BACKGROUND:Direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). However, limited accessibility in resource-constrained settings makes it important to identify patient subgroups in whom VKAs may achieve comparable net clinical outcomes (NCOs). OBJECTIVES:The purpose of this study was to identify AF patient subgroups and explore potential predictors of differential treatment benefit to inform anticoagulant selection where DOAC access is limited. METHODS:Individual patient data from the COMBINE-AF data set pooling 4 pivotal randomized trials of DOACs vs VKAs in AF were analyzed. Model-based clustering identified patient subgroups. Heterogeneity of treatment effects for the NCO-a composite of all-cause death, disabling or fatal stroke, and intracranial or fatal bleeding- was explored using Cox regression and gradient boosting analyses adapted for time-to-event data. RESULTS:A total of 58,634 patients were included (29,272 warfarin; 29,362 standard dose DOACs). Two subgroups were identified: a high-risk cluster (mean creatinine clearance 55.1 mL/min, age 75.6 years, body mass index [BMI] 26.6 kg/m2) and a low-risk cluster (mean creatinine clearance 101 mL/min, age 64.2 years, BMI 32.3 kg/m2). DOACs significantly reduced NCOs in the high-risk cluster (HR: 0.86; 95% CI: 0.81-0.92; P < 0.001), but not in the low-risk cluster (HR: 0.93; 95% CI: 0.85-1.03; P = 0.154, p-interaction = 0.115). Primary predictors of treatment heterogeneity were renal function, age, and BMI; no statistically significant treatment-by-subgroup interactions were identified. CONCLUSIONS:Renal function, age, and BMI are key determinants of anticoagulant treatment benefit in AF. In regions with limited access to DOACs, these findings suggest that some lower-risk patient profiles may derive similar outcomes with VKAs, although differences were not statistically significant.

BACKGROUND:Extracranial bleeding is the most common complication of oral anticoagulant (OAC) therapy for atrial fibrillation (AF), but its clinical importance for patients may be underrecognized. We sought to characterize extracranial bleeding events according to standardized severity definitions, identify baseline risk factors for bleeding, and quantify their population attributable fraction in patients with AF receiving OACs. METHODS:We analyzed patients receiving OACs from 5 pivotal randomized trials testing a direct OAC or warfarin in patients with AF (COMBINE-AF [A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation]). The primary outcome was extracranial clinically relevant bleeding, defined as a first episode of extracranial major or clinically relevant nonmajor bleeding according to International Society on Thrombosis and Haemostasis criteria. The Kaplan-Meier method was used to calculate the cumulative incidence of bleeding by category. Multivariable Cox regression models were used to estimate adjusted hazard ratios (HRs) with 95% CI. Logistic regression models were used to calculate average population attributable fraction with 95% CI. RESULTS:Of 73 737 patients treated with OACs, 10 634 experienced clinically relevant extracranial bleeding over a mean follow-up of 705 days (cumulative incidence, 26% [95% CI, 18%-35%]; 7.6 per 100 person-years). This included 3188 major bleeds (cumulative incidence, 7% [95% CI, 6%-7%]; 2.1 per 100 person-years) and 7446 clinically relevant nonmajor bleeds (cumulative incidence, 19% [95% CI, 12%-28%]; 5.2 per 100 person-years). The distribution of bleeding sites differed by severity, with gastrointestinal bleeds comprising 26% of clinically relevant bleeds, 49% of major bleeds, and 15% of clinically relevant nonmajor bleeds. Risk factors for extracranial bleeding were consistent across severity bleeding categories, and baseline covariates in our multivariable models accounted for 66% to 69% of the population attributable bleeding risk. CONCLUSIONS:Extracranial clinically relevant bleeding is common among patients with AF treated with OACs and may more accurately reflect the overall burden of bleeding than major bleeding alone. Our models explained about two-thirds of the average population attributable risk, suggesting that additional unmeasured or unknown factors contribute to bleeding risk.

