (57%) a decrease in thrombus size or no thrombus at all was detected on control imaging. Nine patients (64%) had a favorable outcome (mRS 0-2) at day 90. CONCLUSIONS: Prolonged low-dose thrombolysis with rtPA may be considered as individual treatment option in selected high-risk patients with basilar artery thrombosis. Presented data may lay the groundwork to further investigate safety and efficacy in a prospective trial.

Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban.

Dabigatran, apixaban, and rivaroxaban have been approved for primary and secondary stroke prevention in patients with atrial fibrillation. However, questions have arisen about how to manage emergency situations, such as when thrombolysis would be required for acute ischemic stroke or for the managing intracranial or gastrointestinal bleedings. We summarize the current literature and provide recommendations for the management of these situations. Peak plasma levels of the direct oral anticoagulants (DOACs) apixaban, dabigatran, or rivaroxaban are observed about 2-4 h after intake. Elimination of dabigatran is mainly dependent on renal function. Consequently, if renal function is impaired, there is a risk of drug accumulation that is highest for dabigatran followed by rivaroxaban and then apixaban and thus dosing recommendations are different. To date, no bedside tests are available that reliably assess the anticoagulatory effect of DOACs, nor are specific antidotes available. We recommend performing the following tests if DOAC intake is unknown: dabigatran-associated bleeding risk is minimized or can be neglected if thrombin time, Hemoclot test, or Ecarin clotting time is normal. Apixaban and rivaroxaban effects can be ruled out if findings from the anti-factor Xa activity test are normal. High plasma levels of DOAC are also mostly excluded if PTT and PTZ are normal four or more hours after DOAC intake. However, normal values of global coagulation tests are not sufficient if thrombolysis is indicated for treating acute stroke. The decision for or against thrombolysis is an individual decision; in these cases, thrombolysis use is off-label. In case of bleeding, prothrombin complex concentrates seems to be the most plausible treatment. For severe gastrointestinal bleeding with life-threatening blood loss, the bleeding source needs to be identified and treated by invasive measures. Use of procoagulant drugs (antifibrinolytics) might also be considered. However, there is very limited clinical experience with these products in conjunction with DOAC.

Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study.

Intracerebral hemorrhage (ICH) is the most devastating complication of oral anticoagulation (OAC). As the number of patients on long-term OAC is expected to rise, the proportion of intracerebral hemorrhage related to OAC (OAC-ICH) in relation to spontaneous ICH (spont-ICH) is expected to increase as well. We determined the proportion of OAC-ICH in consecutive stroke patients and explored differences between OAC-ICH and spont-ICH regarding initial volume, hematoma expansion and outcome. Our prospective study consecutively enrolled patients with supra- and infratentorial ICH. The National Institute of Health Stroke Scale Score and the modified Rankin Scale (mRS) score at baseline and after 3 months, medical history and demographic variables were recorded. All admission and follow-up CTs/MRIs were analysed regarding ICH volume using the ABC/2-method. Intraventricular hemorrhage (IVH) was quantified using the Graeb score. Within 19 months, 2,282 patients were admitted to our ER. 206 ICH patients were included. Overall, 24.8 % of all ICH were related to OAC. Compared to patients with spont-ICH, OAC-ICH patients were older (p = 0.001), more frequently had initial extension of ICH into the ventricles (p = 0.05) or isolated primary IVH (p = 0.03) and a higher Graeb score upon admission (p = 0.01). In contrast, initial ICH volume (p = 0.16) and ICH expansion (p = 0.9) in those receiving follow-up imaging (n = 152) did not differ between the two groups. After correction for age, there was a trend towards poorer outcome in OAC-ICH (p = 0.08). One-fourth of all ICH are related to OAC. Initial extension of ICH into the ventricles and primary IVH are more frequent in OAC-ICH. The rate of hematoma expansion in OAC-ICH patients is similar to non-anticoagulated ICH patients.

Does the STAF score help detect paroxysmal atrial fibrillation in acute stroke patients?

