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: 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: 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: Substance use disorders constitute a major public health crisis in the United States. While overall stroke mortality has declined significantly, trends in stroke mortality among individuals with documented substance use are incompletely understood across demographic and geographic strata. Objective: To compare stroke mortality trends between individuals with and without documented substance use from 1999 to 2023, and to identify demographic and geographic subgroups with elevated burden. Methods: We conducted a comparative retrospective analysis using the CDC WONDER database, examining death certificates from 1999 to 2023. Deaths were identified using ICD-10 codes for stroke and substance use. Age-adjusted mortality rates (AAMRs) per 100 000 were calculated using joinpoint regression, stratified by sex, race/ethnicity, age, census region, and urban-rural status. Results: From 1999 to 2023, stroke accounted for 4 456 273 deaths (average AAMR: 82.85 per 100 000), while stroke with documented substance use resulted in 294 474 deaths (average AAMR: 5.03 per 100 000). Overall stroke AAMR declined from 129.52 to 61.77 per 100 000 (AAPC: − 3.06%, 95% CI: − 3.66% to −2.45%, P <0.001), whereas substance-related stroke AAMR increased from 1.39 to 6.83 per 100 000 (AAPC: 6.64%, 95% CI: 4.93% to 8.38%, P <0.001). Females demonstrated steeper relative increases than males (AAPC: 8.42% vs. 6.27%), with the most dramatic acceleration among older adults ≥65 years (AAPC: 7.36%). Geographic patterns revealed highest rates in Midwest and Western states, with Oregon consistently demonstrating the highest state-level rates (14.28 per 100 000 in 2021–2023). Non-metropolitan areas experienced disproportionate burden compared to metropolitan areas (11.02 vs. 6.38 per 100 000 in 2020). Conclusions: This study identified divergent mortality trends, with declining overall stroke mortality contrasted by a nearly five-fold increase in stroke deaths with documented substance use. These patterns may reflect true epidemiological changes, improved documentation practices, or both, indicating potential for integrated surveillance and targeted interventions in high-burden populations.