Understanding the genetic regulation of circulating protein levels can provide new insights into disease mechanisms. Here, we present the largest proteogenomic study to date (n = 78,664 participants across 38 studies), identifying >24,000 protein quantitative trait loci (QTLs) associated with 1,116 proteins, acting near to (n = 5,040) or distant (n = 19,698) from the cognate gene. Using machine learning-guided effector gene assignment, we provide genetic evidence for pathways, cell types, and tissues that modulate circulating protein levels, highlighting N-linked glycosylation as an important regulatory pathway. We demonstrate that genetic instruments of protein production/function (“cis”) versus modulation (“trans”) reveal distinct phenotypic insights. We identify proteins as candidates for drug targets and engagement (e.g., plasma furin and cardiovascular diseases) by comparing cis-based genetic evidence with protein-disease associations. Systematic triangulation of trans-protein QTLs (pQTLs) with genetic and protein associations across many diseases highlights potential drug repurposing opportunities, e.g., tyrosine kinase 2 (TYK2) inhibitors for rheumatoid arthritis. Our multi-cohort meta-analyses generate proteogenomic insights into disease mechanisms and new treatment opportunities.

BACKGROUND:The direct acting oral anticoagulant (DOAC) score is a bleeding risk score that incorporates 10 common clinical variables to risk stratify major bleeding in patients with atrial fibrillation and demonstrated improved risk stratification compared with HAS-BLED in patients receiving DOACs. This study evaluates the discriminative performance of the DOAC score among patients taking vitamin K antagonists (VKAs). METHODS:Data were obtained from COMBINE-AF and GARFIELD-AF. COMBINE-AF included patients with atrial fibrillation randomized to warfarin from 4 clinical trials: RE-LY, ARISTOTLE, ROCKET-AF, and ENGAGE AF-TIMI 48. GARFIELD-AF included patients with atrial fibrillation prescribed VKAs in a registry. The DOAC score of each patient was determined, based on commonly obtained clinical variables. Patients were then stratified by DOAC score clinical risk categories (very low [score: 0-3], low [score: 4-5], moderate [score: 6-7], high [score: 8-9], and very high [score: 10]), and the rate of major bleeding at 1 year was compared between groups. Discrimination was assessed using C-statistics and compared with HAS-BLED using DeLong's test. RESULTS:A total of 28,818 patients in COMBINE-AF and 20,183 patients in GARFIELD-AF receiving vitamin K antagonists were included. Of these individuals, 994 (3.4%) in COMBINE-AF and 313 (1.6%) in GARFIELD-AF experienced a major bleeding event at 1 year. Patients in higher DOAC score risk categories experienced greater 1-year major bleeding rates in COMBINE-AF, including very low (1.8 events per 100 person-years [events/100p-y]), low (3.0 events/100 p-y), moderate (4.6 events/100 p-y), high (5.6 events/100 p-y), and very high (7.9 events/100 p-y). Discrimination in COMBINE-AF was moderate and higher than HAS-BLED at 1 year (C-statistic: 0.62 vs 0.59, P < .001). In GARFIELD-AF, higher risk categories also had higher 1-year major bleeding rates: very low (0.8 events per 100 person-years [events/100 p-y]), low (1.5 events/100 p-y), moderate (2.2 events/100 p-y), high (3.2 events/100 p-y), and very high (7.6 events/100 p-y). Discrimination in GARFIELD-AF was moderate and higher than the HAS-BLED score at 1 year (C-statistic: 0.65 vs 0.62, P < .001). CONCLUSION:In patients with atrial fibrillation taking VKAs, the DOAC score was able to risk stratify patients based on bleeding risk, had moderate discrimination, and out-performed the HAS-BLED score in both a pooled clinical trials cohort and a usual care registry.

