Vitamin E supplementation (alone or with other antioxidants) and stroke: a meta-analysis.

CONTEXT: A previous study showed that vitamin E is effective in reducing the incidence of myocardial infarction only when it is taken in the absence of other antioxidants. It is unclear if it also reduces the incidence of stroke. OBJECTIVE: The aim of this meta-analysis is to compare the effect of vitamin E supplementation alone or combined with other antioxidants on the incidence of stroke. DATA SOURCES: A search was performed in the following databases: PubMed, ISI Web of Science, SCOPUS, and Cochrane Library. DATA EXTRACTION: Sixteen randomized controlled trials were selected to evaluate the effect of vitamin E supplementation on stroke. DATA ANALYSIS: The range of vitamin E doses used was 33-800 IU. The follow-up period ranged from 6 months to 9.4 years. Compared with controls, when vitamin E was given alone it did not reduce the incidence of ischemic and hemorrhagic stroke. Conversely, compared with controls, supplementation of vitamin E with other antioxidants reduced ischemic stroke (random effects, RR: 0.91; 95% CI: 0.84-0.99; P = 0.02) but with a significant increase in hemorrhagic stroke (random effects, RR: 1.22; 95% CI: 1.0-1.48; P = 0.04). CONCLUSIONS: Supplementation with vitamin E alone is not associated with stroke reduction. Instead, supplementation of vitamin E with other antioxidants reduces the incidence of ischemic stroke but increases the risk of hemorrhagic stroke, cancelling any beneficial effect derived. Thus, vitamin E is not recommended in stroke prevention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022258259.

Interventional study with vitamin E in cardiovascular disease and meta-analysis.

Cardiovascular disease (CVD) is one of the major causes of morbidity and mortality and atherosclerosis is the common root to most of the CVD. Oxidative stress is one of the most important factors driving atherosclerosis and its complications. Thus, strategies for the prevention and treatment of cardiovascular events had oxidative changes as a potential target. Natural vitamin E consists of a family of eight different compounds, four tocopherols and four tocotrienols. All tocopherols and tocotrienols are potent antioxidants with lipoperoxyl radical-scavenging activities. In addition, α-tocopherol possesses also anti-inflammatory as well as anti-atherothrombotic effects by modulating platelet and clotting system. Experimental and in vitro studies described molecular and cellular signalling pathways regulated by vitamin E antithrombotic and antioxidant properties. While observational studies demonstrated an inverse association between vitamin E serum levels and CVD, interventional trials with vitamin supplements provided negative results. This review focus on the impact of vitamin E in the atherothrombotic process and describes the results of experimental and clinical studies with the caveats related to the interventional trials with vitamin E to prevent CVD.

Long-Term Risk of Major Adverse Cardiac Events in Atrial Fibrillation Patients on Direct Oral Anticoagulants.

OBJECTIVE: To determine the association between direct oral anticoagulant (DOAC) use and risk of major adverse cardiac events (MACEs) in patients with atrial fibrillation (AF). PATIENTS AND METHODS: This study is a single-center prospective observational cohort study including 2366 outpatients with non-valvular AF on treatment with DOACs or vitamin K antagonists (VKAs) from February 2008 for patients on VKA and September 2013 for patients on novel oral anticoagulants. The primary endpoint was the incidence of MACE including fatal and non-fatal myocardial infarction (MI), cardiac revascularization, and cardiovascular death. RESULTS: The mean age was 75.1±9.0 years; 44.7% were women. During a mean follow-up of 33.3±21.9 months (6567 patients/years) 133 MACEs occurred (2.03%/year): 79 MI/cardiac revascularization and 54 cardiovascular deaths. Of these, 101 were on VKAs (2.42%/year) and 32 on DOACs (1.34%/year; log-rank test P=.040). This difference was evident also considering MI alone (1.53%/year and 0.63%/year in the VKA and DOAC group, respectively, log-rank test P=.009). At multivariable Cox proportional hazard regression analysis, use of DOACs was associated with a lower risk of MACE (hazard ratio, 0.636; 95% CI, 0.417 to 0.970; P=.036) and MI (hazard ratio, 0.497; 95% CI, 0.276 to 0.896; p=.020). Sensitivity analysis showed that this association was consistent in younger patients (<75 years), in patients with anemia, and in those without chronic obstructive pulmonary disease and heart failure. We also found that both dabigatran and apixaban/rivaroxaban were associated with a lower rate of MACE, with similar efficacy between full and low doses. CONCLUSION: DOACs are associated with a lower risk of MACE in patients with AF independently from dosage.

