Ionized Mg (iMg) is considered the biologically active fraction of circulating total Mg (tMg). It is possible that iMg may be a more physiologically relevant marker than tMg. Using data from a double-blind pilot randomized controlled trial, we tested (1) whether oral Mg supplementation will increase iMg concentrations compared with placebo and (2) the relationship between iMg and tMg at baseline. Additionally, we evaluated the agreement between iMg measured in fresh whole blood versus stored samples. A total of fifty-nine participants were randomized 1:1 to oral Mg supplementation (400 mg/day, Mg Oxide) or placebo for 10 weeks. Fasting blood samples were obtained at baseline and follow-up. The analysis used linear regression and an intent-to-treat approach. Participants were generally healthy, the mean age was 62, and 73% were female. The baseline iMg and tMg were modestly and positively associated (r = 0.50). The ratio of baseline iMg to tMg was 64%. The mean supplement effect on iMg was 0.03 mmol/L (95% CI:0.01, 0.05) for Mg supplementation versus placebo. The supplement effect on iMg was not statistically significantly different according to baseline iMg status (above/below median). Compared to fresh blood, iMg was consistently higher in refrigerated and frozen samples by 0.14 and 0.20 mmol/L, respectively. In this relatively healthy adult population, Mg supplementation over 10 weeks resulted in increased iMg concentrations. Whether iMg is a more appropriate measure of Mg status than tMg, and the public health or clinical utility of measuring iMg remains to be determined.

Objective: Whether endogenous testosterone concentrations are associated with atrial fibrillation (AF) development is not well established. We assessed the association between plasma total testosterone concentrations and incident AF in a population-based longitudinal study. Study design: Using data from the prospective Atherosclerosis Risk in Communities (ARIC) study, we identified incident AF among 9282 participants who had plasma total testosterone measured by liquid chromatography tandem mass spectrometry at Visit 4 (1996–1998). Main outcome measures: AF cases were identified by electrocardiograms performed during study visits, hospital records/discharge codes, and death certificates through 2013. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident AF across quartiles of plasma total testosterone, stratified by sex, with multivariable Cox models. Results: The mean age of the participant sample at ARIC Visit 4 was 63 years (range 52–75); 54.5% were women. Mean (SD) plasma total testosterone levels were 537 ng/dL (213) for men and 27.6 ng/dL (34.7) for women. Over a mean of 13.7 years of follow-up, 1664 incident cases of AF were identified. Comparing those in the highest quartile of plasma total testosterone concentration to those in the lowest quartile and after adjustment for potential confounding variables, there was a positive association between plasma total testosterone and incident AF in men (HR 1.33, 95% CI 1.07, 1.66), but no such association in women (HR 0.99, 95% CI 0.80, 1.22). Conclusion A higher plasma total testosterone concentration was associated with a modestly greater incidence rate of AF in men.

Recent hospital-based cohort studies found the CHA2DS2-VASc score to be associated with ischemic stroke in individuals without atrial fibrillation (AF). Our aim was to determine the distribution of embolic and thrombotic strokes and association with the CHA2DS2-VASc score, among community-dwelling individuals without AF. We included participants from the Atherosclerosis Risk in Communities (ARIC) Study who attended visit 4 (1996 to 1998) and had no previous AF, stroke, or anticoagulant use (n = 10,671). During follow-up through 2008, incident AF cases (n = 760) and participants who started warfarin were censored. Incident AF was ascertained from study electrocardiograms and hospital discharge diagnosis codes, and stroke was physician-adjudicated. After 10 years of follow-up, 280 ischemic strokes were identified, of which 146 were thrombotic and 57 embolic. The hazard ratios (95% confidence intervals [CI]) for thrombotic stroke were 1 (reference), 1.71 (1.13 to 2.59), 2.92 (1.91 to 4.45), 3.22 (1.70 to 6.11), and 1.25 (0.17 to 9.09), with CHA2DS2-VASc scores of 0 to 1, 2, 3, 4, and ≥5, respectively. The hazard ratios (95% CI) for embolic stroke were 1 (ref), 4.91 (2.10 to 11.5), 7.07 (2.93 to 17.0), 14.8 (5.50 to 39.6), and 15.2 (3.16 to 73.3), with CHA2DS2-VASc scores of 0 to 1, 2, 3, 4, and ≥5, respectively. A receiver-operating characteristic model had a C-statistic of 0.65 for ischemic stroke, 0.61 for thrombotic stroke, and 0.71 for embolic stroke. In conclusion, in community-dwelling individuals without AF, the CHA2DS2-VASc score can assess ischemic stroke risk and has good discriminatory capacity for embolic stroke.

