Continuous infusion versus bolus injection of loop diuretics for acute heart failure.

BACKGROUND: Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion in 5% of cases. Treatment often requires urgent escalation of diuretic therapy, mainly through hospitalisation. This Cochrane review evaluated the efficacy of intravenous loop diuretics strategies in treating AHF in individuals with New York Heart Association (NYHA) classification III or IV and fluid overload. OBJECTIVES: To assess the effects of intravenous continuous infusion versus bolus injection of loop diuretics for the initial treatment of acute heart failure in adults. SEARCH METHODS: We identified trials through systematic searches of bibliographic databases and in clinical trials registers including CENTRAL, MEDLINE, Embase, CPCI-S on the Web of Science, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry platform (ICTRP), and the European Union Trials register. We conducted reference checking and citation searching, and contacted study authors to identify additional studies. The latest search was performed on 29 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving adults with AHF, NYHA classification III or IV, regardless of aetiology or ejection fraction, where trials compared intravenous continuous infusion of loop diuretics with intermittent bolus injection in AHF. We excluded trials with chronic stable heart failure, cardiogenic shock, renal artery stenosis, or end-stage renal disease. Additionally, we excluded studies combining loop diuretics with hypertonic saline, inotropes, vasoactive medications, or renal replacement therapy and trials where diuretic dosing was protocol-driven to achieve a target urine output, due to confounding factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened papers for inclusion and reviewed full-texts. Outcomes included weight loss, all-cause mortality, length of hospital stay, readmission following discharge, and occurrence of acute kidney injury. We performed risk of bias assessment and meta-analysis where data permitted and assessed certainty of the evidence. MAIN RESULTS: The review included seven RCTs, spanning 32 hospitals in seven countries in North America, Europe, and Asia. Data collection ranged from eight months to six years. Following exclusion of participants in subgroups with confounding treatments and different clinical settings, 681 participants were eligible for review. These additional study characteristics, coupled with our strict inclusion and exclusion criteria, improve the applicability of the body of the evidence as they reflect real-world clinical practice. Meta-analysis was feasible for net weight loss, all-cause mortality, length of hospital stay, readmission, and acute kidney injury. Literature review and narrative analysis explored daily fluid balance; cardiovascular mortality; B-type natriuretic peptide (BNP) change; N-terminal-proBNP change; and adverse incidents such as ototoxicity, hypotension, and electrolyte imbalances. Risk of bias assessment revealed two studies with low overall risk, four with some concerns, and one with high risk. All sensitivity analyses excluded trials at high risk of bias. Only narrative analysis was conducted for 'daily fluid balance' due to diverse data presentation methods across two studies (169 participants, the evidence was very uncertain about the effect). Results of narrative analysis varied. For instance, one study reported higher daily fluid balance within the first 24 hours in the continuous infusion group compared to the bolus injection group, whereas there was no difference in fluid balance beyond this time point. Continuous intravenous infusion of loop diuretics may result in mean net weight loss of 0.86 kg more than bolus injection of loop diuretics, but the evidence is very uncertain (mean difference (MD) 0.86 kg, 95% confidence interval (CI) 0.44 to 1.28; 5 trials, 497 participants; P < 0.001, I2 = 21%; very low-certainty evidence). Importantly, sensitivity analysis excluding trials with high risk of bias showed there was insufficient evidence for a difference in bodyweight loss between groups (MD 0.70 kg, 95% CI -0.06 to 1.46; 3 trials, 378 participants; P = 0.07, I2 = 0%). There may be little to no difference in all-cause mortality between continuous infusion and bolus injection (risk ratio (RR) 1.53, 95% CI 0.81 to 2.90; 5 trials, 530 participants; P = 0.19, I2 = 4%; low-certainty evidence). Despite sensitivity analysis, the direction of the evidence remained unchanged. No trials measured cardiovascular mortality. There may be little to no difference in the length of hospital stay between continuous infusion and bolus injection of loop diuretics, but the evidence is very uncertain (MD -1.10 days, 95% CI -4.84 to 2.64; 4 trials, 211 participants; P = 0.57, I2 = 88%; very low-certainty evidence). Sensitivity analysis improved heterogeneity; however, the direction of the evidence remained unchanged. There may be little to no difference in the readmission to hospital between continuous infusion and bolus injection of loop diuretics (RR 0.85, 95% CI 0.63 to 1.16; 3 trials, 400 participants; P = 0.31, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show insufficient evidence for a difference in the readmission to hospital between groups. There may be little to no difference in the occurrence of acute kidney injury as an adverse event between continuous infusion and bolus injection of intravenous loop diuretics (RR 1.02, 95% CI 0.70 to 1.49; 3 trials, 491 participants; P = 0.92, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show that continuous infusion may make little to no difference on the occurrence of acute kidney injury as an adverse events compared to the bolus injection of intravenous loop diuretics. AUTHORS' CONCLUSIONS: Analysis of available data comparing two delivery methods of diuretics in acute heart failure found that the current data are insufficient to show superiority of one strategy intervention over the other. Our findings were based on trials meeting stringent inclusion and exclusion criteria to ensure validity. Despite previous reviews suggesting advantages of continuous infusion over bolus injections, our review found insufficient evidence to support or refute this. However, our review, which excluded trials with clinical confounders and RCTs with high risk of bias, offers the most robust conclusion to date.

Men who live alone have worse anticoagulation control: A Danish registry study.

