Meng Lee

Low glomerular filtration rate and risk of stroke: meta-analysis.

Objective To qualitatively and quantitatively investigate the link between a low estimated glomerular filtration rate (eGFR) at baseline and risk of future stroke. Design Systematic review and meta-analysis of prospective studies. Data sources PubMed (1966-October 2009) and Embase (1947-October 2009). Selection criteria Inclusion criteria were studies that prospectively collected data within cohort studies or clinical trials, estimated glomerular filtration rate at baseline using the modification of diet in renal disease or Cockcroft-Gault equations, assessed incident stroke, had a follow-up of at least one year, and reported quantitative estimates of multivariate adjusted relative risk and 95% confidence interval for stroke associated with an eGFR of 60-90 ml/min/1.73 m2 or <60 ml/min/1.73 m2. Data abstraction Two investigators independently abstracted data from eligible studies. Estimates were combined using a random effects model. Heterogeneity was assessed by P value of χ2 statistics and I2. Publication bias was assessed by visual examination of funnel plots. Results 21 articles derived from 33 prospective studies: 14 articles assessed eGFR <60 ml/min/1.73 m2 and seven assessed eGRF at both <60 ml/min/1.73 m2 and 60-90 ml/min/1.73 m2 for a total of 284 672 participants (follow-up 3.2-15 years) with 7863 stroke events. Incident stroke risk increased among participants with an eGFR <60 ml/min/1.73 m2 (relative risk 1.43, 95% confidence interval 1.31 to 1.57; P<0.001) but not among those with an eGFR of 60-90 ml/min/1.73 m2 (1.07, 0.98 to 1.17; P=0.15). Significant heterogeneity existed between estimates among patients with an eGFR <60 ml/min/1.73 m2 (P<0.001). In subgroup analyses among participants with an eGFR <60 ml/min/1.73 m2, heterogeneity was significant in Asians compared with non-Asians (1.96, 1.73 to 2.23 v 1.25, 1.16 to 1.35; P<0.001), and those with an eGFR of 40-60 ml/min/1.73 m2 v <40 ml/min/1.73 m2 (1.28, 1.04 to 1.56 v 1.77, 1.32 to 2.38; P<0.01). Conclusions A baseline eGFR <60 ml/min/1.73 m2 was independently related to incident stroke across a variety of participants and study designs. Prompt and appropriate implementation of established strategies for reduction of vascular risk in people with know renal insufficiency may prevent future strokes.

Efficacy of Intra-Arterial Fibrinolysis for Acute Ischemic Stroke Meta-Analysis of Randomized Controlled Trials

Background and Purpose— Although intra-arterial (IA) fibrinolysis for acute ischemic stroke has been clinically available for many years, it is not a therapy approved by the US Food and Drug Administration. Single, randomized, clinical trials (RCTs) have suggested beneficial effects, but no single RCT has demonstrated that IA fibrinolysis yields increases in both good (modified Rankin Scale score 0 to 2) and excellent (modified Rankin Scale score 0 to 1) outcomes when compared with the control group. Relatively few participants and inadequate statistical power in single RCTs may have contributed to this difficulty. Method— We performed a systematic literature search to identified RCTs of IA fibrinolysis in acute ischemic stroke. Multiple outcomes were analyzed, with emphasis on good and excellent outcomes at 90 days or at trial end point. Results— The systematic search identified 5 RCTs with 395 participants comparing IA fibrinolysis and control. IA fibrinolysis was associated with increased good (odds ratio=2.05; 95% CI, 1.33 to 3.14; P=0.001) and excellent (odds ratio=2.14; 95% CI, 1.31 to 3.51; P=0.003) outcomes. For additional end points, IA fibrinolysis was associated with increased frequencies of minimal neurologic deficit (National Institutes of Health Stroke Scale score 0 to 1), minimal impairment of activities of daily living (Barthel Index 90 to 100 or 95 to 100), and recanalization. IA fibrinolysis was associated with increased radiological and symptomatic intracerebral hemorrhage. However, there was no difference in mortality between groups. Conclusions— Formal meta-analysis suggests that IA fibrinolysis substantially increases recanalization rates and good and excellent clinical outcomes in acute ischemic stroke. Increased hemorrhage frequencies are not associated with any increase in mortality.

Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: A meta-analysis

BACKGROUND Recent data suggest that non-targeted treatment with fibrates modestly reduces the risk of incident cardiovascular events. However the effect of fibrate treatment may be particularly beneficial in patients with guideline-endorsed indications for therapy due to evidence of atherogenic dyslipidemia. We conducted a systematic review and meta-analysis to investigate the influence of fibrates on vascular risk reduction in persons with atherogenic dyslipidemia. METHODS Systematic search of Pubmed, CENTRAL and recent reviews was conducted to identify atherogenic dyslipidemia (serum high density lipoprotein cholesterol [HDL-C]<40 mg/dl or triglycerides >200 mg/dl) cohorts from randomized controlled trials. RR with 95% CI was used as a measure of the association between fibrate therapy and risk of cardiovascular diseases, after pooling data across trials in a random-effects model. RESULTS Six trials met selection criteria. Compared to placebo, the greatest benefit with fibrate treatment was seen in 7389 subjects with high triglycerides, fibrate therapy reduced risk of vascular events (RR 0.75, 95% CI 0.65 to 0.86, P<0.001); and in 5068 subjects with both high triglycerides and low HDL-C (RR 0.71, 95% CI 0.62 to 0.82, P<0.001). Less benefit was noted in 15,303 subjects selected for low HDL-C (RR 0.84, 95% CI 0.77 to 0.91, P<0.001). Among 9872 subjects with neither high triglycerides nor low HDL-C, fibrate therapy did not reduce subsequent vascular events (RR 0.96, 95% CI 0.85 to 1.09, P=0.53). CONCLUSIONS Fibrate treatment directed at markers of atherogenic dyslipidemia substantially reduce subsequent vascular event risk.

Declining Stroke and Vascular Event Recurrence Rates in Secondary Prevention Trials Over the Past 50 Years and Consequences for Current Trial Design

Background— It is widely supposed, but not well-demonstrated, that cumulative advances in standard care have reduced recurrent stroke and cardiovascular events in secondary prevention trials. Methods and Results— Systematic search identified all randomized, controlled trials of medical secondary stroke prevention therapies published from 1960 to 2009. Randomized, controlled trials narrowly focused on single stroke mechanisms, including atrial fibrillation, cervical carotid stenosis, and intracranial stenosis, were excluded. From control arms of individual trials, we extracted data for baseline characteristics and annual event rates for recurrent stroke, fatal stroke, and major vascular events and analyzed trends over time. Fifty-nine randomized controlled trials were identified, enrolling 66 157 patients in control arms. Over the 5 decade periods, annual event rates declined, per decade, for recurrent stroke by 0.996% (P=0.001), fatal stroke by 0.282% (P=0.003), and major vascular events by 1.331% (P=0.001). Multiple regression analyses identified increasing antithrombotic use and lower blood pressures as major contributors to the decline in recurrent stroke. For recurrent stroke, annual rates fell from 8.71% in trials launched in the 1960s to 6.10% in the 1970s, 5.41% in the 1980s, 4.04% in the 1990s, and 4.98% in the 2000s. The sample size required for a trial to have adequate power to detect a 20% reduction in recurrent stroke increased 2.2-fold during this period. Conclusions— Recurrent stroke and vascular event rates have declined substantially over the last 5 decades, with improved blood pressure control and more frequent use of antiplatelet therapy as the leading causes. Considerably larger sample sizes are now needed to demonstrate incremental improvements in medical secondary 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.

Effect of pre-diabetes on future risk of stroke: meta-analysis.

Objectives To assess the association between pre-diabetes and risk of stroke, and to evaluate whether this relation varies by diagnostic criteria for pre-diabetes. Design Systematic review and meta-analysis of prospective studies. Data sources A search of Medline, Embase, and the Cochrane Library (1947 to 16 July 2011) was supplemented by manual searches of bibliographies of key retrieved articles and relevant reviews. Selection criteria Prospective cohort studies that reported multivariate adjusted relative risks and corresponding 95% confidence intervals for stroke with respect to baseline pre-diabetes were included. Data extraction Two independent reviewers extracted data on pre-diabetes status at baseline, risk estimates of stroke, study quality, and methods used to assess pre-diabetes and stroke. Relative risks were pooled using random effects models when appropriate. Associations were tested in subgroups representing different characteristics of participants and studies. Publication bias was evaluated with funnel plots. Results The search yielded 15 prospective cohort studies including 760 925 participants. In 8 studies analysing pre-diabetes defined as fasting glucose 100-125 mg/dL (5.6-6.9 mmol/L), the random effects summary estimate did not show an increased risk of stroke after adjustment for established cardiovascular risk factors (1.08, 95% confidence interval 0.94 to 1.23; P=0.26). In 5 studies analysing pre-diabetes defined as fasting glucose 110-125 mg/dL (6.1-6.9 mmol/L), the random effects summary estimate showed an increased risk of stroke after adjustment for established cardiovascular risk factors (1.21, 1.02 to 1.44; P=0.03). In 8 studies with information about impaired glucose tolerance or combined impaired glucose tolerance and impaired fasting glucose, the random effects summary estimate showed an increased risk of stroke after adjustment for established cardiovascular risk factors (1.26, 1.10 to 1.43; P<0.001). When studies that might have enrolled patients with undiagnosed diabetes were excluded, only impaired glucose tolerance or a combination of impaired fasting glucose and impaired glucose tolerance independently raised the future risk of stroke (1.20, 1.07 to 1.35; P=0.002). Conclusion Pre-diabetes, defined as impaired glucose tolerance or a combination of impaired fasting glucose and impaired glucose tolerance, may be associated with a higher future risk of stroke, but the relative risks are modest and may reflect underlying confounding.

