Antithrombotic and anticoagulation therapy after stroke and transient ischemic attacks

Patients with a transient ischemic attack (TIA) or ischemic stroke are at high risk for a recurrent stroke. Platelet inhibitors can reduce this risk in patients with non-cardioembolic stroke or TIA. Aspirin is used for secondary prevention in patients with a low risk of recurrent stroke while the combination of aspirin and dipyridamole or clopidogrel is recommended in patients with a higher risk. Patients with atrial fibrillation have a five-fold increased risk of stroke. In comparison to placebo oral anticoagulation reduces the risk of stroke by 60-70% in primary and secondary stroke prevention. Aspirin can still reduce the relative stroke risk by 22% in patients with atrial fibrillation who have contraindications against anticoagulation. Given the limitations of oral anticoagulation with vitamin K antagonists a new generation of anticoagulants is currently being investigated which include factor Xa inhibitors and direct thrombin antagonists. Dabigatran has been shown to be as efficacious as warfarin given at a lower dose and significantly more efficacious when administered at a higher dosage. Both cerebral and intracranial hemorrhages were reduced by 60-80% in patients treated with dabigatran when compared to warfarin.     

Intracerebral haemorrhage,microbleeds and antithrombotic drugs

Antithrombotic therapy is a cornerstone for secondary prevention of ischaemic events, cerebral and extra-cerebral. A number of clinical questions remain unanswered concerning the impact of antithrombotic drugs on the risk of first-ever and recurrent macro or micro cerebral haemorrhages, raising the clinical dilemma on the risk/benefit balance of giving antiplatelets and anticoagulants in patients with potential high risk of brain bleeds. High field magnetic resonance imaging (MRI) blood-weighted sequences, including susceptibility weighted imaging (SWI), have expanded the spectrum of these clinical questions, because of their increasing sensitivity in detecting radiological markers of small vessel disease. This review will summarise the literature, focusing on four main clinical questions: how do cerebral microbleeds impact the risk of cerebrovascular events in healthy patients, in patients with previous ischaemic stroke or transient ischaemic attack, and in patients with intracerebral haemorrhage? Is the risk/benefit balance of oral anticoagulants shifted by the presence of microbleeds in patients with atrial fibrillation after recent ischaemic stroke or transient ischaemic attack? Should we restart antiplatelet drugs after symptomatic intracerebral haemorrhage or not? Are oral anticoagulants allowed in patients with a history of atrial fibrillation and previous intracerebral haemorrhage?     

Secondary stroke prevention with apixaban in nonvalvular atrial fibrillation: A subgroup analysis of the STANDARD study

BackgroundData on independent risk factors for stroke recurrence in Japanese patients with nonvalvular atrial fibrillation are limited.MethodsWe performed a subgroup analysis of a postmarketing surveillance study of apixaban (STroke prevention ANticoagulant Drug Apixaban Real-world Data study) in Japanese patients with nonvalvular atrial fibrillation receiving oral apixaban (5 mg/2.5 mg twice daily) in routine clinical practice. Patients were categorized into primary and secondary prevention groups based on the absence or presence of a history of ischemic stroke/transient ischemic attack, respectively.ResultsPatients in the secondary prevention group (1101 of 6306 patients [17.5%] analyzed; mean observation period, 15.7 months) had a higher risk of ischemic stroke or hemorrhage than those in the primary prevention group. The incidence rates of major (3.92%/year vs 2.06%/year), intracranial (1.87%/year vs 0.55%/year), and cerebral (1.14%/year vs 0.37%/year) hemorrhage and effectiveness outcomes (ischemic stroke/systemic embolism/transient ischemic attack, 3.25%/year vs 0.57%/year) were significantly higher (all P < 0.001) in the secondary prevention group than in the primary prevention group. Multivariate analysis identified no independent risk factors in the secondary prevention group, while prior major bleeding, alcohol abuse, advanced age, male sex, lower body weight, higher serum creatinine, and antiplatelet drug use were identified as risk factors for major hemorrhage, and advanced age and antiplatelet drug use for effectiveness outcomes in the primary prevention group.ConclusionsAmong Japanese patients with nonvalvular atrial fibrillation who received apixaban, presence of a history of ischemic stroke/transient ischemic attack was associated with higher incidence rates of hemorrhage and thromboembolic events.     

