Combining SSRIs With Oral Anticoagulants May Increase Bleeding Risk

People with atrial fibrillation who take selective serotonin reuptake inhibitors (SSRIs) and oral anticoagulants have an increased risk of multiple types of major bleeding compared with their peers who take only oral anticoagulants, a study in JAMA Network Open has found. The study findings also suggest that bleeding risk differs depending on the type of anticoagulant.

“In light of these findings, the risk of major bleeding may be a pertinent safety consideration for patients using SSRIs and [oral anticoagulants] concomitantly,” wrote Alvi Rahman, Ph.D., M.Sc., a pharmacoepidemiologist at McGill University in Montreal, and colleagues.

The researchers examined data from 331,305 patients in the United Kingdom aged 18 years or older who had atrial fibrillation and began taking oral anticoagulants between January 2, 1998, and March 29, 2021. The researchers included anticoagulants that directly target blood-clotting proteins (apixaban, dabigatran, edoxaban, and rivaroxaban), as well as warfarin, which indirectly reduces clotting by inhibiting vitamin K. They also identified if these patients were being prescribed SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline) at the same time.

Patients were followed until a first major bleeding event, death, end of registration with the patient’s general medicine practice, or end of the study period, whichever came first.

Rahman and colleagues identified 42,190 patients who experienced a major bleeding event and matched each one with up to 30 similar adults taking an oral anticoagulant who did not experience bleeding (a total of 1,156,641 controls, although these included duplicates who were selected at different time points during follow-up).

Compared with patients who took only oral anticoagulants, patients who took oral anticoagulants and an SSRI had a 33% increased risk of any major bleeding. Among subtypes of events, there was a 38% increased risk of gastrointestinal bleeding, a 56% increased risk of intracranial hemorrhage, and a 23% increased risk of other types of major bleeding.

The increased risk of major bleeding was higher in patients who took warfarin and an SSRI (36%) compared with those who took a direct oral anticoagulant and an SSRI (25%). However, the risk of major bleeding was not higher in patients who took more potent SSRIs like fluoxetine, paroxetine, or sertraline compared with other SSRIs.

Rahman said that the difference in bleeding risk between those who took direct oral anticoagulants and those who took warfarin was small, but that this result aligned with earlier studies.

Overall, the risk of major bleeding was strongest in the first 30 days of taking SSRIs and oral anticoagulants.

“Given that previous studies have shown that SSRIs reduce serotonin content in platelets by 80-90% within a period of two to three weeks, we anticipated that patients most susceptible to bleeding would experience an event shortly after initiating concomitant use of SSRIs and oral anticoagulants. Thus, our findings were in line with our expectations,” said principal investigator Christel Renoux, M.D., Ph.D., an associate professor in the Department of Neurology and Neurosurgery at McGill University. “However, the association between the duration of concomitant SSRI and oral anticoagulant use and the risk of major bleeding had not been previously explored, highlighting the novelty of this result.”

Rahman said that the study’s results do not suggest that treatment with either SSRIs or oral anticoagulants should be withheld. Rather, the results reinforce the need for communication among members of the patient’s health care team.

“By ensuring that all health care providers are aware of the medications being prescribed, including potentially interacting medications such as SSRIs and oral anticoagulants, measures can be taken to mitigate the risk of bleeding,” Rahman said. “Also, individual risk factors for bleeding should be tightly controlled to minimize risk.”

Renoux agreed, noting that other antidepressants may not be as effective as SSRIs for managing a patient’s mental health condition or may also have undesirable adverse effects.

“For instance, serotonin-norepinephrine reuptake inhibitors [SNRIs] may also increase the risk of bleeding, given their role in inhibiting serotonin reuptake. However, this has not been well studied,” she said.

“In practice, patients treated with oral anticoagulants are already monitored, given the increased risk of bleeding. Our results highlight the need for extra vigilance when patients are treated with both oral anticoagulants and SSRIs,” Renoux added. “Whether treatment with SSRIs is still needed should also be reevaluated regularly to limit the duration of concomitant use with oral anticoagulants.”

This study was supported in part by Rahman’s receipt of a Tomlinson Doctoral Fellowship from McGill University, a Canada Graduate Scholarship–Doctoral from the Canadian Institutes of Health Research, and a stipend from the Drug Safety and Effectiveness Cross-Training Program. ■