BACKGROUND AND PURPOSE: Detecting paroxysmal atrial fibrillation (pAF) soon after acute cerebral ischaemia has a major impact on secondary stroke prevention. Recently, the STAF score, a composite of clinical and instrumental findings, was introduced to identify stroke patients at risk of pAF. We aimed to validate this score in an independent study population. METHODS: Consecutive patients admitted to our stroke unit with acute ischaemic stroke were prospectively enrolled. The diagnostic work-up included neuroimaging, neuroultrasound, baseline 12-channel electrocardiogram (ECG), 24-h Holter ECG, continuous ECG monitoring, and echocardiography. Presence of AF was documented according to the medical history of each patient and after review of 12-lead ECG, 24-h Holter ECG, or continuous ECG monitoring performed during the stay on the ward. Additionally, a telephone follow-up visit was conducted for each patient after 3 months to inquire about newly diagnosed AF. Items for each patient-age, baseline NIHSS, left atrial dilatation, and stroke etiology according to the TOAST criteria - were assessed to calculate the STAF score. RESULTS: Overall, 584 patients were enrolled in our analysis. AF was documented in 183 (31.3%) patients. In multivariable analysis, age, NIHSS, left atrial dilatation, and absence of vascular etiology were independent predictors for AF. The logistic AF-prediction model of the STAF score revealed fair classification accuracy in receiver operating characteristic curve analysis with an area under the curve of 0.84. STAF scores of ≥5 had a sensitivity of 79% and a specificity of 74% for predicting AF. CONCLUSION: The value of the STAF score for predicting the risk of pAF in stroke patients is limited.

[Current registry studies of acute ischemic stroke]. / Aktuelle Registerstudien beim akuten ischämischen Schlaganfall.

Study registries offer the opportunity to evaluate the effects of new therapies or to observe the consequences of new treatments in clinical practice. The SITS-MOST registry confirmed the validity of findings from randomized trials on intravenous thrombolysis concerning safety and efficacy in the clinical routine. Current study registries concerning new interventional thrombectomy techniques suggest a high recanalization rate; however, the clinical benefit can only be evaluated in randomized, controlled trials. Similarly, the experiences of the BASICS registry on basilar artery occlusion have led to the initiation of a controlled trial. The benefit of hemicraniectomy in malignant middle cerebral artery infarction has been demonstrated by the pooled analysis of three randomized trials. Numerous relevant aspects are currently documented in the DESTINY-R registry. Finally, the recently started RASUNOA registry examines diagnostic and therapeutic aspects of ischemic and hemorrhagic stroke occurring during therapy with new oral anticoagulants.

Continuous monitoring versus HOLTER ECG for detection of atrial fibrillation in patients with stroke.

BACKGROUND AND PURPOSE: Detection of atrial fibrillation is of vital importance because oral anticoagulation decreases the risk of a stroke by 64%. Current standards for stroke unit treatment require continuous electrocardiogram (ECG) monitoring for at least 24 h. Additionally, a 24-h HOLTER ECG (HOLTER) should be performed in selected patients. It remains unclear whether continuous monitoring at the bedside is equivalent to HOLTER for the detection of atrial fibrillation. Furthermore, we investigate how many additional patients with paroxysmal atrial fibrillation can be identified as a result of a longer duration of continuous monitoring. METHODS: In this study, we prospectively compared the detection rates of HOLTER and 24-h monitoring at the Stroke Unit at the University of Heidelberg over a period of 9 months. Continuous monitoring was analyzed by trained nurses, HOLTER by cardiologists. RESULTS: We included 370 patients with ischemic stroke or transient ischemic attack (TIA) in our study. Of these, 192 patients underwent HOLTER. Previously unknown atrial fibrillation was detected in 44 patients, 13 patients had no atrial fibrillation in baseline ECG, but atrial fibrillation was detected by continuous monitoring. In two patients, the HOLTER showed atrial fibrillation; both patients had also been detected by continuous monitoring. Median time to detection of the atrial fibrillation during continuous monitoring was 43 h after hospitalization. CONCLUSION: In this study, use of HOLTER does not give any additional benefit in comparison with continuous monitoring with intermittent analysis by trained staff alone. The median detection time of 43 h emphasizes the importance of longer continuous monitoring.

Paroxysmal atrial fibrillation is more prevalent than persistent atrial fibrillation in acute stroke and transient ischemic attack patients.

