Clot Chronicles: DOAC Use in Challenging Patient Cases

Hello, my name is Stephanie Carlin, and I’m a thrombosis pharmacist at Hamilton Health Sciences in Hamilton, Ontario. On this episode of Clot Chronicles, I will be discussing some highlights from the recent paper I published in JTH along with my colleague, Dr. John Eikelboom, reviewing dosing of direct oral anticoagulants (DOACs) in challenging patients with atrial fibrillation (Afib) and venous thromboembolism (VTE) where the guidelines do not provide clear recommendations. 

Canadian, American, and European guidelines uniformly recommend using DOACs at the doses tested in the pivotal Phase III trials. Despite this, clinicians often prescribe doses of DOACs that are unproven and off-label. Common scenarios in which clinicians prescribe off-label reduced doses of DOACs in patients with Afib include advanced age, recurrent falls, history of minor bleeding, or history of major bleeding in which the underlying cause has been definitively treated. (For example, patients with subarachnoid hemorrhage secondary to a ruptured aneurysm that has been coiled, or patients with a gastrointestinal bleed secondary to an ulcer from H. pylori that’s been treated and healed.)

In each of these scenarios, we recommend continuing or restarting patients on a full DOAC dose. Less commonly, it may be reasonable to prescribe reduced doses of DOACs even when not supported by the evidence. This includes patients with Afib and a history of recurrent major bleeding or life-threatening bleeding in whom the underlying cause has not been treated.

In these cases, the first priority is to address modifiable risk factors for bleeding, including controlling blood pressure, stopping unnecessary antiplatelet or NSAID medications, and avoiding excessive alcohol intake. If (despite addressing modifiable risk factors) the patient remains at high risk of bleeding and is not a suitable candidate for left atrial appendage occlusion (LAAO), we suggest consideration of off-label reduced DOAC dosing. 

While off-label reduced doses of DOACs will not offer the same stroke prevention as full doses, they can be expected to provide better protection than aspirin with a similar risk of major bleeding. Other scenarios where off-label reduced doses of a DOACs may be reasonable include spontaneous subdural hematoma, recurrent epistaxis requiring hospitalization and transfusion where the underlying cause cannot be treated, and severe thrombocytopenia in patients with a platelet count less than 50. 

Similar dosing challenges can be encountered in patients with VTE. Patients with unprovoked events are typically treated with extended anticoagulation after an initial 3 to 6 months of treatment. Two trials—EINSTEIN-CHOICE and AMPLIFY-EXTENSION—have demonstrated that dose reduction of rivaroxaban and apixaban is effective and safe. Accordingly, we endorse dose reduction in most patients, but there are certain patient populations not well represented in the studies in whom we would suggest using full-dose extended treatment, including in those with previous VTE recurrence on a reduced-dose DOAC, prior limb- or life-threatening VTE events, CTEPH, severe post-thrombotic syndrome, active cancer, body weight above 120 kg, or BMI above 40. 

In summary, guideline-recommended DOAC doses should be used in the majority of patients. In patients with Afib, do not dose reduce for advanced age, recurrent falls, or minor bleeding alone. Address modifiable risk factors for bleeding. Consider whether LAAO is an appropriate option. Off-label DOAC dose reduction should be preferred over aspirin. 

In patients with VTE who require extended anticoagulant treatment, most patients should undergo dose reduction after 3 to 6 months. Certain patient populations not well represented in the trials, however, may not be appropriate for dose reduction and should continue full-dose DOAC treatment for secondary prevention. 

I would like to thank the North American Thrombosis Forum for inviting me to speak with you today and hope you enjoyed this episode of Clot Chronicles.