We compared hemorrhagic event reporting between case reports listing dabigatran and reports listing rivaroxaban in the FAERS database including 53,085 hemorrhagic event reports for rivaroxaban and 13,151 hemorrhagic event reports for dabigatran from 2014 to 2019. We used disproportionality analysis to assess the reporting of hemorrhagic events overall and hemorrhagic events in different physiological systems. We found there was a moderate signal for hemorrhage associated with rivaroxaban use compared with dabigatran (ROR 1.58, 1.54–1.62) (Fig. 1). In adverse event cases involving gastrointestinal systems, nervous systems, renal and urinary systems, skin and subcutaneous tissue, or eye systems, hemorrhagic events were not have a higher risk in case reports of rivaroxaban compared to dabigatran (Fig. 2). It is worth noting that the RORs were increased for the risk of hemorrhage with the use of rivaroxaban compared with dabigatran in patients with PE or DVT (Fig. 3).
Hemorrhage is the most common complication of anticoagulants. There are no head-to-head randomized clinical trials to investigate the hemorrhage risk of different NOACs. Up to now, several studies have been conducted to assess the bleeding risk of NOACs using some spontaneous reporting systems (14,16–17). It should be noted that they all use warfarin or all other drugs present in the database for the reference drug to disproportionality analysis. In this study, we directly use rivaroxaban and dabigatran for comparison. Thus making the baseline characteristics of the study population more consistent.
Overall, we observed a moderate signal for hemorrhagic events associated with rivaroxaban compared with dabigatran (ROR 1.58, 1.54–1.62) (Fig. 1). Patrick et al. compared rivaroxaban with dabigatran at standard and reduced doses in a propensity-score-matched cohort study and found that different doses of dabigatran had lower bleeding risk (dabigatran vs. rivaroxaban harzard ratio, HR, 95% CI: standard dose HR 0.59, 0.39–0.90, reduced dose HR 0.74, 0.57–0.96) . Douros et al. compared the risk of major bleeding between rivaroxaban and dabigatran through a meta-analysis that included 6 studies. The result showed that there was an increased bleeding risk for rivaroxaban versus dabigatran (HR 1.33; 95% CI: 1.20–1.47) .
We compared hemorrhagic event reporting between rivaroxaban and dabigatran by different physiological systems. GI hemorrhage and intracranial hemorrhage are the two main adverse reactions that clinicians focus on. A meta-analysis showed rivaroxaban, but not dabigatran, was associated with an increased risk for major GI hemorrhage (RR 1.39; 95% CI, 1.17–1.65 and HR 1.14; 95% CI, 1.04–1.23) . In our study, compared with hemorrhagic event reporting for dabigatran, there was a moderate signal of hemorrhage for rivaroxaban with the ROR (95% CI) in GI was 1.38 (1.34–1.42). For intracranial hemorrhage, some large clinical trials have reported the bleeding event rates per. Rates of intracranial bleeding with the 110-mg dose of dabigatran was 0.23% and the 150-mg dose of dabigatran was 0.30% , rates of intracranial bleeding with the rivaroxaban was 0.50% . Since it is not a head-to-head study, no clinical conclusion can be drawn from it. We evaluated nervous system hemorrhage as intracranial hemorrhage. Intracranial hemorrhage consisted of hemorrhagic stroke and subdural or subarachnoid hemorrhage. There was not a signal of hemorrhage for rivaroxaban in nervous system compared with dabigatran with the ROR (95% CI) in nervous system was 0.94 (0.90–0.98). In adverse event cases involving GI systems, nervous systems, renal and urinary systems, skin and subcutaneous tissue, or eye systems, hemorrhagic events were not have a higher risk in case reports of rivaroxaban compared to dabigatran (Fig. 2).
In different indications, we found a increased risk of hemorrhage with the use of rivaroxaban compared with dabigatran in patients with PE or DVT (ROR 2.02, 95% CI: 1.67–2.47 in PE and ROR 2.17, 95% CI: 1.82–2.59 in DVT) (Fig. 3). No direct head-to-head comparisons are available for NOACs in venous thrombo-embolism (VTE) treatment. A network meta-analysis, on the basis of indirect comparison of NOACs for the treatment of VTE, revealed a relative risk for a major or clinically relevant nonmajor bleeding 1.50 (95% CI: 1.17–1.92, p = 0.001) for rivaroxaban versus dabigatran . Those findings suggest that VTE treatment including DVT or PE with rivaroxaban is associated with more bleeding compared to administration of dabigatran.
Furthermore, we performed subgroup analyses for the primary outcome by conducting the disproportionality analysis by gender, age, year of reporting, and severity of adverse event. For the secondary analyses, there was a moderate signal for rivaroxaban-associated hemorrhage among case reports of patients over 65 years old (ROR 1.95, 1.89–2.02). Our results are consistent with a previous study on elder patients (> 80 years) with nonvalvular atrial fibrillation  which showed dabigatran was associated with a lower risk of major bleeding (HR 0.77, 0.67–0.90) compared with rivaroxaban. For subgroup analyses by reporting year (Fig. 1), the strikingly low ROR for 2014 may be partly due to the increasing number of patients using rivaroxaban. A study based on IMS Health National Disease and Therapeutic Index found that rivaroxaban treatment visits increased from 2011 Q4 to 2014 Q4, while dabigatran treatment visits remained relatively stable since 2011 Q4 .
The major strength of this study was to provide a head-to-head assessment of hemorrhagic event reporting between rivaroxaban and dabigatran in large pharmacovigilance database and assessed the association in different physiological systems and indications. Certainly there are several limitations. First, FAERS data is prone to reporting biases and missing data, and we were unable to fully control for confounding. Second, because the data lacks a meaningful denominator for causal analyses, we cannot assess incidence and make causal inferences from FAERS data. Third, drug-drug interactions documented in “Reaction” variable of FAERS case reports may not represent all potential interactions as drug-drug interaction may not be reported as an adverse event. And we are not restrict to hemorrhagic drug-drug interaction case reports that have drugs of interest listed as primary or secondary suspect. Lastly, we did not consider the effect of drugs dosage due to missing data, and this could be an important factor in bleeding events.