Background: Patients with diabetes mellitus (DM) and established cardiovascular disease (CVD) face a markedly increased risk of future major adverse cardiovascular events (MACE). This study aimed to assess the clinical characteristics and outcomes of patients with DM with CVD initiating dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin in clinical practice.Methods: The prospective XATOA (Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis) registry enrolled patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD). Baseline characteristics, cardiovascular outcomes, and bleeding rates were analyzed according to diabetes status. Among patients with DM, outcomes were also compared by vascular territory (CAD, PAD, or both), and findings were benchmarked against the randomized COMPASS trial.Results: Among 5532 patients included in XATOA, 2130 (38.5%) had diabetes, predominantly type 2 (96.1%). Patients with DM with PAD alone were less likely to receive optimal preventive therapies than those with CAD or CAD + PAD. Compared to patients without diabetes, patients with DM had a 59% higher risk of major adverse vascular events (MAVE), including MACE and major adverse limb events (MALE) (p < 0.001). Event rates (per 100 patient-years) in patients with DM were 2.1 for CAD, 10.1 for CAD + PAD, and 14.2 for PAD alone. Major bleeding rates were similar across diabetes status (4.3/100 patient-years) and vascular territories. The composite rate of MACE and major bleeding in patients with DM aligned closely with results from the COMPASS trial.Conclusion: Patients with DM with CVD are at significantly high cardiovascular risk, and those with PAD appear to be undertreated. Real-world outcomes observed in the XATOA registry are consistent with randomized trial data, supporting the benefit of DPI in this high-risk population.

QuestionAmong frail older adults with non-ST-elevation myocardial infarction (NSTEMI), does an invasive strategy reduce the risk of cardiovascular death or nonfatal myocardial infarction (MI) compared with a conservative strategy?FindingsIn this subgroup analysis of 469 frail patients from the SENIOR-RITA randomized clinical trial, an invasive strategy did not reduce the risk of cardiovascular death or nonfatal MI. A significant interaction was found between treatment and frailty severity such that patients at the highest levels of frailty had a potential signal for harm with routine invasive strategy.MeaningAmong frail older adults with NSTEMI, an invasive strategy provided no benefit over conservative management and may be associated with worse outcomes at higher levels of frailty, highlighting the importance of incorporating frailty assessment into clinical decision-making. ImportanceFrail older patients with non-ST-elevation myocardial infarction (NSTEMI) experience an increased risk of major adverse cardiovascular events. The beneficial role of an invasive strategy over a conservative strategy among frail patients with NSTEMI is unclear.ObjectiveTo compare the clinical outcomes of an invasive strategy with those of a conservative strategy among older patients with NSTEMI stratified by frailty status.Design, Setting, and ParticipantsIn this prespecified exploratory subgroup analysis from the SENIOR-RITA randomized clinical trial, patients were screened across 48 National Health Service trusts in England and Scotland from November 1, 2016, through March 31, 2023. The SENIOR-RITA trial included patients with NSTEMI aged 75 years or older, randomized to an invasive strategy with coronary angiography, revascularization if needed, and optimal medical therapy vs a conservative strategy with optimal medical therapy only. In this analysis, frailty status was defined using the Fried frailty criteria (frail, >= 3 criteria present). Statistical analysis was performed from March through November 2025.InterventionsInvasive vs conservative strategy.Main Outcomes and MeasuresThe primary composite outcome was the time to cardiovascular death or nonfatal myocardial infarction. All participants were analyzed according to the intention-to-treat principle.ResultsFried frailty criteria were available for 1446 of the 1518 randomized patients (95.3%), of whom 469 (32.4%; median age, 83 years [IQR, 80-86 years]; 240 women [51.2%]) met criteria for frailty. The primary outcome among frail patients occurred among 87 of 231 patients (37.7%) in the invasive group and 70 of 238 patients (29.4%) in the conservative group (hazard ratio [HR], 1.21; 95% CI, 0.88-1.67) over a median follow-up of 4.1 years (IQR, 2.8-4.6 years). When frailty was analyzed as a continuous variable, there was a significant interaction with treatment such that patients at the highest levels of frailty had a potential signal for harm with routine invasive strategy. There were no significant treatment differences across frailty categories for cardiovascular death (HR, 1.44; 95% CI, 0.97-2.10) or nonfatal myocardial infarction (HR, 1.00; 95% CI, 0.61-1.63).Conclusions and RelevanceIn this subgroup analysis of a randomized clinical trial, an invasive strategy did not reduce the risk of a composite outcome of cardiovascular death or nonfatal myocardial infarction compared with a conservative strategy, with a potential signal for increased risk of harm among those at the highest levels of frailty. These findings underscore the need for individualized, frailty-informed treatment strategies.Trial Registrationisrctn.org Identifier: ISRCTN11343602 This secondary analysis of the SENIOR-RITA randomized clinical trial compares the clinical outcomes of an invasive strategy with those of a conservative strategy among older patients with non-ST-elevation myocardial infarction stratified by frailty status.

