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Article

Evaluating Major Bleeding Risks with Concomitant Use of Direct Oral Anticoagulants and Selective Serotonin Reuptake Inhibitors in Nonvalvular Atrial Fibrillation Patients

by
Shu-Yu Yao
1,2,*,
Paul T. Kocis
3,
Terrence E. Murphy
1 and
Wenke Hwang
1
1
Department of Public Health Sciences, Penn State College of Medicine, 90 Hope Drive, Hershey, PA 17033, USA
2
College of Pharmacy, Taipei Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan
3
Department of Pharmacology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA
*
Author to whom correspondence should be addressed.
Pharmacoepidemiology 2025, 4(1), 6; https://doi.org/10.3390/pharma4010006
Submission received: 16 January 2025 / Revised: 26 February 2025 / Accepted: 3 March 2025 / Published: 6 March 2025
Browse Figures
Figure 1
<p>Study cohort selection.</p> "> Figure 2
<p>The association of major bleeding risk with SSRIs among NVAF patients taking DOACs, adjusted by inverse probability of treatment weighting using the propensity score (age, congestive heart failure, hypertension, diabetes, peripheral vascular disorders, renal disease, hepatic disease, stroke/transient ischemic attack, vascular disease, bleeding history, excess alcohol use, concomitant use of aspirin or NSAIDs, CHA2DS2-VASc score, HAS-BLED scores, ACEI, ARB, beta-blocker, calcium channel blocker, diuretic, statin, proton pump inhibitor).</p> "> Figure 3
<p>The association of major bleeding risk with SSRIs among NVAF patients taking individual DOACs. Edoxaban was not included in stratified analysis because the sample size (n = 7) was too small.</p> ">
Versions Notes

Abstract

:
Background/Objectives: Direct oral anticoagulants (DOACs), when compared to the Vitamin K antagonist (VKA) warfarin, exhibit greater safety and effectiveness. However, DOACs may still have potential drug–drug interactions that result in major bleeding events. There is a paucity of studies on medications that have pharmacodynamic interactions with DOACs, such as selective serotonin reuptake inhibitors (SSRIs). This study evaluates the potential major bleeding risk associated with the concomitant use of SSRIs among nonvalvular atrial fibrillation (NVAF) patients who were receiving DOACs. Methods: Adult patients receiving DOACs with consecutive NVAF diagnoses were identified from the Penn State Health Electronic Health Records from 2013 to 2023. These patients were then checked for exposure (i.e., concomitant use of SSRIs). The outcome was time to the first occurrence of a major bleeding event, with a follow-up from the first DOAC prescription until a major bleeding event, death, or end of follow-up. This retrospective cohort study used a Cox cause-specific proportional hazard model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with inverse probability of treatment weighting to adjust for measurable confounding factors (e.g., demographics, comorbidities, comedications). Results: A total of 8657 NVAF patients who were receiving DOACs were identified. The mean age was 70.3 ± 11.95 years, and females comprised 39.8% of the study population. The baseline CHA2DS2-VASc score was 3.77 ± 1.76, and the HAS-BLED score was 2.98 ± 1.27. Among these patients, 2649 (30.6%) were co-prescribed with SSRIs. The unadjusted hazard ratio for SSRIs was 0.87 (95% CI: 0.76–0.99) and the adjusted hazard ratio was 0.68 (95% CI: 0.59–0.78). Conclusions: In patients with NVAF receiving DOACs, concomitant use of SSRIs was not associated with a higher risk of major bleeding.

