Efficacy and Safety of Direct Oral Anticoagulants for Stroke Prevention in Older Patients With Atrial Fibrillation: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Although older patients with atrial fibrillation are at heightened risk of thromboembolic and bleeding events, their optimal treatment choice remains uncertain. METHODS AND RESULTS: This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that compared thromboembolic or bleeding outcomes between a direct oral anticoagulant (DOAC) and a vitamin K antagonist (VKA) and reported outcomes for patients aged ≥75 years with atrial fibrillation. The efficacy outcome was the composite of stroke and systemic embolism. Safety outcomes included major bleeding, any clinically relevant bleeding, and intracranial hemorrhage. Each DOAC and VKA was compared pairwise in a network meta-analysis. High- and low-dose regimens and factor IIa and Xa inhibitors were also compared. Seven randomized controlled trials were included in the analysis. Stroke and systemic embolism risks did not differ significantly among DOACs. There were no significant differences in major bleeding between each DOAC and VKA. Intracranial hemorrhage risk was significantly lower with dabigatran, apixaban, and edoxaban than with VKA and rivaroxaban, which had similar risks. High-dose regimens led to lower risks of stroke or systemic embolism compared with VKA and low-dose regimens, with both doses having similar bleeding risks. CONCLUSIONS: In patients aged ≥75 years with atrial fibrillation, DOACs were associated with fewer thromboembolic events compared with VKA, whereas dabigatran, apixaban, and edoxaban were associated with lower risks of intracranial hemorrhage compared with VKA and rivaroxaban. REGISTRATION: URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42022329557.

Intracranial Hemorrhage Following Anticoagulant Treatment in Denmark: Spontaneous Adverse Drug Reaction Reports Versus Real-World Data.

INTRODUCTION: In Denmark, physicians are legally obliged to report serious adverse drug reactions (ADRs), such as intracranial hemorrhage (ICH) following anticoagulant (AC) treatment, to the Danish Medicines Agency. We were therefore puzzled to discover a high number of reports concerning ICHs following treatment with the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin. This was surprising, as all DOACs have been found to be associated with a lower risk of ICH compared with warfarin in phase III randomized controlled trials. OBJECTIVES: The primary aim of the study was to estimate the level of underreporting of ICH as an ADR following treatment with warfarin, dabigatran, rivaroxaban, and apixaban. METHODS: This observational study covered a 5-year period (2014-2018). Using nationwide registries held by the Danish Health Data Authority, the number of users, exposure time in person-years, and related ICH events for each of the study drugs were estimated. Data on ADR-ICH reports were extracted from the interactive ADR overviews held by the Danish Medicines Agency. RESULTS: From 2014 to 2018, 97.0% of the identified warfarin-related ICH events were not reported as ADRs. For the DOACs, the level of underreporting ranged from 88.8 to 90.8%. CONCLUSION: We found a heavy and differentiated level of underreporting of ICH as an ADR following treatment with the four study drugs.

Comparison of Low-Dose Direct Acting Anticoagulant and Warfarin in patients Aged ≥80 years With Atrial Fibrillation.

