Background The prevention of stroke in patients with atrial fibrillation (AF) involves the use of oral anticoagulation, commonly in the form of direct oral anticoagulants (DOACs). However, it comes with an increased risk of bleeding, and therefore, counselling patients on their individual risks is important. Although the majority of patients initiated on DOACs have been represented within the clinical trials, some cohorts are under-represented in whom clinicians cannot practice evidence-based medicine. Methods Utilising the pooled clinical trial (CT) data sourced from Medidata Enterprise Data Store, five recent open-label industry-sponsored AF trials were compared with real-world data (RWD) sourced from the HealthVerity™ Marketplace with the occurrence of bleeding events as the primary outcome of interest. Results A total of 64,421 patients were included in the analysis, with 3207 patients from the clinical DOAC trials and 61,214 patients from the RWD cohort. Overall, the patients from the RWD cohort had more co-morbidities, were older (72.2 ± 11.9 vs. 65.3 ± 10.7 years old, p < 0.001), had higher mean CHA2DS2VASc (3.98 ± 1.9 vs. 2.87 ± 1.73, p < 0.001), and HAD-BLED scores (2.13 ± 1.02 vs. 1/04 ± 0.93, p < 0.001) when compared to the trial data. When comparing the incidence of the first major bleed at 12 months post-treatment initiation, rates in the RWD cohort were significantly higher (10.69 vs. 18.97 per 100 person-years). The impact of co-morbidities such as age, CHA2DS2VASc, and HAD-BLED scores was similar in both cohorts; however, there was an under-representation of older females and more co-morbid patients within the clinical trial cohort. Conclusions DOAC-treated patients have a higher bleeding incidence rate in the RWD cohort than in clinical trials. This can be explained by the older patient age group with more complex medical h istories and higher HAS-BLED scores. The under-representation of higher-risk patients and lower proportion of females within clinical trials should be addressed to better translate clinical trial data into real-world clinical practice.