Bleeding Risk With SSRIs, Part 1: Cardiovascular and Cerebrovascular Considerations

CATEGORY 1 CME

Premiere Date: September 20, 2023

Expiration Date: March 20, 2025

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

The goal of this activity is to describe current understanding of bleeding risk associated with use of serotonin reuptake inhibitors (SRIs) and to review research-informed literature on related bleeding complications in patients with cardiovascular and cerebrovascular disease.

LEARNING OBJECTIVES

After engaging with the content of this CME activity, you should be better prepared to:

- Understand the mechanisms by which the bleeding risk is thought to occur.

- Understand SRI-related bleeding complications in patients with cardiovascular and cerebrovascular disease.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource®, LLC. No commercial support was received.

OFF-LABEL DISCLOSURE/DISCLAIMER

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource®, LLC.

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FACULTY, STAFF, AND PLANNERS’ DISCLOSURES

The authors; John J. Miller, MD, and Richard Balon, MD (external peer reviewers); and the staff members of Physicians’ Education Resource®, LLC, and Psychiatric Times have no relevant financial relationships with commercial interests.

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Serotonin reuptake inhibitors (SRIs), including selective SRIs (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are common treatments for many psychiatric conditions. SRIs are a first-line therapy for major depressive disorder (MDD), a top cause of disability globally that has a lifetime prevalence rate of 16.6%.¹ Depression is common in patients with medical illness, and the co-occurrence is linked to inferior medical outcomes.^2,3 SRIs are also used for a wide variety of other conditions, including panic disorder, obsessive compulsive disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, bulimia nervosa, neuropathic pain, and fibromyalgia.

Soon after their introduction to the market, SRIs appeared to interfere with platelet aggregation, leading to concern for an increased risk of bleeding.⁴ Platelets are fragments of cytoplasm derived from megakaryocytes, which fill holes in injured endothelial cells. Serotonin is not synthesized in platelets; it is taken up from the circulation via active transport and stored in secretory granules. During a bleeding event, platelets release serotonin (and other substances); this leads to multiple effects, including vasoconstriction of smooth muscle to promote hemostasis and acceleration of platelet aggregation. SRIs inhibit serotonin transport pumps in the platelet membrane, leading to a decrease in available serotonin and impairment of platelet function.^4-7 Other theoretical mechanisms involve SRIs decreasing platelet surface markers (eg, integrins, selectins) required for platelet adhesion, aggregation, and secretion.

SRI use is accepted as a cause of an increased risk of bleeding, yet there is significant variability and lack of consensus in the medical literature regarding the specific degree and clinical relevance of this increased risk. In a large population meta-analysis of 31 case-control and 11 cohort studies with more than 1 million participants, the risk of bleeding at any site was increased among patients given SRIs when compared with those not using these agents (OR, 1.41; 95% CI, 1.27-1.57).⁸ The results of other epidemiologic studies demonstrated approximately doubled odds of bleeding with SRI use; however, the absolute risk of bleeding remained low.⁹ Thus, the clinical significance of the elevated risk of bleeding associated with SRI therapy is still being investigated.

Coagulation and hemostasis are tightly controlled physiologically with multiple checks and balances by health care staff. Consequently, for most patients, the increase in bleeding risk on SRIs is most often silent, and it poses minimal clinical implications. However, certain types of bleeds are more clinically meaningful than are others. For example, gastrointestinal (GI) bleeding may be clinically relevant depending on the size of the bleed, whereas any central nervous system bleed is likely of consequence. In general, the SRI-related increase in bleeding risk is most relevant in patients who have other bleeding risk factors. Even then, there is limited available guidance to help clinicians decide how to manage SRIs in patients who have a greater risk of bleeding events. This leads to uncertainty in managing SRIs when medical illness, concomitant use of other agents that may increase the risk of bleeding, or surgical procedures complicate the clinical scenario.

