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IMPORTANCE: Risk stratification strategies in primary prevention of coronary events lack precision.

OBJECTIVE: To determine whether prediction of first coronary events is improved by adding information on coronary atherosclerosis from coronary computed tomography angiography (CCTA) to a model using the pooled cohort equation (PCE) risk score tool and the coronary artery calcification score (CACS).

DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study including individuals aged 50 to 64 years randomly recruited from the general population and examined at 6 university hospitals in Sweden from 2013 to 2018, with a median follow-up of 7.8 years. A sample of 30 154 individuals underwent cardiopulmonary imaging, physical examinations, routine laboratory tests, questionnaires, and/or functional tests. This study included 24 791 individuals without previous cardiovascular disease for whom high-quality CCTA images were available. Events were followed up via registers until September 2024.

EXPOSURES: The information used from the CCTA images was the extent of coronary atherosclerosis (segment involvement score), presence of noncalcified atherosclerosis, and presence of coronary obstructive disease (stenosis ≥50%).

MAIN OUTCOMES AND MEASURES: The outcome was a composite of first occurrence of nonfatal myocardial infarction or death from coronary heart disease.

RESULTS: During follow-up, 304 coronary events occurred. Segment involvement scores of 3 to 4 and greater than 4 and presence of noncalcified atherosclerosis were associated with hazard ratios of 2.71 (95% CI, 1.34-5.44), 5.27 (95% CI, 2.50-11.07), and 1.66 (95% CI, 1.23-2.22), respectively. In a model based on the PCE and CACS, CCTA-derived data improved risk discrimination (C statistic improved from 0.764 to 0.779; P = .004) and risk reclassification (net reclassification improvement of 0.133 [95% CI, 0.031-0.165]), conferred a net correct upward reclassification of 14.2% in those with events and incorrectly classified 1.6% of participants not experiencing an event into a higher-risk category. Because of the low event rate in the cohort, reclassification mainly occurred in the group classified as at low risk (<5%) according to the PCE.

CONCLUSIONS AND RELEVANCE: Information on coronary atherosclerosis from CCTA modestly improved risk prediction beyond traditional risk factors and CACS in identifying individuals at risk of coronary events and in need of primary prevention.

Introduction

A recent meta-analysis, including the TIMING study, found favourable short-term outcomes after early initiation of a direct-acting oral anticoagulant (DOAC), as compared to delayed initiation, following acute ischaemic stroke in patients with atrial fibrillation. We aimed to investigate 1-year outcomes after early vs delayed DOAC initiation in the TIMING study population and a concurrent observational cohort.

Patients and methods

In TIMING, adults with atrial fibrillation were randomised to initiation of DOAC either within 4 days or at 5–10 days after acute ischaemic stroke. The non-randomised cohort comprised patients with acute ischaemic stroke and atrial fibrillation, observed in the Swedish Stroke Register concurrently with the TIMING study and initiating DOAC within 4 or 5–10 days, respectively. Outcomes in both populations were acute ischaemic stroke, symptomatic intracerebral haemorrhage or death, as a composite and individually, analysed using Cox regression models, with adjustment for risk factors in the observational cohort.

Results

In the TIMING population (n = 888), the composite outcome at 365 days occurred in 64/450 patients (14.2%) with early DOAC initiation and 66/438 (15.1%) with delayed, unadjusted hazard ratio 0.92 (95% CI, 0.66–1.30). In the observational cohort (n = 8951), the composite outcome at 365 days occurred in 1227/6671 (18.4%) patients initiating DOAC early and 511/2280 (22.4%) in the delayed group, adjusted hazard ratio 0.80 (0.69–0.91).

Discussion

At 1-year follow-up, early initiation of DOAC remained safe and effective with no increase in symptomatic intracerebral haemorrhage. The results support early DOAC initiation in patients with acute ischaemic stroke and atrial fibrillation.

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 biomarkerbased 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.

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.

Purpose: The study aimed to investigate the associations between impaired spirometry such as obstructive pattern and preserved ratio impaired spirometry (PRISm) and occurrent cardiovascular events and deaths in patients with acute myocardial infarction.

