The delicate balance between the risk of acute post-angioplasty thrombosis and haemorrhagic complications linked to aggressive antithrombotic therapy has always been a matter of concern for clinicians and the scientific community. It becomes even more complex when an indication for oral anticoagulant therapy coexists, for example, in patients with atrial fibrillation, wearers of prosthetic heart valves, cardiac chamber thrombosis, or with concomitant pulmonary embolism and deep vein thrombosis. In these situations, choice, association, and duration of treatment with antithrombotic drugs may involve multiple pharmacological combinations and different temporal strategies. The current guidelines pose rather flexible indications leaving the clinician the possibility of adjusting the therapy to the patient’s risk profile from time to time. On the other hand, this variability generates inevitable confusion as to which is the most appropriate therapeutic choice.