Perceived risk of bleeding was the leading cause for non-treatment with OACs in high-risk AF patients, and risk prediction modelling indicated that the benefits of anticoagulation in stroke and mortality reduction outweigh the risk of bleeding.
Abstract
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 CHA2DS2-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
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.
Deborah M. Siegal, Marc Carrier, M. Bahit et al.· Circulation· 0 citations
BackgroundNew-onset atrial fibrillation (AF) is a common complication of sepsis, affecting 5-25% of patients, and is associated with increased mortality and ischemic stroke. With limited high-quality evidence, the net clinical benefit of early oral anticoagulant (OAC) initiation in this high-risk setting remains uncertain.MethodsAdults ≥18 hospitalized with sepsis who developed new-onset AF within 3 days were identified from the TriNetX database. Cohort one included patients who received at least three doses of OAC within 3 days after AF onset and was compared to those who did not receive OAC (cohort two). Propensity score matching (1:1; 90 covariates; caliper 0.1) was employed to balance the groups. The primary outcomes assessed were evaluated at 7, 14, and 30 days. Risk ratios and risk differences with 95% confidence intervals were estimated using intention-to-treat analysis.ResultsAmong 136,172 eligible patients, 10,773 were matched per group. Early OAC use was associated with significantly lower mortality at 7, 14, and 30 days (RR 0.19-0.35; all p < 0.001) and reduced ischemic stroke risk across the same intervals (RR 0.74-0.83; p ≤ 0.004). Major bleeding rates were also lower (RR 0.40-0.49; all p < 0.001). MACEs showed a modest reduction at 7 days (RR 0.92; p = 0.001) but not afterward. Thromboembolic events were similar beyond the first week. The need for thrombolytics (RR 0.55-0.59) and anti-hemorrhagic therapy (RR≈0.69) consistently remained lower with OACs (all p < 0.001). Falsification outcomes were neutral, except for a minimal late increase for osteoarthritis at 30 days (RR 1.16; p = 0.03).ConclusionIn sepsis-associated NOAF, early OAC initiation was associated with reduced short-term mortality and ischemic stroke without excess bleeding or thromboembolic risk. The large magnitude of mortality benefit and paradoxical reduction in bleeding likely reflect residual confounding by clinical stability and patient selection. Findings warrant cautious interpretation given the observational design; prospective trials are needed.
A. Qadeer, Michele Fouad, Doaa Bayomi et al.· Journal of Intensive Care Me...· 0 citations
BACKGROUND
Despite the growing use of catheter ablation for atrial fibrillation, large-scale studies assessing the efficacy and safety of oral anticoagulation (OAC) after ablation, particularly in patients with high stroke risk, remain limited.
METHODS
This prospective study enrolled consecutive patients from the China-AF (China Atrial Fibrillation) registry between August 2011 and June 2022. Stroke risk was stratified by CHA2DS2-VA score as low (0-1), intermediate (2), or high (≥3). The study end points were thromboembolism (ischemic stroke or systemic embolism), and bleeding (International Society on Thrombosis and Hemostasis major bleeding and clinically relevant non-major bleeding). A 6-month landmark analysis was applied to evaluate the association of OAC with end points using incidence rates and Cox models.
RESULTS
Among 13 669 patients (median follow-up, 4.0 years), 2637 continued and 11 032 discontinued OAC at the 6-month landmark. OAC was not associated with reduced thromboembolism risk across low- (adjusted hazard ratio [aHR], 1.11 [95% CI, 0.70-1.77]; P=0.649), intermediate- (aHR, 0.64 [95% CI, 0.36-1.16]; P=0.141) or high-stroke risk patients (aHR, 1.05 [95% CI, 0.74-1.48]; P=0.801). In contrast, continued OAC was associated with higher bleeding risk, including clinically relevant non-major bleeding across stroke risk strata, and International Society on Thrombosis and Hemostasis major bleeding among high-risk patients (aHR, 2.32 [95% CI, 1.19-4.50]; P=0.013). These results were consistent across subgroups and sensitivity analyses.
CONCLUSIONS
In this large, real-world cohort of patients with atrial fibrillation undergoing catheter ablation, continued OAC was not associated with lower thromboembolic risk, but with higher major bleeding risk among patients with CHA2DS2-VA scores ≥3. These findings support individualized post-ablation anticoagulation strategies and warrant future investigation.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT06987825.
Lan Ren, Xiaodong Peng, Sitong Li et al.· Journal of the American Hear...· 0 citations
Atrial fibrillation (AF) is highly prevalent in nonagenarians (≥ 90 years). However, this group is often excluded from clinical trials, leaving limited real-world evidence on oral anticoagulant (OAC) use, safety, and efficacy. This study sought to investigate the usage patterns, predictors, and in-hospital outcomes of OAC therapy in nonagenarian patients with AF to provide real-world evidence to inform clinical decision-making.
A retrospective single-center analysis was conducted on 290 nonagenarian AF patients (Beijing Hospital, 2018–2024). Patients were grouped as OAC (
n
= 89) or non-OAC (
n
= 201). Primary endpoints: In-hospital stroke/SE (efficacy) and major bleeding (ISTH criteria; safety). Secondary endpoints included in-hospital composite efficacy, net clinical benefit (stroke/SE/major bleeding/all-cause death), and all-cause death. Multivariate logistic regression identified OAC predictors; OAC temporal trends were analyzed.