To determine characteristics and clinical outcomes of German patients with coronary artery disease (CAD) with or without peripheral artery disease (PAD) who initiated dual pathway inhibition (DPI) using rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily in clinical practice in Germany and to compare those with the results for CAD patients of the COMPASS trial. XATOA was an international prospective registry with a mean follow-up period of 15 months. There were 1641 German CAD patients included, of which 747 patients (45.5

Background:Patients with atherosclerotic cardiovascular disease might benefit from dual pathway inhibition (DPI) therapy, which includes rivaroxaban and aspirin. Patients with concomitant heart failure (HF) are a subgroup with a higher risk for ischemic events. Accordingly, we explored the risks and benefits of DPI therapy in a generalizable population of patients with concomitant atherosclerotic cardiovascular disease and HF. Methods:The Xarelto plus Acetylsalicylic acid Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA) registry is a prospective, multicentre registry of patients with either coronary artery or peripheral artery disease that were given DPI therapy. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke, and the safety outcome was major bleeding. Multivariable logistic regression was performed to assess the association of HF status and ejection fraction (EF) on the outcomes of interest. Results:Of 5532 participants, 4022 (72.7%) had documentation of HF status. Of those 873 (21.5%) had a history of HF (EF > 40%, 461; EF ≤ 40%, 181, EF unknown, 231). Over a median follow-up of 465 days (interquartile range, 372-576), the primary outcome occurred in 4.9% of participants with HF compared with 2.4% in those without HF (adjusted hazard ratio, 1.57; 95% confidence interval, 1.02-2.41). The safety outcome was similar in patients with and without HF (0.9% vs 1.11%; a hazard ratio, 0.7; 95% confidence interval, 0.31-1.67). Conclusions:In a generalizable cohort of patients with atherosclerotic disease and HF, the use of DPI therapy is associated with outcomes similar to those observed in recent randomized controlled clinical trials.

Background: In the COMPASS trial, the combination of acetylsalicylic acid (ASA) plus 2.5 mg rivaroxaban twice daily (dual-pathway inhibition, DPI) has been shown to be superior to ASA monotherapy for the reduction in ischemic major adverse cardiovascular events (MACEs, i.e., cardiovascular death, stroke, or myocardial infarction). Methods: The international XATOA registry (Xarelto plus Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis) is a prospective post-approval registry that investigates the cardiovascular outcomes of patients taking ASA plus 2.5 mg rivaroxaban. The aim of this pre-specified analysis was to determine the net clinical outcome (NCO), i.e., a combination of MACEs and bleeding events, of DPI in patients from daily clinical practice. Results: Among the 5615 patients, the presence of multiple risk factors resulted in an increase in the total risk of experiencing an NCO event, e.g., from 1.27% (one risk factor) to 2.18% (two risk factors) and 4.07% (three or more risk factors), respectively, with ischemic MACE representing the primary driver of bleeding complications. Conclusions: In the real-world XATOA registry, the annual rate of NCO events was low and numerically similar to those seen in the treatment group in the randomized COMPASS trial.

