Yi-Ling Wu

Risk–Benefit Profile of Long-Term Dual- Versus Single-Antiplatelet Therapy Among Patients With Ischemic Stroke: A Systematic Review and Meta-analysis

BACKGROUND Dual-antiplatelet regimens for prevention of recurrent stroke promote antithrombotic effects but may increase the risk for hemorrhage. PURPOSE To qualitatively and quantitatively examine the risk for recurrent stroke and intracranial hemorrhage (ICH) linked to long-term dual- and single-antiplatelet therapy among patients with ischemic stroke and transient ischemic attack. DATA SOURCES PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials through March 2013 without language restrictions. STUDY SELECTION The search identified 7 randomized, controlled trials that involved a total of 39,574 participants and reported recurrent stroke and ICH as outcome measures. DATA EXTRACTION All data from eligible studies were independently abstracted by 2 investigators according to a standard protocol. DATA SYNTHESIS Recurrent stroke risk did not differ between patients receiving dual-antiplatelet therapy and those receiving aspirin monotherapy (relative risk [RR], 0.89 [95% CI, 0.78 to 1.01]) or clopidogrel monotherapy (RR, 1.01 [CI, 0.93 to 1.08]). Risk for ICH did not differ between patients receiving dual-antiplatelet therapy and those receiving aspirin monotherapy (RR, 0.99 [CI, 0.70 to 1.42]) but was greater among patients receiving dual-antiplatelet therapy than among those receiving clopidogrel monotherapy (RR, 1.46 [CI, 1.17 to 1.82]). LIMITATION Agents used in dual- and single-antiplatelet therapies varied across trials, and the relatively modest number of trials limited subgroup analysis. CONCLUSION Compared with monotherapy, dual-antiplatelet therapy lasting more than 1 year after an index ischemic stroke or transient ischemic attack is not associated with a greater reduction in overall recurrent stroke risk. However, long-term dual-antiplatelet therapy is linked to higher risk for ICH than clopidogrel monotherapy in this patient population. PRIMARY FUNDING SOURCE Chang Gung Memorial Hospital.

Effect of Blood Pressure Lowering in Early Ischemic Stroke: Meta-Analysis

Background and Purpose— Elevated blood pressure is common in acute stage of ischemic stroke and the strategy to manage this situation is not well established. We therefore conducted a meta-analysis of randomized controlled trials comparing active blood pressure lowering and control groups in early ischemic stroke. Methods— Pubmed, EMBASE, and Clinicaltrials.gov from January 1966 to March 2015 were searched to identify relevant studies. We included randomized controlled trials with blood pressure lowering started versus control within 3 days of ischemic stroke onset. The primary outcome was unfavorable outcome at 3 months or at trial end point, defined as dependency or death, and the key secondary outcome was recurrent vascular events. Pooled relative risks and 95% confidence intervals were calculated using random-effects model. Results— The systematic search identified 13 randomized controlled trials with 12 703 participants comparing early blood pressure lowering and control. Pooling the results with the random-effects model showed that blood pressure lowering in early ischemic stroke did not affect the risk of death or dependency at 3 months or at trial end point (relative risk, 1.04; 95% confidence interval, 0.96–1.13; P=0.35). Also, blood pressure lowering also had neutral effect on recurrent vascular events, as well as on disability or death, all-cause mortality, recurrent stroke, and serious adverse events. Conclusions— This meta-analysis suggested blood pressure lowering in early ischemic stroke had a neutral effect on the prevention of death or dependency.

Cognitive impairment and risk of future stroke: a systematic review and meta-analysis

Background: Several studies have assessed the link between cognitive impairment and risk of future stroke, but results have been inconsistent. We conducted a systematic review and meta-analysis of cohort studies to determine the association between cognitive impairment and risk of future stroke. Methods: We searched MEDLINE and Embase (1966 to November 2013) and conducted a manual search of bibliographies of relevant retrieved articles and reviews. We included cohort studies that reported multivariable adjusted relative risks and 95% confidence intervals or standard errors for stroke with respect to baseline cognitive impairment. Results: We identified 18 cohort studies (total 121 879 participants) and 7799 stroke events. Pooled analysis of results from all studies showed that stroke risk increased among patients with cognitive impairment at baseline (relative risk [RR] 1.39, 95% confidence interval [CI] 1.24–1.56). The results were similar when we restricted the analysis to studies that used a widely adopted definition of cognitive impairment (i.e., Mini-Mental State Examination score < 25 or nearest equivalent) (RR 1.64, 95% CI 1.46–1.84). Cognitive impairment at baseline was also associated with an increased risk of fatal stroke (RR 1.68, 95% CI 1.21–2.33) and ischemic stroke (RR 1.65, 95% CI 1.41–1.93). Interpretation: Baseline cognitive impairment was associated with a significantly higher risk of future stroke, especially ischemic and fatal stroke.

Warfarin Use and Risk of Stroke in Patients With Atrial Fibrillation Undergoing Hemodialysis: A Meta-Analysis.

