Objectives To evaluate the effect of pioglitazone in people with insulin resistance, pre-diabetes and type 2 diabetes. Design and setting Systematic review and meta-analysis of randomised, controlled trials. Data sources Literature searches were performed across PubMed, EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials from 1966 to May 2016 to identify randomised, controlled trials with more than 1 year follow-up. Outcome measures Relative risk (RR) with 95% CI was used to evaluate the association between pioglitazone and the risk of major adverse cardiovascular events (MACE: composite of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death) and safety outcomes, after pooling data across trials in a fixed-effects model. Results Nine trials with 12 026 participants were enrolled in the current meta-analysis. Pioglitazone therapy was associated with a lower risk of MACE in patients with pre-diabetes or insulin resistance (RR 0.77, 95% CI 0.64 to 0.93), and diabetes (RR 0.83, 95% CI 0.72 to 0.97). Risks of heart failure (RR 1.32; CI 1.14 to 1.54), bone fracture (RR 1.52, 95% CI 1.17 to 1.99), oedema (RR, 1.63; CI 1.52 to 1.75) and weight gain (RR 1.60; CI 1.50 to 1.72) increased in pioglitazone group. Conclusions Pioglitazone was associated with reduced risk of MACE in people with insulin resistance, pre-diabetes and diabetes mellitus. However, the risks of heart failure, bone fracture, oedema and weight gain were increased.

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.

Quiz Ref ID The benefits of low-dose aspirin for secondary prevention of myocardial infarction and ischemic stroke are well established, with prevention of recurrent ischemic events outweighing the risk of hemorrhage.^1,2 However, the value of aspirin for primary prevention of symptomatic cardiovascular disease is controversial because the risk of cardiovascular events among event-free individuals is typically lower than that of patients with symptomatic atherosclerotic disease, and the increased risk of bleeding may offset the overall benefit of aspirin use.^3-5 Of the various major bleeding events related to the use of aspirin, intracranial hemorrhage is a special concern because it is strongly associated with a high risk of mortality⁶ and poorer health over a lifetime.^7,8

Objective To conduct a meta-analysis of randomized trials to comprehensively compare the effect of endovascular thrombectomy (EVT) versus intravenous thrombolysis (IVT) plus EVT on functional independence (modified Rankin Scale (mRS) 0–2) after acute ischemic stroke due to large vessel occlusions (AIS-LVO). Methods We searched Pubmed, EMBASE, CENTRAL, and clinicaltrials.gov from January 2000 to February 2021 and abstracts presented at the International Stroke Conference in March 2021 to identify trials comparing EVT alone versus IVT plus EVT in AIS-LVO. Five non-inferiority margins established in the literature were assessed: −15%, −10%, −6.5%, −5%, and −1.3% for the risk difference for functional independence at 90 days. Results Four trials met the selection criteria, enrolling 1633 individuals, with 817 participants randomly assigned to EVT alone and 816 to IVT plus EVT. Crude cumulative rates of 90-day functional independence were 46.0% with EVT alone versus 45.5% with IVT plus EVT. Pooled results showed the risk difference of functional independence was 1% (95% CI −4% to 5%) between EVT alone versus IVT plus EVT. The lower 95% CI bound of −4% fell within the non-inferiority margins of −15%, −10%, −6.5%, and −5%, but not −1.3%. Pooled results also showed the risk difference between EVT alone versus IVT plus EVT was 1% (95% CI −3% to 5%) for mRS 0–1, and 1% (95% CI −1% to 3%) for symptomatic intracranial hemorrhage. Conclusions This meta-analysis suggests that EVT alone is non-inferior to IVT plus EVT for several, but not the most stringent, non-inferiority margins.

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. 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. 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). 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.

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.