Low dose direct acting oral anticoagulants (LDDOACS) were approved for elderly atrial Fibrillation (AF) patients with limited information. A retrospective analysis collecting baseline characteristics and outcomes in AF patients ≥ 80 prescribed LDDOAC or warfarin (W), from a multidisciplinary practice between 1/1/11 (First LDDOAC available) and 5/31/17 was conducted. From 9660 AF patients, 514 ≥ 80 received a LDDOAC and 422 W. A multivariable comparison found LDDOAC patients were older (p <0.001), had lower creatinine clearance (CrCl) (p = 0.006), used more anti-platelet drugs (p <0.001), and more often had new onset AF verses those prescribed W (p <0.001). There were no clinically significant differences among those patients receiving Dabigatran 75 mgs BID (D), Rivaroxaban 15mgs (R) or Apixaban 2.5mgs BID (A). Forty-eight and 50% of the patients remained on their LDDOAC or W for the observation period (p = 0.55). Stroke/systemic embolism (SSE) and CNS bleeds were 1.16 vs 2.22%/yr., (p = 0.143) and 1.46 vs 0.93%/yr., (p = 0.24). Mortality and major bleeds were 6.26 vs 1.67%/yr., and 12.3vs 3.77%/yr. (p <0.001). SSE were 1.1%/yr for D, R, and A (p = 0.94). CNS bleeds were 2.2 for D, 1.7 for R and 0.8%/yr. for A: p = 0.53. Major bleeding was: 14.3 for D, 14.1 for R and 9.1%/yr. for A, p = 0.048 (with A < R, p = 0.01). Mortality was 5.5 for D, 4.2 for R and 9.5% for A, p = 0.031. In conclusion, half the patients remained on their assigned anti-coagulant. SSE and intracranial bleed rates were similar and low. Major bleeds and deaths were different between groups emphasizing the need for prospective randomized trials in this growing population with AF.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Patients With Cancer and Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Background Several studies have investigated the effect of non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer, but the results remain controversial. Therefore, we conducted a meta-analysis to compare the efficacy and safety of NOACs versus warfarin in this population. Methods and Results We systematically searched the PubMed and Embase databases until February 16, 2019 for studies comparing the effect of NOACs with warfarin in AF patients with cancer. Risk ratios (RRs) with 95% CIs were extracted and pooled by a random-effects model. Five studies involving 8908 NOACs and 12 440 warfarin users were included. There were no significant associations between cancer status and risks of stroke or systemic embolism, major bleeding, or death in AF patients. Compared with warfarin, NOACs were associated with decreased risks of stroke or systemic embolism (RR, 0.52; 95% CI, 0.28-0.99), venous thromboembolism (RR, 0.37, 95% CI, 0.22-0.63), and intracranial or gastrointestinal bleeding (RR, 0.65; 95% CI, 0.42-0.98) and with borderline significant reductions in ischemic stroke (RR, 0.63; 95% CI, 0.40-1.00) and major bleeding (RR, 0.73; 95% CI, 0.53-1.00). In addition, risks of efficacy and safety outcomes of NOACs versus warfarin were similar between AF patients with and without cancer. Conclusions In patients with AF and cancer, compared with warfarin, NOACs had lower or similar rates of thromboembolic and bleeding events and posed a reduced risk of venous thromboembolism.

Branch atheromatous disease diagnosed as embolic stroke of undetermined source: A sub-analysis of NAVIGATE ESUS.

BACKGROUND: Branch atheromatous disease (BAD) is distinctive from large and small arterial diseases, which is single subcortical infarction larger than lacunar stroke in the territories of deep perforators without relevant arterial stenosis. BAD meets the current criteria of embolic stroke of undetermined source. We performed an exploratory analysis of BAD in patients recruited to NAVIGATE embolic stroke of undetermined source, a randomized controlled trial to compare rivaroxaban and aspirin in embolic stroke of undetermined source patients. METHODS AND RESULTS: Among 3972 stroke patients in cerebral hemispheres with intracranial arterial imaging, 502 (12.6%) patients met the criteria for BAD. BAD was associated with younger age (years; OR: 0.97, 95% CI: 0.96-0.98), race (Asian; OR: 1.78, 95% CI: 1.44-2.21), region (Eastern Europe; OR: 2.49, 95% CI: 1.87-3.32), and higher National Institute of Health Stroke Scale (OR: 1.17, 95% CI: 1.12-1.22) at randomization. During follow-up, stroke or systemic embolism (2.5%/year vs. 6.2%/year, p = 0.0022), stroke (2.1%/year vs. 6.2%/year, p = 0.0008), and ischemic stroke (2.1%/year vs. 5.9%/year, p = 0.0013) occurred less frequently in BAD than non-BAD patients. There were no differences in annual rates of stroke or systemic embolism (2.5%/year vs. 2.5%/year, HR: 1.01, 95% CI: 0.33-3.14) or major bleeding (1.3%/year vs. 0.8%/year, HR: 1.51, 95% CI: 0.25-9.05) between rivaroxaban and aspirin groups among BAD patients. CONCLUSIONS: BAD was relatively common, especially in Asian and from Eastern Europe among embolic stroke of undetermined source patients. Stroke severity was higher at randomization but recurrence of stroke was fewer in BAD than non-BAD patients. The efficacy and safety of rivaroxaban and aspirin did not differ among BAD patients.