Background Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear. Objectives The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup. Methods Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data from a genome-wide association study (GWAS) of time-to-event clinical outcomes in patients with HF. A total of 50,636 individuals of European ancestry with established HF from 22 cohorts were included in the genetic analysis: 12 HF trials, 1 prospective case-cohort study, 9 cohorts nested within non-HF cardiovascular trials, and 1 population-based cohort derived from the UK Biobank.The exposure was genetically predicted BMI and the outcome measures were all-cause mortality and a composite of cardiovascular mortality or HF hospitalization. Genetic associations for the outcomes were derived from our GWAS and MR was used to estimate the unbiased association of genetically predicted BMI with these clinical outcomes. Results The mean BMI was 29.2 ± 5.8 kg/m2. Over a median follow-up of 27.0 months, all-cause mortality occurred in 11,454 patients (23%), and 11,360 participants (22%) experienced the composite endpoint. Genetically predicted BMI was associated with an increased rate of both all-cause mortality (HR per SD [4.8 BMI units] 1.21; 95% CI: 1.13-1.29; P = 9 × 10-8) and the composite outcome (HR 1.29; 95% CI: 1.20-1.38; P = 8 × 10-13). Associations were consistent across LVEF ≤40% and >40%: for all-cause mortality, HR: 1.16 (95% CI: 0.99-1.37) and 1.20 (95% CI: 0.94-1.53); and for the composite outcome, HR: 1.30 (95% CI: 1.15-1.48) and 1.57 (95% CI: 1.29-1.91), respectively. Conclusions Among patients with HF, higher BMI was associated with increased all-cause mortality and cardiovascular death or HF hospitalization, supporting the potential role of weight-management strategies across the ejection fraction spectrum.

BACKGROUND:Atrial fibrillation is associated with heart failure (HF) through a complex cause-and-effect relationship. We performed multiplex screening of plasma proteins in patients with atrial fibrillation to identify biomarkers and pathways associated with hospitalization for HF. Additionally, we aimed to identify potential pathophysiological differences between HF with reduced ejection fraction and HF with preserved ejection fraction at baseline in patients with atrial fibrillation. METHODS:Using a case-cohort design of patients with atrial fibrillation from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 596 cases with HF hospitalizations during follow-up and 4029 randomly selected controls without HF hospitalization. Plasma obtained at randomization was analyzed with conventional immunoassays and proximity extension assay panels. Biomarker associations with HF hospitalization were evaluated using random survival forest, Boruta, and Cox-regression analyses. Associations between biomarkers and HF subtype were evaluated with Wilcoxon-Mann-Whitney test with Bonferroni-Holm adjustment for multiplicity. RESULTS:The biomarkers most strongly and significantly associated with increased risk of HF hospitalization after adjustment for clinical characteristics, renal function, and cardiac biomarkers, and after correction for multiplicity (P≤0.00027), were NT-proBNP (N-terminal pro-B-type natriuretic peptide), BNP (B-type natriuretic peptide), hs-cTnT (high-sensitivity cardiac troponin T), fibroblast growth factor 23, spondin 1, insulin-like growth factor binding protein 7, urokinase-type plasminogen activator receptor, osteopontin, pentraxin-related protein 3, and transferrin receptor protein 1R. Among patients with prevalent HF, 9 biomarkers remained significant after adjustment for multiplicity; NT-proBNP, BNP, hs-cTnT, renin, angiotensin-converting enzyme 2, growth differentiation factor 15, and interleukin-6 levels were higher in HF with reduced ejection fraction, whereas levels of stem cell factor and leptin were higher in HF with preserved ejection fraction (all P<0.05). CONCLUSIONS:Of 268 evaluated biomarkers, this study identified biomarkers representing mechanisms strongly associated with subsequent HF hospitalization. HF with reduced ejection fraction was more strongly associated with cardiorenal dysfunction and inflammation markers, while HF with preserved ejection fraction was associated with adipose metabolism and tissue repair proteins.

BACKGROUND:N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker for cardiovascular risk; however, its prognostic value in patients with atrial fibrillation (AF) who are not receiving anticoagulation therapy has not been well established. We investigated the association between NT-proBNP levels, clinical characteristics and cardiovascular outcomes in non-anticoagulated patients with AF and assessed whether baseline heart rhythm modified these associations. METHODS:Plasma samples were obtained at baseline in two multicentre clinical trials involving 3183 patients with AF randomised to aspirin with a median follow-up of 18 months. NT-proBNP was analysed using the Elecsys immunoassay. Associations between NT-proBNP and clinical characteristics were assessed by multivariable linear regression. Associations with clinical outcomes were evaluated using Cox regression models. The prognostic value of NT-proBNP was evaluated with C-statistics. RESULTS:AF on the baseline ECG was the clinical factor most strongly associated with NT-proBNP levels, with concentrations 4.2 times higher in AF than in sinus rhythm. NT-proBNP was independently associated with ischaemic stroke (the third sample quartile compared with the first, HR 2.07, 95% CI 1.46 to 2.94), heart failure hospitalisation (HR 2.16, 95% CI 1.59 to 2.92), cardiovascular death (HR 2.43, 95% CI 1.79 to 3.30) and all-cause death (HR 2.09, 95% CI 1.65 to 2.65) during follow-up. There was no interaction between heart rhythm and the associations between NT-proBNP and outcomes (all p values ≥0.07). CONCLUSIONS:In non-anticoagulated patients with a diagnosis of AF, NT-proBNP levels were significantly associated with the risk of clinical outcomes. Baseline AF rhythm was the clinical factor most strongly associated with NT-proBNP levels. However, the associations between NT-proBNP and outcomes remained consistent regardless of baseline rhythm.