ABC (Atrial fibrillation Better Care) Pathway and Healthcare Costs in Atrial Fibrillation: The ATHERO-AF Study.

BACKGROUND: The Atrial fibrillation Better Care (ABC) pathway has been proposed to streamline patient management in an integrated, holistic manner. Compliance to ABC resulted in lower incidence of cardiovascular events, but its impact on health-related costs has not been evaluated. METHODS: Exploratory analysis of costs related to cardiovascular events in the ATHERO-AF prospective cohort study including atrial fibrillation patients on vitamin K antagonists. A Diagnosis-Related Group code provided by the Italian Ministry of Health was assigned to each event to estimate the relative cost. The analysis was performed by dividing patients according to ABC pathway components. RESULTS: Overall, 118 cardiovascular events incurred a cost of 1,017,354 euros (1,149,610 USD). The mean total costs were 13,050 (14,747 USD) and 11,218 euros (12,676 USD) for a non-fatal cardiac event or ischaemic stroke, respectively. The cost-saving was 719 euros (813 USD) per patient-year for patients in group A vs non-A, 703 euros (794 USD) for B vs non-B, 480 euros (542 USD) for C vs non-C and 2776 euros (3,137 USD) for ABC vs non-ABC. The cost per event increased with the number of uncontrolled ABC components: 507 euros (573 USD) for 1, 965 euros (1,091 USD) for 2 and 3,431 euros (3,877 USD) for patients not having any of the three components of the ABC. CONCLUSIONS: Management of atrial fibrillation patients according to the ABC pathway was associated with significantly lower health-related costs. Application of the ABC pathway may help reduce healthcare costs related to cardiovascular events in this high-risk patient population.

Integrated Care Management of Patients With Atrial Fibrillation and Risk of Cardiovascular Events: The ABC (Atrial fibrillation Better Care) Pathway in the ATHERO-AF Study Cohort.

OBJECTIVE: To investigate the impact on cardiovascular events (CVEs) in a real-world population of patients with atrial fibrillation (AF) by implementing the Atrial fibrillation Better Care (ABC: A, Avoid stroke with anticoagulation; B, better symptom management; C, Cardiovascular and comorbidity risk management) pathway. PATIENTS AND METHODS: This prospective single-center cohort study included 907 consecutive patients with nonvalvular AF on vitamin K antagonists from February 2008 to December 2016. The A, B, and C groups were defined as follows: "A" by a Time in Therapeutic Range ≥65%; "B" by a European Heart Rhythm Association (EHRA) symptom scale I-II, and "C" as optimized cardiovascular comorbidity management. Primary end point was a composite outcome of CVEs. RESULTS: During a median follow-up of 36.9 months (interquartile range [IQR] 20.0-57.5; 3022 patient-years), 118 CVEs occurred (3.9% per year; 95% confidence interval [CI], 3.2-4.7). Symptomatic patients (EHRA III-IV) had a higher risk of CVEs compared with those in EHRA I (hazard ratio [HR], 2.73, 95% CI, 1.61-4.63, P<.001). Optimally managed patients in the ABC group (n=198) had a lower risk of CVEs (1.8 [95% CI, 0.9-3.0] vs 4.5% [95% CI, 3.7-5.5] per year, P=.001) compared with those presenting with at least 1 suboptimal ABC factor (HR, 0.40, 95% CI, 0.22-0.74, P=.003). This association was evident using multivariate Cox proportional regression analysis (HR, 0.44, 95% CI, 0.24-0.80, P=.007). CONCLUSION: Integrated care management according to the ABC pathway resulted in a significantly lower rate of CVEs, suggesting a clear benefit of a holistic approach to optimize the management of patients with AF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01882114.