Hemorrhagic risk and intracranial complications in patients with minor head injury (MHI) taking different oral anticoagulants.

The correlation between direct oral anticoagulants (DOACs) or Vitamin K Antagonist (VKAs) intake and the incidence of intracranial complications after minor head injury (MHI) is still object of debate: preliminary observation seems to demonstrate lower incidence in intracranial bleeding complications (ICH) in patients taking DOACs than VKA. METHODS. This prospective and observational study was performed to clarify the incidence of ICH in patients in DOACs compared to VKAs. Between January 2016 and April 2018 we have recorded in our ED patients with MHI taking oral anticoagulants. Their hemorragic risk score was calculated and recorded for each patient (Has Bled, Atria and Orbit). RESULTS A total of 402 patients with MHI taking anticoagulant were collected: 226 were receiving one of the four DOACs (dabigatran, rivaroxaban, apixaban or edoxaban) while 176 patients were in therapy with VKA. The rate of intracranial complications was significantly lower in patients receiving DOACs than in patients treated with VKA (p < 0.01). In the VKA group two patients died because of intracranial bleeding. No deaths were recorded in the DOACs group. DISCUSSION patients with MHI who take DOACs have a significant lower incidence of intracranial bleeding complications than those treated with vitamin k antagonists. This statement is supported by the observation that the hemorrhagic risk, measured according to the chosen scores, was similar between the two groups.

Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients.

Background and Purpose- This ARISTOPHANES study (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) used multiple data sources to compare stroke/systemic embolism (SE) and major bleeding (MB) among a large number of nonvalvular atrial fibrillation patients on non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods- A retrospective observational study of nonvalvular atrial fibrillation patients initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015, was conducted pooling Centers for Medicare and Medicaid Services Medicare data and 4 US commercial claims databases. After 1:1 NOAC-warfarin and NOAC-NOAC propensity score matching in each database, the resulting patient records were pooled. Cox models were used to evaluate the risk of stroke/SE and MB across matched cohorts. Results- A total of 285 292 patients were included in the 6 matched cohorts: 57 929 apixaban-warfarin, 26 838 dabigatran-warfarin, 83 007 rivaroxaban-warfarin, 27 096 apixaban-dabigatran, 62 619 apixaban-rivaroxaban, and 27 538 dabigatran-rivaroxaban patient pairs. Apixaban (hazard ratio [HR], 0.61; 95% CI, 0.54-0.69), dabigatran (HR, 0.80; 95% CI, 0.68-0.94), and rivaroxaban (HR, 0.75; 95% CI, 0.69-0.82) were associated with lower rates of stroke/SE compared with warfarin. Apixaban (HR, 0.58; 95% CI, 0.54-0.62) and dabigatran (HR, 0.73; 95% CI, 0.66-0.81) had lower rates of MB, and rivaroxaban (HR, 1.07; 95% CI, 1.02-1.13) had a higher rate of MB compared with warfarin. Differences exist in rates of stroke/SE and MB across NOACs. Conclusions- In this largest observational study to date on NOACs and warfarin, the NOACs had lower rates of stroke/SE and variable comparative rates of MB versus warfarin. The findings from this study may help inform the discussion on benefit and risk in the shared decision-making process for stroke prevention between healthcare providers and nonvalvular atrial fibrillation patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT03087487.

Higher Incidence of Ischemic Stroke in Patients Taking Novel Oral Anticoagulants.

