Anticoagulation in patients with atrial fibrillation (AF) and liver cirrhosis is challenging due to competing risks of thrombosis and bleeding. While direct oral anticoagulants (DOACs) have emerged as alternatives to warfarin, their comparative safety and effectiveness in cirrhosis remain incompletely defined. We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adult patients (≥ 18 years) with AF and cirrhosis receiving DOACs or warfarin were identified. Propensity score matching (1:1) was performed to balance baseline characteristics. The primary outcomes were hepatic decompensation and ischemic stroke within 1 year. Secondary outcomes included all-cause mortality, major bleeding, intracranial hemorrhage, gastrointestinal bleeding, and all-cause hospitalization. Survival (Kaplan–Meier) analysis and hazard ratios were estimated. After propensity score matching, 2,522 matched pairs (5,044 patients) were included. Over 1-year follow-up, hepatic decompensation occurred in 8.8% of DOAC patients and 11.1% of warfarin patients, with a significantly lower risk observed in the DOAC group (HR 0.79, 95% CI 0.67–0.95; p = 0.010). Ischemic stroke occurred in 2.9% of DOAC patients and 2.4% of warfarin patients, with no statistically significant difference between groups (HR 1.22, 95% CI 0.85–1.75; p = 0.289). All-cause mortality was lower in the DOAC group (17.7% vs. 20.3%; HR 0.87, 95% CI 0.77–0.99; p = 0.035). No significant differences were observed in major bleeding (HR 0.84, 95% CI 0.70–1.02), intracranial hemorrhage (HR 0.98, 95% CI 0.59–1.62), gastrointestinal bleeding (HR 0.97, 95% CI 0.77–1.23), or all-cause hospitalization (HR 1.04, 95% CI 0.97–1.12). In patients with atrial fibrillation and cirrhosis, DOAC use was associated with lower risks of hepatic decompensation and all-cause mortality compared with warfarin, while no significant difference was observed in ischemic stroke or other safety outcomes. Given the observational design and modest absolute differences, these findings should be interpreted as associative and hypothesis-generating rather than causal or definitive. Graphical abstract

Background: Finerenone and sodium–glucose cotransporter-2 inhibitors provide cardiovascular and renal benefits in patients with chronic kidney disease (CKD) and heart failure (HF), but real-world comparative evidence is limited. Methods: This retrospective study used the TriNetX database. Adults ≥ 40 years with CKD stages 1–5 and HF [LVEF > 40%; excluding end-stage renal disease (ESRD) or dialysis] receiving finerenone were compared with those on SGLT2 inhibitors. Propensity score matching (1:1) yielded 333 patients per cohort. Kaplan–Meier and Cox models estimated hazard ratios (HRs) with 95% confidence intervals. Results: After matching, baseline characteristics were reasonably balanced, with some residual imbalance remaining. All-cause mortality was similar between finerenone and SGLT2 inhibitors at 6 months (HR 0.98; 95% CI 0.50–1.90) and 1 year (HR 0.93; 95% CI 0.53–1.66). All-cause hospitalization or ER visits were also comparable at 6 months (HR 1.07; 95% CI 0.84–1.36) and 1 year (HR 1.04; 95% CI 0.83–1.29). Finerenone was associated with a modest, borderline reduction in HF hospitalization at 1 year, without consistent effects across timepoints or a mortality benefit; thus, this finding is hypothesis-generating (HR 0.81; 95% CI 0.66–0.99). Safety outcomes were similar between groups. Conclusions: In this real-world analysis, finerenone was associated with similar all-cause mortality, overall hospitalization, and renal safety outcomes compared with SGLT2 inhibitors, with a modest reduction in HF hospitalization at 1 year that should be interpreted cautiously given the exploratory nature of the study. These findings are hypothesis-generating and underscore the need for prospective head-to-head trials to better define optimal therapy sequencing in patients with HFpEF and CKD.