Patients and Methods: Cohort study of 517 patients with age >= 40 years and >= 10 pack-years of smoking, hospitalized for myocardial infarction at eight sites in Sweden and the United Kingdom. The Vitalograph (R) COPD-6 device was used to assess the ratio of forced expiratory volume in 1 and 6 seconds (FEV1/FEV6) and FEV1 as a percentage of the predicted value (FEV1%pred). Obstructive pattern was defined as FEV1/FEV6 < 0.7, PRISm as FEV1/FEV6 > 0.7 and FEV1%pred < 80, and normal findings as FEV1/FEV6 >= 0.7 and FEV1%pred >= 80. Follow-up data were obtained from national registers or follow-up visits. Multivariable Cox regression was used to analyze the associations of obstructive pattern and PRISm with the incidence of acute ischemic cardiovascular events or major adverse cardiovascular events (MACE), respectively, within one year.

Results: Obstructive pattern was found in 95 (18%), PRISm in 192 (37%) and normal spirometry in 230 (45%) patients. A cardiovascular event occurred in 21 (4%) and MACE in 28 (5%). Compared with normal spirometry, PRISm was independently associated with both new cardiovascular events (HR (95% CI) 3.44 (1.07- 11.0)) and MACE (4.94 (1.63 to 15.0)), and obstructive pattern with MACE (3.87 (1.08- 13.8)). Further adjustment for cardiac or COPD treatment did not substantially change the results.

Conclusion: About half of patients with acute myocardial infarction and a >= 10 pack-year smoking history have abnormal spirometry findings. Both obstructive pattern and PRISm are independently associated with increased risk for MACE within one year. We suggest that spirometry should be considered as a routine assessment in patients with smoking history and recent myocardial infarction.

Inter-arm blood pressure differences (IABPDs) can be caused by atherosclerosis. We investigated 29 921 men and women aged 50-64 years from the nationwide population-based Swedish CArdio Pulmonary bioImage Study (SCAPIS) to evaluate if IABPD is related to risk factors for atherosclerosis and can be used as a marker of atherosclerosis as evaluated by coronary artery calcium score, arterial segment involvement score on computed tomography, carotid ultrasound, and ankle-brachial index (ABI). The overall prevalence of systolic IABPD at least 10 mmHg was 2110/29 921 (7.1%). Individuals with IABPD at least 10 mmHg were significantly (P < 0.001) older, more often women, had higher BMI, nonhigh-density lipoprotein cholesterol, triglycerides, SBP and DBPs, and were more likely to have diabetes. In unadjusted analyses, IABPD at least 10 mmHg was associated with presence of coronary atherosclerosis, with more carotid arteries with plaque, and with pathological ABI. These associations were largely attenuated after adjustment for cardiovascular risk factors (age, sex, nonhigh-density lipoprotein cholesterol, systolic BP, smoking, diabetes, and the use of BP lowering drugs). Only ABI retained significance after these adjustments. In conclusion, a systolic IABPD of at least 10 mmHg in middle aged men and women is common in the general population, and can be used as a screening tool for subclinical atherosclerotic changes in coronary, carotid, and lower extremity arteries. However, these relationships were largely explained by correlations between IABPD and traditional cardiovascular risk factors.

Background

Alcohol intake increases recurrence of atrial fibrillation (AF), but its relationship with cardiovascular outcomes is less well characterized. We aimed to study the association between different levels of alcohol intake and cardiovascular outcomes in a global cohort of patients with AF.

Methods

This is a cross-sectional analysis of the RE-LY AF registry, including 15,400 patients with AF who visited emergency departments in 47 countries. Patients were categorized into abstainers, light (< 7 standard drinks [SD]/week), moderate (7–13 SD/week), and heavy drinkers (≥ 14 SD/week). Outcomes were stroke/systemic embolism, heart failure (HF) hospitalization, and major bleeding at 1-year follow-up. Logistic mixed-effects regression models were used to calculate multivariable-adjusted odds ratios (aOR) with a 95% confidence interval (CI).