Men living alone may have particular difficulty in managing chronic medical conditions. Anticoagulation control, a sensitive indicator of self-management, was significantly worse among men living alone.

Association between metabolically healthy obesity and risk of atrial fibrillation: taking physical activity into consideration.

The modification of physical activity (PA) on the metabolic status in relation to atrial fibrillation (AF) in obesity remains unknown. We aimed to investigate the independent and joint associations of metabolic status and PA with the risk of AF in obese population. Based on the data from UK Biobank study, we used Cox proportional hazards models for analyses. Metabolic status was categorized into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). PA was categorized into four groups according to the level of moderate-to-vigorous PA (MVPA): none, low, medium, and high. A total of 119,424 obese participants were included for analyses. MHO was significantly associated with a 35% reduced AF risk compared with MUO (HR = 0.65, 95% CI: 0.57-0.73). No significant modification of PA on AF risk among individuals with MHO was found. Among the MUO participants, individuals with medium and high PA had significantly lower AF risk compared with no MVPA (HR = 0.84, 95% CI: 0.74-0.95, and HR = 0.87, 95% CI: 0.78-0.96 for medium and high PA, respectively). As the severity of MUO increased, the modification of PA on AF risk was elevated accordingly. To conclude, MHO was significantly associated with a reduced risk of AF when compared with MUO in obese participants. PA could significantly modify the relationship between metabolic status and risk of AF among MUO participants, with particular benefits of PA associated with the reduced AF risk as the MUO severity elevated.

Antiplatelet agents and anticoagulants for hypertension.

BACKGROUND: The main complications of elevated systemic blood pressure (BP), coronary heart disease, ischaemic stroke, and peripheral vascular disease, are related to thrombosis rather than haemorrhage. Therefore, it is important to investigate if antithrombotic therapy may be useful in preventing thrombosis-related complications in patients with elevated BP. OBJECTIVES: To conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with elevated BP, including elevations in systolic or diastolic BP alone or together. To assess the effects of antiplatelet agents on total deaths or major thrombotic events or both in these patients versus placebo or other active treatment. To assess the effects of oral anticoagulants on total deaths or major thromboembolic events or both in these patients versus placebo or other active treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials (RCTs) up to January 2021: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 12), Ovid MEDLINE (from 1946), and Ovid Embase (from 1974). The World Health Organization International Clinical Trials Registry Platform and the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) were searched for ongoing trials.  SELECTION CRITERIA: RCTs in patients with elevated BP were included if they were ≥ 3 months in duration and compared antithrombotic therapy with control or other active treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data for inclusion criteria, our prespecified outcomes, and sources of bias. They assessed the risks and benefits of antiplatelet agents and anticoagulants by calculating odds ratios (OR), accompanied by the 95% confidence intervals (CI). They assessed risks of bias and applied GRADE criteria.  MAIN RESULTS: Six trials (61,015 patients) met the inclusion criteria and were included in this review. Four trials were primary prevention (41,695 patients; HOT, JPAD, JPPP, and TPT), and two secondary prevention (19,320 patients, CAPRIE and Huynh). Four trials (HOT, JPAD, JPPP, and TPT) were placebo-controlled and two studies (CAPRIE and Huynh) included active comparators. Four studies compared acetylsalicylic acid (ASA) versus placebo and found no evidence of a difference for all-cause mortality (OR 0.97, 95% CI 0.87 to 1.08; 3 studies, 35,794 participants; low-certainty evidence). We found no evidence of a difference for cardiovascular mortality (OR 0.98, 95% CI 0.82 to 1.17; 3 studies, 35,794 participants; low-certainty evidence). ASA reduced the risk of all non-fatal cardiovascular events (OR 0.63, 95% CI 0.45 to 0.87; 1 study (missing data in 3 studies), 2540 participants; low-certainty evidence) and the risk of all cardiovascular events (OR 0.86, 95% CI 0.77 to 0.96; 3 studies, 35,794 participants; low-certainty evidence). ASA increased the risk of major bleeding events (OR 1.77, 95% CI 1.34 to 2.32; 2 studies, 21,330 participants; high-certainty evidence). One study (CAPRIE; ASA versus clopidogrel) included patients diagnosed with hypertension (mean age 62.5 years, 72% males, 95% Caucasians, mean follow-up: 1.91 years). It showed no evidence of a difference for all-cause mortality (OR 1.02, 95% CI 0.91 to 1.15; 1 study, 19,143 participants; high-certainty evidence) and for cardiovascular mortality (OR 1.08, 95% CI 0.94 to 1.26; 1 study, 19,143 participants; high-certainty evidence). ASA probably reduced the risk of non-fatal cardiovascular events (OR 1.10, 95% CI 1.00 to 1.22; 1 study, 19,143 participants; high-certainty evidence) and the risk of all cardiovascular events (OR 1.08, 95% CI 1.00 to 1.17; 1 study, 19,143 participants; high-certainty evidence) when compared to clopidogrel. Clopidogrel increased the risk of major bleeding events when compared to ASA (OR 1.35, 95% CI 1.14 to 1.61; 1 study, 19,143 participants; high-certainty evidence). In one study (Huynh; ASA verus warfarin) patients with unstable angina or non-ST-segment elevation myocardial infarction, with prior coronary artery bypass grafting (CABG) were included (mean age 68 years, 79.8% males, mean follow-up: 1.1 year). There was no evidence of a difference for all-cause mortality (OR 0.98, 95% CI 0.06 to 16.12; 1 study, 91 participants; low-certainty evidence). Cardiovascular mortality, non-fatal cardiovascular events, and all cardiovascular events were not available. There was no evidence of a difference for major bleeding events (OR 0.13, 95% CI 0.01 to 2.60; 1 study, 91 participants; low-certainty evidence).  AUTHORS' CONCLUSIONS: There is no evidence that antiplatelet therapy modifies mortality in patients with elevated BP for primary prevention. ASA reduced the risk of cardiovascular events and increased the risk of major bleeding events.  Antiplatelet therapy with ASA probably reduces the risk of non-fatal and all cardiovascular events when compared to clopidogrel. Clopidogrel increases the risk of major bleeding events compared to ASA in patients with elevated BP for secondary prevention.  There is no evidence that warfarin modifies mortality in patients with elevated BP for secondary prevention.  The benefits and harms of the newer drugs glycoprotein IIb/IIIa inhibitors, clopidogrel, prasugrel, ticagrelor, and non-vitamin K antagonist oral anticoagulants for patients with high BP have not been studied in clinical trials. Further RCTs of antithrombotic therapy including newer agents and complete documentation of all benefits and harms are required in patients with elevated BP.