Here, we describe the current state of the medical literature as it pertains to SRIs—specifically, SSRIs and SNRIs—and bleeding risk. A summary of clinical trials related to SRI-associated bleeding that is organized by specific complication can be found in Table 1, Table 1 cont. Table 2 outlines factors, such as concomitant use of anticoagulant medication or Helicobacter pylori infection, and their impact on SRI-related bleeding risk. These tables are cited throughout the review, and they may serve as a clinical reference guide. This review is organized by specific medical condition and comorbid clinical factors, which were chosen according to their relevance to clinical practice, the frequency with which they are encountered in clinical settings, and the availability of clinical data to guide recommendations. It is intended to be a summary and guide for consultant psychiatrists as they consider use of SRIs in medically ill patients, especially those with elevated risks of bleeding.

A note on terminology: In this paper, SRIs is used as a general term for medications that inhibit serotonin reuptake at the serotonin transporter, as this is the primary mechanism that drives increased bleeding risk. SRIs can include medications that selectively affect this transporter (SSRIs) as well as other medications with this action (eg, tricyclic antidepressants [TCAs], SNRIs). The term SRIs should not be used interchangeably with antidepressants, both because medications that are not antidepressants may also block the serotonin transporter, and there are a variety of antidepressants that do not have SRI properties. The studies cited in this paper may have examined SSRIs specifically, SSRIs/SNRIs, antidepressants with SRI activity, and antidepressants generally; therefore, we specify which medications were studied when relevant.

Coronary Artery Disease

Coronary artery disease (CAD) is one of the major cardiovascular diseases and the most common cause of death worldwide.¹⁰ Coronary disease is associated with depression, especially for patients with severe CAD who undergo major coronary operations.¹¹ The SADHART study, a multicenter randomized controlled trial of sertraline in patients with MDD and angina or recent myocardial infarction, showed that sertraline was a safe and effective treatment in this cohort.¹² CAD is also associated with other cardiac conditions, including heart failure, cardiomyopathy, and arrhythmias. These conditions regularly require surgical or endovascular procedures and treatment with thrombolytic, antiplatelet, or anticoagulant medications, all of which may increase a patient’s risk of bleeding. Psychiatric clinicians must weigh the risks of concomitant prescription, polypharmacy, and bleeding against potential benefits when deciding on whether use of SRIs is appropriate for patients with cardiac disease.

Patients with CAD often receive aspirin with or without another antiplatelet agent (eg, clopidogrel), thereby offering protection against thrombotic events but increasing the risk of bleeding events. Often, data vary and conflict, yet the results of observational studies indicate that use of an SRI with low-dose aspirin and clopidogrel may increase the risk of upper GI bleeding.¹³ A systematic review of 32 studies found a higher risk of bleeding among patients taking a combination of an SRI and either antithrombotic or antiplatelet agents compared with those taking antithrombotic/antiplatelet therapy alone.¹⁴ Among patients on anticoagulant or antiplatelet therapy, concurrent SRI use was associated with a higher risk of major bleeding events (odds ratio [OR], 1.39 and 1.45, respectively).¹⁴ Current guidelines from the National Institute of Health and Care Excellence recommend initiation of gastroprotective agents (eg, acid-suppressing drugs) when using SRIs with aspirin, nonsteroidal anti-inflammatory drugs, or antiplatelet agents to mitigate the risk of GI bleeding.¹⁵

Patients presenting with acute complications of chronic and severe CAD (eg, myocardial infarction) often require interventions that may cause adverse bleeding events. Percutaneous coronary intervention (PCI) is a vascular procedure that targets coronary lesions; it is the standard of care for unstable CAD. PCI can be administered with or without thrombolytic therapy; use of thrombolytic agents, however, may increase periprocedural bleeding risk. Given the frequency of major bleeding events after PCI, the American College of Cardiology (ACC) has released a publicly available calculator to estimate patient bleeding risk after PCI.¹⁶ Notably, SRI use is not included in this risk calculator.

