Keith A. A. Fox

Aims: In the SENIOR-RITA trial, among older adults with non-ST-elevation myocardial infarction (NSTEMI), an invasive strategy did not reduce the composite outcome of cardiovascular death or non-fatal myocardial infarction compared with a conservative strategy over a median follow-up of 4.1 years. Objectives: To describe the angiographic characteristics of patients randomized to the invasive arm. Methods and results: SENIOR-RITA was a prospective, multicentre, randomized controlled trial recruiting NSTEMI patients aged ≥75 years. From November 2016 to March 2023, 1518 patients from 48 UK sites were randomized 1:1 to an invasive or conservative strategy. Procedural data were collected, and angiographic data were analysed using quantitative coronary angiography at the Newcastle University angiographic core laboratory using QAngio® XA Medis. Of 680 patients undergoing angiography, quantitative coronary angiography analysis was performed in 667 participants. Obstructive coronary artery disease was found in 76.8%, and 13% had prior coronary surgical revascularization. A total of 1173 lesions were identified. Most lesions (29.5%) were classified as type B2 according to the ACC/AHA classification. Lesions in patients not receiving percutaneous coronary intervention (PCI) were angiographically more complex than those treated with PCI, with a higher prevalence of type C lesions, bifurcation, ostial lesions, and the presence of collaterals. Overall, 330 patients (49.5%) underwent PCI, which was successful in 96.5% with minimal complications. Conclusion: The SENIOR-RITA angiography sub-study is the largest subgroup analysis to date in older NSTEMI adults, providing important insights into the angiographic characteristics and emphasizing the importance of a holistic, patient-centred care for older adults.

Background: GARDENIA is a global, multicentre, prospective, non-interventional study in high-risk atrial fibrillation (AF) patients, who were untreated with anticoagulants. Objectives: Provide contemporary evidence on reasons for non-treatment with an anticoagulant, and outcomes in high-risk AF patients. Methods: GARDENIA enrolled 704 AF patients with a CHA ₂ DS ₂ -VA score ≥2 and an elevated risk of bleeding (older age (≥70 years), reduced renal function, concomitant antiplatelet or NSAID use, or other conditions associated with increased bleeding risk), and had not been recently treated with an oral anticoagulant (OAC). Patients were followed for at least 4 months. The two-year risks of mortality, stroke and major bleeding with or without direct OACs (DOACs) in these patients was estimated using the GARFIELD risk score. Results: History of major bleeding (18.7%), physician-assessed high-risk of bleeding (17.1%), and patient refusal (17.6%) were the top reasons for not initiating OACs. The 100-person-year event rates (95% CI) for mortality, stroke/systemic embolism (SE)/transient ischemic attack (TIA), and ISTH major bleeding were 13.22 (10.33, 16.92), 2.12 (1.14, 3.94), and 2.21 (1.13, 3.91), respectively. GARFIELD risk analysis indicated a 31% and 40% increase in the risk of mortality and stroke, respectively, and a ~ 30% decrease in risk of major bleeding, compared to the estimated risk, had the patients been anticoagulated. The study was prematurely terminated due to low rate of patient accrual. Conclusions: Perceived risk of bleeding was the leading cause for non-treatment with OACs in high-risk AF patients. Risk prediction modelling indicated that the benefits of anticoagulation in stroke and mortality reduction outweigh the risk of bleeding.

Background: Days alive out of hospital (DAOH) is an objective and patient‐centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. Methods and Results: 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) was an international double‐blind, double‐dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator‐reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin ( P =0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P =0.88). Conclusions: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

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.

Individuals with kidney failure undergoing hemodialysis are at elevated risk for thromboembolic events. Factor (F) XI, which is in the intrinsic pathway of coagulation, is emerging as an attractive target for new anticoagulants that may be safer than existing agents. Osocimab—an inhibitory FXIa antibody—is a potential treatment option for such patients. We conducted a phase 2b, double-blind, placebo-controlled trial, in which 704 participants (448 male, 256 female) with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo. In total, 686 participants (436 male, 250 female) received treatment for ≤18 months (planned minimal treatment period of 6 months). The co-primary outcomes were clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) and a composite of the incidence of moderate, severe or serious adverse events. Clinically relevant bleeding occurred in 16/232 (6.9%) and 11/224 (4.9%) participants who received lower- and higher-dose osocimab, respectively, and in 18/230 participants (7.8%) who received a placebo. For the composite adverse event endpoint, incidences were 51%, 47% and 43% in the lower-dose osocimab, higher-dose osocimab and placebo groups, respectively. These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220.

Accurate risk assessment is key to advance personalized treatment strategies in the heterogeneous group of patients with acute coronary syndromes (ACS). In an effort to improve individual mortality and adverse outcomes forecasts the global registry of acute coronary events (GRACE) scoring system was introduced around two decades ago and has become a central tool to guide patient stratification.^1,2 To date, improved outcomes following risk-stratified patient management are well-documented by clinical trials and individual patient data meta-analyses.³ Yet, the continuous evolution of ACS phenotypes and changing ACS treatment strategies warrant periodical re-evaluation of established risk tools in current patient populations.

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 P _interaction =0.08). Compared with warfarin, standard-dose DOAC use resulted in a significantly lower hazard of S/SE with CrCl P _interaction =0.01). The hazard of death was significantly lower with standard-dose DOACs for patients with 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.

The management of atrial fibrillation (AF), the most common sustained arrhythmia, impacts healthcare resource utilization (HCRU). This study aims to estimate global resource use in AF patients, using the GARFIELD-AF registry. A prospective cohort study was conducted to characterize HCRU in AF patients enrolled in sequential cohorts from 2012 to 2016 in 35 countries. Components of HCRU studied were hospital admissions, outpatient care visits, and diagnostic and interventional procedures occurring during follow-up. AF-related HCRU was reported as the percentage of patients demonstrating at least one event and was quantified as rate-per-patient-per-year (PPPY) over time. A total of 49,574 patients was analyzed, having an overall median follow-up of 719 days. Almost all patients (99.5%) had at least one outpatient care visit, while hospital admissions were the second most frequent medical contact, with similar proportions in North America (37.5%) and Europe (37.2%), and slightly higher in the other GARFIELD-AF countries (42.0%; namely Australia, Egypt, and South Africa). Asia and Latin America showed lower percentages of hospitalizations, outpatient care visits, and diagnostic and interventional procedures. Analyses of GARFIELD-AF highlighted the vast AF-related HCRU, underlying significant geographical differences in the type, quantity, and frequency of AF-related HCRU. These differences were likely attributable to health service availability and differing models of care.