Background: Apixaban and rivaroxaban are commonly used direct oral anticoagulants for venous thromboembolism (VTE), but comparative real-world effectiveness and safety data remain limited. Methods: We conducted a retrospective cohort study using the TriNetX database. Adults with VTE were stratified into apixaban and rivaroxaban treatment groups. Propensity score matching balanced baseline characteristics. Time-to-event outcomes up to 2 years were assessed using Kaplan–Meier analysis and Cox proportional hazards models. Results: Following propensity score matching, well-balanced cohorts (8247) were obtained, with a mean age of 58.3 ± 18.0 versus 57.3 ± 18.1 years. Recurrent VTE rates were broadly comparable at 3 months (22.14% vs. 22.26%; HR 1.02, 95% CI 0.95–1.09; p = 0.6, ARD −0.001, 95% CI: −0.014 to 0.011), with small but statistically significant increases observed with apixaban at 6-month (HR 1.07, 95% CI 1.01–1.13; p = 0.016, ARD 0.009, 95% CI: −0.005 to 0.023), 1-year (HR 1.07, 95% CI 1.01–1.12; p = 0.019, ARD 0.004, 95% CI: −0.010 to 0.019), and 2-year follow-ups (HR 1.08, 95% CI 1.04–1.13; p = 0.000, ARD −0.001, 95% CI: −0.013 to 0.011). All-cause mortality was comparable through 1 year; however, a statistically significant increase was observed at the 2-year follow-up for apixaban (HR 1.20, 95% CI 1.06–1.37; p = 0.005, ARD 0.005, 95% CI: −0.002 to 0.013). Bleeding outcomes were largely comparable in the overall cohort, with no statistically significant differences in composite major bleeding (2-year ARD: −0.004, 95% CI: −0.012–0.004), major bleeding (2-year ARD: 0.002, 95% CI: −0.004 to 0.007), gastrointestinal bleeding (2-year ARD: −0.001, 95% CI: −0.004–0.003), or intracerebral hemorrhage (2-year ARD: 0.000, 95% CI: −0.002–0.003) across follow-up periods. A statistically significant reduction in non-major bleeding with regard to apixaban was observed at the 6-month follow-up only (HR 0.79, 95% CI 0.63–0.98; p = 0.033) (2-year ARD: −0.004, 95% CI: −0.010–0.002). Subgroup analyses revealed important heterogeneity: among patients with obesity, composite major bleeding was significantly lower with respect to apixaban at the 2-year follow-up (HR 0.39, 95% CI 0.20–0.76; p = 0.004), whereas among patients with cancer, composite major bleeding was significantly higher with apixaban at the 1-year (HR 1.31, 95% CI 1.02–1.70; p = 0.037) and 2-year follow-ups (HR 1.32, 95% CI 1.04–1.68; p = 0.023). Conclusions: In this real-world propensity-matched analysis, apixaban and rivaroxaban demonstrated broadly comparable effectiveness and safety for VTE treatment, with largely similar bleeding outcomes in the overall cohort. Small but statistically significant increases in recurrent VTE and 2-year mortality with apixaban, alongside subgroup-specific bleeding differences, underscore the importance of individualized treatment selection based on patient-specific risk factors.

Background: Heart failure patients are frequently prescribed SGLT2 inhibitors, but the incremental real-world benefit of adding GLP-1 receptor agonists is uncertain. Methods: A retrospective propensity-matched cohort study was conducted using the TriNetX Global Collaborative Network (171 healthcare organizations). Adults aged ≥18 years with incident heart failure who initiated either dual SGLT2 inhibitor and GLP-1 receptor agonist therapy or SGLT2 inhibitor monotherapy within 1 month of the first heart failure diagnosis were compared. Outcomes over 365 days included all-cause mortality, all-cause hospitalization, acute myocardial infarction, atrial fibrillation/flutter, acute kidney failure, pulmonary edema, new-onset diuretic use, urinary tract infection, retinopathy, and laboratory hypoglycemia (glucose ≤ 70 mg/dL). Cox proportional hazards models were used; the proportional hazards assumption was formally tested. Bonferroni and Benjamini–Hochberg adjustments were applied for multiple comparisons. E-values quantified robustness to unmeasured confounding. Appendicitis was used as a negative control outcome. Results: After 1:1 propensity score matching, 3421 patients were included in each cohort. Cohorts were well-balanced (all standardized mean differences < 0.10). Over 365 days of follow-up, no significant differences were observed between dual therapy and monotherapy in all-cause mortality (HR 0.92, 95% CI 0.77–1.09), all-cause hospitalization (HR 1.16, 95% CI 0.96–1.40), acute myocardial infarction (HR 1.20, 95% CI 0.92–1.55), atrial fibrillation/flutter (HR 1.05, 95% CI 0.85–1.30), acute kidney failure (HR 1.05, 95% CI 0.89–1.26), new-onset diuretic use (HR 0.92, 95% CI 0.78–1.09), or urinary tract infection (HR 1.16, 95% CI 0.90–1.48). Dual therapy was associated with a significant increase in retinopathy (HR 2.66, 95% CI 1.81–3.93; Bonferroni p = 0.001; E-value 4.77, lower CI bound 3.01), and a modest increase in laboratory hypoglycemia (HR 1.22, 95% CI 1.04–1.44) and pulmonary edema (HR 1.35, 95% CI 1.06–1.70), both of which survived FDR but not Bonferroni adjustment. Prespecified subgroup analyses showed lower mortality with dual therapy in patients aged 18–64 (HR 0.64, 95% CI 0.43–0.93) and in women (HR 0.60, 95% CI 0.45–0.81). The negative control outcome (appendicitis) was non-significant. Conclusions: In a propensity-matched real-world cohort with a conservative cohort definition, dual SGLT2 inhibitor and GLP-1 receptor agonist therapy was not associated with significant differences in mortality or major cardiovascular outcomes compared with SGLT2 inhibitor monotherapy. Subgroup signals favoring dual therapy in younger and female patients, alongside safety signals for retinopathy and laboratory hypoglycemia, are hypothesis-generating and should be confirmed in prospective trials.