Data on incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants.

This article contains the data showing the different characteristics of atrial fibrillation (AF) patients treated with vitamin K (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) screened for the presence of liver fibrosis (LF) and followed to record the occurrence of bleeding and cardiovascular events (CVEs). A detailed description of major and minor bleedings is provided according to anticoagulant treatment (VKAs vs. NOACs) and to the presence of LF. Data here reported also show a higher incidence rate of CVEs in VKA-treated patients, but not in those on NOACs. The data are supplemental to our original research article titled "Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonists oral anticoagulants" (Pastori et al., 2018) [1].

Anti Xa oral anticoagulants inhibit in vivo platelet activation by modulating glycoprotein VI shedding.

Anti Xa non-vitamin K oral anticoagulants (anti Xa NOACs) seem to possess antiplatelet effect in vitro, but it is unclear if this occurs also in vivo. Aim of the study was to compare the effect on platelet activation of two anti Xa NOACs, namely apixaban and rivaroxaban, to warfarin, and to investigate the potential underlying mechanism by evaluating soluble glycoprotein GPVI (sGPVI), a protein involved in platelet activation. We performed a cross-sectional including AF patients treated with warfarin (n=30), or apixaban 10mg/day (n=40), or rivaroxaban 20mg/day (n=40). Patients were balanced for sex, age and cardiovascular risk factors. Platelet activation by urinary excretion of 11-dehydro-thromboxane (Tx) B2 and soluble GPVI (sGPVI) were analysed at baseline and after 3 months of treatment. Baseline TxB2 value was 155.2±42.7ng/mg creatinine. The 3 months-variation of urinary excretion of TxB2 was -6.5% with warfarin (p=0.197), -29% with apixaban (p<0.001) and -31% with rivaroxaban (p<0.001). Use of anti Xa NOACs was independently associated to the variation of urinary TxB2 (B: -0.469, p<0.001), after adjustment for clinical characteristics; sGPVI was significantly lower in patients treated with NOACs at 3 months (p<0.001), while only a trend for the warfarin group (p=0.116) was observed. The variation of sGPVI was correlated with that of TxB2 in the NOACs group (Rs: 0.527, p<0.001). In 15 patients (5 per each group) platelet recruitment was significantly lowered at 3 months by NOACs (p<0.001), but not by warfarin. The study provides evidence that anti Xa NOACs significantly inhibit urinary TxB2 excretion compared to warfarin, suggesting that NOACs possess antiplatelet property.

Interaction Between Dietary Vitamin K Intake and Anticoagulation by Vitamin K Antagonists: Is It Really True?: A Systematic Review.