Antithrombotic and interventional treatment options in cardioembolic transient ischaemic attack and ischaemic stroke

Peer-reviewed data pertaining to anti-thrombotic and interventional therapy for transient ischaemic attack (TIA) or ischaemic stroke patients with non-valvular atrial fibrillation, atrial flutter, interatrial septal abnormalities, or left ventricular thrombus were reviewed. Long-term oral anticoagulant therapy with warfarin is the treatment of choice for secondary stroke prevention following TIA or minor ischaemic stroke in association with persistent or paroxysmal non-valvular atrial fibrillation or atrial flutter. If warfarin is contraindicated, long-term aspirin is a safe, but much less effective alternative treatment option in this subgroup of patients with cerebrovascular disease. Management of young patients with TIA or stroke in association with an interatrial septal defect is controversial. Various treatment options are outlined, but readers are encouraged to include these patients in one of the ongoing randomised clinical trials in this area. It is reasonable to consider empirical anticoagulation in patients with TIA or ischaemic stroke in association with left ventricular thrombus formation following myocardial infarction or in association with idiopathic dilated cardiomyopathy. If warfarin is prescribed, one should aim for a target international normalised ratio of 2.5 (range 2-3) to achieve the best balance between adequate secondary prevention of cardioembolic events and the risk of major haemorrhagic complications.     

Non-vitamin K oral anticoagulants as first-line regimen for acute ischemic stroke with non-valvular atrial fibrillation

PurposeThere are various patterns in determining the choice of the first-line antithrombotic agent for acute stroke with non-valvular atrial fibrillation. We investigated the efficacy and safety of non-vitamin K oral anticoagulants as first-line antithrombotics for patients with acute stroke and non-valvular atrial fibrillation.Materials and MethodsPatients with non-valvular atrial fibrillation and ischemic stroke or transient ischemic attack within 24 h from stroke onset were included. On the basis of the first regimen used and the regimen within 7 days after admission, the study population was divided into three groups: 1) antiplatelet switched to warfarin (A-W), 2) antiplatelet switched to NOAC (A-N), and 3) NOAC only (N only). We compared the occurrence of early neurologic deterioration, symptomatic intracranial hemorrhage, systemic bleeding, and poor functional outcome at 90 days.ResultsOf 314 included patients, 164, 53, and 97 were classified into the A-W, A-N, and N only groups, respectively. Early neurologic deterioration was most frequently observed in the A-W group (9.1%), followed by the A-N (5.7%) and N only (1.0%) groups (p = 0.017). Multivariable analysis adjusting for potential confounders demonstrated that the N only group was independently associated with a lower rate of early neurologic deterioration (odds ratio [OR] 0.104, 95% CI 0.013-0.831) or poor functional outcome at 90 days (OR 0.450, 95% CI 0.215-0.940) than the A-W group. However, the rate of symptomatic intracranial hemorrhage or any systemic bleeding event did not differ among the groups.ConclusionUsing non-vitamin K oral anticoagulants as the first-line regimen for acute ischemic stroke may help prevent early neurologic deterioration without increasing the bleeding risk.     

The Role of Nonvitamin K Antagonist Oral Anticoagulants (NOACs) in Stroke Prevention in Patients with Atrial Fibrillation

Anticoagulation is important in stroke prevention in patients with atrial fibrillation. Until recently, heparins and vitamin K antagonists were the only available therapy for stroke reduction in atrial fibrillation (AF) patients. Non-vitamin K antagonist oral anticoagulants (NOACs) including direct thrombin inhibitor (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) are now available and offer new options for stroke prevention. This article reviews the available data on the use of NOACs for primary and secondary stroke prevention in AF patients and describes specific patient populations to guide clinician in making the informed decision regarding appropriate use of those agents. It also addresses the use of NOACs early after acute stroke and use of thrombolysis while on NOAC.     