Abstract Background Physiologic changes due to extremes of body weight may affect the efficacy and tolerability of antiplatelet treatment. However, it remains unclear whether the risks and benefits of intensified antiplatelet therapy among patients with diabetes and stable coronary artery disease (CAD) are affected by body mass index (BMI). Purpose To assess the relationship between baseline BMI and major adverse cardiovascular (CV) events, and to determine if the effects of ticagrelor vs. placebo varied across the BMI spectrum, in patients with diabetes and stable CAD. Methods THEMIS was a randomized, controlled trial of 19,220 individuals aged ≥50 years with type 2 diabetes and stable CAD, randomly allocated to ticagrelor or placebo on top of aspirin. Patients with a prior myocardial infarction (MI) or stroke, or already on dual antiplatelet therapy, were excluded. The primary efficacy outcome was a composite of CV death, MI, or stroke. The primary safety outcome was TIMI major bleeding. We examined prognostic implications of BMI using 1) restricted cubic splines for the overall trends with outcomes; 2) Cox regression models with predefined BMI intervals (<25 kg/m2, 25-29.9 kg/m2, and ≥30 kg/m2) adjusted for demographic, clinical, and laboratory variables; and 3) Cox regression models for the effects of ticagrelor vs. placebo on outcomes across the spectrum of BMI values (test for interaction). A two-sided P-value <0.01 was considered statistically significant to control the overall chance of type I errors. Results BMI was available in 19,202 (99.9%) participants, with a median of 29 kg/m2 (interquartile range: 26-33). A total of 3352 (17.5%) individuals had a BMI <25 kg/m2, 7644 (39.8%) had a BMI 25-29.9 kg/m2, and 8206 (42.7%) had a BMI ≥30 kg/m2. Median follow-up was 39.9 months (range 0-57), with 1554 primary efficacy events and 306 primary safety events occurring over the course of the study. BMI was not associated with the primary efficacy or safety outcome, or with their individual components. However, BMI was significantly associated with hospitalization for heart failure (HHF) (BMI <25 kg/m2: reference; hazard ratio [HR] for BMI 25-29.9 kg/m2: 1.07, 95% confidence interval [CI], 0.82 to 1.40; HR for BMI ≥30 kg/m2: 1.41, 95% CI, 1.07 to 1.84) and with the composite of HHF or CV death (comparable estimates) after multivariable adjustment (Figure). BMI was also significantly, positively associated with serious adverse events (BMI <25 kg/m2: reference; HR for BMI 25-29.9 kg/m2: 0.99, 95% CI, 0.93 to 1.06; HR for BMI ≥30 kg/m2: 1.20, 95% CI, 1.12 to 1.29). BMI did not modify the risks and benefits of ticagrelor vs. placebo. Conclusions BMI was independently associated with the risk of HHF and the composite of HHF or CV death, but not with other efficacy or safety outcomes, in patients with stable CAD and type 2 diabetes. Ticagrelor was of similar benefit on the primary efficacy outcome vs. placebo across the full range of BMI.

Background Patients with coronary and peripheral artery disease (PAD) have a residual risk of major adverse cardiovascular and limb events despite standards of care. Among patients with coronar y arter y disease (CAD) and/or PAD selected for low dose rivaroxaban (2.5 mg BID) and aspirin, we sought to determine the highest risk vascular patients. Methods Xarelto pluc Acetylsalicylic acid: Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA) is a single-arm registry of CAD and/or PAD patients. All participants were initiated on low dose rivaroxaban (2.5 mg BID) and aspirin. We report the incidence risk of major adverse cardiovascular events (MACE) or major adverse limb events (MALE) and major bleeding. A classification and regression tree analysis determined independent subgroups. Results Between November 2018 and May 2020, 5,808 participants were enrolled in XATOA; 5,532 were included in the full analysis. The median follow-up (interquartile range) was 462 (371-577) days. The incidence risk per 100 patientyears of MACE or MALE was highest among participants with polyvascular disease (2 or more vascular beds affected, n = 2,889). The incidence risk was 9.16 versus 2.48 per 100 patient-years in polyvascular and nonpolyvascular patients respectively. Other subgroups of high-risk patients included participants 75 years or older, with a history of diabetes, heart failure, or chronic renal insufficiency (CRI). Rates of major bleeding were low overall. A classification and regression tree analysis showed that polyvascular disease was the most dominant factor separating higher from lower risk participants, and this was heightened with CRI or diabetes. Conclusion Patients with polyvascular disease represent a substantial subset of patients in clinical practice and should be prioritized to receive maximal medical therapy including low dose rivaroxaban (2.5 mg BID) and aspirin. (Am Heart J 2024;269:191-200.)