Educational advice is often given to patients starting treatment with vitamin K Antagonists (VKAs). A great emphasis is made on nutritional information. Common belief is that dietary vitamin K intake could counteract the anticoagulant effect by VKAs and for many years, patients have been discouraged to consume vitamin-K-rich foods, such as green leafy vegetables.The objective of this study is to summarize the current evidence supporting the putative interaction between dietary vitamin K intake and changes in INR with the VKAs.Data sources are MEDLINE via PubMed and Cochrane database.All clinical studies investigating the relationship between dietary vitamin K and measures of anticoagulation were included. We excluded all studies of supplementation of vitamin K alone.We performed a systematic review of the literature up to October 2015, searching for a combination of "food," "diet," "vitamin K," "phylloquinone," "warfarin," "INR," "coagulation," and "anticoagulant."Two dietary interventional trials and 9 observational studies were included. We found conflicting evidence on the effect of dietary intake of vitamin K on coagulation response. Some studies found a negative correlation between vitamin K intake and INR changes, while others suggested that a minimum amount of vitamin K is required to maintain an adequate anticoagulation. Median dietary intake of vitamin K1 ranged from 76 to 217 µg/day among studies, and an effect on coagulation may be detected only for high amount of vitamin intake (>150 µg/day).Most studies included patients with various indications for VKAs therapy, such as atrial fibrillation, prosthetic heart valves, and venous thromboembolism. Thus, INR target was dishomogeneous and no subanalyses for specific populations or different anticoagulants were conducted. Measures used to evaluate anticoagulation stability were variable.The available evidence does not support current advice to modify dietary habits when starting therapy with VKAs. Restriction of dietary vitamin K intake does not seem to be a valid strategy to improve anticoagulation quality with VKAs. It would be, perhaps, more relevant to maintain stable dietary habit, avoiding wide changes in the intake of vitamin K.

Nutritional and therapeutic approaches to modulate NADPH oxidase-derived ROS signaling in platelets.

Experimental and clinical studies provided evidence that formation of intra-platelet reactive oxidant species (ROS) is implicated in the process of thrombosis. Animal models demonstrated that enhanced ROS formation was associated with serious thrombotic complications and death. In recent years, nutritional and therapeutic approaches were tested to modulate ROS mediated thrombus formation. The use of a nutritional approach stems from the observation that foods rich in antioxidant elements, such as polyphenols, were able to modulate ROS formation. Similarly, some drugs used for different diseases (i.e. statins) showed the ability to modulate oxidative stress. Aim of this review is to summarize current evidences supporting the role of nutrients rich in polyphenols, such as olive oil and cocoa, and of some drugs, such as statins as antiplatelet agents interfering with the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase signaling. Indeed, for nutrients and statins, the antiplatelet activity seems to be dependent, at least in part, upon the inhibition of platelet NADPH oxidase-derived ROS formation, resulting in down-regulation of isoprostanes, which are pro-aggregating molecules, and up-regulation of nitric oxide, which is a platelet inhibitor.

Similar Reduction of Cholesterol-Adjusted Vitamin E Serum Levels in Simple Steatosis and Non-Alcoholic Steatohepatitis.

OBJECTIVES: Reduced vitamin E levels have been reported in patients with non-alcoholic steatohepatitis (NASH), but no conclusive data on patients with simple steatosis (SS) are available. Aim of this study was to investigate the association between serum vitamin E levels and SS. METHODS: A cohort of 312 patients with cardio-metabolic risk factors was screened for liver steatosis by ultrasonography (US). We reasonably classified as SS patients with US-fatty liver, normal liver function tests (LFTs) and with Cytokeratin 18 <246 mIU/ml. Liver biopsy was performed in 41 patients with US-fatty liver and persistent elevation of LFTs (>6 months). Serum cholesterol-adjusted vitamin E (Vit E/chol) levels were measured. RESULTS: Mean age was 53.9±12.5 years and 38.4% were women. Non-alcoholic fatty liver disease (NAFLD) was detected at US in 244 patients; of those 39 had biopsy-proven NASH and 2 borderline NASH. Vit E/chol was reduced in both SS (3.4±2.0, P<0.001), and NASH (3.5±2.1, P=0.006) compared with non-NAFLD patients (4.8±2.0 µmol/mmol chol). No difference was found between SS and NASH (P=0.785). After excluding patients with NASH, a multivariable logistic regression analysis found that Vit E/chol (odds ratio (OR): 0.716, 95% confidence interval (CI) 0.602-0.851, P<0.001), alanine aminotransferase (ALT, OR: 1.093, 95% CI 1.029-1.161, P=0.004), body mass index (OR: 1.162, 95% CI 1.055-1.279, P=0.002) and metabolic syndrome (OR: 5.725, 95% CI 2.247-14.591, P<0.001) were factors independently associated with the presence of SS. CONCLUSIONS: Reduced vitamin E serum levels are associated with SS, with a similar reduction between patients with SS and NASH, compared with non-NAFLD patients. Our findings suggest that the potential benefit of vitamin E supplementation should be investigated also in patients with SS.