Anticoagulation versus placebo for heart failure in sinus rhythm.

BACKGROUND: People with chronic heart failure (HF) are at risk of thromboembolic events, including stroke, pulmonary embolism, and peripheral arterial embolism; coronary ischaemic events also contribute to the progression of HF. The use of long-term oral anticoagulation is established in certain populations, including people with HF and atrial fibrillation (AF), but there is wide variation in the indications and use of oral anticoagulation in the broader HF population. OBJECTIVES: To determine whether long-term oral anticoagulation reduces total deaths and stroke in people with heart failure in sinus rhythm. SEARCH METHODS: We updated the searches in CENTRAL, MEDLINE, and Embase in March 2020. We screened reference lists of papers and abstracts from national and international cardiovascular meetings to identify unpublished studies. We contacted relevant authors to obtain further data. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing oral anticoagulants with placebo or no treatment in adults with HF, with treatment duration of at least one month. We made inclusion decisions in duplicate, and resolved any disagreements between review authors by discussion, or a third party. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, and assessed the risks and benefits of antithrombotic therapy by calculating odds ratio (OR), accompanied by the 95% confidence intervals (CI). MAIN RESULTS: We identified three RCTs (5498 participants). One RCT compared warfarin, aspirin, and no antithrombotic therapy, the second compared warfarin with placebo in participants with idiopathic dilated cardiomyopathy, and the third compared rivaroxaban with placebo in participants with HF and coronary artery disease. We pooled data from the studies that compared warfarin with a placebo or no treatment. We are uncertain if there is an effect on all-cause death (OR 0.66, 95% CI 0.36 to 1.18; 2 studies, 324 participants; low-certainty evidence); warfarin may increase the risk of major bleeding events (OR 5.98, 95% CI 1.71 to 20.93, NNTH 17). 2 studies, 324 participants; low-certainty evidence). None of the studies reported stroke as an individual outcome. Rivaroxaban makes little to no difference to all-cause death compared with placebo (OR 0.99, 95% CI 0.87 to 1.13; 1 study, 5022 participants; high-certainty evidence). Rivaroxaban probably reduces the risk of stroke compared to placebo (OR 0.67, 95% CI 0.47 to 0.95; NNTB 101; 1 study, 5022 participants; moderate-certainty evidence), and probably increases the risk of major bleeding events (OR 1.65, 95% CI 1.17 to 2.33; NNTH 79; 1 study, 5008 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Based on the three RCTs, there is no evidence that oral anticoagulant therapy modifies mortality in people with HF in sinus rhythm. The evidence is uncertain if warfarin has any effect on all-cause death compared to placebo or no treatment, but it may increase the risk of major bleeding events. There is no evidence of a difference in the effect of rivaroxaban on all-cause death compared to placebo. It probably reduces the risk of stroke, but probably increases the risk of major bleedings. The available evidence does not support the routine use of anticoagulation in people with HF who remain in sinus rhythm.

Excessive Supraventricular Ectopic Activity and Adverse Cardiovascular Outcomes: a Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Excessive supraventricular ectopic activity (ESVEA), in the form of frequent premature atrial contractions (PACs) and runs of PACs, is commonly observed in clinical practice and is frequently considered to be benign. Yet, recent studies have demonstrated a link between ESVEA and adverse cardiovascular outcomes. The aim of this meta-analysis was to examine the association between ESVEA and the risk of atrial fibrillation (AF), stroke, and mortality. RECENT FINDINGS: A systematic search was performed in PubMed, EMBASE, and the Cochrane Library up to December 2017 to identify studies assessing adverse cardiovascular outcomes in patients with ESVEA, recorded on ambulatory electrocardiography. ESVEA was defined as a burden of PACs > 30 PACs/h or any runs of ≥20 PACs. The risk estimates for EVSEA and each clinical endpoint were pooled and analyzed separately. RESULTS: Five studies comprising 7545 participants were included in this meta-analysis. The pooled analysis showed that ESVEA doubled the risk of AF (HR 2.19, 95% CI 1.70-2.82). ESVEA was also associated with a higher incidence of stroke (HR 2.23, 95% CI 1.24-4.02). Finally, ESVEA was associated with higher all-cause mortality (HR 1.61, 95% CI 1.25-2.07). Our meta-analysis found that ESVEA is closely associated with AF, stroke, and all-cause mortality. Further studies are required to examine the implication of therapeutic strategies in patients with ESVEA, in order to prevent potential subsequent adverse cardiovascular outcomes.