BACKGROUND Whether a conservative strategy of medical therapy alone or a strategy of medical therapy plus invasive treatment is more beneficial in older adults with non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. METHODS We conducted a prospective, multicenter, randomized trial involving patients 75 years of age or older with NSTEMI at 48 sites in the United Kingdom. The patients were assigned in a 1:1 ratio to a conservative strategy of the best available medical therapy or an invasive strategy of coronary angiography and revascularization plus the best available medical therapy. Patients who were frail or had a high burden of coexisting conditions were eligible. The primary outcome was a composite of death from cardiovascular causes (cardiovascular death) or nonfatal myocardial infarction assessed in a time-to-event analysis. RESULTS A total of 1518 patients underwent randomization; 753 patients were assigned to the invasive-strategy group and 765 to the conservative-strategy group. The mean age of the patients was 82 years, 45% were women, and 32% were frail. A primary-outcome event occurred in 193 patients (25.6%) in the invasive-strategy group and 201 patients (26.3%) in the conservative-strategy group (hazard ratio, 0.94; 95% confidence interval [CI], 0.77 to 1.14; P=0.53) over a median follow-up of 4.1 years. Cardiovascular death occurred in 15.8% of the patients in the invasive-strategy group and 14.2% of the patients in the conservative-strategy group (hazard ratio, 1.11; 95% CI, 0.86 to 1.44). Nonfatal myocardial infarction occurred in 11.7% in the invasive-strategy group and 15.0% in the conservative-strategy group (hazard ratio, 0.75; 95% CI, 0.57 to 0.99). Procedural complications occurred in less than 1% of the patients. CONCLUSIONS In older adults with NSTEMI, an invasive strategy did not result in a significantly lower risk of cardiovascular death or nonfatal myocardial infarction (the composite primary outcome) than a conservative strategy over a median follow-up of 4.1 years.

Abstract Background Atrial fibrillation (AF) is associated with cardio-embolic stroke. It remains unclear whether AF outcomes are related to the care speciality at AF diagnosis. Purpose To explore associations between the care speciality at AF diagnosis and the risks of clinical outcomes in newly diagnosed AF patients. Methods GARFIELD-AF is an international registry of consecutively recruited newly diagnosed AF patients with ≥1 stroke risk factors. Participants were divided based on the care specialty at AF diagnosis: primary care, cardiology, or other medical specialties (internal medicine, neurology, or geriatrics). The follow-up period was from the date of enrolment, truncated at first event occurrence, death, loss to follow-up, or two years after enrolment, whichever occurred first. Hazard ratios for the associations of care speciality with selected clinical outcomes were estimated using Cox proportional-hazards models adjusted for the confounding factors, which included demographics, AF type, medical history, baseline comorbidities, and treatment information. Results The study population comprised 52,011 prospectively enrolled GARFIELD-AF patients with available care speciality and follow-up information. Most participants were diagnosed by a cardiology specialist (n=34,172, 65.7%), and fewer by other medical specialists (n=10,443, 20.1%) or primary care practitioners (n=7,396, 14.2%). Patients diagnosed by cardiologists were on average younger, had lower BMI, and were more likely to have paroxysmal AF when first diagnosed. These patients also received NOAC more frequently (30.1%), compared to patients diagnosed by other medical specialties (24.2%) or primary care practitioners (20.4%, Table 1). CHA2DS2-VASc and HAS-BLED scores were similar across care specialities. The proportion of patients treated by a cardiologist differed substantially between countries, ranging from 9% in Finland to 97% in Egypt. Patients cared for by non-cardiology medical specialties had a greater risk of all-cause mortality (HR 1.23, 95%CI 1.08 to 1.39), non-cardiovascular mortality (HR 1.31, 1.12 to 1.53) and non-haemorrhagic stroke/systemic embolism (HR 1.45, 1.18 to 1.80) compared with participants cared for by a cardiologist. Patients treated by primary care practitioners had a lower all-cause mortality risk compared with those diagnosed by cardiologists (HR 0.86, 0.74 to 0.99) (Figure 1). Conclusions Overall, patients developing new AF were most often diagnosed by cardiologists, but substantial regional variation existed. Patients diagnosed by cardiologists received NOACs more frequently compared to patients diagnosed from other care specialties. Patients treated by non-cardiology medical specialities experienced a comparatively greater risk of death and non-haemorrhagic stroke. Cardiology expertise could have important implications for the care of newly diagnosed AF patients.Figure 1Table 1