Dual Antiplatelet Therapy of Clopidogrel and Aspirin in Secondary Prevention of Ischemic Stroke: Evidence and Indications

Nowadays the dual antiplatelet therapy (DAPT) becomes more widely used in patients with ischemic stroke. Nevertheless, controversies exist for indications of DAPT. In view of evidence‐based medicine analysis, patients with high‐risk transient ischemic attack and minor stroke, severe symptomatic intracranial artery stenosis, symptomatic intracranial and extracranial artery stenosis causing artery‐to‐artery embolism, ischemic stroke attributed to aortic arch plaques, high‐risk atrial fibrillation not suitable for oral anticoagulants, intracranial and extracranial stent implantation, and ischemic stroke with acute coronary syndrome may gain great benefit from DAPT of clopidogrel and aspirin. In clinical practice, individualized antiplatelet therapy strategies should be taken by weighing risks of ischemia and hemorrhage.     

Anticoagulants, aspirin and dipyridamole in the secondary prevention of cerebral ischaemia: which is the best for which patient?

In this paper, an overview is given of trials with oral anticoagulants and dipyridamole in the secondary prevention after transient ischaemic attack or minor stroke. In patients with atrial fibrillation, the secondary preventive treatment of first choice is oral anticoagulation with an aimed international normalised ratio between 2.0 and 3.0. In patients without a cardiac source of embolism, a combination therapy of low-dose aspirin and dipyridamole 200 mg twice daily is the treatment of choice. These treatment strategies do however not prevent all recurrent strokes or vascular complications, and research for more effective strategies is warranted.     

Use of rivaroxaban in patients with stroke

Rivaroxaban, an inhibitor of Factor Xa, is a direct oral anti-coagulant that has been found to be non-inferior to warfarin in preventing cerebral ischemia in patients with non-valvular atrial fibrillation and in the subgroup of patients with a history of the previous stroke or transient ischemic attack. Vascular neurologists in daily clinical practice may encounter patients taking rivaroxaban or patients who may benefit from its use. In this paper, we review the current clinical indications, contraindications, and clinical management guidelines for rivaroxaban while providing a special focus on neurological aspects and expert opinions on rivaroxaban therapy management in various situations that a neurologist may encounter when treating patients with an ischemic stroke (including those requiring intravenous or intra-arterial reperfusion therapy) and patients with an intracerebral hemorrhage. Since data from clinical trials and real-life data are missing in some clinical situations, strong recommendations are not always available. Nevertheless, practical guidelines should be adopted to maximize benefits from this oral anti-coagulant.     

Comparison of primary and secondary stroke prevention in patients with nonvalvular atrial fibrillation: Results from the RAFFINE registry

ObjectivesClinical outcome data of primary and secondary prevention in patients with nonvalvular atrial fibrillation (NVAF) after the introduction of direct oral anticoagulant (DOAC) therapy are limited.Materials and MethodsA subgroup analysis of the RAFFINE registry, an observational, multicenter, prospective registry of Japanese patients with AF, was performed. Incidence rates of stroke or systemic embolism, all-cause death, major bleeding, and intracranial hemorrhage were compared between patients with and without a history of stroke or transient ischemic attack (TIA).ResultsOf 3,706 NVAF patients at baseline, 557 (15.0%) had a history of ischemic stroke or TIA (secondary prevention group), and 3,149 (85.0%) had no history of ischemic stroke or TIA (primary prevention group). The proportion of patients receiving oral anticoagulants was 87.2% (42.5% warfarin, 44.7% DOACs). The secondary prevention group had higher rates of stroke or systemic embolism (2.6% vs 1.0%/year, p<0.001), all-cause death (3.6% vs 2.4%/year, p<0.01), and major bleeding (2.0% vs 1.3%/year, p<0.01), and similar rates of intracranial hemorrhage (0.6% vs 0.5%/year, p=0.66) compared with the primary prevention group. A Cox proportional hazards model showed that a history of ischemic stroke or TIA was independently associated with an increased risk of stroke or systemic embolism (adjusted hazard ratio, 2.22; 95% confidence interval, 1.57 – 3.15; p<0.001).ConclusionsIn a contemporary cohort of NVAF patients, a history of ischemic stroke or TIA was still an independent predictor of stroke or systemic embolism, despite advances in anticoagulation therapy.     