AbstractIn spite of the substantial burden of atrial fibrillation and associated elevated ischemic stroke risk in patients undergoing hemodialysis, the role of warfarin in these high-risk patients remains uncertain. Our objective was to clarify the association between warfarin use and risk of stroke for patients with atrial fibrillation undergoing dialysis.PubMed and Embase from January 1966 to January 2015 were searched to identify relevant studies. Inclusion criteria were cohort studies, patients with atrial fibrillation undergoing hemodialysis, and reported quantitative estimates of the multivariate adjusted relative risk (RR) and 95% confidence interval (CI) for future stroke associated with warfarin use. We identified 8 studies, with a total of 9539 participants and 706 stroke events. Three studies reported total stroke as primary endpoint and other studies reported ischemic stroke as primary endpoint. Pooling the results showed that warfarin use was associated with higher risk of any stroke (RR 1.50, 95% CI: 1.13–1.99). By stroke type, warfarin was not significantly linked to risk of ischemic stroke (RR 1.01, 95% CI: 0.65–1.57, P = 0.97), but was related to greater hemorrhagic stroke risk (RR 2.30, 95% CI: 1.62–3.27). Warfarin heightened overall bleeding risk (RR 1.27, 95% CI: 1.03–1.56), but not death (RR 0.67, 95% CI: 0.37–1.21).Among patients with atrial fibrillation undergoing hemodialysis, use of warfarin is associated with a higher risk of hemorrhagic stroke, but did not increase overall mortality.

Is clopidogrel better than aspirin following breakthrough strokes while on aspirin? A retrospective cohort study

Objective There is insufficient evidence on which to base a recommendation for optimal antiplatelet therapy following a stroke while on aspirin. The objective was to compare clopidogrel initiation vs aspirin reinitiation for vascular risk reduction among patients with ischaemic stroke on aspirin at the time of their index stroke. Design Retrospective. Setting We conducted a nationwide cohort study by retrieving all hospitalised patients (≥18 years) with a primary diagnosis of ischaemic stroke between 2003 and 2009 from Taiwan National Health Insurance Research Database. Participants Among 3862 patients receiving aspirin before the index ischaemic stroke and receiving either aspirin or clopidogrel after index stroke during follow-up period, 1623 were excluded due to a medication possession ratio <80%. Also, 355 were excluded due to history of atrial fibrillation, valvular heart disease or coagulopathy. Therefore, 1884 patients were included in our final analysis. Interventions Patients were categorised into two groups based on whether clopidogrel or aspirin was prescribed during the follow-up period. Follow-up was from time of the index stroke to admission for recurrent stroke or myocardial infarction, death or the end of 2010. Primary and secondary outcome measures The primary end point was hospitalisation due to a new-onset major adverse cardiovascular event (MACE: composite of any stroke or myocardial infarction). The leading secondary end point was any recurrent stroke. Results Compared to aspirin, clopidogrel was associated with a lower occurrence of future MACE (HR=0.54, 95% CI 0.43 to 0.68, p<0.001, number needed to treat: 8) and recurrent stroke (HR=0.54, 95% CI 0.42 to 0.69, p<0.001, number needed to treat: 9) after adjustment of relevant covariates. Conclusions Among patients with an ischaemic stroke while taking aspirin, clopidogrel initiation was associated with fewer recurrent vascular events than aspirin reinitiation.

Effects of Non–Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: A Systematic Review and Meta‐Analysis

Background The original non–vitamin K antagonist oral anticoagulant (NOAC) trials in nonvalvular atrial fibrillation (AF) enrolled patients with native valve pathologies. The object of this study was to quantify the benefit–risk profiles of NOACs versus warfarin in AF patients with native valvular heart disease (VHD). Methods and Results Trials were identified by exhaustive literature search. Trial data were combined using inverse variance weighting to produce a meta‐analytic summary hazard ratio (HR) and 95% confidence interval (CI) of efficacy and safety of NOACs versus warfarin. Our final analysis included 4 randomized controlled trials that enrolled 71 526 participants, including 13 574 with VHD. Pooling results from included trials showed that NOACs versus warfarin reduced stroke or systemic embolism (HR: 0.70; 95% CI, 0.60–0.82) and intracranial hemorrhage (HR: 0.47; 95% CI, 0.24–0.92) in AF patients with VHD. However, risk reduction of major bleeding and intracranial hemorrhage was driven by apixaban, edoxaban, and dabigatran (HR for major bleeding: 0.79 [95% CI, 0.69–0.91]; HR for intracranial hemorrhage: 0.33 [95% CI, 0.25–0.45]) but not rivaroxaban (HR for major bleeding: 1.56 [95% CI, 1.20–2.04]; HR for intracranial hemorrhage: 1.27 [95% CI, 0.77–2.10]). Conclusions Among patients with AF and native VHD, NOACs reduce stroke and systemic embolism compared with warfarin. Evidence shows that apixaban, dabigatran, and edoxaban also reduce bleeding in this patient subgroup, whereas major bleeding (but not intracranial hemorrhage or mortality rate) is significantly increased in VHD patients treated with rivaroxaban. NOACs are a reasonable alternative to warfarin in AF patients with VHD.

Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin: A Systematic Review and Meta-Analysis.