Abstract Objective To determine the effectiveness of risk stratification using the Global Registry of Acute Coronary Events (GRACE) risk score (GRS) for patients presenting to hospital with suspected non-ST elevation acute coronary syndrome. Design Parallel group cluster randomised controlled trial. Setting Patients presenting with suspected non-ST elevation acute coronary syndrome to 42 hospitals in England between 9 March 2017 and 30 December 2019. Participants Patients aged ≥18 years with a minimum follow-up of 12 months. Intervention Hospitals were randomised (1:1) to patient management by standard care or according to the GRS and associated guidelines. Main outcome measures Primary outcome measures were use of guideline recommended management and time to the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospital admission, and readmission for cardiovascular event. Secondary measures included the duration of hospital stay, EQ-5D-5L (five domain, five level version of the EuroQoL index), and the composite endpoint components. Results 3050 participants (1440 GRS, 1610 standard care) were recruited in 38 UK clusters (20 GRS, 18 standard care). The mean age was 65.7 years (standard deviation 12), 69% were male, and the mean baseline GRACE scores were 119.5 (standard deviation 31.4) and 125.7 (34.4) for GRS and standard care, respectively. The uptake of guideline recommended processes was 77.3% for GRS and 75.3% for standard care (odds ratio 1.16, 95% confidence interval 0.70 to 1.92, P=0.56). The time to the first composite cardiac event was not significantly improved by the GRS (hazard ratio 0.89, 95% confidence interval 0.68 to 1.16, P=0.37). Baseline adjusted EQ-5D-5L utility at 12 months (difference −0.01, 95% confidence interval −0.06 to 0.04) and the duration of hospital admission within 12 months (mean 11.2 days, standard deviation 18 days v 11.8 days, 19 days) were similar for GRS and standard care. Conclusions In adults presenting to hospital with suspected non-ST elevation acute coronary syndrome, the GRS did not improve adherence to guideline recommended management or reduce cardiovascular events at 12 months. Trial registration ISRCTN 29731761

ImportanceMost epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries.ObjectiveTo examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development.Design, Setting, and ParticipantsMultinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years.Main Outcomes and MeasuresHF cause, HF medication use, hospitalization, and death.ResultsMean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a β-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies.Conclusions and RelevanceThis study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Abstract Background Oral anticoagulation (OAC) is key in preventing stroke in patients with atrial fibrillation (AF). However, patients with AF and dementia pose practical therapeutic challenges, such as compliance and haemorrhagic complications, resulting in possible underuse of cardiovascular (CV) treatment. Purpose The aim of this study is two-fold: a) to determine whether AF patients with dementia are undertreated for stroke prevention with OAC and for their CV comorbidities and b) to assess the risks and benefits of OAC in AF patients with dementia. Methods Analyses were conducted in newly diagnosed AF patients enrolled in GARFIELD-AF, the largest multinational prospective AF registry. Medical history of dementia was recorded at enrolment. Guideline-directed medical therapy (GDMT), defined according to ESC guidelines, was explored for coronary artery disease (CAD), diabetes, heart failure (HF), hypertension, and peripheral vascular disease (PVD). Propensity score weighting was applied to obtain estimates of OAC effect on all-cause mortality and stroke within two-year follow-up. Major bleeding occurrence is simply reported due to the low number of events. Results The study comprised 764 (1.5%) AF patients with dementia and 50,966 (98.5%) without dementia. Patients with dementia were more often female (58% vs 44%), older (median age 82 vs 71) and had higher prevalence of comorbidities, resulting in higher CHA2DS2-VASc (excl. sex; median 5.0 vs 3.0) and HAS-BLED score (median 2.0 vs 1.0) compared to patients without dementia. The proportion anticoagulated was lower among those with dementia (60% vs 70%), with fewer patients receiving VKA (27% vs 42%) (Fig. 1). Despite the increase in NOAC use among patients with dementia (17% in 2010-2013 vs 48% in 2015-2016), 35% remained non-anticoagulated in 2015-2016. Appropriate GDMT was lower among patients with dementia for the five considered comorbidities combined (35% vs 45%), with substantial differences observed for HF (35% vs 50%), CAD (27% vs 39%) and PVD (36% vs 48%) compared to patients without dementia. In patients with dementia, OAC usage was associated with lower all-cause mortality (HR 0.69; 95% CI 0.48-1.00). In contrast to patients without dementia, no evidence of a stroke risk reduction with OAC was observed among patients with dementia (HR 1.10; 95% CI 0.50-2.43) (Fig. 2). This finding might be explained by the higher proportion of patients with dementia receiving a reduced NOAC dose (73% vs 39% of NOAC receivers) and their lower VKA quality control (37% vs 46%, defined as time in therapeutic range >65%). Seven (1.6%) and eight (2.7%) major bleeding events occurred among patients with dementia who were on or not on OAC, respectively. Conclusions Despite their high risk of stroke, patients with AF and dementia are often undertreated for their AF and CV comorbidities. Our results support the use of OAC and should help inform treatment decisions in this vulnerable population.

