Folic Acid in Stroke Prevention in Countries without Mandatory Folic Acid Food Fortification: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND PURPOSE: Additional folic acid (FA) treatment appears to have a neutral effect on reducing vascular risk in countries that mandate FA fortification of food (e.g., USA and Canada). However, it is uncertain whether FA therapy reduces stroke risk in countries without FA food fortification. The purpose of this study was to comprehensively evaluate the efficacy of FA therapy on stroke prevention in countries without FA food fortification. METHODS: PubMed, EMBASE, and clinicaltrials.gov from January 1966 to August 2016 were searched to identify relevant studies. Relative risk (RR) with 95% confidence interval (CI) was used as a measure of the association between FA supplementation and risk of stroke, after pooling data across trials in a random-effects model. RESULTS: The search identified 13 randomized controlled trials (RCTs) involving treatment with FA that had enrolled 65,812 participants, all of which stroke was reported as an outcome measure. After all 13 RCTs were pooled, FA therapy versus control was associated with a lower risk of any future stroke (RR, 0.85; 95% CI, 0.77 to 0.95). FA alone or combination of FA and minimal cyanocobalamin (≤0.05 mg/day) was associated with a lower risk of future stroke (RR, 0.75; 95% CI, 0.66 to 0.86) whereas combination of FA and cyanocobalamin (≥0.4 mg/day) was not associated with a lower risk of future stroke (RR, 0.95; 95% CI, 0.86 to 1.05). CONCLUSIONS: FA supplement reduced stroke in countries without mandatory FA food fortification. The benefit was found mostly in patients receiving FA alone or combination of FA and minimal cyanocobalamin.

Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial.

Importance: In atrial fibrillation (AF)-related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear. Objective: To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke. Design, Setting, and Participants: A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis. Interventions: Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks. Main Outcomes and Measures: The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length. Results: Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70-1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic hemorrhagic transformations. Hospitalization length was reduced with rivaroxaban compared with warfarin (median, 4.0 days [interquartile range, 2.0-6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P < .001). Conclusions and Relevance: In mild AF-related acute ischemic stroke, rivaroxaban and warfarin had comparable safety and efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02042534.

Characteristics of the Drip-and-Ship Paradigm for Patients with Acute Ischemic Stroke in South Korea.

BACKGROUND: Data on the drip-and-ship paradigm in Korea are limited. The present study aimed to evaluate the use of the drip-and-ship paradigm and the time delays and outcomes associated with the paradigm in Korea. METHODS: We used data from the Clinical Research Center for Stroke-5 registry between January 2011 and March 2014. Among patients treated with tissue-type plasminogen activator (tPA), the use of the drip-and-ship paradigm was evaluated, and time delays and functional outcomes at 3 months were compared between patients treated with the paradigm and those treated directly at visits. RESULTS: Among 1843 patients who met the eligibility criteria, 244 patients (13.2%) were treated with the drip-and-ship paradigm. Subsequent endovascular recanalization therapy was used in 509 patients (27.6%). The median time from symptom onset to groin puncture was greater in patients treated with the paradigm than in those treated directly at visits (305 versus 200 minutes, P < .001). In multivariate analysis, the risks of unfavorable functional outcomes and symptomatic intracranial hemorrhage were higher inpatients treated with the paradigm than in those directly treated at visits (odds ratio [OR] 2.15; 95% confidence interval [CI], 1.50-3.08; P < .001 and OR 1.78; 95% CI, 1.02-3.12; P = .041, respectively). CONCLUSIONS: In Korea, the drip-and-ship paradigm was used in less than 15% of all patients treated with tPA. The use of the paradigm might cause an increase in the onset-to-groin puncture time. Additionally, clinical outcomes might be worse in patients treated with the paradigm than in those treated directly at visits.

Rationale and design of Triple AXEL: trial for early anticoagulation in acute ischemic stroke patients with nonvalvular atrial fibrillation.