Results

In total,14,058 patients (mean age = 65.9 ± 14.7 years, 48.0% women) with available alcohol intake level data were included. This consisted of 12,091 (86.0%) abstainers, 1150 (8.2%) light, 458 (3.3%) moderate, and 359 (2.6%) heavy drinkers. The odds of stroke/systemic embolism were not significantly different in light (aOR = 0.88, 95% CI: 0.60–1.28), moderate (aOR = 0.91, 95% CI: 0.53–1.57) or heavy drinkers (aOR = 0.79, 95% CI: 0.41–1.54) compared to abstainers. Major bleedings were numerically, but not statistically significantly, higher among heavy drinkers (aOR = 1.52, 95% CI: 0.82–2.80). Compared to abstainers, alcohol intake was associated with fewer HF hospitalizations (light: aOR = 0.73, 95% CI: 0.58–0.92; moderate: aOR = 0.53, 95% CI: 0.35–0.78; heavy: aOR = 0.63, 95% CI: 0.41–0.98). However, this protective association was observed only in upper-middle and high-income countries (p-interaction < 0.001).

Conclusion

Alcohol drinking is unlikely to be associated with increased thromboembolic events in patients with AF, but may be associated with a lower risk of HF hospitalizations.

Aim: Habitual physical activity (PA) affects metabolism and homeostasis in various tissues and organs. However, detailed knowledge of associations between PA and cardiovascular disease (CVD) risk markers is limited. We sought to identify associations between accelerometer-assessed PA classes and 183 proteomic and 154 metabolomic CVD-related biomarkers.

Method: We utilized cross-sectional data from the main SCAPIS cohort (n = 4647, median age: 57.5 yrs, 50.5% female) as a discovery sample and the SCAPIS pilot cohort (n = 910, median age: 57.5 yrs, 50.3% female) as a validation sample. PA was assessed via hip-worn accelerometers, while plasma concentrations of proteomic biomarkers were measured using Olink CVD II and III panels. Metabolomic markers were assessed using the Nightingale NMR platform. We evaluated associations between four PA classes (moderate-to-vigorous PA [MVPA], low-intensity PA [LIPA], sedentary [SED], and prolonged SED [prolSED]) and biomarkers, controlling for potential confounders and applying a false discovery rate of 5% using multiple linear regressions.

Results: A total of eighty-five metabolomic markers and forty-three proteomic markers were validated and found to be significantly associated with one or more PA classes. LIPA and SED markers demonstrated significant mirroring or opposing relations to biomarkers, while prolSED mainly shared relations with SED. Notably, HDL species were predominantly negatively associated with SED, whereas LDL species were positively associated with SED and negatively associated with MVPA. Among the proteomic markers, eighteen were uniquely associated with MVPA (among those Interleukin - 6 [IL6] and Growth/differentiation factor 15 [GDF15] both negatively related), seven with SED (among those Metalloproteinase inhibitor 4 [TIMP4] and Tumor necrosis factor receptor 2 [TNFR2], both positively related), and eight were related to both SED/prolSED (among those Lipoprotein lipase [LPL] negatively related to SED and leptin [LEP] positively related to SED) and MVPA (with LPL positively related to MVPA and LEP negatively related to MVPA).

Conclusion: Our findings suggest the existence of specific associations between PA classes and metabolomic and cardiovascular protein biomarkers in a middle-aged population. Beyond validation of previous results, we identified new associations. This multitude of connections between PA and CVD-related markers may help elucidate the previously observed relationship between PA and CVD. The identified cross-sectional associations could inform the design of future experimental studies, serving as important outcome measures.

Importance  In patients with atrial fibrillation (AF), oral anticoagulants (OACs) reduce the risk of stroke.

Objective  To investigate if patients with less prior OAC exposure respond differently to a new OAC than patients with more OAC exposure.

Design, Setting, and Participants  In this prespecified exploratory subgroup analysis of the Oral Factor 11a Inhibitor Asundexian as Novel Antithrombotic–Atrial Fibrillation (OCEANIC-AF) randomized clinical trial, patients enrolled in the OCEANIC-AF trial were categorized as OAC naive or OAC experienced based on whether they had 6 or fewer weeks or more than 6 weeks of prior OAC use. The effect of asundexian vs apixaban was then compared on outcomes among patients who were OAC naive and OAC experienced. The study setting included 1035 sites in 38 countries, and participants were those enrolled in the OCEANIC-AF trial. Data were analyzed from June to July 2024.