Background: There is uncertainty surrounding the use of direct oral anticoagulants (DOACs) in patients with kidney dysfunction. Methods: Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY [Randomized Evaluation of Long-term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48]), we performed an individual patient-level network meta-analysis to evaluate the safety and efficacy of DOACs versus warfarin across continuous creatinine clearance (CrCl). A multivariable Cox model including treatment-by-CrCl interaction with random effects was fitted to estimate hazard ratios for paired treatment strategies (standard-dose DOAC, lower-dose DOAC, and warfarin). Outcomes included stroke and systemic embolism (S/SE), major bleeding, intracranial hemorrhage (ICH), and death. Results: Among 71 683 patients (mean age, 70.6±9.4 years; 37.3% female; median follow-up, 23.1 months), the mean CrCl was 75.5±30.5 mL/min. The incidence of S/SE, major bleeding, ICH, and death increased significantly with worsening kidney function. Across continuous CrCl values down to 25 mL/min, the hazard of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin ( P interaction =0.61). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of ICH at CrCl values <122 mL/min, with a trend for increased safety with DOAC as CrCl decreased (6.2% decrease in hazard ratio per 10-mL/min decrease in CrCl; P interaction =0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl <87 mL/min, with a significant treatment-by-CrCl effect (4.8% decrease in hazard ratio per 10-mL/min decrease in CrCl; P interaction =0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with CrCl <77 mL/min, with a trend toward increasing benefit with lower CrCl (2.1% decrease in hazard ratio per 10-mL/min decrease in CrCl; P interaction =0.08). Use of lower-dose rather than standard-dose DOACs was not associated with a significant difference in incident bleeding or ICH in patients with reduced kidney function but was associated with a higher incidence4 of death and S/SE. Conclusions: Standard-dose DOACs are safer and more effective than warfarin down to a CrCl of at least 25 mL/min. Lower-dose DOACs do not significantly lower the incidence of bleeding or ICH compared with standard-dose DOACs but are associated with a higher incidence of S/SE and death. These findings support the use of standard-dose DOACs over warfarin in patients with kidney dysfunction.

This study aims to describe both management and prognosis of patients with diabetes mellitus (DM) and newly diagnosed atrial fibrillation (AF), overall as well as by antidiabetic treatment, and to assess the influence of oral anticoagulation (OAC) on outcomes by DM status.

Anticoagulants reduce the risk of stroke in patients with atrial fibrillation (AF). However, due to various causes, including concerns for bleeding, there is treatment variability, including undertreatment or non-treatment, especially in patients with high bleeding risk. The aim of the GARDENIA registry is threefold, 1) to understand the real-world usage of oral anticoagulants (OAC) in patients with AF and elevated risk of bleeding, 2) to evaluate the factors associated with treatment or non-treatment with OACs and adherence to guideline recommended doses of OACs and 3) to determine the incidence of clinical outcomes in this population in relation to the treatment strategy adopted.

