01. Can SSRIs Be Safely Prescribed With Oral Anticoagulants?

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SSRIs and Oral Anticoagulants: A Risky Combination?

We know that SSRIs are generally safe and well-studied in medical populations. They are, for example, the most studied psychiatric medications in cardiac populations and have a good track record in that regard. We certainly think of them as being safer than tricyclic antidepressants or monoamine oxidase inhibitors.

One of the concerns that does seem to be present with SSRIs though is an increased risk of bleeding. We think about this on the consult service. For example, we might be more hesitant to prescribe an SSRI to a patient who is hospitalized for a GI bleed.

One question that has previously been studied but up till now lack a large well-controlled cohort trial is whether SSRIs further increase the risk for bleeding when added to a regimen that already includes an oral anticoagulant. That’s the question we’re going to tackle today.

Study Design: Population-Based Nested Case-Control

We’re looking today at a population-based nested case-control study recently published in JAMA Network Open. The study used a 23-year time frame and examined patients with a new incident diagnosis of atrial fibrillation during that time who were started on any of the commonly prescribed direct oral anticoagulants, those are commonly referred to as DOACs, or warfarin.

The use of DOACs in particular has exploded over the past decade increasing from 10% to 15% of all oral anticoagulant prescriptions in 2015 to nearly 75% in 2019. Outcomes in this study were hospitalization for or death from bleeding. So the bleeding events examined were significant.

Over 330,000 patients were started on an oral anticoagulant during the study period and more than 42,000 of them were hospitalized for a major bleeding event during an average four-year followup period. For each case, up to 30 controls were selected, matched by age, sex, date of cohort entry and duration of followup.

Major Findings: Increased Bleeding Risk with SSRI + Anticoagulant

The major finding of the study was that concomitant SSRI and oral anticoagulant use was associated with a 33% increased risk of major bleeding when compared to the use of oral anticoagulants alone. That risk was highest in the first month of concomitant use, declining after 30 days and being substantially lower than peak by six months.

The association was present for multiple types of bleeding including:

• Intracranial hemorrhage
• GI bleeding
• Other major bleeding

The risk remained constant after controlling for age, sex, a history of major bleeding, the presence of chronic kidney disease and the type of oral anticoagulant. There was a suggestion that overall bleeding risk with SSRIs might be lower for DOACs than for warfarin.

Notably, the risk of bleeding did not vary according to the potency of SSRIs, meaning that a more potent serotonin reuptake inhibitor like paroxetine was not associated with a higher risk of bleeding than a less potent SSRI like escitalopram. Finally, the authors ran an interaction analysis to try to determine whether the risk was due specifically to cytochrome P450 drug-drug interactions and concluded that this likely represented only a minimal contribution.

Why Is This Study Important?

After all, SSRIs have previously been shown to increase bleeding risk and as I mentioned earlier it’s already something we think about when prescribing them. The general consensus is that this has to do with platelet activity.

The authors of this study posit that by blocking the serotonin reuptake transporter on platelet membranes and drastically reducing serotonin concentration in platelets, SSRIs diminish platelet activation and aggregation. So the findings aren’t necessarily surprising.

Well mainly, the importance of the study relates to its size and design. Prior observational studies had suggested some increased risk when combining SSRIs and oral anticoagulants but these studies were often underpowered. A meta-analysis of eight studies also suggested an increased risk of bleeding with the combination but was missing some key data about certain patient populations.

This study reinforces those earlier conclusions and fills in some important gaps including suggesting that the risk is the same regardless of age or sex and that drug-drug interactions likely play a minimal role. The issue is an important one because both SSRIs and oral anticoagulants are extremely commonly prescribed and co-prescription is increasingly common.

As the authors point out, current guidelines for SSRIs do highlight the increased risk of bleeding when used as monotherapy and some mention potential interactions with NSAIDs but the risk of interactions with oral anticoagulants aside from potential drug-drug interactions is actually not mentioned.

Practical Implications for Prescribers

So what do you do if you’re seeing a new patient already taking an oral anticoagulant who presents with a new onset major depressive disorder? Importantly, these findings don’t suggest that you shouldn’t prescribe an SSRI if indicated but they might lead you to take some steps to try to reduce the risk.

If the patient is taking warfarin, the risk seems higher and it might be worth a conversation with their PCP or cardiologist to see whether a DOAC would be an option. There is also some evidence that prescribing a proton pump inhibitor may decrease the risk of bleeding. So that might also be worth discussing with their PCP.

Among SSRIs, potency doesn’t seem to matter in terms of bleeding risk. So it’s probably not worth choosing a less potent SSRI specifically to reduce risk. You could consider a different class of antidepressants but keep in mind that other classes haven’t really been studied in this regard and that almost all antidepressants except bupropion have serotonergic properties.

Perhaps most importantly, the studies suggest that in conjunction with other providers you should think about and attempt to mitigate other risk factors for bleeding and make sure all prescribers are aware of the risk. Patients should be monitored most closely in the first 30 days after starting an SSRI as the risk decreases after that.

The good news is that for patients who tolerate the combination for the first six months without bleeds, the risk of future bleeds seems substantially lower than it is at the start of treatment.

Abstract

Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding

Alvi A. Rahman, M.Sc.; Robert W. Platt, PhD; Sarah Beradid, M.Sc.; et al. JAMA Netw Open. 2024;7(3):e243208.

Importance 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.

Reference

Rahman, A., Platt, R., Beradid, S. (2024). Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding. JAMA Netw Open. 2024;7(3):e243208.