Selective serotonin reuptake inhibitor use and bleeding risk under VKAs

Why did you (and your colleagues) write this paper? What was its main purpose?

There was still uncertainty regarding the increased risk of major bleeding due to selective serotonin reuptake inhibitor (SSRI) use in patients treated with a Vitamin K antagonist (VKA) and the possible mechanisms of these bleeds. The potential mechanisms were CYP2C9 enzyme inhibition, decreased platelet function, and increased gastric acid secretion. In addition, no research conducted before studied phenprocoumon use, which is one of the two used VKAs in the Netherlands. We studied whether the risk of major bleeding was increased and which mechanisms cause the major bleeding, which could guide us towards the most optimal treatment for depression and thrombosis when combining these drugs is necessary.

Furthermore, we took confounding by indication (depression) into account by including tricyclic antidepressants (TCAs) as a negative control to ensure that our findings were caused by SSRIs rather than depression.

What are the main conclusions?

SSRI initiation and in particular the initiation of CYP2C9 inhibiting SSRIs is associated with an increased risk of a high INR during VKA use, which could result in major bleeding. Based on our results, an association between SSRI use and increased risk of major bleeding during VKA use is highly possible. These results suggest that platelet inhibition and a pharmacokinetic interaction (by CYP2C9 enzyme inhibition) both may play a role in the occurrence of a high INR and major bleeding after SSRI initiation and during SSRI use.

What are the paper's implications?- to the public?-to medical professionals?

The results imply that patients who use VKAs and SSRIs may be at increased risk for major bleeding compared with non-SSRI users. These major bleeds may be caused by a CYP2C9 interaction between SSRIs and VKAs, by platelet inhibition by SSRIs, and by the indication of depression.

Are the findings clinically significant? Should the findings change practice?

To take our results into account in clinical practice, several aspects must be considered. The risk of a high INR for the CYP2C9-inhibiting SSRI users was higher than for non-CYP2C9-inhibiting SSRIs and non-users. Therefore, when a patient has to start SSRI when already using a VKA, we would suggest starting a non-CYP2C9 inhibiting SSRI, based on our results. Since the INR increase may also be caused by the indication of depression, one may consider more intensive monitoring during the first two months of SSRI and TCA use.