Incidence of myocardial infarction and vascular death in elderly patients with atrial fibrillation taking anticoagulants: relation to atherosclerotic risk factors.

BACKGROUND: Recent findings suggest that patients with atrial fibrillation (AF), in addition being at thromboembolic risk, are at risk of myocardial infarction (MI). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants. METHODS: We prospectively followed up 1,019 patients with AF for a median of 33.7 months (3,223 person-years). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events (CVEs) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death. RESULTS: The mean age of the patients was 73.2 years, and 43.8% were women. At follow-up, 111 CVEs (3.43%/y) had occurred: 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks (0.96%/y) were recorded. Patients experiencing CVEs were older (P < .001) and had a higher prevalence of metabolic syndrome (MetS) (P = .005), heart failure (P = .001), and prior cardiac (P < .001) and cerebrovascular events (P < .001). On a Cox proportional hazard analysis, age (hazard ratio [HR], 1.083; 95% CI, 1.053-1.113; P < .001), smoking (HR, 2.158; 95% CI, 1.193-3.901; P = .011), history of cerebrovascular (HR, 1.704; 95% CI, 1.119-2.597; P = .013) and cardiac (HR, 1.658; 95% CI, 1.105-2.489; P = .015) events, MetS (HR, 1.663; 95% CI, 1.107-2.499; P = .014), heart failure (HR, 1.584; 95% CI, 1.021-2.456; P = .040), and male sex (HR, 1.499; 95% CI, 1.010-2.223; P = .044) predicted CVEs. CONCLUSIONS: Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01882114; URL: www.clinicaltrials.gov.

Extra virgin olive oil blunt post-prandial oxidative stress via NOX2 down-regulation.

OBJECTIVE: Olive oil protects against cardiovascular disease but the underlying mechanism is still unclear. We speculated that olive oil could inhibit oxidative stress, which is believed to be implicated in the atherosclerotic process. METHODS AND RESULTS: Post-prandial oxidative stress and endothelial dysfunction were investigated in twenty-five healthy subjects who were randomly allocated in a cross-over design to a Mediterranean diet added with or without extra virgin olive oil (EVOO, 10 g) (first study, n = 25) or Mediterranean diet with EVOO (10 g) or corn oil (10 g) (second study, n = 25). Oxidative stress biomarkers including platelet reactive oxidant species (ROS) and 8-iso-PGF2α-III, activity of NOX2, the catalytic sub-unit of NADPH oxidase, as assessed in platelets and serum, serum vitamin E and endothelial dysfunction, were measured before and 2 h after lunch. In the first study a significant increase of platelet ROS, 8-iso-PGF2α-III, NOX2 activity, sE-selectin, sVCAM1 and a decrease of serum vitamin E were detected in controls but not when EVOO was included in the Mediterranean diet; oxidative stress and endothelial dysfunction increase were also observed in the second study in subjects given corn oil. A significant correlation was found between NOX2 activity and platelet oxidative stress. In vitro study demonstrated that EVOO but not corn oil significantly decreased platelet and PMNs oxidative stress and NOX2 activity. CONCLUSION: The study provides the first evidence that post-prandial oxidative stress may be triggered by NOX2 up-regulation. EVOO but not corn oil, is able to counteract such phenomenon suggesting that addition of EVOO to a Mediterranean diet protects against post-prandial oxidative stress.

Polyunsaturated fatty acids balance affects platelet NOX2 activity in patients with liver cirrhosis.