The limited data on this topic suggest minimal to no additional risk of bleeding from concomitant use of SRIs with PCI.¹⁰ Nevertheless, such scenarios are generally acute, and the baseline risk of bleeding after PCI substantial. Therefore, psychiatric clinicians may choose to err on the side of caution and recommend that initiation of SRI therapy be deferred until after the acute event is managed and the associated bleeding risk is resolved.

Unfortunately, there is little evidence to guide decision-making on holding and restarting SRIs perioperatively in such situations. As another complication, patients undergoing PCI often receive intravenous unfractionated heparin infusions. One study examining the risk of bleeding in patients taking SSRIs with unfractionated or low-molecular-weight heparin found no increased risk (except with use of escitalopram, interestingly); however, this study involved patients receiving heparin for venous thromboembolisms and did not involve PCI.¹⁷

During PCI, high-risk occlusive coronary lesions often are treated with placement of drug-eluting stents. According to the most recent guidelines from the ACC and the American Heart Association, dual-antiplatelet therapy after PCI involving stent placement is recommended for at least 12 months after an acute coronary syndrome or 6 months after revascularization of stable coronary disease.¹⁸ Again, data on the use of SRIs in these patients are limited. Gastroprotective medications may be beneficial in this population to reduce the risk of GI bleeds.

Severe CAD, which often involves multiple vessels and is not amenable to PCI, is typically managed with coronary artery bypass grafting (CABG). Perioperative bleeding is reported to occur in up to 70% of CABG procedures.^19,20 The cardiac safety and efficacy of SRI therapy in patients with cardiovascular disease undergoing CABG has been well studied, with several articles indicating that cardioprotective effects may be secondary to tempering of serotonin-driven platelet function.^21,22 The clinical trials outlining CABG procedures and SRI-associated bleeding risk can be found in Table 1, Table 1 cont.

No significant effect on perioperative bleeding events related to SRI use, even when assessing objective measures of bleeding (eg, chest tube output), was found in several studies.^23,24 The results of 1 meta-analysis examining the association of SRI use and surgical complications showed an increased risk of mortality in the CABG subanalysis; however, increased bleeding was not addressed specifically.²⁵ One study examining bleeding events in patients who underwent CABG found that SRI use was not associated with an increased risk of bleeding. Furthermore, there was no difference in bleeding outcomes between the group that discontinued SRI use before surgery and did not restart therapy during the hospitalization and the group that discontinued use of SRIs throughout.²⁶ According to these data, there appears to be insufficient evidence to suggest that SRI therapy be discontinued in patients undergoing CABG.

Heart Failure and Ventricular Assist Devices

Continuous-flow left ventricular assist devices (LVADs) are becoming the cornerstone of care for end-stage heart failure when transplant options are limited. LVADs require chronic anticoagulation and cause a myriad of physiologic changes as blood circulation is maintained via continuous pumping of a machine rather than the systole and diastole of an organic heart. These 2 issues make GI bleeding a vexing problem for patients with an LVAD.^27,28

The results of a retrospective study found that SRI therapy was associated with a higher risk of GI bleeding in patients with an LVAD (number needed to harm, 7.6).²⁹ The authors noted that this did not imply that use of SRIs was absolutely contraindicated in those with an LVAD, especially when relapse of psychiatric symptoms was at stake. Therefore, although additional research on SRI use in these patients is warranted, clinicians should be careful to weigh the increased risk of GI bleeds against the risk of uncontrolled psychiatric symptoms in these individuals. When SRIs are used, patients and clinicians should be especially vigilant in monitoring for GI bleeds.