Abstract Background Clinical use of the GRACE scoring system is recommended across international guidelines to guide early treatment stratification in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). Recently, the machine learning-based GRACE 3.0 score was derived from patients with NSTE-ACS undergoing contemporary treatment approaches. External validation studies and the reassessment of clinical risk categories are lacking. Purpose We aimed to evaluate the predictive performance of the GRACE 3.0 score and to explore clinically meaningful risk groups in contemporary patients with NSTE-ACS. Methods We studied the GRACE 3.0 score in 8070 patients with NSTE-ACS in contemporary ACS cohorts from Denmark (VERDICT, n=2147), Germany (Heidelberg-ACS, n=2034), Italy and Spain (CORALYS, n=1650), and Switzerland (SPUM-ACS, n=2239). Heterogeneity in the treatment effect of very early invasive management (within 12 hours) or standard invasive management (within 48 to 72 hours) on the primary composite outcome of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure in relation to baseline mortality risk was assessed in 2147 patients enrolled in the VERDICT trial who were randomized to different timing of invasive treatment. Results The GRACE 3.0 score showed excellent discriminatory properties with an area under the receiver operating characteristic curve (AUC) for in-hospital death of 0.89 (95% CI, 0.85–0.93) in the total study cohort. Similar results were observed in Denmark (AUC 0.93, 95% CI, 0.88–0.98), Germany (AUC 0.90, 95% CI, 0.85–0.94), and Italy and Spain (AUC 0.85, 95% CI, 0.77–0.94), and Switzerland (AUC 0.93, 95% CI, 0.86–1.00). Early invasive treatment reduced the composite endpoint (absolute risk reduction: 0.12, 95% CI, 0.03–0.21, P=0.011) in patients at high risk (≥1.7%), but not in those with lower risk profiles (P interaction=0.033). Based on this new high-risk threshold, GRACE 3.0 stratified 475 (42.2%) more patients into the high-risk group, as compared to traditional GRACE risk categories (P<0.001). Conclusion GRACE 3.0 shows unprecedented predictive performance in patients with NSTE-ACS. In the context of a comprehensive clinical evaluation, GRACE 3.0 can support clinical decision making for the timing of invasive treatment. The high-risk group of patients with NSTE-ACS who benefit from early invasive treatment is substantially larger than previously described.ROC curve and risk groupsRestratfication towards high risk group

Abstract Aims This study aimed to identify relationships in recently diagnosed atrial fibrillation (AF) patients with respect to anticoagulation status, use of guideline-directed medical therapy (GDMT) for comorbid cardiovascular conditions (co-GDMT), and clinical outcomes. The Global Anticoagulant Registry in the FIELD (GARFIELD)-AF is a prospective, international registry of patients with recently diagnosed non-valvular AF at risk of stroke (NCT01090362). Methods and results Guideline-directed medical therapy was defined according to the European Society of Cardiology guidelines. This study explored co-GDMT use in patients enrolled in GARFIELD-AF (March 2013–August 2016) with CHA2DS2-VASc ≥ 2 (excluding sex) and ≥1 of five comorbidities—coronary artery disease, diabetes mellitus, heart failure, hypertension, and peripheral vascular disease (n = 23 165). Association between co-GDMT and outcome events was evaluated with Cox proportional hazards models, with stratification by all possible combinations of the five comorbidities. Most patients (73.8%) received oral anticoagulants (OACs) as recommended; 15.0% received no recommended co-GDMT, 40.4% received some, and 44.5% received all co-GDMT. At 2 years, comprehensive co-GDMT was associated with a lower risk of all-cause mortality [hazard ratio (HR) 0.89 (0.81–0.99)] and non-cardiovascular mortality [HR 0.85 (0.73–0.99)] compared with inadequate/no GDMT, but cardiovascular mortality was not significantly reduced. Treatment with OACs was beneficial for all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use; only in patients receiving all co-GDMT was OAC associated with a lower risk of non-haemorrhagic stroke/systemic embolism. Conclusion In this large prospective, international registry on AF, comprehensive co-GDMT was associated with a lower risk of mortality in patients with AF and CHA2DS2-VASc ≥ 2 (excluding sex); OAC therapy was associated with reduced all-cause mortality and non-cardiovascular mortality, irrespective of co-GDMT use. Clinical Trial Registration Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