1. Introduction

Direct oral anticoagulants (DOACs), also known as Non-Vitamin K antagonist oral anticoagulants (NOACs) [1], are commonly prescribed to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) [2,3,4]. DOACs can be divided into two categories: direct oral thrombin inhibitors (i.e., dabigatran) and direct oral factor Xa inhibitors (i.e., apixaban, edoxaban, rivaroxaban) [2,3,4]. Compared with the Vitamin K antagonist (VKA) warfarin, DOACs have the advantages of rapid onset, short half-life, no need for laboratory monitoring, and exhibit fewer drug and food interactions [5,6]. Studies have also shown that DOACs are more effective at reducing stroke risk, along with having a lower risk of bleeding than warfarin [7,8,9,10,11,12].
Even with these benefits, DOACs still have potential drug–drug interactions (DDIs) that may result in major bleeding events due to pharmacokinetic (PK) and pharmacodynamic (PD) interactions. Many of studies and guidelines have focused on PK drug interactions with DOAC that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. These PK-interacting medications (e.g., amiodarone, ketoconazole, clarithromycin) may inhibit DOAC metabolism and thus increase DOAC plasma concentrations, leading to increased bleeding risk [2,13,14,15]. Food and Drug Administration (FDA)-approved prescribing information has also recommended adjusting the dose or avoiding concomitant use of some PK-interacting medications with DOACs [16,17,18,19]. Research focusing on PD-interacting medications with DOACs is relatively absent, but there is still the potential for additive effects that increase bleeding risk. Potential PD-interacting class of medications include antiplatelet, non-steroidal anti-inflammatory analgesics (NSAIDs), other anticoagulants, and selective serotonin reuptake inhibitors (SSRIs) [15,20,21]. Other studies have shown that coadministration of DOACs with antiplatelets, NSAIDs, and other anticoagulants increase the risk of bleeding [22,23,24,25].
SSRIs are among the most commonly prescribed medications in the United States [26,27]. Because SSRIs have a broad efficacy with relatively few side effects when compared to other antidepressants, they have been widely prescribed, especially in the elderly [28,29,30]. However, some studies have pointed out that SSRIs themselves have bleeding-related adverse reactions, including increased gastrointestinal bleeding and intracranial bleeding [31,32,33,34]. Both SSRIs and DOACs are often prescribed for an extended period of time for their respective indications. There are likely a lot of patients receiving both medications, especially in elderly population where multiple medications are often prescribed. There is a paucity of studies that evaluate the major bleeding risk associated with the concomitant use of SSRIs among NVAF patients prescribed DOACs. Some studies describe patients’ concomitant prescriptions of DOACs with SSRIs being associated with increased risks of major bleeding [22,35,36,37,38], while others showed no significant increase or lower risk of bleeding [39,40,41,42]. This study aims to use real-world data to confirm whether concomitant use of SSRIs is associated with an increased risk of major bleeding among NVAF patients who were receiving DOACs.

2. Materials and Methods

2.1. Data Set

This study used electronic health records (EHRs) from the Penn State Health system—a large health system serving the central Pennsylvania region. Penn State College of Medicine/Penn State Health is a member of the PCORnet Clinical Research Network, funded by the Patient Center Outcomes Research Institute. The PCORnet Common Data Model [43,44] standardizes all individual-level data variables and leverages data interoperability across health systems so the data repository can serve as a national resource for clinical and translational research. This model provides essential predictors, covariates, and outcomes for clinical researchers, streamlining data collection for study participants and reducing the workload for both patients and researchers. The study was approved by the Penn State Office of Research Protections (STUDY00021114).

2.2. Study Population

Patients with two or more outpatient visits to Penn State Health between 1 June 2013 and 31 May 2023 were included, to ensure they were regular patients (i.e., not one-time visitors). We then selected patients prescribed the following DOACs: apixaban, dabigatran, edoxaban, rivaroxaban, and who were ≥18 years of age. Among these DOACs’ users, we only included patients with prior consecutive NVAF diagnoses, defined as at least two diagnoses of atrial fibrillation at least 30 days apart with no evidence of mitral stenosis or a prosthetic heart valve [45]. The excluded indications were based on European Heart Rhythm Association and American Heart Association (AHA) guidelines [3,4]. These patients were then assessed for SSRIs exposure after receiving DOACs to identify whether concomitant use of both medications occurred. Cohort entry was marked by the first DOAC prescription, with follow-up continuing until a major bleeding event, death, or end of the study period.

2.3. Primary Outcome

The primary outcome was the occurrence of major bleeding events in either inpatient or outpatient settings. Major bleeding events were categorized as intracranial bleeding, gastrointestinal bleeding, and other-site bleeding (e.g., respiratory, retinal) [46,47]. People with traumatic bleeding were excluded from this analysis. The diagnostic codes used to define major bleeding events were listed in Supplementary Table S1.

2.4. Covariates

The following covariates were assessed at cohort entry and considered potential confounding factors for the association between SSRI prescription and the risk of major bleeding: age, sex, individual DOACs, race, smoking status, excess alcohol use and CHA2DS2-VASc score and HAS-BLED score. CHA2DS2-VASc score included the following: congestive heart failure, hypertension, age (>65, 1 point; ≥75, 2 points), diabetes, prior stroke or transient ischemic attack (2 points), vascular disease, female. HAS-BLED score included the following: hypertension, abnormal renal and liver function (1 point each), stroke, bleeding tendency or predisposition, labile INRs (not applicable), elderly (>65), medications (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each). Comorbidities included congestive heart failure, hypertension, diabetes, peripheral vascular disorders, renal disease, hepatic disease, stroke or transient ischemic attack, vascular disease, bleeding history or predisposition. Other comedications included aspirin or NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β-blockers, calcium channel blockers, diuretics, statins, and proton pump inhibitors. A detailed medication selection was listed in Supplementary Table S2.