BACKGROUND:Systemic embolic events (SEEs) are a serious but underrecognized complication of atrial fibrillation. Although non-vitamin K antagonist oral anticoagulants prevent ischemic stroke (IS), their efficacy in SEE and the clinical characteristics of patients who experience SEE remain poorly understood. METHODS:We analyzed individual patient data from 4 pivotal randomized trials enrolling patients between 2005 and 2010 comparing non-vitamin K antagonist oral anticoagulants versus warfarin in atrial fibrillation. We characterized the incidence, clinical features, management, and outcomes of clinically overt SEE and compared results in these patients with patients who had an IS. RESULTS:Among 71 683 patients, 188 experienced SEE (26 with concurrent IS), yielding an annualized event rate of 0.13% per patient-year, compared with 1.25% per patient-year for IS (n=1797). Among 171 patients with SEE as their first event, median age was 75 years (interquartile range, 68-80), 49.7% were female, and mean±SD CHA2DS2-VASc score was 4.7±1.5. Compared with IS, patients with SEE had higher rates of peripheral arterial disease (PAD, 16.5% versus 5.4%; P<0.001), previous myocardial infarction (24% versus 17%; P=0.02), previous vitamin K antagonist exposure (57% versus 46%; P=0.007), worse renal function (median creatinine clearance 58 versus 62 mL/min; P=0.02), and higher incidence of nonparoxysmal atrial fibrillation (86% versus 80%; P=0.047). Interventions (surgical or percutaneous) were performed in 62 patients (31%) with SEE. Standard-dose non-vitamin K antagonist oral anticoagulants reduced the risk of SEE by 29% compared with warfarin over a median follow-up of 25.2 months (interquartile range, 17.5-32.0; hazard ratio, 0.71 [95% CI, 0.51-0.99]; P=0.04). Thirty-day mortality after SEE was similar to IS (18% versus 17%), and SEE was associated with a nearly 3-fold increased risk of long-term mortality compared with patients without SEE or IS (hazard ratio, 2.85 [95% CI, 2.11-3.85]). Independent predictors of SEE included peripheral artery disease, smoking, nonparoxysmal atrial fibrillation, female sex, previous myocardial infarction, previous stroke or transient ischemic attack, vitamin K antagonist experience, and renal dysfunction. CONCLUSIONS:In this large individual patient data meta-analysis, non-vitamin K antagonist oral anticoagulants significantly reduced the risk of SEE compared with warfarin. Although SEEs were approximately one-tenth as frequent as IS, they were associated with comparable mortality and substantial morbidity.

BACKGROUND:We performed an individual patient data analysis of COMBINE AF to assess differences in 14 clinically relevant outcomes between patients with paroxysmal (PAF) vs. non-PAF. METHODS:Cox-proportional-hazards models stratified by trial and adjusted for CHA2DS2-VASc elements were constructed. Sensitivity analyses were performed across subgroups. RESULTS:Among 71,466 patients with AF, 16,609 (23 %) had PAF. The overall follow-up period was 157,225 patient-years (median 2.2 years). Compared with non-PAF patients, PAF patients were more likely to be women (43 % vs 35 %), have prior coronary artery disease (35 % vs 31 %), and use aspirin (41 % vs 32 %), but were less likely to be Asian (12 % vs 15 %) or have CHA₂DS₂-VASc ≥4 (59 % vs 60 %) (all p<0.01). In adjusted analyses, PAF was associated with a lower risk of stroke/systemic embolic event (HR, 0.81; 95 % CI, 0.73-0.90; p<0.001) and all-cause death (HR, 0.81; 95 % CI, 0.75-0.86; p<0.001), but higher risk of major or clinically relevant non-major bleeding (HR, 1.07; 95 % CI, 1.02-1.13; p=0.005). Risk of myocardial infarction was numerically higher in PAF (HR, 1.15; 95 % CI, 1.00-1.32; p=0.057). Major bleeding risk was similar between groups (HR, 1.04; 95 % CI, 0.96-1.12; p=0.36). Findings were consistent across subgroups, trials, anticoagulant types, and sensitivity analyses. CONCLUSIONS:Compared to non-PAF, adjusted risks in PAF patients were lower for stroke/systemic embolic event and all-cause death, and higher for major or clinically relevant non-major bleeding and myocardial infarction.These findings highlight clinically important differences in outcomes by AF type that may have clinical applications for AF patients.