Thromboembolic Disease

As with CAD, other conditions are often treated with vascular procedures, anticoagulants, and antiplatelet agents; in these circumstances, the risks and benefits of concomitant SRI therapy must be weighed. For example, atrial fibrillation can lead to the development of thrombi resulting from pooling of blood in the atrium of the heart. These thrombi may embolize and cause thromboembolic cerebrovascular accidents (CVAs). Patients with stable, rate-controlled atrial fibrillation are usually treated with anticoagulation (unless it is contraindicated) to mitigate this risk of ischemic CVA.30 In the recent ROCKET AF study, outcomes among 737 patients with atrial fibrillation who were taking either rivaroxaban or warfarin to prevent stroke plus SRIs were reported.30 There was no increase in bleeding risk in patients taking SRIs concurrently with these anticoagulants.

Deep vein thromboses and pulmonary emboli are also treated with full-dose anticoagulation using heparin products or a novel oral anticoagulant (NOAC) (eg, dabigatran, rivaroxaban). As with use of unfractionated heparin in acute coronary syndrome, concomitant SRI therapy and full-dose anticoagulation with either unfractionated or low-molecular-weight heparin or NOACs has not demonstrated harm according to limited data.¹⁷

The same cannot be said about concomitant use of SRIs and warfarin. Although NOACs are being used more frequently in clinical practice, warfarin is still frequently prescribed, given its affordability and considerable evidence that supports its efficacy in a variety of conditions. It is also the sole therapy recommended for thromboprophylaxis in patients with concomitant atrial fibrillation and valvular heart disease. However, warfarin can be challenging to manage, especially in acute settings, because it interacts with many other drugs. Furthermore, its anticoagulant effect is diet-dependent—it relies on inhibition of vitamin K, such that increased consumption of foods rich in vitamin K can reduce the efficacy of the warfarin.

Several studies have linked use of SRIs, typically SSRIs, to increased bleeding and mortality when combined with warfarin (Table 2).^31-34 Schelleman and colleagues published a case-control study examining Medicaid claims of 430,000 warfarin users.³¹ Use of nearly all antidepressants studied (SSRIs, SNRIs, and TCAs) was related to an increased risk of GI bleeding when combined with warfarin that was statistically significant. Notably, these results also showed that the increased bleeding risk was highest within the first 30 days of antidepressant prescription (adjusted OR, 1.18-1.75).³²

Some SSRIs (eg, fluvoxamine, sertraline, and fluoxetine) may increase risk of bleeding via inhibition of cytochrome P (CYP)-1A2, CYP2C19, or CYP2C9, which metabolizes warfarin and its isomers. A 2014 retrospective cohort study found that SSRIs, but not TCAs, were associated with an increased risk of severe bleeding requiring hospitalization when combined with warfarin (OR, 1.41).³³ Based on these results, clinicians should exercise caution when prescribing SSRIs for patients who are taking warfarin.

Cerebrovascular Accidents

In CVAs, or “strokes,” the blood supply to the brain is disrupted, resulting in tissue damage. CVAs are generally divided into the more common ischemic CVAs (≈ 85% of total CVAs) and the hemorrhagic subtypes. There is growing evidence that SRIs may improve neuronal cell survival and brain plasticity after ischemic strokes, and their use is becoming the standard of care for patients being treated for CVA, even in the absence of depression.^35,36 Thus, SRIs are very commonly prescribed in the peristroke period, and an understanding of their association with bleeding risk is important for psychiatric clinicians.

There is significant variability in the mechanism, severity, and distribution of ischemic CVA, but these factors are mostly driven by atherosclerotic and/or thromboembolic disease. As described previously, the risk of stroke in patients with atrial fibrillation is mitigated by anticoagulant medications, but this comes with an increased risk of bleeding. SRIs and warfarin should be used together cautiously, but available data have not demonstrated an increased risk of harm when SRIs are used with heparin products or an NOAC.^17,32-34

Depending on the timing of presentation and other factors (including risk of bleeding), patients presenting with an acute ischemic CVA may receive thrombolytic tissue plasminogen activator (TPA) therapy. Although timely use of TPA can significantly improve outcomes after ischemic strokes, treatment carries a significant risk of hemorrhage. Despite this high risk of bleeding, no relationship between SRI and TPA in regard to risk or severity of bleeding events has been shown.