Time to therapeutic range (TtTR), anticoagulation control, and cardiovascular events in vitamin K antagonists-naive patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists (VKAs) reduce cardiovascular events (CVEs) in atrial fibrillation (AF) when a time in therapeutic range (TiTR) >70% is achieved. Factors affecting the time to achieve the TR (TtTR) are unknown. METHODS: Prospective observational study including 1,406 nonvalvular AF patients starting VKAs followed for a mean of 31.3months (3,690 patient/year); TiTR, TtTR, and SAMe-TT2R2 score were calculated, and CVEs were recorded. RESULTS: Median TtTR was 8.0days (interquartile range 5.0-18.0). Patients with high TtTR (ie, >75th percentile) were more likely to be in AF than in sinus rhythm at entry (odds ratio [OR]: 1.423, P=.011). Median TiTR was 60.0%; low TiTR (below median) was associated with SAMe-TT2R2 score (OR: 1.175, P=.001), high TtTR (>75th percentile, OR: 1.357, P=.017), and number of international normalized ratio checks (OR: 0.998, P=.049). We recorded 113 CVEs (3.1%/y), with a higher rate seen in patients with TtTR >75th percentile compared to those below (log-rank test, P=.006). A multivariable Cox regression analysis showed that SAMe-TT2R2 score (hazard ratio [HR]: 1.331, P<.001), TtTR >75th percentile (HR: 1.505, P=.047), TiTR <70% (HR: 1.931, P=.004), number of international normalized ratio checks (HR: 0.988, P<.001), digoxin (HR: 1.855, P=.008), and proton-pump inhibitors (HR: 0.452, P<.001) were independently associated with CVEs. CONCLUSIONS: High TtTR is associated with poorer long-term quality of VKAs therapy. Patients with TtTR >18days or with high SAMe-TT2R2 score should be considered for treatment with non-vitamin K oral anticoagulants.

10-year nationwide trends of the incidence, prevalence, and adverse outcomes of non-valvular atrial fibrillation nationwide health insurance data covering the entire Korean population.

BACKGROUND: Most data on the clinical epidemiology of atrial fibrillation (AF) are reported from Western populations, and data for Asians are limited. We aimed to investigate the 10-year trends of the prevalence and incidence of non-valvular AF and provide prevalence projections till 2060 in Korea. We also investigated the annual risks of adverse outcomes among patients with AF. METHODS: Using the Korean National Health Insurance Service database involving the entire Korean population, a total of 679,416 adults with newly diagnosed AF were identified from 2006 to 2015. The incidence and prevalence of AF and risk of adverse outcomes following AF onset were assessed. RESULTS: The prevalence of AF progressively increased by 2.10-fold from 0.73% in 2006 to 1.53% in 2015. The trend of its incidence was flat with a 10-year overall incidence of 1.77 per 1,000 person-years. The prevalence of AF is expected to reach 5.81% (2,290,591 patients with AF) in 2060. For a decade, the risk of all-cause mortality following AF declined by 30% (adjusted hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.68-0.72), heart failure by 52% (adjusted HR: 0.48, 95% CI: 0.44-0.51), and ischemic stroke by 9% (adjusted HR: 0.91, 95% CI: 0.88-0.93). CONCLUSIONS: The burden of AF among Asian patients is increasing. Although the overall risks of cardiovascular events and death following AF onset have decreased over a decade, the event rates are still high. Optimized management of any associated comorbidities should be part of the holistic management approach for patients with AF.

Silent Cerebral Infarction in East Asian vs. Non-Asian Atrial Fibrillation Patients　- Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in the ageing population in East Asia. Silent cerebral infarction (SCI) is defined as cerebral infarction in the absence of corresponding clinical symptoms, and is a highly prevalent and morbid condition in AF. SCI is increasingly being recognized as a risk factor for future stroke, which can lead to cognitive decline or dementia. The latter is an increasingly common health problem in East Asia.Methods and Results:We conducted a meta-analysis to compare the association of AF and SCI between East Asian and non-Asian patients. AF was associated with SCI in patients with no symptomatic stroke history (relative risk [RR], 2.24; 95% CI: 1.26-3.99, I2=83%; P=0.006) although the prevalence varied widely between studies (P for heterogeneity<0.001). In non-Asian patients, the prevalence of SCI in AF is higher than that in controls (RR, 1.85; 95% CI: 1.65-2.08, I2=17%; P<0.001). There was no significant racial difference between Asian and non-Asian studies (P=0.53). CONCLUSIONS: In East Asia, AF was significantly associated with SCI and no racial difference was seen between East Asian and non-Asian patients. The present findings offer clinicians new insights into the association between AF and SCI.

Time in therapeutic range and major adverse outcomes in atrial fibrillation patients undergoing percutaneous coronary intervention: The Atrial Fibrillation Undergoing Coronary Artery Stenting (AFCAS) registry.