Background and Purpose- The increased use of novel oral anticoagulants (NOACs) to control atrial fibrillation is largely driven by the assumption that they are equally effective as warfarin at preventing ischemic stroke while putting patients at lower risk of hemorrhages. To test this hypothesis, a retrospective study of the relative incidence of strokes among patients taking NOACs versus those taking warfarin is performed. Methods- Relative stroke incidence in the 2 groups of patients was compared using odds ratios and Fisher exact tests for significance using a data set of 71 365 on NOACs and 59 546 patients on warfarin. In addition, the 7033 patients with a record of both warfarin and NOAC use were analyzed as a separate cohort. Results- There is a significantly higher (odds ratio=1.29, <0.001) frequency of ischemic strokes among patients prescribed NOACs compared with those on warfarin. The relative frequency of ischemic strokes was also higher for every individual NOAC compared with warfarin (these higher frequencies are statistically significant for dabigatran and apixaban, though not for edoxaban and rivaroxaban). There is a lower incidence of intracranial hemorrhages and nontraumatic hemorrhages in general among patients taking NOACs, consistent with the published literature. Comparisons of the demographic and clinical profiles of the patients taking NOACs to those on warfarin do not show significantly higher background stroke risk in NOAC patients; in fact, patients on NOACs tend to be at lower background risk overall for ischemic strokes. Conclusions- Because NOAC use is associated with higher ischemic stroke risk together with a lower risk of hemorrhages than warfarin use, it can be concluded that patients on warfarin are more strongly anticoagulated. The observed effect could be a secondary consequence of dosage control or alternatively a result of different anticoagulant effects among the different medications.

Intravenous tPA (Tissue-Type Plasminogen Activator) in Patients With Acute Ischemic Stroke Taking Non-Vitamin K Antagonist Oral Anticoagulants Preceding Stroke.

Background and Purpose- Although there are no trials or large cohorts to inform clinical care, current guidelines caution against giving intravenous tPA (tissue-type plasminogen activator) to patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs). We performed a literature review of intravenous tPA in patients treated with NOACs preceding stroke. Methods- A literature search of PubMed was performed encompassing January 2010 to March 2018. Patient characteristics, timing of last medication intake, laboratory testing, use of reversal, and outcomes ≤3 months after discharge were summarized. Results- We identified 55 studies with 492 NOAC patients receiving tPA (dabigatran, 181; rivaroxaban, 215; apixaban, 40; and unspecified NOAC, 56). Among patients with complete data, the median time from the last NOAC intake to symptom onset was 8 hours (interquartile range, 2.5-14.5), with 55.2% (80/145) within 12 hours. Few patients underwent sensitive laboratory tests, such as thrombin time, diluted thrombin time, or anti-Xa assays before tPA administration. The overall observed rates of symptomatic intracranial hemorrhage, mortality, and favorable outcomes (National Institutes of Health Stroke Scale score, ≤1; modified Rankin Scale score, 0-2; or neurological improvement in the National Institutes of Health Stroke Scale score, ≥8 points) were 4.3% (20/462), 11.3% (48/423), and 43.7% (164/375), respectively. Among dabigatran-treated patients, reversal with idarucizumab was associated with fewer symptomatic intracranial hemorrhage (4.5% [2/44] versus 7.4% [8/108]; unadjusted odds ratio, 0.60; 95% CI, 0.12-2.92), death (4.5% [2/44] versus 12.0% [13/108]; unadjusted odds ratio, 0.35; 95% CI, 0.08-1.61), and more favorable outcomes (79.1% [34/43] versus 39.2% [29/74]; unadjusted odds ratio, 5.86; 95% CI, 2.45-14.00), although the differences were not statistically significant for symptomatic intracranial hemorrhage and death. Conclusions- These preliminary observations suggest that tPA may be reasonably well tolerated without prohibitive risks of bleeding complications in selected patients on NOACs. Reversal of anticoagulant effects by idarucizumab for dabigatran-treated patients before tPA is an emerging strategy that was associated with more favorable outcomes.

Estimated Effectiveness and Safety of Nonvitamin K Antagonist Oral Anticoagulants Compared With Optimally Acenocoumarol Anticoagulated "Real-World" in Patients With Atrial Fibrillation.