Background: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) usually coexist and are related to increased morbidity and mortality. Cardiovascular benefits have been demonstrated by drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) and GLP-1 receptor agonists including the dual GIP/GLP-1 receptor agonist tirzepatide (collectively, incretin-based therapies); however, their relative effectiveness in patients with concomitant AF and HFpEF remains undefined. Methods: We conducted a retrospective, propensity score-matched cohort study utilizing the TriNetX Global Collaborative Network. Adults with AF or atrial flutter with a diagnosis of HFpEF who initiated incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) or SGLT2i were included; index medication was required to be initiated within 30 days of a qualifying AF/HFpEF diagnosis. 1:1 matching was performed based on baseline medications, demographics, and comorbidities. Co-primary outcomes were all-cause mortality, inpatient visits, and emergency department (ED) visits at 1 year. Secondary outcomes included myocardial infarction, ischemic stroke, acute kidney injury, transient ischemic attack, major adverse cardiovascular events (MACE; all-cause mortality/MI/stroke composite), and AF-related procedures. Agent-specific subgroup analyses were performed for semaglutide and tirzepatide separately. Sensitivity analyses were conducted at 6 months and 2 years. Results: 7624 patients were included in each cohort after matching (mean age: 70.8 years; 52% women). At 1 year, incretin-based therapy was associated with lower all-cause mortality (5.3% vs. 7.3%, HR 0.721, 95% CI 0.634–0.820; p < 0.001), fewer inpatient visits (30.0% vs. 37.4%, HR 0.743, 95% CI 0.702–0.787; p < 0.001), and no statistically significant difference in ED visits (27.0% vs. 28.0%; HR 0.946, 95% CI 0.888–1.007; p = 0.081) compared with SGLT2i. Incretin-based therapy was also associated with lower risk of MACE (HR 0.709), acute kidney injury (HR 0.751), myocardial infarction (HR 0.583), catheter ablation (HR 0.685), and electrical cardioversion (HR 0.472). No significant differences were observed in ischemic stroke or transient ischemic attack. These findings were broadly consistent at 6-month and 2-year follow-up, and directionally consistent in agent-specific subgroup analyses of semaglutide and tirzepatide. Conclusions: In this large propensity-matched cohort of patients with AF and HFpEF, initiation of incretin-based therapy (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) was associated with lower all-cause mortality, fewer inpatient visits, and reduced cardiovascular events compared with SGLT2i. These findings, while subject to observational limitations, suggest potential benefits of incretin-based therapy in this high-risk population and support the need for prospective comparative trials.

Introduction : Cardiac amyloidosis (CA), most commonly caused by transthyretin (ATTR) or light chain (AL) deposition, is increasingly recognized as a contributor to heart failure, particularly in older adults and patients with heart failure with preserved ejection fraction (HFpEF). Despite advances in diagnostic imaging and disease-modifying therapies, CA remains underdiagnosed, and population-level data on its combined mortality burden with cardiovascular disease (CVD) are limited. Aims : This study aimed to analyze two decades of consecutive mortality data to investigate amyloidosis and cardiovascular disease (CVD) across the United States (US), identifying patterns and disparities in mortality rates. Methods : A retrospective analysis was conducted using mortality data from the CDC WONDER database spanning 1999–2020. Age-adjusted mortality rates (AAMRs) per 1,000,000 persons were calculated, and trends were assessed using Average Annual Percentage Change (AAPC) and Annual Percent Change (APC) using Joinpoint 5.0.2. Results : Between 1999 and 2020, 26,391 Amyloidosis and CVD-related deaths occurred among adults aged 25 and older in the US. The overall AAMR for Amyloidosis and CVD-related mortality increased from 4.40 in 1999 to 9.31 in 2020, with an AAPC of 3.49 (p < 0.001). Most striking was the recent steep rise in AAMRs from 2018 to 2020 with an APC of 13.60. Men exhibited higher AAMRs compared to women. Similar to the overall trend, AAMRs for both men and women had a steep incline in the last decade. African Americans or Blacks had the highest AAMRs (11.4) followed by White (5.11) and Hispanics (3.86). The highest mortality was in the Northeast region (AAMR: 6.71). Nonmetropolitan areas had higher AAMRs than metropolitan areas (5.73 vs 4.76), however, with a more remarkable increase in metropolitan areas. Conclusions :The prevalence of amyloidosis and cardiovascular disease-related deaths has risen markedly, especially between 2018 and 2020. Increased mortality rates were noted among men, African Americans, and individuals in the Northeast region. These patterns emphasize the necessity for focused public health initiatives.