BACKGROUND: Combination of oral anticoagulation (OAC) and antiplatelets is used in atrial fibrillation (AF) patients undergoing percutaneous coronary intervention and stent (PCI-S) procedure but is associated with increased bleeding when triple antithrombotic therapy (TAT) is used. Our aim was to analyze the impact of time in therapeutic range (TTR) on outcomes, in patients prescribed with TAT. METHODS: Ancillary analysis from the AFCAS registry in patients assigned to TAT. TTR was calculated with Rosendaal method. Outcomes were analyzed according to TTR tertiles (T1 [≤56.8%] vs. T2 [56.9-93.8%] vs. T3 [≥93.9%]). Major bleeding was the primary outcome. RESULTS: Of 963 patients enrolled, 470(48.8%) were prescribed with TAT at discharge and qualified for this analysis. Median [IQR] TTR was 80.0% [45.3-100%]. After 359 [341-370] days, major bleeding rates were progressively lower with increasing TTR tertiles (T1 vs. T2 vs. T3: 10.3% vs. 4.7% vs. 2.3%, P=.006). Kaplan-Meier analysis demonstrated a progressively lower risk for major bleeding across tertiles (P=.006). Patients in the highest TTR tertile had a non-significant lower risk for major adverse coronary and cerebrovascular events (MACCE) (log-rank: 4.905, P=.086). Cox regression analysis showed that T2 and T3 were inversely associated with major bleeding (hazard ratio [HR]:0.39, P=.050 and HR: 0.21, P=.005). Continuous TTR was inversely associated with major bleeding (HR: 0.98, P<.001). For MACCE, adjusted Cox analysis found a non-significant lower risk for T3 (HR: 0.64, P=.128). CONCLUSIONS: In AF patients undergoing PCI-S prescribed TAT, good quality anticoagulation control (as reflected by TTR) was closely related to bleeding outcomes during follow-up. Despite some suggestive trends for an inverse relationship between TTR and MACCE, no definitive conclusions can be drawn, and further large studies are needed.

Sex-Related Differences in the Clinical Events of Patients With Atrial Fibrillation　- The Fushimi AF Registry.

BACKGROUND: Female sex is considered a risk factor for thromboembolism in patients with atrial fibrillation (AF), and is included in the risk stratification scheme, CHA2DS2-VASc score. The purpose of the present study was to investigate the clinical outcomes of female Japanese AF patients.Methods and Results:The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto. Follow-up data were available for 3,878 patients. Female AF patients (n=1,551, 40.0%) were older (77.0 vs. 71.4 years; P<0.001) than male patients (n=2,327, 60.0%). Female patients were more likely to have heart failure (31.1% vs. 23.7%; P<0.001). Previous stroke incidence (19.2% vs. 21.4%; P=0.083) was comparable between male and female patients. During the median follow-up period of 1,102 days, Cox regression analysis demonstrated that female sex was not independently associated with a risk of stroke or systemic embolism (adjusted hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.54-1.00, P=0.051). However, female sex showed an association with a lower risk of intracranial hemorrhage (adjusted HR 0.54; 95% CI: 0.30-0.95, P=0.032) and all-cause death (adjusted HR 0.56; 95% CI: 0.46-0.68, P<0.001). CONCLUSIONS: We demonstrated that female sex is not independently associated with an increased risk of thromboembolism, but is associated with a decreased risk of intracranial hemorrhage and all-cause death in Japanese AF patients enrolled in the Fushimi AF Registry.

Temporal Trends in Stroke Severity and Prior Antithrombotic Use Among Acute Ischemic Stroke Patients in Japan.

BACKGROUND: Few existing stroke registries allow for evaluation of stroke severity, stroke subtype and antithrombotic usage prior to stroke onset over a given time period. The present study aimed to elucidate temporal trends in initial presenting stroke severity, stroke subtype and prior antithrombotic use over a 12-year period in a Japanese multicenter stroke registry. METHODS AND RESULTS: We included 71,017 acute ischemic stroke patients (72±12 years old; 27,445 women) from the Japan Standard Stroke Registry Study (JSSRS) who were admitted to 94 hospitals between 2001 and 2012. The mean age of stroke onset increased gradually over time (P<0.001). Cardioembolic stroke patients (n=19,247) exhibited more severe NIHSS scores when compared with those with non-cardioembolic stroke (n=50,427). The proportion of cardioembolic stroke patients tended to increase over time, rising from 25.9% in 2001-2002 to 30.2% in 2011-2012 (P<0.001). Among the cardioembolic stroke patients, the frequency of prior anticoagulant use significantly increased from 15.6% in 2001-2002 to 24.8% in 2011-2012 (P<0.001). The frequency of prior antiplatelet use increased from 2001-2002 to 2007-2008 but decreased after 2007-2008. Among both cardioembolic and non-cardioembolic stroke patients, initial stroke severity at admission decreased over time, particularly after 2008. CONCLUSIONS: In this Japanese study, the mean age of ischemic stroke onset increased, while the initial neurological severity at presentation decreased, over a 12-year period. (Circ J 2016; 80: 2033-2036).

Long-Term Predictors of Thromboembolic Events in Nonvalvular Atrial Fibrillation Patients Undergoing Electrical Cardioversion.