Nonvitamin K antagonist oral anticoagulants (NOACs) have been proposed as an alternative to vitamin K antagonists in atrial fibrillation (AF) patients but the comparative benefits between NOACs and optimally anticoagulated patients is unknown. We estimated the absolute benefit in clinical outcomes rates of real-world effect of NOACs in optimally anticoagulated AF patients with acenocoumarol. We included 1,361 patients stable on acenocoumarol with time in therapeutic range of 100% and 6.5 years of follow-up. Estimation of clinical events avoided was calculated applying hazard ratio, absolute and relative risk reduction from the real-world meta-analysis. Compared with an optimally anticoagulated population, dabigatran 110 mg had the highest estimated stroke reduction (0.97%/year vs 1.47%/year; p = 0.002), and the benefit was higher than in RE-LY trial. For major bleeding, apixaban showed the highest estimated reduction (1.81%/year vs 2.83%/year; p <0.001). For mortality, the largest estimated reduction was with apixaban (2.68%/year). For gastrointestinal bleeding, only apixaban had a significant reduction compared with acenocoumarol (0.69%/year vs 1.10%/year; p = 0.004), and the reduction was significantly higher than in ARISTOTLE trial. All NOACs showed significantly lower rates for intracranial hemorrhage and had a positive Net Clinical Benefit compared with acenocoumarol. Apixaban showed the highest extended estimated Net Clinical Benefit 2.64 (95%CI 2.34 to 2.96). In conclusion, in optimally acenocoumarol anticoagulated AF patients, estimated reductions in all clinical outcomes with various NOACs are evident, with the best effectiveness and safety profile with apixaban. Indeed, the estimated effect with "real world" NOACs would probably be higher than that seen in phase-III clinical trials.

Intracranial Hemorrhage in Deep Vein Thrombosis/Pulmonary Embolus Patients Without Atrial Fibrillation.

Background and Purpose- Deep vein thrombosis (DVTs) is a common disease with high morbidity if it progresses to pulmonary embolus (PE). Anticoagulation is the treatment of choice; warfarin has long been the standard of care. Early experience with direct oral anticoagulants (DOACs) suggests that these agents may be may be a safer and equally effective alternative in the treatment of DVT/PE. Nontraumatic intracranial hemorrhage (ICH) is one of the most devastating potential complications of anticoagulation therapy. We sought to compare the rates of ICH in patients treated with DOACs versus those treated with warfarin for DVT/PE. Methods- The MarketScan Commercial Claims and Medicare Supplemental databases were used. Adult DVT/PE patients without known atrial fibrillation and with prescriptions for either a DOAC or warfarin were followed for the occurrence of inpatient admission for ICH. Coarsened exact matching was used to balance the treatment cohorts. Cox proportional-hazards regressions and Kaplan-Meier survival curves were used to estimate the association between DOACs and the risk of ICH compared with warfarin. Results- The combined cohort of 218 620 patients had a median follow-up of 3.0 months, mean age of 55.4 years, and was 52.1% women. The DOAC cohort had 26 980 patients and 8 ICH events (1.0 cases per 1000 person-years), and the warfarin cohort had 191 640 patients and 324 ICH events (3.3 cases per 1000 person-years; P<0.0001). The DOAC cohort had a lower hazard ratio for ICH compared with warfarin in both the unmatched (hazard ratio=0.26; P=0.0002) and matched (hazard ratio=0.20; P=0.0001) Cox proportional-hazards regressions. Conclusions- DOACs show superior safety to warfarin in terms of risk of ICH in patients with DVT/PE.

Efficacy and safety of rivaroxaban in extreme elderly patients with atrial fibrillation: Analysis of the Shikoku Rivaroxaban Registry Trial (SRRT).

BACKGROUND: The Shikoku Rivaroxaban Registry Trial (SRRT) is a retrospective survey of the use of rivaroxaban for stroke prevention in elderly patients in Shikoku, Japan. METHODS: The SRRT enrolled 1339 patients from 8 hospitals. Patients were divided into two groups according to their age, the extreme elderly group (453 patients aged ≧80 years) and the control group (886 patients aged <80 years). RESULTS: In the extreme elderly group, 41.5% of the patients had low body weight (<50kg) and 65.1% had abnormal renal function (creatinine clearance <50ml/min). The mean CHADS2, CHA2DS2-VASc, and HAS BLED scores were 2.7, 4.4, and 2.3, respectively. There were 333 (73.5%) patients who met the dosing criteria, and of these patients, 81.2% received rivaroxaban 10mg daily. Thromboembolic events occurred in 4 patients (0.94%/person year) and intracranial hemorrhage occurred in 4 patients (0.89%/person year). The incidence of these events was not significantly different from the control group. In addition, all patients with cerebral infarction had been treated with a smaller dose of rivaroxaban than recommended by the dosing criteria, suggesting that dosing criteria should be adhered to. CONCLUSION: These results suggest that rivaroxaban is effective and safe in extreme elderly patients with atrial fibrillation.