Results from a 2017 large, retrospective database cohort study indicated that SSRI exposure before ischemic stroke in patients who received thrombolytic treatment was not associated with bleeding complications, functional outcome, or mortality.³⁷ Even so, future research is needed to guide clinical decisions regarding the optimal timing, dosage, and concomitant use of antidepressant therapy in the peristroke period, especially in those patients who receive TPA.

In patients with acute hemorrhagic CVA, extreme caution should be used when prescribing SRI therapy. In a large cohort trial, SSRI use prior to intracranial hemorrhage was not associated with an increased risk of intracranial hemorrhage, but use after an intracranial hemorrhage was associated with unfavorable 3-month neurologic outcomes.³⁸ Typically, all agents associated with an increased risk of bleeding are discontinued in the setting of a major, life-threatening intracranial hemorrhage. Generally, we recommend against initiating use of a new SRI during this acute period. Neurology and/or neurosurgical consultation is indicated.

Concluding Thoughts

SRIs are among the most prescribed medications; via a variety of mechanisms, they can increase bleeding risk to a clinically significant degree. Many psychiatric clinicians are aware of the increased risk of bleeding associated with this type of therapy, but the literature is complex and evolving, and the risk of bleeding events varies according to condition and concomitantly prescribed medications. Thus, offering recommendations on management of SRIs in these contexts can be a daunting challenge for psychiatric clinicians.

In the first half of this 2-part review, we summarize the literature on SRI use in a variety of cardiovascular and cerebrovascular conditions, especially those involving concomitantly prescribed anticoagulant and antiplatelet agents. Although general “rules of thumb” would be more convenient, the literature suggests that a granular and nuanced approach that is tailored to the patient, the exact cardiovascular condition being treated, and the specific anticoagulant/antiplatelet agent(s) being co-prescribed is optimal.

Dr Robbins-Welty is chief resident of the combined Internal Medicine & Psychiatry residency program in the departments of medicine and psychiatry at Duke University Medical Center in Durham, North Carolina. Dr Tuck is a medical instructor in the department of psychiatry and behavioral sciences at Duke University Medical Center.
Dr Marchant is affiliated with the department of psychiatry at Westmead Hospital and the department of consultation-liaison psychiatry at Concord Repatriation General Hospital in Sydney, Australia. Dr Gleason is affiliated with the Department of Consultation-Liaison Psychiatry at Concord Repatriation General Hospital and the Florey Institute of Neuroscience and Mental Health at the University of Melbourne in Melbourne, Australia. Dr Key is an assistant professor in the department of psychiatry & behavioral sciences; a courtesy assistant professor in the department of oncology; and program director of the consultation-liaison psychiatry fellowship at the University of Texas at Austin Dell Medical School in Austin, Texas. Dr Lubrano di Ciccone is an associate professor in the department of behavioral medicine at Moffitt Cancer Center in Tampa, Florida. Dr Chopra is affiliated with the University of Texas MD Anderson Cancer Center in Houston, Texas. Dr Mojtahedzadeh is affiliated with the department of psychiatry and Simms/Mann-UCLA Center for Integrative Oncology at the University of California, Los Angeles, in California. Dr Fonseca is a fellow in consultation-liaison psychiatry at the Mayo Clinic in Rochester, Minnesota. Dr Amonoo is an assistant professor of psychiatry at Brigham and Women’s Hospital in Boston, Massachusetts. Dr DeSimone is a clinical assistant professor at Philadelphia College of Osteopathic Medicine and a consultation-liaison psychiatrist at Bayhealth Medical Center in Dover, Delaware. Dr McFarland is an associate professor in the departments of psychiatry and medicine at the Wilmot Cancer Centre of the University of Rochester Medical Center in Rochester, New York.

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