BACKGROUND: Patients with nonvalvular atrial fibrillation (AF) who undergo electrical cardioversion (ECV) tend to be younger and have less comorbidity. Long-term anticoagulation after ECV should be based on thromboembolic risk. We sought to study the long-term incidence of thromboembolic events (TE), factors related to TE and compare the predictive value of the CHADS2and CHA2DS2-VASc scores in this particular population. METHODS AND RESULTS: From January 2008 to June 2012, 571 ECV were performed in 406 consecutive patients with nonvalvular AF. Risk factors for TE and factors related to anticoagulation therapy after ECV were registered. During a follow-up of approximately 2 years, the annual incidence of TE was 1.9%. Factors associated with TE were: poor quality anticoagulation control (hazard ratio [HR]: 2.91; 95% confidence interval [CI]: 1.10-7.80; P=0.03), cessation of anticoagulation after ECV (HR: 8.80; 95% CI: 3.11-25.10; P<0.001), age ≥65 years (HR: 13.65; 95% CI: 1.74-107.16; P=0.01), CHADS2score (HR: 1.59; 95% CI: 1.10-2.29; P=0.01) and CHA2DS2-VASc score (HR: 1.67; 95% CI: 1.30-2.22; P<0.001). Both risk scores predicted TE [c-statistic for CHADS2: 0.68 (95% CI: 0.62-0.74; P=0.005), for CHA2DS2-VASc: 0.75 (95% CI: 0.70-0.80; P<0.001)]. Based on c-statistics, the predictive accuracy of CHA2DS2-VASc was superior (difference between areas: 0.064±0.031; P=0.0403). CONCLUSIONS: Important determinants of long-term occurrence of TE after ECV were related to anticoagulant therapy (poor quality anticoagulation and cessation of this therapy over follow-up). The CHA2DS2-VASc score successfully predicts TE after ECV, having better predictive accuracy than the CHADS2score. (Circ J 2016; 80: 605-612).

Antiplatelet versus anticoagulation treatment for patients with heart failure in sinus rhythm.

BACKGROUND: Morbidity in patients with chronic heart failure is high, and this predisposes them to thrombotic complications, including stroke and thromboembolism, which in turn contribute to high mortality. Oral anticoagulants (e.g. warfarin) and antiplatelet agents (e.g. aspirin) are the principle oral antithrombotic agents. Many heart failure patients with sinus rhythm take aspirin because coronary artery disease is the leading cause of heart failure. Oral anticoagulants have become a standard in the management of heart failure with atrial fibrillation. However, a question remains regarding the appropriateness of oral anticoagulants in heart failure with sinus rhythm. This update of a review previously published in 2012 aims to address this question. OBJECTIVES: To assess the effects of oral anticoagulant therapy versus antiplatelet agents for all-cause mortality, non-fatal cardiovascular events and risk of major bleeding in adults with heart failure (either with reduced or preserved ejection fraction) who are in sinus rhythm. SEARCH METHODS: We updated the searches in September 2015 on CENTRAL (The Cochrane Library), MEDLINE and Embase. We searched reference lists of papers and abstracts from cardiology meetings and contacted study authors for further information. We did not apply any language restrictions. Additionally, we searched two clinical trials registers: ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal apps.who.int/trialsearch/) (searched in July 2016). SELECTION CRITERIA: We included randomised controlled trials comparing antiplatelet therapy versus oral anticoagulation in adults with chronic heart failure in sinus rhythm. Treatment had to last at least one month. We compared orally administered antiplatelet agents (aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor, dipyridamole) versus anticoagulant agents (coumarins, warfarin, non-vitamin K oral anticoagulants). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed the risks and benefits of antithrombotic versus antiplatelet therapy using relative measures of effects, such as risk ratios (RR), accompanied with 95% confidence intervals (CI). The data extracted included data relating to the study design, patient characteristics, study eligibility, quality, and outcomes. We used GRADE criteria to assess the quality of the evidence. MAIN RESULTS: This update identified one additional study for inclusion, adding data for 2305 participants. This addition more than doubled the overall number of patients eligible for the review. In total, we included four randomised controlled trials (RCTs) with a total of 4187 eligible participants. All studies compared warfarin with aspirin. One RCT additionally compared warfarin with clopidogrel. All included RCTs studied patients with heart failure with reduced ejection fraction.Analysis of all outcomes for warfarin versus aspirin was based on 3663 patients from four RCTs. All-cause mortality was similar for warfarin and aspirin (RR 1.00, 95% CI 0.89 to 1.13; 4 studies; 3663 participants; moderate quality evidence). Oral anticoagulation was associated with a reduction in non-fatal cardiovascular events, which included non-fatal stroke, myocardial infarction, pulmonary embolism, peripheral arterial embolism (RR 0.79, 95% CI 0.63 to 1.00; 4 studies; 3663 participants; moderate quality evidence). The rate of major bleeding events was twice as high in the warfarin groups (RR 2.00, 95% CI 1.44 to 2.78; 4 studies; 3663 participants; moderate quality evidence). We generally considered the risk of bias of the included studies to be low.Analysis of warfarin versus clopidogrel was based on a single RCT (N = 1064). All-cause mortality was similar for warfarin and clopidogrel (RR 0.93, 95% CI 0.72 to 1.21; 1 study; 1064 participants; low quality evidence). There were similar rates of non-fatal cardiovascular events (RR 0.85, 95% CI 0.50 to 1.45; 1 study; 1064 participants; low quality evidence). The rate of major bleeding events was 2.5 times higher in the warfarin group (RR 2.47, 95% CI 1.24 to 4.91; 1 study; 1064 participants; low quality evidence). Risk of bias for this study can be summarised as low. AUTHORS' CONCLUSIONS: There is evidence from RCTs to suggest that neither oral anticoagulation with warfarin or platelet inhibition with aspirin is better for mortality in systolic heart failure with sinus rhythm (high quality of the evidence for all-cause mortality and moderate quality of the evidence for non-fatal cardiovascular events and major bleeding events). Treatment with warfarin was associated with a 20% reduction in non-fatal cardiovascular events but a twofold higher risk of major bleeding complications (high quality of the evidence). We saw a similar pattern of results for the warfarin versus clopidogrel comparison (low quality of the evidence). At present, there are no data on the role of oral anticoagulation versus antiplatelet agents in heart failure with preserved ejection fraction with sinus rhythm. Also, there were no data from RCTs on the utility of non-vitamin K antagonist oral anticoagulants compared to antiplatelet agents in heart failure with sinus rhythm.