Interventions  Asundexian, a novel factor XIa inhibitor, was compared with apixaban in patients with AF.

Main Outcomes and Measures  The primary efficacy outcome was stroke or systemic embolism. The main safety outcome was major bleeding.

Results  Of patients in the OCEANIC-AF trial, 2493 (17%) were OAC naive (mean [SD] age, 72.6 [8.6] years; 1464 male [59%]) and 12 317 (83%) were OAC experienced (mean [SD] age, 74.2 [7.5] years; 8132 male [66%]). In the asundexian arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.8% (10 of 1238) compared with 1.4% (88 of 6177) in those who were OAC experienced. In the apixaban arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.6% (7 of 1255) compared with 0.3% (19 of 6140) in those who were OAC experienced. Thus, patients who were OAC naive had a smaller increase in stroke or systemic embolism with asundexian compared with apixaban (hazard ratio [HR], 1.42; 95% CI, 0.54-3.73) than patients who were OAC experienced (HR, 4.66; 95% CI, 2.84-7.65; P for interaction =.03). Bleeding rates were lower among both OAC-naive patients (0.2% [2 of 1228]) and OAC-experienced patients (0.2% [15 of 6145]) assigned asundexian than among OAC-naive patients (1.0% [13 of 1249]) and OAC-experienced patients (0.7% [40 of 6115]) assigned apixaban.

Conclusions and Relevance  In the OCEANIC-AF randomized clinical trial, patients with AF who were OAC naive had a smaller increase in stroke or systemic embolism and a similar lower rate of bleeding with asundexian compared with apixaban than patients who were OAC experienced. The mechanism of these findings is unknown and deserves further research.

Trial Registration  ClinicalTrials.gov Identifier: NCT05643573

BACKGROUND: Stroke prevention with direct-acting oral anticoagulant agents in patients with atrial fibrillation confers a risk of bleeding and limits their use. Asundexian, an activated factor XI (XIa) inhibitor, is an oral anticoagulant that may prevent strokes with less bleeding.

METHODS: In a phase 3, international, double-blind trial, we randomly assigned high-risk patients with atrial fibrillation in a 1:1 ratio to receive asundexian at a dose of 50 mg once daily or standard-dose apixaban. The primary efficacy objective was to determine whether asundexian is at least noninferior to apixaban for the prevention of stroke or systemic embolism. The primary safety objective was to determine whether asundexian is superior to apixaban with respect to major bleeding events.

RESULTS: A total of 14,810 randomly assigned patients were included in the intention-to-treat population. The mean (±SD) age of the patients was 73.9±7.7 years, 35.2% were women, 18.6% had chronic kidney disease, 18.2% had a previous stroke or transient ischemic attack, 16.8% had received oral anticoagulants for no more than 6 weeks, and the mean CHA₂DS₂-VASc score (range, 0 to 9, with higher scores indicating a greater risk of stroke) was 4.3±1.3. The trial was stopped prematurely at the recommendation of the independent data monitoring committee. Stroke or systemic embolism occurred in 98 patients (1.3%) assigned to receive asundexian and in 26 (0.4%) assigned to receive apixaban (hazard ratio, 3.79; 95% confidence interval [CI], 2.46 to 5.83). Major bleeding occurred in 17 patients (0.2%) who received asundexian and in 53 (0.7%) who received apixaban (hazard ratio, 0.32; 95% CI, 0.18 to 0.55). The incidence of any adverse event appeared to be similar in the two groups.

CONCLUSIONS: Among patients with atrial fibrillation at risk for stroke, treatment with asundexian at a dose of 50 mg once daily was associated with a higher incidence of stroke or systemic embolism than treatment with apixaban in the period before the trial was stopped prematurely. There were fewer major bleeding events with asundexian than with apixaban during this time. (Funded by Bayer; OCEANIC-AF ClinicalTrials.gov number, NCT05643573; EudraCT number, 2022-000758-28.).