Stroke risk and antithrombotic strategies in atrial fibrillation

BACKGROUND AND PURPOSE: Although the stroke rate associated with atrial fibrillation has declined over the last 10 years, the emerging atrial fibrillation epidemic threatens to increase the incidence of cardioembolic stroke. Summary of Review-Oral anticoagulants are superior antithrombotic agents but are underused due to fear of bleeding and uncertainty about which patients will benefit. Individualized decisions on antithrombotic therapy require balancing the competing risks of thromboembolism and bleeding. The CHADS? (Congestive heart failure, Hypertension, Age > 75 years, and Diabetes mellitus, and 2 points for prior Stroke/transient ischemic attack) score and other schemes provide an estimate of thromboembolic risk; however, the external validity of these estimates in the context of well-controlled risk factors, or a hypercoagulable state, is uncertain. Moreover, it is very difficult to estimate bleeding risk. Recent studies highlight the need for meticulous international normalized ratio control to achieve optimal outcomes hampered by the high bleeding risk during oral anticoagulant inception and other limitations of warfarin. Dabigatran is at least as efficacious as warfarin in preventing stroke and systemic embolism for patients in whom the risk of thromboembolism outweighs bleeding risk. In addition, the results of ongoing trials evaluating alternative anticoagulants such as oral anti-Xa agents are awaited. In this review, we discuss emerging therapies including available and completed trials of direct antithrombins and anti-Xa agents, including ximelagatran, idraparinaux, and dabigatran; and new device therapies including left atrial appendage occlusion devices. CONCLUSIONS: In light of these promising new therapies, it is likely that atrial fibrillation thromboembolism guidelines will need to be rewritten and frequently updated.     

Atrial fibrillation as a relevant risk factor for stroke

Atrial fibrillation, one of the most frequent heart rhythm disturbances and the most common source of embolic material in cerebral circulation, is associated with a fivefold increased risk of ischemic stroke. Except thromboembolic complications, atrial fibrillation affects hemodynamic activity of the heart, reduces cardiac output and might decrease cerebral blood flow. It is possible that atrial fibrillation disturbs autoregulation mechanisms of cerebral circulation in patients suffering from an acute stroke. This could be the reason of higher early mortality and more severe clinical outcome versus strokes in patients with the sinus rhythm. An ongoing increase of population with atrial fibrillation is observed. Such patients often need intensive antithrombotic prevention with oral anticoagulants. Worldwide prescribing effective anticoagulant therapy is insufficient in relation to the needs. The leading reason underlying the under-utilization of oral anticoagulation in patients with atrial fibrillation is the lack of knowledge about importance of this kind of stroke prevention and fear of bleeding among doctors, particularly among general practitioners.     

Association Between Oral Anticoagulants and Stroke Severity at Onset in Elderly Patients with Cardioembolic Stroke Due to Non-Valvular Atrial Fibrillation