Bare-metal vs. drug-eluting stents in patients with atrial fibrillation undergoing percutaneous coronary intervention.

BACKGROUND: We explored 12-month clinical outcomes of 929 patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) with bare-metal stents (BMS) vs. drug-eluting stents (DES) from the prospective multicenter AFCAS (Atrial Fibrillation undergoing Coronary Artery Stenting) registry. METHODS AND RESULTS: Endpoints included the first occurrence of major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), target vessel revascularization, definite/probable stent thrombosis (ST), transient ischemic attack or stroke. Bleeding events were defined according to the Bleeding Academic Research Consortium criteria. Altogether, 673 (72.4%) patients received BMS and 220 (23.7%) at least one DES. Patients treated with DES more often had diabetes and prior ischemic events, and a longer stent length (P<0.05 for all), whereas patients treated with BMS more often had heart failure and were more likely to present with acute ST-elevation MI (P<0.05 for both). At 12-month follow-up, rates and risks of MACCE and total bleeding events were comparable between the groups (22.0% with BMS vs. 19.5% with DES, P=0.51, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.63-1.25 for DES) and (19.5% vs. 15.0%, respectively, P=0.16, HR 0.75, 95% CI 0.51-1.09 for DES). Definite/probable ST was more frequent in the BMS group (1.9% vs. 0%, respectively, P=0.046). CONCLUSIONS: In real-world patients with AF undergoing PCI, DES use was associated with outcomes comparable to those with BMS without excess bleeding complications. More ST was seen in BMS-treated patients.

Risk of Atrial Fibrillation and Adverse Outcomes in Patients With Cardiac Implantable Electronic Devices.

BACKGROUND AND OBJECTIVES: Comprehensive epidemiological data are lacking on the incident atrial fibrillation (AF) in patients with cardiac implantable electronic devices (CIEDs). This study aimed to examine the incidence, risk factors, and AF-related adverse outcomes of patients with CIEDs. METHODS: This was an observational cohort study that analyzed patients without prevalent AF who underwent CIED implantation in 2009-2018 using a Korean nationwide claims database. The subjects were divided into three groups by CIED type and indication: pacemaker (n=21,438), implantable cardioverter defibrillator (ICD)/cardiac resynchronization therapy (CRT) with heart failure (HF) (n=3,450), and ICD for secondary prevention without HF (n=2,146). The incidence of AF, AF-associated predictors, and adverse outcomes were evaluated. RESULTS: During follow-up, the incidence of AF was 4.3, 7.3, and 5.1 per 100 person-years in the pacemaker, ICD/CRT with HF, and ICD without HF cohorts, respectively. Across the three cohorts, older age and valvular heart disease were commonly associated with incident AF. Incident AF was consistently associated with an increased risk of ischemic stroke (3.8-11.4-fold), admission for HF (2.6-10.5-fold), hospitalization for any cause (2.4-2.7-fold), all-cause death (4.1-5.0-fold), and composite outcomes (3.4-5.7-fold). Oral anticoagulation rates were suboptimal in patients with incident AF (pacemaker, 51.3%; ICD/CRT with HF, 51.7%; and ICD without HF, 33.8%, respectively). CONCLUSIONS: A substantial proportion of patients implanted CIED developed newly diagnosed AF. Incident AF was associated with a higher risk of adverse events. The importance of awareness, early detection, and appropriate management of AF in patients with CIED should be emphasized.

Regular use of fish oil supplements and course of cardiovascular diseases: prospective cohort study.

Objective: To examine the effects of fish oil supplements on the clinical course of cardiovascular disease, from a healthy state to atrial fibrillation, major adverse cardiovascular events, and subsequently death. Design: Prospective cohort study. Setting: UK Biobank study, 1 January 2006 to 31 December 2010, with follow-up to 31 March 2021 (median follow-up 11.9 years). Participants: 415 737 participants, aged 40-69 years, enrolled in the UK Biobank study. Main outcome measures: Incident cases of atrial fibrillation, major adverse cardiovascular events, and death, identified by linkage to hospital inpatient records and death registries. Role of fish oil supplements in different progressive stages of cardiovascular diseases, from healthy status (primary stage), to atrial fibrillation (secondary stage), major adverse cardiovascular events (tertiary stage), and death (end stage). Results: Among 415 737 participants free of cardiovascular diseases, 18 367 patients with incident atrial fibrillation, 22 636 with major adverse cardiovascular events, and 22 140 deaths during follow-up were identified. Regular use of fish oil supplements had different roles in the transitions from healthy status to atrial fibrillation, to major adverse cardiovascular events, and then to death. For people without cardiovascular disease, hazard ratios were 1.13 (95% confidence interval 1.10 to 1.17) for the transition from healthy status to atrial fibrillation and 1.05 (1.00 to 1.11) from healthy status to stroke. For participants with a diagnosis of a known cardiovascular disease, regular use of fish oil supplements was beneficial for transitions from atrial fibrillation to major adverse cardiovascular events (hazard ratio 0.92, 0.87 to 0.98), atrial fibrillation to myocardial infarction (0.85, 0.76 to 0.96), and heart failure to death (0.91, 0.84 to 0.99). Conclusions: Regular use of fish oil supplements might be a risk factor for atrial fibrillation and stroke among the general population but could be beneficial for progression of cardiovascular disease from atrial fibrillation to major adverse cardiovascular events, and from atrial fibrillation to death. Further studies are needed to determine the precise mechanisms for the development and prognosis of cardiovascular disease events with regular use of fish oil supplements.