Background: Outcomes among atrial fibrillation (AF) patients may differ according to race/ethnicity and sex due to differences in biology, the prevalence of cardiovascular risk factors, and the use and effectiveness of AF treatments. We aimed to characterize patterns of cardiovascular risk across subgroups of AF patients by sex and race/ethnicity, since doing so may provide opportunities to identify interventions. We also evaluated whether these patterns changed over time. Methods: We utilized administrative claims data from the Optum Clinformatics® Datamart database from 2009 to 2015. Patients with AF with ≥6 months of enrollment prior to the first non-valvular AF diagnosis were included in the analysis. Final analysis utilized Cox proportional hazard models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for cardiovascular outcomes stratified by sex and race/ethnicity. An additional analysis stratified outcomes by calendar year of AF diagnosis to evaluate changes in outcomes over time. Results: In a cohort of 380,636 AF patients, women had a higher risk of ischemic stroke [HR (95% CI): 1.25 (1.19, 1.31)] and lower risk of heart failure and myocardial infarction [HR (95% CI): 0.91 (0.88, 0.94) and 0.81 (0.77, 0.86), respectively)] compared to men. Black patients had elevated risk across all endpoints compared to whites, while Hispanics and Asian Americans showed no significant differences in any outcome compared to white patients. These sex and race/ethnic differences did not change over time. Conclusions: We found sex and race/ethnic differences in risk of cardiovascular outcomes among AF patients, without evidence of improvement over time.

We have previously identified associations of 2 circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk in 1,919 blacks in the Atherosclerosis Risk in Communities cohort. We aimed to replicate these findings in an independent sample of 2,003 white and black Atherosclerosis Risk in Communities participants, and performed a new metabolomic analysis in the combined sample of 3,922 participants, followed between 1987 and 2013. Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by 1 standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95% CI 1.00, 1.21 and HR 1.13, 95% CI 1.04, 1.22, respectively). Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95% CI 0.92, 1.13). An analysis of 245 metabolites in the combined cohort identified 3 additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95% CI 1.10, 1.28), uridine (HR 0.86, 95% CI 0.79, 0.93) and acisoga (HR 1.17, 95% CI 1.09, 1.26). In conclusion, we replicated a prospective association among a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk.

Background Effectiveness data on novel oral anticoagulants (NOACs) versus warfarin for stroke prevention in non-valvular atrial fibrillation (NVAF) by prior warfarin use are limited. Methods We used data from the US MarketScan databases from 2009 to 2012. NVAF patients initiating dabigatran or rivaroxaban were matched with up to 5 warfarin users. Propensity score-adjusted Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for relevant endpoints in NOACs versus warfarin users. Separate analyses were conducted to compare anticoagulant-naïve users of NOACs and those switching from warfarin. Results Among 32,918 dabigatran, 3301 rivaroxaban, and 109,447 warfarin users with NVAF, 225 intracranial bleeds, 1035 ischemic strokes, 958 myocardial infarctions, and 1842 gastrointestinal bleeds were identified. Compared to warfarin users, patients initiating NOACs had similar ischemic stroke rates and lower intracranial bleeding rates, while the gastrointestinal bleeding rate was higher in dabigatran users than warfarin users. Associations of dabigatran with ischemic stroke risk differed between anticoagulant-naïve initiators and patients switching from warfarin; dabigatran was associated with lower ischemic stroke rates in naïve users (HR 0.65, 95% CI 0.52–0.82) but not in switchers (HR 1.20, 95% CI 0.95–1.51), compared to warfarin. Risk of stroke and bleeding was not different between rivaroxaban and warfarin users. Conclusions Real-world effectiveness of NOACs (compared to warfarin) for diverse outcomes was comparable to efficacy reported in published clinical trials. However, harms and benefits of switching from warfarin to dabigatran need to be evaluated.

Objective: To assess the risk of liver injury hospitalisation in patients with atrial fibrillation (AF) after initiation of direct oral anticoagulants (DOACs) or warfarin and to determine predictors of liver injury hospitalisation in this population. Methods: We studied 113 717 patients (mean age 70, 39% women) with AF included in the MarketScan Commercial and Medicare Supplemental databases with a first prescription for oral anticoagulation after 4 November 2011, followed through 31 December 2014. Of these, 56 879 initiated warfarin, 17 286 initiated dabigatran, 30 347 initiated rivaroxaban and 9205 initiated apixaban. Liver injury hospitalisation and comorbidities were identified from healthcare claims. Results: During a median follow-up of 12 months, 960 hospitalisations with liver injury were identified. Rates of liver injury hospitalisation ( per 1000 person-years) by oral anticoagulant were 9.0 (warfarin), 4.0 (dabigatran), 6.6 (rivaroxaban) and 5.6 (apixaban). After multivariable adjustment, liver injury hospitalisation rates were lower in initiators of DOACs compared with warfarin: HR (95% CI) of 0.57 (0.46 to 0.71), 0.88 (0.75 to 1.03) and 0.70 (0.50 to 0.97) for initiators of dabigatran, rivaroxaban, and apixaban, respectively (vs. warfarin). Compared with dabigatran initiators, rivaroxaban initiators had a 56% increased risk of liver injury hospitalisation (HR 1.56, 95% CI 1.22 to 1.99). In addition to type of anticoagulant, prior liver, gallbladder and kidney disease, cancer, anaemia, heart failure and alcoholism significantly predicted liver injury hospitalisation. A predictive model including these variables had adequate discriminative ability (C-statistic 0.67, 95% CI 0.64 to 0.70). Conclusions: Among patients with non-valvular AF, DOACs were associated with lower risk of liver injury hospitalisation compared with warfarin, with dabigatran showing the lowest risk.