RATIONALE: Patients with atrial fibrillation (AF) in the acute stage of ischemic stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke, but the optimal anticoagulation strategy remains unclear due to the concern of intracranial bleeding. Novel oral anticoagulants compared to warfarin might be more safe and efficacious in patients suitable for early anticoagulation. AIMS: This trial is to evaluate the feasibility of early anticoagulation with rivaroxaban in acute ischemic stroke or TIA patients with nonvalvular AF. DESIGN: This is a randomized, open-label, blinded endpoint evaluation trial. Inclusion criteria are (1) nonvalvular AF, (2) presumed cardioembolic stroke or transient ischemic attack (TIA) confirmed by MRI within five-days from onset, and (3) mild to moderate stroke severity. We will randomize 196 patients to either rivaroxaban (10 mg once daily for five-days followed by 15 mg or 20 mg once daily) or dose-adjusted warfarin (coadministration of aspirin 100 mg per day until achieving international normalized ratio of 1·7). The study is registered in ClinicalTrials.gov (NCT02042534). STUDY OUTCOMES: The primary endpoint is the composite of recurrent ischemic lesion and intracranial bleeding on MRI at four-weeks. Secondary endpoints are recurrent ischemic lesions, intracranial bleeding, major bleeding, major vascular events, four-week modified Rankin Scale score, and duration of hospitalization after randomization. DISCUSSION: The results of this proof-of-concept trial will guide go/no-go decision to a large phase 3 confirmatory trial.

Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials.

BACKGROUND: In observational studies, lower serum homocysteine levels are associated with a lower incidence of cardiovascular disease (CVD). However, individual randomized controlled trials (RCTs) have yielded mixed findings regarding the efficacy of therapeutic homocysteine in lowering cardiovascular risk. Our aim was to perform an updated meta-analysis of relevant RCTs to assess the efficacy of folic acid supplementation in the prevention of CVD, coronary heart disease (CHD), and stroke. METHODS: We performed systematic search to identify RCTs reported at least one of the CVD, CHD, or stroke as outcomes. Relative risk (RR) with 95% confidence interval was used as a measure of the association between folic acid supplementation and risk of CVD, CHD, stroke, and all-cause mortality. The analysis was further stratified by factors that could affect the treatment effects. RESULTS: The systematic search identified 26 RCTs enrolling 58,804 participants. Pooling the RRs showed that folic acid supplementation was not associated with any significant change in the risk of CVD (RR 0.98, 0.95 to 1.02; p=0.36), CHD (RR 1.03, 0.98 to 1.08; p=0.23), and all-cause mortality (RR 1.00, 0.96 to 1.04; p=0.92), but was linked to a decreasing trend in stroke risk (RR 0.93, 0.86 to 1.00; p=0.05). In stratified analyses, the only heterogeneity was found for stroke risk reduction among groups with (RR 1.07, 0.92 to 1.25) vs. without (RR 0.88, 0.81 to 0.96) mandatory grain fortification (P for heterogeneity=0.03). CONCLUSIONS: This meta-analysis suggests that there might be a potentially modest benefit of folic acid supplementation in stroke prevention.

Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis.

BACKGROUND AND PURPOSE: Although a lower serum homocysteine concentration is associated with a reduced risk of stroke in epidemiologic studies, randomized, controlled trials have yielded mixed findings regarding the effect of therapeutic homocysteine lowering on stroke prevention. We performed a meta-analysis of randomized, controlled trials to assess the efficacy of folic acid supplementation in the prevention of stroke. METHODS: Salient trials were identified by formal literature search. Relative risk (RR) with 95% CI was used as a measure of the association between folic acid supplementation and risk of stroke, after pooling data across trials in a fixed-effects model. RESULTS: The search identified 13 randomized, controlled trials that had enrolled 39 005 participants for folic acid therapy to reduce homocysteine in which stroke was reported as an outcome measure. Across all trials, folic acid supplementation was associated with a trend toward mild benefit that did not reach statistical significance in reducing the risk of stroke (RR=0.93; 95% CI, 0.85-1.03; P=0.16). The RR for nonsecondary prevention trials was 0.89 (95% CI, 0.79-0.99; P=0.03). In stratified analyses, a greater beneficial effect was seen in the trials testing combination therapy of folic acid plus vitamins B6 and B12 (RR=0.83; 95% CI, 0.71-0.97; P=0.02) and in the trials that disproportionately enrolled male patients (men:women >2; RR=0.84; 95% CI, 0.74-0.94; P=0.003). CONCLUSIONS: Folic acid supplementation did not demonstrate a major effect in averting stroke. However, potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in male patients, merit further investigation.