Impact of Microalbuminuria on Incident Stroke A Meta-Analysis

Background and Purpose— Microalbuminuria, a marker of both kidney disease and endothelial dysfunction, may be associated with global vascular risk, but the nature and magnitude of the link between microalbuminuria and incident stroke has not been clearly defined. The purpose of this study was to assess the consistency and strength of the association of microalbuminuria with risk of stroke in prospective studies using meta-analysis. Methods— We conducted a systematic search of electronic databases and bibliographies for studies reporting a multivariate-adjusted estimate, represented as relative risk with 95% CI, of the association between microalbuminuria and stroke risk. Studies were excluded if a majority of study participants had established kidney disease or pre-eclampsia. Estimates were combined using a random-effect model. Results— We identified 12 studies, with a total of 48 596 participants and 1263 stroke events. Overall, presence of microalbuminuria was associated with greater stroke risk (relative risk, 1.92; 95% CI, 1.61 to 2.28; P<0.001) after adjustment for established cardiovascular risk factors. There was evidence of significant heterogeneity in the magnitude of the association across studies (P for heterogeneity <0.001, I2=68%), which was partially explained by differences in study population, microalbuminuria definition, and different microalbuminuria-related risk among stroke subtypes. However, in stratified analyses, microalbuminuria was associated with increased risk of subsequent stroke in all subgroups (general population, diabetics, those with known stroke). Conclusions— Microalbuminuria is strongly and independently associated with incident stroke risk. Future studies should explore whether microalbuminuria is just a risk marker or a modifiable risk factor for stroke.

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.

Impact of Elevated Cystatin C Level on Cardiovascular Disease Risk in Predominantly High Cardiovascular Risk Populations A Meta-Analysis

Background—Chronic kidney disease is a growing public health problem that carries substantial risk for cardiovascular disease (CVD). Single studies have differentially examined the role of cystatin C, a novel renal index, with varying cut-point use. We undertook a meta-analysis of prospective studies to properly assess the link between cystatin C (dichotomized and continuous) versus CVD. Methods and Results—Systematic literature search for studies reporting a multivariate-adjusted estimate, represented as relative risk (RR) with 95% confidence interval (CI), of the association between cystatin C and subsequent risk of (1) any CVD event and (2) specific CVD events. Data were collated from 14 studies, with 13 high cardiovascular risk population cohorts and 1 general population cohort, involving 22 509 subjects with 2321 CVD events, 741 coronary heart disease events, and 828 stroke events. Highest cystatin C category versus lowest was associated with greater risk of CVD (RR, 2.62; 95% CI, 2.05 to 3.37, P<0.001), coronary heart disease (RR, 1.72; 95% CI, 1.27 to 2.34; P<0.001), and stroke (RR, 1.83; 95% CI, 1.12 to 3.00; P=0.02) after adjustment for established cardiovascular risk factors. Each standard deviation rise in cystatin C concentration boosted CVD risk (RR, 1.34; 95% CI, 1.18 to 1.51; P<0.001). Highest cystatin C category was also independently linked to greater risk of all-cause mortality and heart failure. Conclusions—The meta-analysis, mostly derived from high cardiovascular populations, showed that cystatin C is strongly and independently associated with subsequent CVD risk. Further investigation is warranted to clarify whether measurement of cystatin C can usefully enhance CVD stratification beyond established predictors already in clinical use.

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.