The potential impact of sleep-related movement disorders on stroke risk: a population-based longitudinal study.

BACKGROUND: Sleep-related movement disorders (SRMD) have been shown to increase the risk of cardiovascular diseases. However, the relationship between SRMD and stroke remains unclear. AIM: To explore the relationship between SRMD and stroke in the general population. DESIGN: Two cohorts of patients with SRMD and without SRMD were followed up for the occurrence of hemorrhagic and ischemic stroke. METHODS: The study cohort enrolled 604 patients who were initially diagnosed as SRMD between 2000 and 2005. 2,416 age- and sex-matched patients without prior stroke were selected as the comparison cohort. A Cox-proportional hazard regression analysis was performed for multivariate adjustment. RESULTS: Patients with SRMD had a higher risk for developing all-cause stroke [adjusted hazard ratio (HR) = 2.29, 95% confidence interval (CI) = 1.42-3.80]. Patients of below 45 years old had the greatest stroke risk (HR = 4.03, 95% CI = 3.11-5.62), followed by patients aged ≥65 years (HR = 2.64, 95% CI = 1.12-3.44) and 45-64 years (HR = 1.07, 95% CI = 1.02-1.71). The age-stratified analysis suggested that the increased risk of hemorrhagic stroke was more significant than ischemic stroke among all age groups. Furthermore, males with SRMD were at greater risk to develop all-cause stroke (HR = 2.98, 95% CI = 1.74-4.50) than that of females (HR = 1.94, 95% CI = 1.01-3.77). CONCLUSIONS: Patients with SRMD were found to have an increased risk of all-cause stroke along with a higher possibility of hemorrhagic stroke over ischemic stroke.

Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis.

BACKGROUND: The goal of this study was to compare the safety and effectiveness of individual antiembolic interventions in nonvalvular atrial fibrillation (AF): novel oral anticoagulants (NOACs) (apixaban, dabigatran, edoxaban, and rivaroxaban); vitamin K antagonists (VKA); aspirin; and the Watchman device. METHODS AND RESULTS: A network meta-analysis of randomized, clinical trials (RCTs) was performed. RCTs that included patients with prosthetic cardiac valves or mitral stenosis, mean or median follow-up <6 months, <200 participants, without published report in English language, and NOAC phase II studies were excluded. The placebo/control arm received either placebo or no treatment. The primary efficacy outcome was the combination of stroke (of any type) and systemic embolism. All-cause mortality served as a secondary efficacy outcome. The primary safety outcome was the combination of major extracranial bleeding and intracranial hemorrhage. A total of 21 RCTs (96 017 nonvalvular AF patients; median age, 72 years; 65% males; median follow-up, 1.7 years) were included. In comparison to placebo/control, use of aspirin (odds ratio [OR], 0.75 [95% CI, 0.60-0.95]), VKA (0.38 [0.29-0.49]), apixaban (0.31 [0.22-0.45]), dabigatran (0.29 [0.20-0.43]), edoxaban (0.38 [0.26-0.54]), rivaroxaban (0.27 [0.18-0.42]), and the Watchman device (0.36 [0.16-0.80]) significantly reduced the risk of any stroke or systemic embolism in nonvalvular AF patients, as well as all-cause mortality (aspirin: OR, 0.82 [0.68-0.99]; VKA: 0.69 [0.57-0.85]; apixaban: 0.62 [0.50-0.78]; dabigatran: 0.62 [0.50-0.78]; edoxaban: 0.62 [0.50-0.77]; rivaroxaban: 0.58 [0.44-0.77]; and the Watchman device: 0.47 [0.25-0.88]). Apixaban (0.89 [0.80-0.99]), dabigatran (0.90 [0.82-0.99]), and edoxaban (0.89 [0.82-0.96]) reduced risk of all-cause death as compared to VKA. CONCLUSIONS: The entire spectrum of therapy to prevent thromboembolism in nonvalvular AF significantly reduced stroke/systemic embolism events and mortality.