The overall OAC utilization rate was 30.69% and showed a steady annual increase. Positive predictors of OAC use included a history of ischemic stroke (OR = 2.653) and heart failure (OR = 2.083), while negative predictors included bedridden status (OR = 0.134), and concomitant antiplatelet use (OR = 0.203). DOAC accounted for 82.02% of OAC prescription, and 63.01% of DOAC users were inappropriately underdosed. Compared with the non-OAC group, OAC use was significantly associated with a lower risk of in-hospital stroke/SE (6.74% vs. 15.42%, OR = 0.396, 95% CI = 0.159–0.987,
p
= 0.047) and improved secondary composite efficacy outcomes (OR = 0.491,
p
= 0.024). The OAC group also demonstrated a numerically lower incidence of net clinical benefit outcomes (20.22% vs. 30.85%), though it did not differ significantly between groups (2.25% vs. 0.50%,
p
= 0.215), though total bleeding events were higher in the OAC group (49.44% vs. 36.32%,
p
= 0.037).
Although the overall OAC utilization rate in AF patients aged ≥ 90 years remains relatively low, it has shown a steady annual increase, with DOACs emerging as the predominant choice. OAC therapy is significantly associated with a lower risk of in-hospital stroke and demonstrates favorable net clinical benefit, highlighting the potential value of the judicious use of OAC in this population.
Chinese Clinical Trial Registry, identifier ChiCTR2300076161.
BACKGROUND
Current U.S. and European guidelines recommend oral anticoagulation as a class IIa indication in patients with atrial fibrillation at intermediate risk for stroke; however, evidence from randomized trials is needed.
METHODS
We conducted a multicenter, open-label, adjudicator-masked superiority trial in South Korea involving patients with atrial fibrillation and an intermediate risk of stroke (a score of 1 in men and 2 in women on the CHA2DS2-VASc scale; range, 0 to 9, with higher scores indicating a greater risk of stroke). Patients were randomly assigned in a 1:1 ratio to receive either direct oral anticoagulant (DOAC) therapy or no anticoagulation. The primary end point was a composite of stroke, systemic embolism, major bleeding, or death from cardiovascular causes at 24 months.
RESULTS
Of 1803 patients who underwent randomization, 902 were assigned to receive DOAC therapy and 901 were assigned to receive no anticoagulant therapy. The mean age of the patients was 60.4 years, and 23.7% were women. At 24 months, a primary end-point event had occurred in 4 patients (cumulative incidence, 0.5%) in the DOAC group and in 13 (cumulative incidence, 1.5%) in the no-anticoagulant group (difference, -1.0 percentage points; 95% confidence interval [CI], -2.0 to -0.1; P = 0.03; hazard ratio, 0.31; 95% CI, 0.10 to 0.94). Stroke occurred in 3 patients (cumulative incidence, 0.3%) in the DOAC group and in 10 (cumulative incidence, 1.1%) in the no-anticoagulant group. The incidence of systemic embolism and major bleeding appeared to be similar in the two trial groups, and no deaths from cardiovascular causes occurred in either group. Serious adverse events occurred in 80 patients (8.9%) in the DOAC group and in 84 (9.3%) in the no-anticoagulant group.
CONCLUSIONS
Among patients with atrial fibrillation at intermediate risk for stroke, DOAC therapy led to a lower risk of stroke, systemic embolism, major bleeding, or death from cardiovascular causes at 24 months than no anticoagulation. (Funded by the Ministry of Health and Welfare, South Korea, and others; SINGLE-AF ClinicalTrials.gov number, NCT04437654.).
Daehoon Kim, Young-soo Lee, J. Shim et al.· New England Journal of Medic...· 0 citations
Anticoagulant therapy is the cornerstone of stroke prevention in atrial fibrillation (AF), yet its management in elderly and frail patients remains particularly challenging. This review aims to summarize current evidence, guideline recommendations, and future perspectives regarding the optimal anticoagulant strategy in this vulnerable population. Main findings A narrative review of pivotal randomized clinical trials and major real-world registries was conducted, focusing on outcomes of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients aged ≥75 years or meeting frailty criteria. Across studies, DOACs consistently demonstrated similar or superior efficacy compared with VKAs for the prevention of stroke and systemic embolism, with a substantially lower risk of intracranial hemorrhage. Apixaban and edoxaban, particularly at adjusted doses, showed the most favorable balance between thromboembolic protection and bleeding risk. Conversely, switching stable elderly patients from long-term VKAs to DOACs, as in the FRAIL-AF trial, was associated with an early excess of clinically relevant non-major bleeding. Frailty, multimorbidity, renal impairment, and polypharmacy remain critical modifiers of both efficacy and safety, underlining the need for individualized dosing and regular renal function monitoring. Recent European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) and the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guidelines recommend DOACs as the preferred treatment for non-valvular AF, emphasizing comprehensive risk assessment and shared decision-making. Emerging agents, such as factor XI inhibitors, offer a promising approach to minimizing bleeding risk in the elderly, though confirmation of their efficacy against ischemic events remains to be fully established. Conclusions In elderly and frail patients with AF, DOACs represent the first-line anticoagulant therapy when appropriately dosed and monitored. A personalized, multidisciplinary approach incorporating frailty assessment, renal evaluation, and patient preference is essential to optimize outcomes. Future trials specifically enrolling very old and severely frail patients are urgently needed to close existing evidence gaps.
Lorenzo Scalia, Laura Gatto, Federica Agnello et al.· American Journal of Cardiolo...· 1 citation