OBJECTIVE:There is a substantial incidence of stroke in patients with atrial fibrillation (AF) not receiving anticoagulation. The reasons for not receiving anticoagulation are generally attributed to clinician's choice, however, a proportion of AF patients refuse anticoagulation. The aim of our study was to investigate factors associated with patient refusal of anticoagulation and the clinical outcomes in these patients.METHODS:Our study population comprised patients in the Global Anticoagulant Registry in the FIELD (GARFIELD-AF) registry with CHA2DS2-VASc≥2. A logistic regression was developed with predictors of patient anticoagulation refusal identified by least absolute shrinkage and selection operator methodology. Patient demographics, medical and cardiovascular history, lifestyle factors, vital signs (body mass index, pulse, systolic and diastolic blood pressure), type of AF and care setting at diagnosis were considered as potential predictors. We also investigated 2-year outcomes of non-haemorrhagic stroke/systemic embolism (SE), major bleeding and all-cause mortality in patients who refused versus patients who received and patients who did not receive anticoagulation for other reasons.RESULTS:Out of 43 154 AF patients, who were at high risk of stroke, 13 283 (30.8%) did not receive anticoagulation at baseline. The reason for not receiving anticoagulation was unavailable for 38.7% (5146/13 283); of the patients with a known reason for not receiving anticoagulation, 12.5% (1014/8137) refused anticoagulation. Diagnosis in primary care/general practitioner, Asian ethnicity and presence of vascular disease were strongly associated with a higher risk of patient refusal of anticoagulation. Patient refusal of anticoagulation was associated with a higher risk of non-haemorrhagic stroke/SE (adjusted HR (aHR) 1.16 (95% CI 0.77 to 1.76)) but lower all-cause mortality (aHR 0.59 (95% CI 0.43 to 0.80)) compared with patients who received anticoagulation. The GARFIELD-AF mortality score corroborated this result.CONCLUSION:The data suggest patient refusal of anticoagulation is a missed opportunity to prevent AF-related stroke. Further research is required to understand the patient profile and mortality outcome of patients who refuse anticoagulation.

AIMS Peripheral artery disease (PAD) patients suffer a high risk of major cardiovascular (CV) events, with athero-thrombo-embolism as the underlying pathophysiologic mechanism. Recently, two large randomized clinical trials evaluated the efficacy and safety of low-dose rivaroxaban twice daily plus aspirin in stable PAD outpatients and those immediately after peripheral revascularization. We sought to determine if the effects of low-dose rivaroxaban and aspirin compared to aspirin alone are consistent across this broad spectrum of PAD patients. METHODS AND RESULTS We conducted a random-effects meta-analysis of the COMPASS and VOYAGER randomized trials among 11 560 PAD patients (4996 from COMPASS and 6564 from VOYAGER) in the primary analysis and 9332 (2768 from COMPASS and 6564 from VOYAGER) with lower extremity (LE)-PAD in the secondary analysis. The hazard ratio (HR) for the composite of CV death, myocardial infarction, ischaemic stroke, acute limb ischaemia, or major vascular amputation was 0.79 (95% confidence interval, CI: 0.65-0.95) comparing low-dose rivaroxaban plus aspirin to aspirin alone. While the risk of major bleeding was increased with low-dose rivaroxaban plus aspirin compared to aspirin alone [HR: 1.51 (95% CI: 1.22-1.87)], there was no significant increase in severe bleeding [HR: 1.18 (95% CI: 0.79-1.76)]. Similar effects were observed in the subset with symptomatic LE-PAD. CONCLUSIONS Among PAD patients, low-dose rivaroxaban plus aspirin is superior to aspirin alone in reducing CV and limb outcomes including acute limb ischaemia and major vascular amputation. This reduction is offset by a relative increase in major bleeding, but not by an excess of fatal or critical organ bleeding. The consistency of findings of these trials supports the use of combination low-dose rivaroxaban plus aspirin in PAD patients across a broad spectrum of disease.