BACKGROUND: Atrial fibrillation (AF) is a common cause of ischemic stroke and transient ischemic attack (TIA). More extensive diagnostic effort is required to detect paroxysmal AF (pxAF) than persistent AF (pAF); the prevalence of pxAF in stroke patients is unknown. We evaluated the prevalence of pAF and pxAF in ischemic stroke and TIA patients. METHODS: Consecutive patients with acute ischemic stroke/TIA were enrolled prospectively. We aimed to detect patients with a history of AF, with AF newly diagnosed in the emergency room (ER), or with newly diagnosed AF during a 3-month period following the event. Differences in the frequency of AF diagnosis with respect to the disposition of patients after ER work-up were assessed. RESULTS: A total of 692 patients were enrolled (male: 52.2%; ischemic stroke: 69.1%; TIA: 30.9%). A previously documented history of AF was present in 19.7% (pAF: 47.1%, pxAF: 52.9%). In 3.8% of patients, AF was newly diagnosed in the ER (pxAF: 61.5%) and in 5.2% during the 3-month follow-up period. The overall prevalence of AF was 28.6% (pxAF: 62.6%). Previously documented pxAF evaded diagnosis at ER presentation in 48.6%. The prevalence of AF increased with age (p < 0.001). Patients with pxAF were younger than those with pAF (p = 0.004) and more often female (p = 0.05). The presence of any AF was associated with higher initial NIHSS scores (p < 0.001) and higher modified Rankin scores after 3 months (p < 0.001). CONCLUSION: pxAF occurs more often than pAF in stroke/TIA patients. As effective stroke prevention is available for AF, it is important to develop and evaluate sensitive methods for detecting pxAF.

[New oral anticoagulants in atrial fibrillation]. / Neue orale Antikoagulanzien beim Vorhofflimmern.

Atrial fibrillation (AF) causes at least 20% of all ischemic strokes. In large randomized trials of primary and secondary stroke prevention, anticoagulation with vitamin K antagonists (VKA) protected much more efficiently than antiplatelet agents against stroke. Because of the problematic pharmacological properties of VKA only part of the AF patients are currently being treated with oral anticoagulants (OAK). The targeted development of specific oral inhibitors of the central coagulation factors thrombin and factor Xa allows reliable anticoagulation without regular coagulation monitoring. In the present review, pharmacological properties of the different agents are compared. Of the four large randomized phase 3 studies in AF (RELY, ROCKET-AF, ARISTOTLE, ENGAGE-AF) with the primary efficacy endpoint stroke and systemic embolism, the published data from the RELY trial indicate a superior efficacy of dabigatran etexilate (2 × 150 mg/day) and a lower risk of intracranial hemorrhage compared to warfarin. Favorable preliminary results have been demonstrated for the factor Xa inhibitor rivaroxaban. Apixaban was more efficacious than ASA and had a similar risk of hemorrhage in the AVERROES study. Thus, the available data suggest a favorable benefit-risk ratio for the new substances in addition to improved patient comfort. Currently unresolved issues relate to the verification of patient adherence by suitable coagulation tests and to the emergency coagulation diagnostics and therapy in acute ischemic or hemorrhagic strokes under the new OAC.

Detection of paroxysmal atrial fibrillation in acute stroke patients.

BACKGROUND: Atrial fibrillation (AF) is a frequent cause of stroke, but detecting paroxysmal AF (pAF) poses a challenge. We investigated whether continuous bedside ECG monitoring in a stroke unit detects pAF more sensitively than 24-hour Holter ECG, and tested whether examining RR interval dynamics on short-term ECG recordings using an automated screening algorithm (ASA) for pAF detection is a useful tool to predict the risk of pAF outside periods of manifest AF. METHODS: Patients >60 years with acute ischemic stroke or transient ischemic attacks (TIA) were prospectively enrolled unless initial ECG revealed AF or they had a history of paroxysmal or persistent AF. ASA was performed on 1- to 2-hour ECG recordings in the emergency room and patients were classified into 5 risk categories for pAF. All patients underwent continuous bedside ECG monitoring for >48 h. Additionally, 24-hour Holter ECG was performed. RESULTS: 136 patients were enrolled (median age: 72 years, male: 58.8%). In 29 (21.3%), pAF was newly diagnosed by continuous bedside ECG monitoring. pAF increased with age (p = 0.031). Median time to first pAF detection on continuous bedside ECG monitoring was 36 h. In 16 patients, pAF was detected by continuous bedside ECG monitoring prior to the performance of 24-hour Holter ECG. Thirteen of the remaining patients were pAF positive on continuous bedside ECG monitoring, but 24-hour Holter detected only 3 patients. Accordingly, the sensitivity of 24-hour Holter was 0.23. Sensitivity of higher-risk categories of ASA compared to continuous bedside ECG monitoring was 0.72, and specificity 0.63. CONCLUSION: Continuous bedside ECG monitoring is more sensitive than 24-hour Holter ECG for pAF detection in acute stroke/TIA patients. Screening patients for pAF outside AF episodes using ASA requires further development.

