Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) Study.

BACKGROUND: The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention. METHODS AND RESULTS: Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA2DS2-VASc score >4 and less reduced renal function. Thirty-two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOACs within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated >14 days after acute stroke. CONCLUSIONS: In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke.

OBJECTIVE: To investigate the genetic contributors to cerebrovascular disease and variation in biomarkers of ischemic stroke. METHODS: The Vitamin Intervention for Stroke Prevention Trial (VISP) was a randomized, controlled clinical trial of B vitamin supplementation to prevent recurrent stroke, myocardial infarction, or death. VISP collected baseline measures of C-reactive protein (CRP), fibrinogen, creatinine, prothrombin fragments F1+2, thrombin-antithrombin complex, and thrombomodulin prior to treatment initiation. Genome-wide association scans were conducted for these traits and follow-up replication analyses were performed. RESULTS: We detected an association between CRP single nucleotide polymorphisms (SNPs) and circulating CRP levels (most associated SNP, rs2592902, p = 1.14 × 10(-9)) in 2,100 VISP participants. We discovered a novel association for CRP level in the AKR1D1 locus (rs2589998, p = 7.3 × 10(-8), approaching genome-wide significance) that also is an expression quantitative trait locus for CRP gene expression. We replicated previously identified associations of fibrinogen with SNPs in the FGB and LEPR loci. CRP-associated SNPs and CRP levels were significantly associated with risk of ischemic stroke and recurrent stroke in VISP as well as specific stroke subtypes in METASTROKE. Fibrinogen levels but not fibrinogen-associated SNPs were also found to be associated with recurrent stroke in VISP. CONCLUSIONS: Our data identify a genetic contribution to inflammatory and hemostatic biomarkers in a stroke population. Additionally, our results suggest shared genetic contributions to circulating CRP levels measured poststroke and risk for incident and recurrent ischemic stroke. These data broaden our understanding of genetic contributors to biomarker variation and ischemic stroke risk, which should be useful in clinical risk evaluation.

The changing risk factor profile of participants enrolled in a secondary stroke prevention trial: Vitamin intervention for stroke prevention.

OBJECTIVE: To determine if the stroke risk factor profile of participants in a large, multicenter secondary stroke prevention trial changed over the recruitment period. METHODS: The 3,680 participants in the Vitamin Intervention for Stroke Prevention (VISP) were categorized into four groups by enrollment date. Baseline patient characteristics and stroke risk factors were compared across groups. RESULTS: Hypertension and hypercholesterolemia management improved but prevalence of three major stroke risk factors did not change. Patients enrolled later had better Mini-Mental State and lower NIH Stroke Scale scores, higher multivitamin use, lower prevalence of cortical infarctions, cardiac symptoms and prior stroke, and lower serum creatinine levels. CONCLUSIONS: Those participants enrolled in the later recruitment periods had a different risk factor profile and risk factors were managed differently compared to those enrolled earlier.

Homocyst(e)ine and stroke.

Homocyst(e)ine elevation is associated with a two- to threefold fold increased risk of ischemic stroke. Although most commonly associated with large-artery atherosclerosis and venous thrombosis, hyperhomocysteinemia may contribute to stroke by other mechanisms as well. Levels of homocysteine are determined by genetic regulation of the enzymes involved in homocyst(e)ine metabolism and by levels of the vitamin cofactors (folate, B (6), and B (12)) associated with those reactions. Emerging evidence suggests that genetic variation within this pathway, such as the methyleneterahydrofolate reductase and cystathionine beta-synthase and nicotinamide N-methyltransferase genes, increases the risk of ischemic stroke. The introduction of grain folate fortification in 1998 has reduced homocyst(e)ine concentrations in the U.S. population. However, it is important to screen for vitamin B (12) deficiency and be cognizant that vitamin B (6) levels may be low in the elderly and in individuals with inflammatory disorders. The Vitamin Intervention in Stroke Prevention study failed to prove that high-dose supplementation with folate, B (6), and B (12) reduced the risk of recurrent stroke or myocardial infarction at 2 years; however, there is an ongoing clinical trial evaluating the potential benefit of vitamin supplementation.

Low vitamin B6 but not homocyst(e)ine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification.

BACKGROUND AND PURPOSE: The introduction of cereal grain folic acid fortification in 1998 has reduced homocyst(e)ine (tHcy) concentrations in the US population. We performed a case-control study to determine the risk of stroke and transient ischemic attack (TIA) associated with tHcy and low vitamin status in a postfortification US sample. METHODS: Consecutive cases with new ischemic stroke/TIA were compared with matched controls. Fasting tHcy, folate, pyridoxal 5'-phosphate (PLP), B12, and MTHFR 677C-->T genotype were measured. RESULTS: Mean PLP was significantly lower in cases than controls (39.97 versus 84.1 nmol/L, P<0.0001). After stroke risk factors were controlled for, a strong independent association was present between stroke/TIA and low PLP (adjusted odds ratio [OR], 4.6; 95% CI, 1.4 to 15.1; P<0.001) but not elevated tHcy (OR, 0.92; 95% CI, 0.4 to 2.1). CONCLUSIONS: Low B6 but not tHcy was strongly associated with cerebrovascular disease in this postfortification, folate-replete sample.

Management and Prevention of Stroke Associated with Elevated Homocysteine.

Observational data from prospective and retrospective studies indicate that elevated homocyst(e)ine (Hcy) is associated with preclinical markers of cerebrovascular disease and ischemic stroke. Although the exact mechanisms of this association are unresolved, data indicate that elevated Hcy promotes cerebral, arterial, and venous thrombosis, and may predispose to premature atherosclerosis and craniocervical arterial dissection. Plasma Hcy is a sensitive marker of low folate, B(12), and B(6) status. Data consistently indicate that folic acid supplementation in the form of vitamin tablets is the most effective strategy to lower mild-to-moderately elevated Hcy, with maximal benefit occurring in individuals with higher pretreatment Hcy or lower pretreatment folate levels. B(12) supplementation confers a minor additional benefit, whereas B(6) supplementation has not been demonstrated to confer further benefit. Despite reports that Hcy-lowering therapy may improve surrogate measures of vascular disease, the outcomes of clinical trials for secondary stroke prevention are pending. Until this information is available, we concur with the American Stroke Association guidelines for stroke prevention. Specifically, we recommend good dietary intake of foods rich in folic acid, B(6), and B(12) for primary prevention, and supplemental multivitamins (folic acid 400 g to 1 mg daily, B(12) 400 to 600 g daily, B(6) 2 to 10 mg daily) for individuals with known cerebrovascular disease and hyper-Hcy.