Background Patients with atrial fibrillation (AF) experience an increased risk of heart failure (HF). However, data are lacking on current trends in the risk of HF after AF. Objective The purpose of this study was to describe the temporal trends in HF occurrence after AF in a community cohort of patients with incident AF from 2000 to 2013. Methods Cox regression was used to examine the association of year of AF diagnosis with HF and the predictors of developing HF after AF. Results Among 3491 AF patients without prior HF, 750 (21%) developed incident HF over mean follow-up of 3.7 years. Among those with an echocardiogram, 422 (61%) had HF with preserved ejection fraction (HFpEF), and 270 (39%) had HF with reduced ejection fraction (HFrEF). After adjusting for demographics and comorbidities, the risk of developing HF did not change over time (hazard ratio [HR] (95% confidence interval [CI]) per year of AF diagnosis: 1.01 (0.98–1.03) overall; 1.00 (0.98–1.03) for HFpEF; 1.00 (0.96–1.03) for HFrEF). Increasing age, obesity, smoking, diabetes, chronic pulmonary disease, and renal disease were predictors of developing HF. Compared to the Olmsted County, Minnesota, population, a substantial excess risk of developing HF was observed after AF diagnosis [standardized morbidity ratio (95% CI): 9.60 (7.44–12.19), 2.13 (1.56–2.84), and 1.70 (1.34–2.14) at 90 days, 1 year, and 3 years after diagnosis]. Conclusion In the community, HF is a frequent adverse outcome among patients with AF, and HFpEF is more common than HFrEF. The rates of HF after AF have not declined, thus highlighting the importance of continued efforts to improve outcomes in AF.

Background: Stroke risk stratification scores (eg, CHA2DS2-VASc) are used to tailor therapeutic recommendations for patients with atrial fibrillation (AF) in different risk groups. Objective: The purpose of this study was to develop a tool to estimate stroke risk in patients receiving oral anticoagulants (OACs) and to identify patients who remain at high risk for stroke despite anticoagulation therapy. Methods: Patients with nonvalvular AF initiating OACs were identified in the MarketScan data from 2007 to 2015. Using bootstrapping methods and backward selection of 44 candidate variables, we developed a model that selected variables predicting stroke. The final model was validated in patients with nonvalvular AF in the Optum database in the period 2009–2015. In both databases, the discrimination of existing stroke scores were individually evaluated and compared with our new model termed the AntiCoagulaTion-specific Stroke (ACTS) score. Results: Among 135,523 patients with AF initiating OACs in the MarketScan dataset, 2028 experienced an ischemic stroke after anticoagulant initiation. The stepwise model identified 11 variables (including type of OAC) associated with ischemic stroke. The discrimination (C statistic) of the model was adequate (0.68; 95% confidence interval [CI] 0.66–0.70), showing excellent calibration (χ2 = 6.1; P = .73). ACTS was then applied to 84,549 AF patients in the Optum dataset (1408 stroke events) and showed similar discrimination (C statistic 0.67; 95% CI 65-0.69). However, previously developed predictive models had similar discriminative ability (CHA2DS2-VASc 0.67; 95% CI 0.65–0.68). Conclusion: A novel model to identify AF patients at higher risk of ischemic stroke, using extensive administrative health care data including type of anticoagulant, did not perform better than established simpler models.

Understanding of the comparative bleeding risks of oral anticoagulant (OAC) therapies for the primary treatment of venous thromboembolism (VTE) is limited. Therefore, among anticoagulant-naïve VTE patients, we conducted comparisons of apixaban, rivaroxaban and warfarin on the rate of hospitalised bleeding within 180 days of OAC initation. MarketScan databases for the time-period from 2011 to 2016 were used and, for each OAC comparison, new users were matched with up to five initiators of a different OAC. The final analysis included 83 985 VTE patients, who experienced 1944 hospitalised bleeding events. In multivariable-adjusted Cox regression models, rate of hospitalised bleeding was lower among new users of apixaban when compared to new users of rivaroxaban [hazard ratio (95% confidence interval) 0·58 (0·41–0·80)] or warfarin [0·68 (0·50–0·92)]. Overall, the hospitalised bleeding rate was similar when comparing new users of rivaroxaban to new users of warfarin [0·98 (0·68–1·11)], though there was some suggestion that rivaroxaban was associated with lower bleeding risk among younger individuals. Findings from this large real-world population concur with results from the randomised trial which found lower bleeding risk with apixaban versus warfarin and, for the first time, reveal a lower risk of bleeding in a comparison of apixaban versus rivaroxaban.