Quantitative Susceptibility Mapping in Cerebral Cavernous Malformations: Clinical Correlations.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been shown to assess iron content in cerebral cavernous malformations. In this study, our aim was to correlate lesional iron deposition assessed by quantitative susceptibility mapping with clinical and disease features in patients with cerebral cavernous malformations. MATERIALS AND METHODS: Patients underwent routine clinical scans in addition to quantitative susceptibility mapping on 3T systems. Data from 105 patients met the inclusion criteria. Cerebral cavernous malformation lesions identified on susceptibility maps were cross-verified by T2-weighted images and differentiated on the basis of prior overt hemorrhage. Mean susceptibility per cerebral cavernous malformation lesion (χ̄lesion) was measured to correlate with lesion volume, age at scanning, and hemorrhagic history. Temporal rates of change in χ̄lesion were evaluated in 33 patients. RESULTS: Average χ̄lesion per patient was positively correlated with patient age at scanning (P < .05, 4.1% change with each decade of life). Cerebral cavernous malformation lesions with prior overt hemorrhages exhibited higher χ̄lesion than those without (P < .05). Changes in χ̄lesion during 3- to 15-month follow-up were small in patients without new hemorrhage between the 2 scans (bias = -0.0003; 95% CI, -0.06-0.06). CONCLUSIONS: The study revealed a positive correlation between mean quantitative susceptibility mapping signal and patient age in cerebral cavernous malformation lesions, higher mean quantitative susceptibility mapping signal in hemorrhagic lesions, and minimum longitudinal quantitative susceptibility mapping signal change in clinically stable lesions. Quantitative susceptibility mapping has the potential to be a novel imaging biomarker supplementing conventional imaging in cerebral cavernous malformations. The clinical significance of such measures merits further study.

Increased Risk of Post-Trauma Stroke after Traumatic Brain Injury-Induced Acute Respiratory Distress Syndrome.

This study determines whether acute respiratory distress syndrome (ARDS) is an independent risk factor for an increased risk of post-traumatic brain injury (TBI) stroke during 3-month, 1-year, and 5-year follow-ups, respectively, after adjusting for other covariates. Clinical data for the analysis were from the National Health Insurance Database 2000, which covered a total of 2121 TBI patients and 101 patients with a diagnosis of TBI complicated with ARDS (TBI-ARDS) hospitalized between January 1, 2001 and December 31, 2005. Each patient was tracked for 5 years to record stroke occurrences after discharge from the hospital. The prognostic value of TBI-ARDS was evaluated using a multivariate Cox proportional hazard model. The main outcome found that stroke occurred in nearly 40% of patients with TBI-ARDS, and the hazard ratio for post-TBI stroke increased fourfold during the 5-year follow-up period after adjusting for other covariates. The increased risk of hemorrhagic stroke in the ARDS group was considerably higher than in the TBI-only cohort. This is the first study to report that post-traumatic ARDS yielded an approximate fourfold increased risk of stroke in TBI-only patients. We suggest intensive and appropriate medical management and intensive follow-up of TBI-ARDS patients during the beginning of the hospital discharge.

Multivitamin use and risk of stroke mortality: the Japan collaborative cohort study.

