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Concomitant Use of Selective Serotonin Reuptake Inhibitors With OACs and Risk of Major Bleeding
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants associated with a small increased risk of major bleeding. However, the risk of bleeding associated with the concomitant use of SSRIs and oral anticoagulants (OACs) has not been well characterized.
OBJECTIVES
To assess whether concomitant use of SSRIs with OACs is associated with an increased risk of major bleeding compared with OAC use alone, describe how the risk varies with duration of use, and identify key clinical characteristics modifying this risk.
DESIGN, SETTING, AND PARTICIPANTS
A population-based, nested case-control study was conducted among patients with atrial fibrillation initiating OACs between January 2, 1998, and March 29, 2021. Patients were from approximately 2000 general practices in the UK contributing to the Clinical Practice Research Datalink. With the use of risk-set sampling, for each case of major bleeding during follow-up, up to 30 controls were selected from risk sets defined by the case and matched on age, sex, cohort entry date, and follow-up duration.
EXPOSURES
Concomitant use of SSRIs and OACs (direct OACs and vitamin K antagonists [VKAs]) compared with OAC use alone.
MAIN OUTCOMES AND MEASURES
The main outcome was incidence rate ratios (IRRs) of hospitalization for bleeding or death due to bleeding.
RESULTS
There were 42 190 patients with major bleeding (mean [SD] age, 74.2 [9.3] years; 59.8% men) matched to 1 156 641 controls (mean [SD] age, 74.2 [9.3] years; 59.8% men). Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OACs alone (IRR, 1.33; 95% CI, 1.24-1.42). The risk peaked during the initial months of treatment (first 30 days of use: IRR, 1.74; 95% CI, 1.37-2.22) and persisted for up to 6 months. The risk did not vary with age, sex, history of bleeding, chronic kidney disease, and potency of SSRIs. An association was present both with concomitant use of SSRIs and direct OACs compared with direct OAC use alone (IRR, 1.25; 95% CI, 1.12-1.40) and concomitant use of SSRIs and VKAs compared with VKA use alone (IRR, 1.36; 95% CI, 1.25-1.47).
CONCLUSIONS AND RELEVANCE
This study suggests that among patients with atrial fibrillation, concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OAC use alone, requiring close monitoring and management of risk factors for bleeding, particularly in the first few months of use.
Additional Info
Disclosure statements are available on the authors' profiles:
Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding
JAMA Netw Open 2024 Mar 04;7(3)e243208, AA Rahman, RW Platt, S Beradid, JF Boivin, S Rej, C RenouxFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
SSRI and anticoagulation may increase bleeding risk
The greatest fear physicians have regarding the use of anticoagulation in patients with atrial fibrillation is bleeding. We know about many medications that increase the bleeding risk with anticoagulation. For example, we are careful with antiplatelet and NSAID use. However, what about selective serotonin reuptake inhibitors (SSRIs)? Would they increase the risk of bleeding?
The authors of this study looked at the UK database and they identified 42,190 patients with atrial fibrillation receiving oral anticoagulant (OAC) therapy who were hospitalized for major bleeding. They matched these patients to 1,156,641 controls.
When they looked at patients who used both SSRIs and OACs, there was a 33% increase in the risk of major bleeding complications (IRR, 1.33; 95% CI, 1.24–1.42). The bleeding risk was highest at 74% during the first 30 days of starting the combination (IRR, 1.74; 95% CI, 1.37–2.22).
They then looked at SSRIs combined with the different types of anticoagulants and found an increase in bleeding risk across the board.
For example, SSRIs in combination with direct oral anticoagulants (DOACs), compared with DOACs alone, was associated with a 25% increase in bleeding risk (IRR, 1.25; 95% CI, 1.12–1.40). SSRIs in combination with vitamin K antagonists (VKAs; such as warfarin), compared with VKAs alone, was associated with a 36% increase in bleeding risk (IRR, 1.36; 95% CI, 1.25–1.47).
And if we put them all together and compared SSRIs in combination with OACs with just OACs alone, there was a 22% increase in the risk of bleeding (IRR, 1.22; 95% CI, 1.16–1.28).
The authors said one explanation is that serotonin is involved in platelet function. Platelets release serotonin, which enhances platelet activation and aggregation, and serotonin primes the platelets to interact with the coagulation factors. In other words, serotonin is critical to platelet function and clot formation.
SSRIs block the reuptake pumps on the surface of the platelet. So now the serotonin released cannot be recycled and brought back into the platelet. This depletes the platelet store of serotonin by 80% to 90%. This means that there will not be enough serotonin to get the platelet primed for clot formation, increasing the risk of bleeding.
So, let us think carefully about the medications we add to anticoagulation therapies. Let us remember that SSRIs reduce platelet function; thus, we should think of SSRI as an “anti-platelet” agent.
Selective serotonin reuptake inhibitors (SSRIs) are recommended as a first-line treatment for major depressive disorder and are considered to have an efficacy comparable to other antidepressants as well as better safety and tolerability; however, they have been associated with major bleeding in several studies. This is linked to their inhibition of the serotonin reuptake transporter, which reclaims serotonin released by platelets in response to vascular injury. Gradually, this leads to a depletion of platelet serotonin content, diminishing the potency of hemostasis over time. While the absolute risk of major bleeding with SSRIs remains relatively low, it may be of concern in patients already at an elevated risk, including those treated with oral anticoagulants (OACs).
In this large population-based study involving patients with atrial fibrillation on OAC therapy, 42,190 cases of hospitalization for bleeding were identified and matched to 1,156,641 controls based on age, sex, calendar year, and duration of OAC use. The concomitant use of SSRIs and OACs was associated with a 33% increased risk of major bleeding compared with OAC use alone. The risk of major bleeding was highest during the initial months of treatment (first 30 days of continuous use; IRR, 1.74; 95% CI, 1.37–2.22) and remained substantial for up to 6 months of use. The association was also present across several important subgroups, including those matched by age, sex, history of bleeding, history of chronic kidney disease, potency of SSRIs, and type of OACs (ie, direct OACs or vitamin K antagonists [VKAs]).
These findings do not imply that treatment with either of these classes of drugs should be withheld as both are highly effective treatments for their primary indications (depression for SSRIs and atrial fibrillation for OACs). Nonetheless, some measures may be taken to mitigate the risk of bleeding. For example, among OACs, direct OACs may be preferred over VKAs as they have a lower potential for pharmacokinetic interactions than VKAs. Moreover, to specifically decrease the risk of gastrointestinal bleeding (in patients at high risk), proton pump inhibitors may be considered. Lastly, individual modifiable risk factors for bleeding should be controlled more closely in patients concomitantly using SSRIs and OACs, and extra caution should be taken within the first few months of concomitant use.