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Direct oral anticoagulants (DOACs) such as apixaban or dabigatran are excellent options in preventing embolic cardiovascular events. Observational studies have shown that gastrointestinal bleeding risks produced by DOACs could be lowered when correcting some host co-factors i.e. Helicobacter pylori (HP) infection. The upper digestive bleeding (UDB) rates in patients with DOAC indication and the usefulness of anti-HP therapy addition were compared. An observational retrospective study was conducted of medical records of 260 patients treated with DOACs, 130 of whom were concomitantly treated for HP infection in accordance with Maastricht V/Florence consensus. The severity of bleeding, the complexity of endoscopic treatment required to stop the bleeding, the re-bleeding rates, the surgical treatment indication and the overall mortality rates were compared between the groups. The risk of UDB was higher in HP-untreated patients in both types of DOACs used (respectively 2.08, 2.02). HP-untreated Forrest Ia/Ib/IIa and IIb DOACs patients had more severe bleedings compared with same class of HP-treated patients (P=0.007/0.005; 0.009/0.006; 0.048/0.005, 0.044/0.049, respectively). Endoscopic treatments such as adrenaline injections combined with metallic clip attachments were more frequently mandatory in HP-untreated DOACs patients for classes Ia/b and IIa (respectively, P=0.000/0.001, P=0.003/0.003). The re-bleeding rates were higher in HP-untreated patients with concomitant DOACs (OR 82.5; 95% CI 30.1-121.7; P=0.005). A history of peptic ulcer or UDB was associated with a 2.9-fold higher risk of UDB in HP-untreated compared with HP-treated patients, slightly increased for dabigatran compared with apixaban (RR 3.06, 2.72, P<0.5, respectively). Surgical intervention and the UDB-related mortality rates were higher in HP-untreated patients (P=0.041/0.044, P=0.007, respectively). HP-eradication treatment and bacterial clearance improve the safety profile of DOACs treatment, especially in fragile patients, in whom the UDB rates can be lowered, and the overall outcome can be enhanced by this combined approach. [ABSTRACT FROM AUTHOR]