EVALUATION OF RISK OF BLEEDING IN COMPARISON OF DOACS VERSUS WARFARIN IN CONCOMITANT LIVER CIRRHOSIS AND ATRIAL FIBRILLATION - A SYSTEMATIC REVIEW AND META-ANALYSIS

Background
Over the last few years, the prevalence of atrial fibrillation (AF) has increased, and it is frequently diagnosed in cirrhotic patients. Current guidelines recommend anticoagulation in AF for prevention of stroke with CHA2DS2-VASc scores ≥2. Cirrhosis has been excluded from the previous studies which have evaluated the efficacy and safety of AC treatment in AF. Being on warfarin, poses a challenge for patients and clinicians due to maintaining a therapeutic INR, food and drugs interactions with warfarin, and narrow therapeutic index. Currently there is no definitive data on clinical outcomes for DOACs and warfarin in cirrhotic patients with AF. We aimed to review the risk of major bleeding and gastrointestinal bleeding with DOACs in comparison of Warfarin in patients with liver cirrhosis and atrial fibrillation.

Methods
We systematically searched Medline, and Embase from inception till Sep 15,2023. The outcome of interest in our meta-analysis was incidence of major bleeding, while secondary outcome was gastrointestinal bleeding. The random effects model was used to calculate the weighted pooled Hazard ratio in assessing Time to event data outcomes with the corresponding 95% confidence intervals for desired outcomes. A p value of < 0.05 was considered statistically significant. Heterogeneity was assessed using the I² Index. Risk of Bias in studies were assessed using ROBINS-1 tool. Data analysis was performed using the Revman software (version 5.4.1).

Results
In our meta-analysis, 5 studies were included with a total population of 13,838 participants of which 7,589 were on DOACs and 6,240 on Warfarin; Men comprised 71.4% in DOACs group; 70.8% in Warfarin group; Average age of 68.4 in DOACs group, and 70.8 in warfarin group. Patients using Antiplatelets comprised of 30.64% In DOAC and 23.85% of Warfarin group; Mean HAS-BLED score in DOACs was 3.30 and in Warfarin group was 3.29. Compared to Warfarin, DOACs use for Atrial fibrillation in patients with cirrhosis was associated with a lower risk of major bleeding, Hazard Ratio 0.66, 95% CI 0.57 to 0.77, random effect, I² = 0%, P <0.00001 (Figure 1) and Gastrointestinal bleeding Hazard Ratio 0.65, 95% CI 0.47 to 0.90, random effect, I² = 47%, P = 0.01 (Figure 2). Comparing Apixaban with Warfarin for gastrointestinal bleeding Hazard Ratio 0.50, 95% CI 0.37 to 0.69, random effect, I² = 0.81%, P <0.0001 (Figure 3) and Rivaroxaban with Warfarin for gastrointestinal bleeding Hazard Ratio 0.61, 95% CI 0.27 to 0.1.42, random effect, I² = 83%, P = 0.26 (Figure 4).

Conclusions
In summary, our study demonstrated the safe bleeding profile of DOACs in comparison with warfarin. However, these findings need to be validated with well-designed clinical studies.

Keywords.
Liver Cirrhosis, Atrial Fibrillation, Direct oral anticoagulants, DOACs, Warfarin, Vitamin K Antagonists.