BACKGROUND AND PURPOSE: An effect of multivitamin supplement on stroke risk is uncertain. We aimed to examine the association between multivitamin use and risk of death from stroke and its subtypes. METHODS: A total of 72 180 Japanese men and women free from cardiovascular diseases and cancers at baseline in 1988 to 1990 were followed up until December 31, 2009. Lifestyles including multivitamin use were collected using self-administered questionnaires. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of total stroke and its subtypes in relation to multivitamin use. RESULTS: During a median follow-up of 19.1 years, we identified 2087 deaths from stroke, including 1148 ischemic strokes and 877 hemorrhagic strokes. After adjustment for potential confounders, multivitamin use was associated with lower but borderline significant risk of death from total stroke (HR, 0.87; 95% confidence interval, 0.76-1.01), primarily ischemic stroke (HR, 0.80; 95% confidence interval, 0.63-1.01), but not hemorrhagic stroke (HR, 0.96; 95% confidence interval, 0.78-1.18). In a subgroup analysis, there was a significant association between multivitamin use and lower risk of mortality from total stroke among people with fruit and vegetable intake <3 times/d (HR, 0.80; 95% confidence interval, 0.65-0.98). That association seemed to be more evident among regular users than casual users. Similar results were found for ischemic stroke. CONCLUSIONS: Multivitamin use, particularly frequent use, was associated with reduced risk of total and ischemic stroke mortality among Japanese people with lower intake of fruits and vegetables.

Association of short-term use of nonsteroidal anti-inflammatory drugs with stroke in patients with hypertension.

BACKGROUND AND PURPOSE: Limited studies have investigated the risk of cerebrovascular events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects at high risk. We examined the short-term (defined as 30-day period) effect of selective and nonselective NSAIDs use on the risk of ischemic and hemorrhagic stroke in patients with hypertension. METHODS: We conducted a case-crossover study using the National Health Insurance Research Database in Taiwan. We identified 1653 hypertensive subjects with stroke (defined as International Classification of Diseases-Ninth Revision-CM-codes: 433.x, 434.x, and 436.x for ischemic stroke; 430 and 431 for hemorrhagic stroke) in 2010. We investigated the transient effect of NSAIDs use on stroke using conditional logistic regressions with the adjustment of potential confounders. RESULTS: The results suggested that NSAIDs use during the 30 days before stroke was associated with a 1.57-fold increased risk of ischemic stroke, but not of hemorrhagic stroke (adjusted odds ratio, 1.57; 95% confidence interval, 1.26-1.97 for ischemic stroke; and adjusted odds ratio, 1.38; 95% confidence interval, 0.79-2.40 for hemorrhagic stroke). When classifying NSAIDs into selective and nonselective groups, nonselective NSAIDs use significantly increased the risk of ischemic stroke (adjusted odds ratio, 1.55; 95% confidence interval, 1.24-1.94), but not of hemorrhagic stroke (adjusted odds ratio, 1.56; 95% confidence interval, 0.90-2.73). CONCLUSIONS: The results demonstrate an increased risk of stroke, specifically ischemic stroke among hypertensive subjects with NSAIDs use. It would be important to closely monitor the transient effect of initial NSAIDs treatment, particularly in patients with hypertension.

Rise in late onset vitamin K deficiency bleeding in young infants because of omission or refusal of prophylaxis at birth.

BACKGROUND: Newborns are at risk for vitamin K deficiency and subsequent bleeding unless supplemented at birth. Vitamin K deficiency bleeding is an acquired coagulopathy in newborn infants because of accumulation of inactive vitamin K-dependent coagulation factors, which leads to an increased bleeding tendency. Supplementation of vitamin K at birth has been recommended in the United States since 1961 and successfully reduced the risk of major bleeding. Refusal or omission of vitamin K prophylaxis is increasing and puts newborn infants at risk for life-threatening bleeding. PATIENTS: Over an eight month period, we encountered seven infants with confirmed vitamin K deficiency; five of these patients developed vitamin K deficiency bleeding. RESULTS: The mean age of the seven infants with vitamin K deficiency was 10.3 weeks (range, 7-20 weeks); manifestations ranged from overt bleeding to vomiting, poor feeding, and lethargy. None of the infants had received vitamin K at birth, and all were found to have profound derangement of coagulation parameters, which corrected rapidly with administration of vitamin K in IV or intramuscular form. Four of the seven infants had intracranial hemorrhage; two of these infants required urgent neurosurgical intervention. CONCLUSION: Supplementation of vitamin K at birth for all newborns prevents major hemorrhagic complications, such as intracranial bleeding, due to vitamin K deficiency. Parental refusal of vitamin K is increasingly common. It is critical that health care providers and the public be made aware of the varied presentation of this preventable acquired coagulopathy.