Background Oral anticoagulation (OAC) reduces stroke in patients with atrial fibrillation (AF), but increases bleeding. Objectives This study aimed to evaluate an updated version of the Age, Biomarkers, and Clinical history of bleeding in AF (ABC-AF)-bleeding score (2.0) including consideration of OAC type (direct oral anticoagulant [DOAC] or warfarin) and compare its performance with other bleeding risk scores in 25 962 patients from the COMBINE AF cohort. Methods The COMBINE AF biomarker cohort contains individual participant data from patients with AF enrolled in 3 pivotal randomized trials comparing DOACs with warfarin. The biomarkers in the ABC-AF-bleeding score (growth differentiation factor 15, hemoglobin, and troponin-T) were analyzed in baseline samples. The biomarker-based ABC-AF-bleeding score was updated (version 2.0) by incorporating OAC type into the model (DOAC or warfarin). Discrimination was assessed by Harrell C-index and compared with clinically based bleeding scores; HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol), DOAC, and ORBIT (Older age, Reduced haemoglobin/haematocrit or history of anaemia, Bleeding history, Insufficient renal function, Treatment with antiplatelet agents). Results During follow-up, 1321 patients (5.1%) had an International Society on Thrombosis and Haemostasis major bleeding event, including 480 gastrointestinal, and 248 intracranial hemorrhages. The ABC-AF-bleeding 2.0 risk score showed better discrimination and calibration than the original version and provided superior discrimination than clinical risk scores for all outcomes. The ABC-AF-bleeding score 2.0 C-indices for major bleeding were 0.69 (95% CI, 0.68-0.71); gastrointestinal bleeding, 0.72 (95% CI, 0.69-0.74); and intracranial bleeding, 0.66 (95% CI, 0.63-0.70). The ABC-AF-bleeding score 2.0 also provided consistent superior discrimination in clinically relevant subgroups. Conclusion The updated ABC-AF-bleeding score 2.0 provided better discrimination and calibration for the risk of major bleeding than clinical risk scores, which was consistent across multiple subgroups. These findings support the utility of the ABC-AF-bleeding score for advancing precision medicine in AF.

Introduction: Controversy surrounds the relationship between HDL subclasses and cardiovascular (CV) risk. To assess associations between HDL subclasses and CV events, we applied targeted NMR metabolomics to plasma from participants with prevalent CAD in the ISCHEMIA (The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) and UK Biobank (UKBB) biorepositories. Hypothesis: HDL subclasses are differentially associated with the incidence of CV events. Methods: The metabolomics panel (Nightingale) available in 595 ISCHEMIA participants quantifies HDL particle number in four subclasses: small (mean diameter 8.7 nm), medium (10.9), large (12.1), and extra-large (14.3). For each participant, subclass proportions were calculated as each subclass divided by the total number of HDL particles. Cox proportional hazards modeling was used to evaluate associations between subclass proportions and a composite outcome of CV death or MI (CVD/MI) (median follow-up 3.4 years). To identify potential mechanistic pathways underlying the association of HDL size with CV events, we performed linear modeling with empirical Bayes moderation, relating subclass proportions to levels of 335 proteins from a targeted proteomics panel (OLink). Findings were externally validated in 9,046 UKBB participants with prevalent CAD (defined as in Honigberg et al. (2021)). Results: In ISCHEMIA, a higher proportion of extra-large HDL particles was associated with increased CVD/MI risk [Fig A]. There were no associations between other HDL subclass proportions and CVD/MI in fully adjusted models. The extra-large HDL proportion was inversely correlated with total number of HDL particles (r=-0.24, p<0.001) and directly correlated with HDL cholesterol concentration (r=0.07, p=0.054). Of 11 participants with HDL cholesterol > 80 mg/dL, 7 were in the top quartile of the extra-large HDL proportion. Participants with a high proportion of extra-large HDL showed differential expression of 31 proteins, including higher PLTP and ANGPTL1 expression and lower PCSK9 and LDLR expression. The association between extra-large HDL and CV event risk was replicated in the UKBB [Fig B], and differential protein expression was concordant between ISCHEMIA and the UKBB [Fig C]. Conclusions: In ISCHEMIA, a higher proportion of extra-large HDL particles was associated with greater CV event risk and altered expression of HDL metabolism proteins. These findings were validated in the UKBB.

