What is the interaction between Selective Serotonin Reuptake Inhibitors (SSRIs) and Direct Oral Anticoagulants (DOAC)?

From the Guidelines

Combining selective serotonin reuptake inhibitors (SSRIs) with direct oral anticoagulants (DOACs) requires careful monitoring due to potential increased bleeding risk, and this combination can be used when clinically necessary, but patients should be informed about the elevated bleeding risk and monitored closely. The interaction between SSRIs and DOACs is a concern because SSRIs inhibit platelet aggregation by reducing serotonin reuptake in platelets, while DOACs already prevent clotting by inhibiting specific coagulation factors. Common SSRIs include fluoxetine, sertraline, escitalopram, and paroxetine, while common DOACs include apixaban, rivaroxaban, edoxaban, and dabigatran.

When prescribing both medication classes together, consider using the lowest effective SSRI dose and regularly assess for bleeding signs such as unusual bruising, nosebleeds, blood in urine or stool, or excessive menstrual bleeding. For patients with additional risk factors like advanced age, renal impairment, or concomitant use of NSAIDs or antiplatelet drugs, even greater caution is warranted. Alternative antidepressants with potentially lower bleeding risk, such as mirtazapine or bupropion, might be considered for patients at particularly high bleeding risk who require anticoagulation. According to a study published in Circulation: Arrhythmia and Electrophysiology 1, DOACs are susceptible to drug-drug interactions, and strong inducers of CYP3A4 or P-gp should be avoided in all patients taking DOACs unless previously proven to be otherwise safe.

Some key points to consider when combining SSRIs and DOACs include:

• Monitoring for bleeding signs and symptoms
• Using the lowest effective SSRI dose
• Considering alternative antidepressants with lower bleeding risk
• Being aware of potential drug-drug interactions with DOACs, as reported in a study published in the European Respiratory Review 1
• Taking into account patient characteristics, such as age, renal function, and concomitant medication use, as discussed in a study published in the European Respiratory Review 1
• Being mindful of the potential for increased bleeding risk with certain combinations of medications, as noted in a study published in Circulation: Arrhythmia and Electrophysiology 1

Overall, the combination of SSRIs and DOACs requires careful consideration and monitoring to minimize the risk of bleeding complications, as emphasized in a study published in the European Respiratory Review 1.

From the Research

Interaction between SSRIs and DOACs

The interaction between Selective Serotonin Reuptake Inhibitors (SSRIs) and Direct Oral Anticoagulants (DOACs) has been studied in various research papers.

• The study 2 found that the use of SSRIs with anticoagulant therapy did not significantly increase the bleeding risk, although there was a suggestion of increased bleeding risk with SSRIs added to warfarin.
• Another study 3 found that the concomitant use of antidepressants, including SSRIs, and DOACs was associated with a significantly higher risk of major bleeding.
• The study 4 compared the safety and effectiveness of DOACs and vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation at high risk for gastrointestinal bleeding, but did not specifically examine the interaction between SSRIs and DOACs.

Bleeding Risk

The bleeding risk associated with the concomitant use of SSRIs and DOACs is a concern.

• The study 2 found that the rate of major and nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators.
• The study 3 found that the risk of intracranial bleeding was increased when SSRIs and DOACs were used concomitantly.
• The study 5 found that over-dosing of DOACs was associated with an increased risk of major bleeding, but did not specifically examine the interaction between SSRIs and DOACs.

Clinical Implications

The interaction between SSRIs and DOACs has important clinical implications.

• The study 2 suggests that physicians should be vigilant regarding bleeding risk when prescribing SSRIs and anticoagulants concomitantly.
• The study 3 emphasizes the importance of caution when considering the concomitant use of SSRIs and DOACs.
• The study 4 suggests that DOACs may be a safer alternative to VKAs in patients with non-valvular atrial fibrillation at high risk for gastrointestinal bleeding, but does not provide guidance on the use of SSRIs with DOACs.