03. Do SSRIs Increase Major Bleeding Risk with Oral Anticoagulants?

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SSRIs and Anticoagulants: Increased Bleeding Risk

Among the serious adverse effects of SSRIs is an increased risk of major bleeding, including GI and intracranial hemorrhage. When SSRIs are used alone and in the absence of other risk factors, the absolute risk is relatively small.

But what if your patient is also taking an oral anticoagulant—like warfarin or one of the newer direct oral anticoagulants (DOACs) such as apixaban or rivaroxaban? A new meta-analysis has pooled available data to assess exactly that question: how much risk do we add when combining SSRIs with anticoagulants?

Meta-Analysis Reveals Significant Risk

The authors searched for clinical trials and observational studies that assessed the risk of major bleeding with concomitant use of SSRIs and oral anticoagulants. They defined major bleeding as

• Bleeding requiring hospitalization
• Bleeding requiring transfusion
• A decrease in hemoglobin of at least 2 g/dL

Even though they didn’t find any randomized trials, the researchers identified 14 observational studies:

• 7 cohort studies
• 7 nested case-control studies

After discarding 6 studies with outcome measures that could not be pooled, 8 studies were left to combine in a meta-analysis with a total of 98,000 patients.

The study reported an increased hazard ratio of 1.35 of major bleeding with the addition of an SSRI to oral anticoagulant medication. This elevated risk was significant with a confidence interval of 1.14 to 1.58.

Baseline Bleeding Risks In Context

To put this in perspective, let’s consider the baseline risk for patients on warfarin alone:

• Annual incidence of major bleeding: 2-5%
• Annual incidence of fatal bleeding: 0.5-1%

Several factors contribute to this variability, including:

• Advanced age
• Female sex
• Poor anticoagulation control
• History of bleeding
• Hepatic or renal disease
• Concomitant medications

Direct Oral Anticoagulants Show Higher Risk

Warfarin has been largely replaced by newer direct oral anticoagulant medication for the most common indications including non-valvular atrial fibrillation and venous thromboembolism offering similar to improved efficacy without a requirement for routine coagulation monitoring. These medications are direct in the sense that apixaban, edoxaban and rivaroxaban directly inhibit clotting factor Xa while dabigatran directly inhibits thrombin. The risk of a major bleed is significantly lower with apixaban, edoxaban and low-dose dabigatran than warfarin with no significant difference with higher-dose dabigatran or rivaroxaban.

As direct oral anticoagulant medication has become the preferred choice in treating the most common indications, the authors added a separate secondary analysis to determine the risk of a major bleed in subjects taking concomitant SSRIs with direct oral anticoagulants. Based on 4 studies, the pooled hazard ratio of major bleeding increased to 1.47 with a slightly larger but still significant confidence interval of 1.03 to 2.10.

Study Limitations: Age and Sex Strongly Influence Risk

The authors note that one limitation of the studies included in their meta-analysis is that most of the studies did not stratify for age. In the lone study that did, they reported:

• Patients 75 or older: Significantly elevated risk (HR 1.95)
• Patients under 75: No significant increased risk
• Females: Significantly elevated risk (HR 2.06)
• Males: Non-significant increase (HR 1.45)

Additionally, as all 8 included studies were observational, there’s a risk of bias due to residual confounding. The authors attempted to address this risk by assessing each study for adequate controls along with other sources of bias. Four studies with a serious risk of bias were removed and a secondary analysis was performed in which the authors report their results were consistent with their primary analysis.

It is very difficult to anticipate all the possible confounding factors in an observational study as there could be some unanticipated clinical factor that increases the risk of major bleeding in patients with an indication for an antidepressant.

Mechanism of Increased Bleeding Risk

For me, the most compelling evidence to address the concern of a confound by indication is the study that stratified for type of antidepressant. They found the risk of a major bleed was only significantly increased when SSRIs were added to oral anticoagulant medication but not when tricyclic antidepressants were in which the risk was nominally reduced. Although there could still be a confound in clinical factors involved in the decision to prescribe a tricyclic antidepressant or an SSRI, it is possible that the difference in risk of a major bleed is due to a difference in mechanism of action.

As SSRIs specifically inhibit the reuptake of serotonin, they deplete the serotonin in circulating platelets by 80% to 90%. This deficit becomes apparent during platelet activation with less serotonin release, less platelet aggregation and a prolonged bleeding time. Antiplatelet medications are a known risk factor for a major bleed in patients taking anticoagulant medication. As the risk of serious bleeding is the primary adverse effect in the prescription of anticoagulant medication, an additional increase of 35% to 47% with the addition of an SSRI is of concern.

Clinical Implications and Recommendations

So, what do we do with this information? The authors are not saying to stop prescribing antidepressants in anticoagulated patients. But we do need to be careful—especially in patients with other bleeding risk factors:

• Advanced age
• Liver or kidney disease
• Prior major bleed

In those cases, consider antidepressants with lower affinity for the serotonin transporter. By staying informed and carefully weighing risks and benefits, we can provide the best care for our patients requiring both antidepressants and anticoagulation.

Abstract

Concomitant Use of Selective Serotonin Reuptake Inhibitors and Oral Anticoagulants and Risk of Major Bleeding: A Systematic Review and Meta-analysis

Alvi A. Rahman, Na He, Soham Rej, Robert W. Platt, Christel Renoux

Background: Selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants, are associated with a modestly increased risk of major bleeding. However, in patients treated with both SSRIs and oral anticoagulants (OACs), the risk of major bleeding may be substantial.

Objective: To assess the risk of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone.

Methods: We searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials (from inception to December 1, 2021) for clinical trials and observational studies assessing the association between concomitant use of SSRIs and OACs and the risk of major bleeding. Given sufficient homogeneity of studies, we conducted a random-effects meta-analysis to estimate a pooled hazard ratio (HR) of major bleeding associated with concomitant use of SSRIs and OACs, compared with OAC use alone.

Results: The review comprised 14 studies, including 7 cohort and 7 nested case–control studies. Following assessment of clinical and methodological heterogeneity, eight studies with a total of 98,070 patients were eligible for the meta-analysis. The pooled HR of major bleeding associated with concomitant use of SSRIs and OACs was 1.35 (95% confidence interval [CI]: 1.14–1.58). In secondary analyses, the pooled HR for concomitant use of SSRIs and direct OACs was 1.47 (95% CI: 1.03–2.10).

Conclusion: Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding. Overall, our findings suggest that physicians may need to tailor treatment according to individual patient risk factors for bleeding when prescribing SSRIs to patients using OACs.

Reference

Rahman, A.; He, N.; Rej, S.; Platt, R. & Renoux, C. (2023). Concomitant Use of Selective Serotonin Reuptake Inhibitors and Oral Anticoagulants and Risk of Major Bleeding: A Systematic Review and Meta-analysis. Thromb Haemost 2023; 123(01): 054-063