BACKGROUND AND AIMS:Oral anticoagulation reduces stroke risk in patients with atrial fibrillation (AF) but increases bleeding. Longer fibrin clot lysis time has been shown to predict adverse cardiovascular outcomes in acute coronary syndromes. This study explored relationships between fibrin clot lysis time at randomization and clinical outcomes in patients with AF enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial. METHODS:Plasma samples were obtained from anticoagulation-naïve participants, before initiation of study medication (n = 1841). Fibrin clot turbidimetry was performed, and lysis time determined. Associations between lysis time and characteristics, biomarkers, and on-treatment bleeding and cardiovascular events were assessed by lysis time quartile (Q1-4, shortest to longest). RESULTS:A shorter lysis time was associated with being older, male, permanent AF, lower body mass index, estimated glomerular filtration rate and C-reactive protein, and higher N-terminal pro-B-type natriuretic peptide. Major and clinically relevant non-major bleeding was significantly more frequent in lysis time Q1 vs. Q4 [6.3%/yr vs. 2.1%/yr; HR, 2.99 (95% CI, 1.75-5.12); P = .001], including after multifactorial adjustment [HR, 2.61 (1.45-4.69); P = .016]. Those in Q2 and Q3 had intermediate bleeding risk vs. Q4 [HR, 2.21 (1.27-3.87); 2.08 (1.18-3.66) respectively], suggesting a graduated effect. Treatment allocation to apixaban vs. warfarin did not affect the relationship between lysis time and bleeding (interaction-P = .80). There was no significant association between lysis time and a composite of cardiovascular death, stroke, systemic embolism or myocardial infarction. CONCLUSIONS:Shorter pre-treatment fibrin clot lysis time independently predicted higher bleeding risk in patients receiving oral anticoagulation for AF.

BACKGROUND:Warfarin remains widely used for stroke prevention in atrial fibrillation (AF), particularly where access to direct oral anticoagulants (DOACs) is limited. Updated outcome data across clinical risk groups are needed. OBJECTIVES:The objectives of the study were to identify predictors of adverse outcomes with warfarin, evaluate the TIMI-AF risk score, and assess the benefit of standard-dose (SD) DOACs vs warfarin across risk strata. METHODS:Individual patient-level data from 58,634 patients (29,272 warfarin and 29,362 DOAC) enrolled in 4 pivotal randomized trials were analyzed. The net clinical outcome (NCO), defined as all-cause death, disabling or fatal stroke, or intracranial/fatal bleeding, was assessed using trial-stratified Cox models across key clinical subgroups and TIMI-AF risk score categories. Outcomes with SD-DOACs vs warfarin were compared across risk strata. RESULTS:Older age (adjusted HR [aHR]: 1.55; 95% CI: 1.31-1.83), male sex (aHR: 1.30; 95% CI: 1.20-1.40), impaired kidney function (aHR: 2.21; 95% CI: 1.90-2.56), lower body mass index (aHR: 1.25; 95% CI: 1.15-1.36), vitamin K antagonist-naïve status (aHR: 1.17; 95% CI: 1.08-1.27), and nonparoxysmal AF (aHR: 1.31; 95% CI: 1.19-1.44) were independently associated with increased NCO risk (P < 0.001 for each). Annualized NCO rates were 3.5%, 7.6%, and 12.9% in low-, intermediate-, and high-risk TIMI-AF groups (P trend<0.001). SD-DOACs reduced NCO across all risk strata; however, absolute benefit with DOACs was modest in low-risk patients (0.3%; 95% CI: 0.1% to 0.6%). CONCLUSIONS:Several predictors of poor warfarin outcomes were identified. Although SD-DOACs reduced NCO across the risk spectrum, patients with low TIMI-AF scores derived modest absolute benefit. In settings with limited DOAC access, warfarin may be a reasonable option for lower-risk patients.