Background and Purpose— Optimal antiplatelet therapy after an ischemic stroke or transient ischemic attack while on aspirin is uncertain. We, therefore, conducted a systematic review and meta-analysis. Methods— We searched PubMed (1966 to August 2016) and bibliographies of relevant published original studies to identify randomized trials and cohort studies reporting patients who were on aspirin at the time of an index ischemic stroke or transient ischemic attack and reported hazard ratio for major adverse cardiovascular events or recurrent stroke associated with a switch to or addition of another antiplatelet agent versus maintaining aspirin monotherapy. Estimates were combined using a random effects model. Results— Five studies with 8723 patients with ischemic stroke or transient ischemic attack were identified. Clopidogrel was used in 4 cohorts, and ticagrelor was used in 1 cohort. Pooling results showed that addition of or a switch to another antiplatelet agent, versus aspirin monotherapy, was associated with reduced risks of major adverse cardiovascular events (hazard ratio, 0.68; 95% confidence interval, 0.54–0.85) and recurrent stroke (hazard ratio, 0.70; 95% confidence interval, 0.54–0.92). Each of the strategies of addition of and switching another antiplatelet agent showed benefit versus continued aspirin monotherapy, and studies with regimen initiation in the first days after index event showed more homogenous evidence of benefit. Conclusions— Among patients who experience an ischemic stroke or transient ischemic attack while on aspirin monotherapy, the addition of or a switch to another antiplatelet agent, especially in the first days after index event, is associated with fewer future vascular events, including stroke.

Utilization of Statins Beyond the Initial Period After Stroke and 1‐Year Risk of Recurrent Stroke

Background In‐hospital discontinuation of statins has been linked to poorer early stroke outcomes, but the consequences of postdischarge discontinuation or dose reduction of statin treatment are unknown. The objective of this study was to explore the effects of statin discontinuation or statin dose reduction on recurrent stroke risk. Methods and Results We conducted a nationwide cohort study using the data from the Taiwan National Health Insurance Research Database. Our source population comprised all patients who were prescribed a statin within 90 days of discharge after an ischemic stroke between 2001 and 2012. Patients were categorized into 3 groups: statin‐discontinued, statin‐reduced, and statin‐maintained. Cox proportional hazard models were used to estimate the hazard ratios and 95%CIs of recurrent stroke during 1‐year follow‐up in the groups who discontinued statins or reduced statin dose compared with the group who maintained statins as the reference. Among the 45 151 ischemic stroke patients meeting criteria, during the day‐90 to day‐180 period, 7.0% were on reduced statin therapy, and 18.5% were not on any statin therapy. Compared with maintained‐statin intensity therapy, discontinuation of statins was associated with an increased hazard of recurrent stroke (adjusted hazard ratio 1.42, 95%CI 1.28‐1.57), whereas reduced‐statin dose was not associated with an additional risk (adjusted hazard ratio 0.94, 95%CI 0.78‐1.12). Propensity‐matching analysis obtained similar results. Conclusions Discontinuation of statin therapy between 3 and 6 months after an index ischemic stroke was associated with a higher risk of recurrent stroke within 1 year after statin discontinuation.

Association of Renal Biomarkers with 3-Month and 1-Year Outcomes among Critically Ill Acute Stroke Patients

Background The comparative relationships of widely recognized biomarkers of renal injury with short-term and long-term outcomes among critically ill acute stroke patients are unknown. We evaluated the impact of baseline albuminuria [urine albumin-creatinine ratio (UACR)≥30 mg/g] or low estimated glomerular filtration rate (eGFR<60 ml/min per 1.73 m2) on stroke patients admitted to the intensive care unit (ICU). Methods We reviewed data on consecutive stroke patients admitted to a hospital ICU in Taiwan from September 2007 to August 2010 and followed-up for 1 year. Baseline UACR was categorized into <30 mg/g (normal), 30–299 mg/g (microalbuminuria), and ≥300 mg/g (macroalbuminuria), while eGFR was divided into ≥60, 45–59, and <45 ml/min per 1.73 m2. The outcome measure was death or disability at 3-month and 1-year after stroke onset, assessed by dichotomizing the modified Rankin Scale at 3–6 versus 0–2. Results Of 184 consecutive patients, 153 (83%) met study entry criteria. Mean age was 67.9 years and median admission NIHSS score was 16. Among the renal biomarkers, only macroalbuminuria was associated with poorer 3-month outcome (OR 8.44, 95% CI 1.38 to 51.74, P = 0.021) and 1-year outcome (OR 18.06, 95% CI 2.59 to 125.94, P = 0.003) after adjustment of relevant covariates. When ischemic and hemorrhagic stroke were analyzed separately, macroalbuminuria was associated with poorer 1-year outcome among ischemic (OR 17.10, 95% CI 1.04 to 280.07, P = 0.047) and hemorrhagic stroke patients (OR 1951.57, 95% CI 1.07 to 3561662.85, P = 0.048), respectively, after adjustment of relevant covariates and hematoma volume. Conclusions Presence of macroalbuminuria indicates poor 3-month and 1-year outcomes among critically ill acute stroke patients.

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.