Asymptomatic vs. symptomatic atrial fibrillation: Clinical outcomes in heart failure patients.

BACKGROUND: The outcome implications of asymptomatic vs. symptomatic atrial fibrillation (AF) in specific groups of patients according to clinical heart failure (HF) and left ventricular ejection fraction (LVEF) need to be clarified. METHODS: In a prospective observational study, patients were categorized according to overt HF with LVEF≤40 %, or with LVEF>40 %, or without overt HF with LVEF40 %≤ or > 40 %, as well as according to the presence of asymptomatic or symptomatic AF. RESULTS: A total of 8096 patients, divided into 8 groups according to HF and LVEF, were included with similar proportions of asymptomatic AF (ranging from 43 to 48 %). After a median follow-up of 730 [699 -748] days, the composite outcome (all-cause death and MACE) was significantly worse for patients with asymptomatic AF associated with HF and reduced LVEF vs. symptomatic AF patients of the same group (p = 0.004). On adjusted Cox regression analysis, asymptomatic AF patients with HF and reduced LVEF were independently associated with a higher risk for the composite outcome (aHR 1.32, 95 % CI 1.04-1.69) and all-cause death (aHR 1.33, 95 % CI 1.02-1.73) compared to symptomatic AF patients with HF and reduced LVEF. Kaplan-Meier curves showed that HF-LVEF≤40 % asymptomatic patients had the highest cumulative incidence of all-cause death and MACE (p < 0.001 for both). CONCLUSIONS: In a large European cohort of AF patients, the risk of the composite outcome at 2 years was not different between asymptomatic and symptomatic AF in the whole cohort but adverse implications for poor outcomes were found for asymptomatic AF in HF with LVEF≤40 %.

Heightened risks of cardiovascular disease in South Asian populations: causes and consequences.

INTRODUCTION: South Asian individuals comprise almost a quarter of the world's population and have an excess risk of atherosclerotic cardiovascular disease (ASCVD) compared to other ethnicities. In part, this can be explained by higher prevalence, earlier onset, and suboptimal control of traditional cardiovascular risk factors, such as insulin resistance, metabolic syndrome, and dyslipidaemia. However, there remains a significant residual excess risk associated with South Asian ethnicity after controlling for traditional risk factors. AREAS COVERED: In this review, we describe the epidemiology of ASCVD in both native and diaspora South Asian populations. We explore how traditional cardiovascular risk factors, novel cardiovascular risk factors, and social determinants of health may contribute to the excess ASCVD risk seen in South Asian populations. EXPERT OPINION: There should be increased awareness of the relative importance of South Asian ethnicity and related social determinants of health, as risk factors for ASCVD. Systematic screening processes should be tailored to this population, and modifiable risk factors should be treated aggressively. Further research is required to quantify determinants of the excess ASCVD risk seen in South Asian populations and to develop targeted interventions to address these factors.

Three-year outcomes of patients with non-valvular atrial fibrillation: the COOL-AF registry.

BACKGROUND: Clinical outcomes of patients with non-valvular atrial fibrillation (AF) in Asian populations may be different from non-Asians. In this study, we aimed to determine the incidence of ischemic stroke/systemic embolism (SSE), major bleeding, and death, and the predictors for clinical outcomes in a contemporary Asian cohort of newly diagnosed AF patients. METHODS: This is a prospective multicenter nationwide registry of patients with AF from 27 hospitals in Thailand. Baseline data and follow-up data were collected every 6 months until 3 years. Data collections included demographic, medical history, laboratory, and medication details. Clinical outcomes were SSE, major bleeding, and all-cause mortality. Incidence rates for each clinical outcome were calculated and presented as rate per 100 person-years. Univariate and multivariate analysis was performed to determine the independent predictors for clinical outcomes. RESULTS: There was a total of 3405 patients: mean age was 67.8 ± 11.3 years, 1981 (58.2%) were male. During 30.8 ± 9.7 months follow-up, there was a total of 132 SSE (3.9%), 191 major bleeding (5.6%), and 357 all-cause deaths (10.5%). The incidence rates of SSE, major bleeding, and death were 1.56 (1.30-1.84), 2.26 (1.96-2.61), and 4.17 (3.33-4.25), per 100 person-years respectively. Independent predictors for clinical outcomes were age, type of AF, and the presence of comorbid conditions. CONCLUSION: The incidence rate of SSE, major bleeding, and death remains high reflecting the unmet needs in AF management.