Renal dysfunction increases cardiovascular (CV) risk. We compared cystatin C-based estimated glomerular filtration rate (eGFRcys), creatinine-based eGFR (eGFRcr), and their ratio (eGFRcys/eGFRcr) in relation to major adverse cardiovascular events (MACE) and all-cause mortality in chronic coronary syndrome, assessing the added prognostic value of the eGFRratio. In this post hoc analysis of 14,513 Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial patients, we investigated associations between baseline eGFRcys, eGFRcr, their ratio, and MACE and all-cause death using Cox regression models, unadjusted and adjusted for eGFRcys, eGFRcr, and their combination. Discrimination was assessed using Harrell's C -index; added value by the fraction of new information (FNI). Median age was 65 years; 82% were male. Median eGFRcys was 77 (interquartile range [IQR]: 61–94) and eGFRcr 79 (IQR: 65–91) mL/min/1.73 m 2 . Over 3.7 years, 1449 MACE and 1063 deaths occurred. Lower eGFR values and eGFRratio were associated with increased MACE risk, primarily driven by CV death. For eGFRcys 60 versus 90, the hazard ratio (HR) for MACE adjusted for eGFRcr was 1.77 (95% CI: 1.49–2.09, FNI 54%). In contrast, eGFRcr adjusted for eGFRcys showed no positive association (HR 0.82, 95% CI: 0.68–0.97, FNI 3%). A lower eGFRratio was linked to higher MACE risk (HR 1.99, 95% CI: 1.80–2.21), which remained after eGFRcr adjustment (HR 1.89, 95% CI: 1.70–2.10, FNI 54%) but was attenuated after eGFRcys adjustment (HR 1.29, 95% CI: 1.13–1.46, FNI 5%). In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value.

AIMS:Patients with acute myocardial infarction (MI) and atrial fibrillation (AF) present challenges in antithrombotic treatment. Effects of newer treatment strategies on outcomes remain uncertain. We assessed implementation of antithrombotic treatment and occurrence of cardiovascular (CV) events and major bleeding in patients with MI and AF. METHODS AND RESULTS:Nationwide data from SWEDEHEART and national health registries were used to identify 71 513 survivors of an acute MI with AF between 2000 and 2021. Changes in antithrombotic therapies over time in 2-year cohorts were analysed, and associations with 1-year outcomes were assessed. The outcomes were ischaemic stroke or systemic embolism, MI, major bleeding, CV mortality and all-cause mortality. Logistic regression was used to standardize for changes in patient characteristics and treatment over time. Oral anticoagulant use increased from 21% in 2000-2001 to 75% in 2020-2021, largely due to adoption of direct oral anticoagulants (DOACs) after the first DOAC approval in 2011, most often combined with a single antiplatelet. Over time, particularly in the last decade, 1-year risk of ischaemic stroke or systemic embolism declined from 6.0% to 2.1%, and CV mortality decreased from 19.8% to 10.5%. Major bleeding increased from 3.9% to 7.6% in 2014-2015, then declined to 6.4% in 2020-2021, simultaneously with adoption of single rather than dual antiplatelet therapy in combination with DOAC. CONCLUSION:Between 2000 and 2021, among patients with MI and AF, we observed reductions in 1-year risks of ischaemic stroke or systemic embolism and CV mortality, occurring during a period of increased prescription of oral anticoagulants, particularly DOACs. KEY QUESTION AND FINDINGS:Key QuestionHave recent clinical trial findings on antithrombotic therapy in patients with myocardial infarction and concomitant atrial fibrillation been implemented, and have they resulted in any improvement in 1-year outcomes?Key FindingIn patients with myocardial infarction and atrial fibrillation, we observed substantial reductions in 1-year risks of ischaemic stroke or systemic embolism and cardiovascular mortality, associated with increased prescribing of oral anticoagulants, particularly DOACs.