ObjectivesThis study aimed to determine whether oral anticoagulant therapy affects the severity of cerebral infarction at onset in elderly patients with non-valvular atrial fibrillation.Materials and MethodsThis retrospective study included 330 elderly patients (aged ≥75 years) who were hospitalized for cardioembolic stroke due to non-valvular atrial fibrillation. Patients’ medical history, stroke severity at onset (National Institutes of Health Stroke Scale score), and the prevalence of large vessel occlusion were compared between patients who received oral anticoagulant therapy (n = 109) and those who did not receive oral anticoagulant therapy (n = 221).ResultsStroke severity was significantly lower in patients who received anticoagulants than in those who did not receive anticoagulants (6 versus 12; P = 0.021). Patients who did not receive anticoagulants had a significantly higher prevalence of large vessel occlusion (52% versus 37%; P = 0.010). After resampling based on propensity score matching, both median stroke severity (7 versus 12; P = 0.046) and large vessel occlusion prevalence (36% versus 57%; P = 0.019) were significantly lower in patients who received anticoagulant therapy.ConclusionsThe results of this study suggest that elderly patients with non-valvular atrial fibrillation who are administered oral anticoagulant therapy before the onset of cerebral infarction develop less severe stroke than those who are not receiving oral anticoagulant therapy. Thus, oral anticoagulant therapy should be actively considered in patients with non-valvular atrial fibrillation as it does not only prevents cerebral embolism, but also reduces the risk of severe sequelae.     

Progress in clinical neurosciences: pharmacotherapies for the secondary prevention of stroke

Stroke is a leading cause of mortality and long-term disability worldwide. Survivors of a previous stroke or transient ischemic attack are vulnerable to further cerebrovascular events, as well as myocardial infarction, peripheral vascular disease, congestive heart failure and vascular death. Traditional approaches to the secondary prevention of stroke have included aspirin after ischemic stroke, warfarin for stroke associated with cardioembolic sources, and carotid endarterectomy for eligible candidates with significant carotid artery stenosis. In recent years, much evidence has emerged to support a broader array of pharmacotherapies, including newer antiplatelet agents, lipid lowering drugs, and several classes of blood pressure lowering therapies. Also under study are B vitamins for patients with cerebrovascular disease and hyper-homocysteinemia, and oral direct thrombin inhibitors for high-risk patients with atrial fibrillation. We review the literature to determine the clinical significance of these therapies, and provide recommendations regarding their use in the prevention of recurrent stroke.     

Anticoagulant treatment in stroke prevention.

This review aims to summarise the value of long-term oral anticoagulant treatment in stroke prevention. Oral anticoagulation is the treatment of first choice in patients with atrial fibrillation (AF) and vascular risk factors and in AF patients with recent cerebral ischemia. The treatment also substantially reduces the risk of stroke in patients after myocardial infarction. The optimal target intensity of anticoagulation in stroke prevention is an International Normalized Ratio (INR) between 2.0 and 3.0. The treatment has been found to be hazardous at INR intensities between 3.0 and 4.5 in patients with transient ischemic attack (TIA) or minor stroke of presumed arterial origin. The value of the treatment in lower intensity in such patients still has to be established.     

Pharmacotherapy for Patients with Atrial Fibrillation and Cerebral Microbleeds

Background: Patients with cerebral microbleeds have increased risk of intracranial hemorrhage and ischemic stroke. No trial specifically informs antithrombotic therapy for patients with cerebral microbleeds and atrial fibrillation. We investigated the safety of anticoagulation versus no anticoagulation with regard to cerebrovascular outcomes and mortality. Methods: All consecutive atrial fibrillation patients from 2015 to 2018 with MRI evidence of ≥1 cerebral microbleed at time of imaging were reviewed. Patients were treated with warfarin, direct oral anticoagulants, or neither. Primary outcome was all-cause mortality informed by National Death Registry and the composite of ischemic and hemorrhagic stroke. All statistical tests were 2-sided and significant at P < .05. Results: The median interval from patient identification until the end of electronic health record surveillance was 9.93 months (interquartile range, 2.83-19.17 months). We identified 308 atrial fibrillation patients with cerebral microbleeds; 128(41.6%) were on warfarin, 88(28.6%) on direct oral anticoagulants, and 92(29.9%) on neither. Over the surveillance interval, 87 deaths, 51 ischemic strokes, and 14 hemorrhagic strokes occurred. The estimated likelihoods of the composite stroke outcome and ischemic stroke only did not differ significantly among the 3 groups. However, patients taking direct oral anticoagulants had a significantly smaller likelihood of all-cause mortality than patients who were not anticoagulated (adjusted hazard ratio: .44[.23, .83], P=.012). Conclusions: In patients with coprevalent atrial fibrillation and cerebral microbleeds, we did not detect differences in subsequent ischemic stroke, hemorrhagic stroke, or both, comparing warfarin, direct oral anticoagulants, or neither. Patients treated with direct oral anticoagulants had better survival than nonanticoagulated patients.     