BACKGROUND: NADPH-oxidase-2 up-regulation has been suggested in liver damage perpetuation via an oxidative stress-mediated mechanism. n-6/n-3 polyunsaturated fatty acids ratio derangement has been reported in liver disease. AIM: To explore polyunsaturated fatty acids balance and its interplay with platelet oxidative stress in liver cirrhosis. METHODS: A cross-sectional study in 51 cirrhotic patients and sex- and age-matched controls was performed. Serum polyunsaturated fatty acids and oxidative stress markers (urinary isoprostanes and serum soluble NADPH-oxidase-2-derived peptide) were measured. The effect on platelet oxidative stress of n-6/n-3 polyunsaturated fatty acids ratio in vitro and in vivo (1-week supplementation with 3g/daily n-3-polyunsaturated fatty acids) was tested. RESULTS: Compared to controls, cirrhotic patients had significantly higher n-6/n-3 polyunsaturated fatty acids ratio. n-6/n-3 polyunsaturated fatty acids ratio correlated significantly with disease severity and oxidative stress markers. In vitro experiments showed that in Child-Pugh C patients' platelets incubation with low n-6/n-3 polyunsaturated fatty acids ratio resulted in dose-dependent decrease of radical oxigen species (-39%), isoprostanes (-25%) and NADPH-oxidase-2 regulation (-51%). n-3 polyunsaturated fatty acids supplemented patients showed significant oxidative stress indexes reduction. CONCLUSIONS: In cirrhosis, n-6/n-3 polyunsaturated fatty acids imbalance up-regulates platelet NADPH-oxidase-2 with ensuing oxidative stress. Further study to evaluate if n-3 supplementation may reduce disease progression is warranted.

Antioxidant and antiplatelet effects of atorvastatin by Nox2 inhibition.

In recent years, it became evident that reactive oxygen species (ROS) are implicated in the thrombotic process. Statins are lipid-lowering agents able to lower serum cholesterol levels and retard atherosclerotic complications and their clinical sequelae. There is evidence that, among statins, atorvastatin may exert antiplatelet effects by interfering with redox signaling. Recent studies demonstrated that atorvastatin possesses antiplatelet activity via inhibition of platelet formation of NADPH oxidase-derived ROS. This effect results in down-regulation of isoprostanes, which are pro-aggregating molecules, and up-regulation of nitric oxide, which is a platelet inhibitor; such changes occurred immediately after atorvastatin administration and were independent from lipid-lowering property. Experimental and clinical studies documented that statins possess antithrombotic effects, which may account for the reduction of thrombotic-related vascular outcomes. This has been evidenced in different cardiovascular clinical settings such as percutaneous coronary intervention (PCI), myocardial infarction (MI), and venous thrombosis. Future studies should be addressed to analyze if the antiplatelet effect of atorvastatin may preferentially occur at high dosage. Interestingly, the antiplatelet effects of statins could be useful in clinical settings where the clinical efficacy of aspirin and other antiplatelet drugs is still uncertain.

Nutraceuticals in the early infancy.

Atherosclerosis disease and its extent in childhood correlate positively with established risk factors, namely obesity, hypercholesterolemia, diabetes mellitus, and hypertension. The safety and efficacy of some dietary interventions to modulate risk factors in childhood are documented by an increasing body of evidence. The present review analyzes nutritional and nutraceutical current strategies addressed to modify some risk factors of atherosclerosis in childhood. In particular, studies concerning nutrients such as fibers, omega-3-fatty acids, vitamin D, antioxidants, and calcium have been evaluated. An overall analysis suggests that some nutraceuticals might represent an attractive tool to lower the development of atherosclerotic-related cardiovascular complication in children. Nevertheless, at this moment, due to the methodological weakness that characterizes the majority of the analyzed studies, nutrients or supplements should not be considered as a therapeutic tool potentially usable for clinical purpose in children at risk for cardiovascular disease.