Direct Oral Anticoagulants Versus Warfarin Across the Spectrum of Kidney Function: Patient-Level Network Meta-Analyses From COMBINE AF.

Harrington J ，Carnicelli AP ，Hua K ，Wallentin L ，Patel MR ，Hohnloser SH ，Giugliano RP ，Fox KAA ，Hijazi Z ，Lopes RD ，Pokorney SD ，Hong H ，Granger CB ... -  《-》

Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex.

Carnicelli AP ，Hong H ，Connolly SJ ，Eikelboom J ，Giugliano RP ，Morrow DA ，Patel MR ，Wallentin L ，Alexander JH ，Cecilia Bahit M ，Benz AP ，Bohula EA ，Chao TF ，Dyal L ，Ezekowitz M ，A A Fox K ，Gencer B ，Halperin JL ，Hijazi Z ，Hohnloser SH ，Hua K ，Hylek E ，Toda Kato E ，Kuder J ，Lopes RD ，Mahaffey KW ，Oldgren J ，Piccini JP ，Ruff CT ，Steffel J ，Wojdyla D ，Granger CB ，COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) Investigators ... -  《-》

Effectiveness and Safety of Dose-Specific DOACs in Patients With Atrial Fibrillation: A Systematic Review and Network Meta-Analysis.

Background: Dose adjustments of direct-acting oral anticoagulants (DOACs) for atrial fibrillation are based on pivotal clinical trials assessing their effectiveness and safety in controlled settings. However, the appropriateness of these dosing strategies in real-world practice is uncertain. The purpose of this study is to compare the effectiveness and safety of dose-specific DOACs with those of warfarin. Methods: This study retrieved articles from MEDLINE, Embase, and CENTRAL until March 5, 2024. Primary outcomes were the incidence of stroke/systemic embolisms (S/SEs) and major bleeding (MB). Direct pairwise meta-analyses compared each dose-specific DOAC with warfarin. Heterogeneity was assessed using Higgin's I 2 and Q statistics, while publication bias was evaluated through funnel plots and Begg's and Egger's tests, with adjusted pooled estimates calculated via trim-and-fill and precision-effect estimate with standard error (PET-PEESE) methods. A network analysis was conducted, with additional comparisons made using a Bayesian random-effects model for indirect evidence. Results: A total of 32 studies with 2,332,770 patients were included. Both standard-dose (SD) and low-dose (LD) DOACs significantly reduced S/SE, except for LD apixaban and LD edoxaban. Rivaroxaban did not show significant difference in MB compared to warfarin. In East Asian patients, all doses of DOACs exhibited lower hazard ratios (HRs) for S/SE and MB than those observed in the primary analysis, with LD rivaroxaban significantly reducing MB, a finding not observed in the primary analysis. Rank probability analysis indicated that the dose-specific DOACs had different safety profiles and small but meaningful differences in effectiveness. SD apixaban (S/SE: second, MB: second) and edoxaban (S/SE: first, MB: fourth) and LD edoxaban (S/SE: fourth, MB: first) had high ranks. LD apixaban had the most significant difference in rank for S/SE from SD apixaban, ranking eighth compared to second. Conclusions: This study found that all DOACs provided comparable or superior effectiveness and safety to warfarin. SD apixaban, SD edoxaban, and LD edoxaban achieved a favorable balance between preventing S/SE and MB risk.

Oh SH ，Cheon S ，Choi SY ，Kim YS ，Choi HG ，Chung JE ... -  《-》

Individual Patient Data from the Pivotal Randomized Controlled Trials of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (COMBINE AF): Design and Rationale: From the COMBINE AF (A Collaboration between Multiple institutio

Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date. COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771). In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.

Carnicelli AP ，Hong H ，Giugliano RP ，Connolly SJ ，Eikelboom J ，Patel MR ，Wallentin L ，Morrow DA ，Wojdyla D ，Hua K ，Hohnloser SH ，Oldgren J ，Ruff CT ，Piccini JP ，Lopes RD ，Alexander JH ，Granger CB ，COMBINE AF Investigators ... -  《-》

Long-term risks and benefits of oral anticoagulation in atrial fibrillation patients with cancer: A report from the GLORIA-AF registry.

Anticoagulation therapy in patients with atrial fibrillation (AF) and concomitant cancer can be challenging due to the significantly increased risk of both embolism and bleeding. Moreover, the benefits and risks of vitamin K antagonists (VKA, eg. warfarin) versus non-vitamin K antagonist oral anticoagulants (NOACs) in such patients are less well understood. From the prospective, global, multi-centered Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), we characterized these patients according to their history of prior cancer when enrolled. All patients received anticoagulant therapy. The primary outcome was the composite of all-cause mortality, stroke, transient ischemic attack, systemic embolism. The secondary endpoints were all-cause mortality, cardiovascular death, stroke, major bleeding and thromboembolism during the 3 years follow-up period. Cox regression analyses were used to calculate the hazard ratio (HR) and confidence interval (CI) following propensity score matching (PSM). Overall, among 16,700 patients enrolled in Phase III in GLORIA-AF, 1725 (10%) patients had concomitant cancer(s) at enrolment. After PSM, the primary outcome occurred in 250 (14.8%) of patients with cancer(s) and 160 (9.3%) without cancer(s) (HR, 1.62 [95% CI, 1.33-1.97], p < .001) during the 3 years follow-up period. The risk of all-cause mortality was significantly higher in patients with cancer(s) versus non- cancer(s) (HR, 1.71 [95% CI, 1.37-2.12], p < .001). In patients with cancer(s), after PSM, the use of NOACs was associated with reduced risk of the primary outcome compared with that of VKA (HR, .69 [95% CI, .49-.99], p = .043), as well as a lower risk of thromboembolism (HR, .49 [95% CI, .24-1.00], p = .051), but the risk of major bleeding was not significantly different (HR, .87 [95% CI, .48-1.56], p = .635). Subgroup analysis in patients with cancers showed a reduced risk of major bleeding with NOACs compared with VKA (HR, .18 [95% CI, .04-.8], p = .024) in patients with coronary artery disease (CAD). For the main cancer subtypes (genitourinary, breast, gastrointestinal, haematological and skin), the trends for the risk of primary outcome were consistently favouring NOACs compared with VKA without any significant interaction among these five cancers. Cancer is a common comorbidity in patients with AF and is associated with increased risk of composite of all-cause mortality and thromboembolism. Compared with VKA, NOACs was associated with a lower risk of composite events and showed an advantage in lower risk of thromboembolism, as well as a reduced risk of major bleeding when CAD was also present.

Li M ，Huang B ，Lam SHM ，Ishiguchi H ，Liu Y ，Olshansky B ，Huisman MV ，Chao TF ，Lip GYH ... -  《-》