血清Galectin-3水平联合CHA2DS2-VASc评分对非瓣膜性房颤患者发生缺血性脑卒中的预测价值

目的 探讨血清半乳糖凝集素-3(Gal-3)水平联合CHA2DS2-VASc评分对非瓣膜性房颤患者发生缺血性脑卒中的预测价值。方法 选取2017年8月-2018年8月在本院接受治疗的非瓣膜性房颤患者226例,所有患者均进行为期1年的随访,根据随访将发生缺血性脑卒中的患者纳入到脑卒中组(32例),将未发生缺血性脑卒中的患者纳入到无脑卒中组(194例),收集患者的一般资料及常规指标水平,采用酶联免疫吸附试验检测血清Gal-3的水平,记录所有患者的CHA2DS2-VASc评分。结果 脑卒中组的收缩压、左心房内径(LAD)、Gal-3水平、CHA2DS2-VASc评分均高于无脑卒中组(P<0.05); LAD、Gal-3水平、CHA2DS2-VASc评分过高均是非瓣膜性房颤患者发生缺血性脑卒中的独立危险因素(P<0.05); 非瓣膜性房颤患者的血清Gal-3水平与空腹血糖、LAD、CHA2DS2-VASc评分均呈正相关(P<0.05); ROC分析显示,Gal-3水平与CHA2DS2-VASc评分对非瓣膜性房颤患者发生缺血性脑卒中的预测价值均较高,曲线下面积分别为0.708和0.797,而二者联合分析可使得预测价值进一步提升。结论 血清Galectin-3水平联合CHA2DS2-VASc评分对非瓣膜性房颤患者发生缺血性脑卒中的预测价值较高     

Stroke severity in patients with preceding direct oral anticoagulant therapy as compared to vitamin K antagonists

Journal of Neurology - Although direct oral anticoagulants (DOAC) have proven at least equally effective in the prevention of acute ischemic stroke (AIS) in patients with atrial fibrillation as...     

Predictors of cerebral microbleeds in acute ischemic stroke and TIA patients

BACKGROUND: Cerebral microbleeds (CMB) detected on gradient-echo T2*-weighted MRI have been associated with cognitive impairment and the potential for increased risk of intracranial hemorrhage. We evaluated risk factors for these microangiopathic lesions in a cohort of stroke and transient ischemic attack patients. METHODS: Presence and number of CMB in consecutive acute stroke patients admitted to a university hospital stroke service over an 18-month period were rated. Multivariate models were generated to determine the contribution of 21 demographic and clinical variables to the frequency and number of CMB. RESULTS: Of 164 patients (mean age 71 years, 52% female), 57 (35%) had CMB evident on gradient-echo T2*-weighted MRI. CMB were more commonly noted among patients with small vessel disease ischemic stroke mechanism (47%) than large vessel atherothromboembolic (12%) or cardioembolic (18%, p = 0.0001). In univariate analysis, patients with CMB were older, (p = 0.008), more likely to have been on >1 antihypertensive prior to admission (p = 0.024) than those without CMB. In multivariate logistic regression analyses, presumed small vessel stroke subtype, history of atrial fibrillation, being on >1 antihypertensive prior to admission, and smoking were independent factors increasing the risk of CMB. Logistic regression analysis by number of CMB showed almost similar findings. CONCLUSIONS: CMB are more frequently noted in hospitalized stroke and transient ischemic attack patients with small vessel ischemia, as well as those with important modifiable vascular risk factors like atrial fibrillation and smoking.