Regulatory CD4+ CD25+ T cells prevent thymic dysfunction in experimental chronic colitis.

Chronic colitis in T-cell deficient Tg epsilon26 mice develops due to a dysfunction of the thymus which generates colitogenic T cells after bone marrow (BM) transplantation. Regulatory CD4+ CD25+ T cells have been shown to prevent colitis in this model by normalizing the peripheral T-cell pool. We tested the hypothesis that T-cell normalization takes place in the thymus. Tg epsilon26 mice were transplanted with BM (BM-->Tg epsilon26 mice) and consequently received either CD4+ CD25+ or CD4+ CD25- cells from syngenic wild type mice. Furthermore, untransplanted Tg epsilon26 mice received CD4+ CD25+ or CD4+ CD25- cells or complete mesenteric lymph node cells. Transfer of regulatory. CD4+ CD25+ cells normalized the total number of thymocytes and the percentage and number of double positive CD4+ CD8+ cells in transplanted mice while percentage of single positive CD4+ and CD8+ thymocytes in BM-->Tg epsilon26 mice was reduced upon CD4+ CD25+ transfer. Timing of CD4+ CD25+ cell injection was important as transfer later than 7 days after BM transplantation failed to prevent abnormal thymic T-cell distribution in BM-->Tg epsilon26 mice. Isolated CD4+ CD25+ cell transfer without preceding BM transplantation failed to reconstitute thymic architecture. Differences of thymic cell composition could not be exclusively explained by presence or absence of colitis, respectively, because 19 days after BM transplantation when both groups showed no histological signs of colitis, animals transferred with CD4+ CD25+ T cells had a significantly higher percentage and number of CD4+ CD25+ thymocytes and CD4+ Foxp3+ cells than BM-->Tg epsilon26 mice. In conclusion, early CD4+ CD25+ cotransfer prevents thymic dysfunction which underlies immune-mediated bowel inflammation in BM-->Tg epsilon26 mice.

Regulatory CD4+CD25+ cells reverse imbalances in the T cell pool of bone marrow transplanted TGepsilon26 mice leading to the prevention of colitis.

BACKGROUND AND AIMS: Erroneous thymic selection of developing T lymphocytes may be responsible for the expansion of self reactive T cells or may contribute to the absence of regulatory T cells important in controlling peripheral inflammatory processes. Colitis in bone marrow (BM) transplanted Tgepsilon26 mice is induced by abnormally activated T cells developing in an aberrant thymic microenvironment. We investigated the protective role of regulatory CD4+CD25+ T cells in this model. METHODS: BM from (C57BL/6 x CBA/J) F1 mice was transplanted into specific pathogen free Tgepsilon26 mice (BM-->Tgepsilon26). Transplanted mice received no cells (control), sorted CD4+CD25+, or CD4+CD25- cells from mesenteric lymph nodes (MLN) of normal mice. MLN cell subsets were analysed using membrane markers. Cytokine secretion of MLN cells was measured using intracellular cytokine staining and cytokine secretion in anti-CD3 stimulated cell cultures. Colitis was measured by histological scores. RESULTS: CD4+CD25+ cells were reduced in the MLNs of BM-->Tgepsilon26 mice. Transfer of regulatory CD4CD4+CD25+ but not of CD4+CD25- cells reduced the number of MLN CD4+ T cells in BM-->Tgepsilon26 recipients and increased the number of MLN CD8+ cells, thereby normalising the CD4+/CD8+ ratio. CD4+CD25+ but not CD4+CD25- cell transfer into BM-->Tgepsilon26 mice reduced the number of tumour necrosis factor alpha+ CD4+ cells and increased the secretion of transforming growth factor beta by MLN cells. Transfer of 3 x 10(5) CD4+CD25+ cells after BM transplantation into Tgepsilon26 mice prevented colitis whereas CD4+CD25- cells had no protective effect. CONCLUSIONS: These results suggest that defective selection or induction of regulatory T cells in the abnormal thymus is responsible for the development of colitis in BM-->Tgepsilon26 mice. Transfer of CD4+CD25+ cells can control intestinal inflammation in BM-->Tgepsilon26 mice by normalising the number and function of the MLN T cell pool.