2.5. Statistical Analyses

Descriptive statistics were used to assess the baseline characteristics of our cohort. Continuous variables (e.g., age, CHA2DS2-VASc and HAS-BLED scores) are presented using means with standard deviations (SDs), and compared using the t-test; categorical variables (e.g., sex, comorbidities, comedications) are presented using frequencies (%) and compared using the Chi-square tests.
The major bleeding risk associated with the concomitant use of SSRIs and DOACs among NVAF patients was estimated using the Cox cause-specific proportional hazard model and reported as hazard ratios (HRs) and 95% confidence intervals (CIs). To adjust for the confounding factors, we used inverse probability of treatment weighting (IPTW) by fitting a propensity score model (PS model) for the use of SSRIs. To ensure the comparability of patients, we employed propensity score truncating, resetting the value of weights greater than (or less than) the 98th (or 2nd) percentile to the value of the 98th (or 2nd) percentile [48,49]. The propensity score, calculated from a multivariable logistic regression model, represents the probability of a patient being prescribed an SSRI. In this approach, each patient is weighted by the inverse of the probability of receiving an SSRI. We calculated the stabilized weights by multiplying the weights derived from the propensity scores by the sample proportions of those either using or not using SSRIs [50], as in Equation (1). Given that death may be a competing risk for major bleeding events, we performed a sensitivity analysis using the Fine and Gray model [51]. Inverse probability of treatment weighting (IPTW) was also applied in the competing risk setting. In all cases statistical significance was defined as a p-value < 0.05. All analyses were performed using SAS version 9.4.
Equation (1) Stabilized weights.
S W i = P ( T = 1 ) P S i ,   i f   p a t i e n t   i   r e c e i v e d   S S R I P ( T = 0 ) 1 − P S i ,   i f   p a t i e n t   i   d i d   n o t   r e c e i v e d   S S R I
where P(T = 1) and P(T = 0) are the overall proportions of patients receiving and not receiving SSRIs, respectively.

3. Results

3.1. Patient Demographics and Baseline Characteristics

A total of 8657 patients prescribed with DOACs, ≥18 years old, with NVAF diagnoses were identified between 1 June 2013, and 31 May 2023 (see Figure 1). The mean age of these patients was 70.3 ± 11.95 years, and 39.8% were female. More than 40% of the patients had congestive heart failure and more than 80% of the patients had hypertension. The baseline CHA2DS2-VASc score was 3.77 ± 1.76 and the HAS-BLED score was 2.98 ± 1.27. The most prescribed DOACs were apixaban (n = 5337, 61.65%) and rivaroxaban (n = 2712, 31.33%). Among these patients, 2649 (30.60%) patients were prescribed SSRIs. They were more likely to be female and have more comorbidities and comedications than patients not prescribed SSRIs. All baseline characteristics of the cohort are listed in Table 1.

3.2. Incidence of Major Bleeding Events

After a mean follow-up of 42 months, 1,032 major bleeding events were identified, including intracranial bleeding (n = 194, 18.80%), gastrointestinal bleeding (n = 707, 68.51%) and bleeding of other sites (n = 131, 12.69%). Among patients prescribed DOACs, concomitant use of SSRIs was associated with a lower risk of major bleeding (unadjusted HR = 0.87, (95% CI: 0.76–0.99); adjusted HR = 0.68, (95% CI: 0.59–0.78)). The balance was achieved for each categorical and continuous variable for a standardized difference of <0.20. The forest plot of the unadjusted and adjusted HR is in Figure 2.

3.3. Bleeding Risk with Individual DOACs

The association between SSRIs and bleeding risk among patients prescribed with DOACs did not differ much among the individual DOACs (apixaban: adjusted HR = 0.68, 95% CI: 0.56–0.84; rivaroxaban: adjusted HR = 0.65, 95% CI: 0.52–0.82; dabigatran: adjusted HR = 0.76, 95% CI: 0.49–1.18) (see Figure 3). We did not present the adjusted hazard ratio for edoxaban because the sample size (n = 7) was too small. Table 2 showed the incidence rate of major bleeding events for NVAF patients co-prescribed with DOACs and SSRIs and was stratified by individual DOACs.

3.4. Sensitivity Analysis

Results from the Fine and Gray model were consistent with the primary analysis, with a subdistribution HR of 0.67 (95% CI: 0.58–0.77). This Fine–Gray analysis suggests that the truncation of follow-up due to death does not appear to have injected any substantive bias into the association estimated for the use of any SSRI regarding the hazard of major bleeding among DOAC users.

4. Discussion

The potential pharmacodynamic interaction between SSRIs and DOACs may theoretically increase bleeding risk [20,21]. Studies have indicated that serotonin is released from platelets during vessel injury, resulting in platelet aggregation. SSRIs may inhibit the serotonin transporter responsible for transporting serotonin to the platelets, and may potentially deplete platelet serotonin. This depletion may decrease the ability of blood to clot, thereby increasing the risk of bleeding [52,53,54,55]. However, studies show inconsistent results regarding bleeding risk [22,35,36,37,38,39,40,41,42].
This retrospective cohort study utilized real-world data to evaluate the association between concomitant use of SSRIs and the risk of major bleeding among patients prescribed DOACs with a NVAF diagnosis. After adjusting for confounding factors, our findings showed a lower risk of major bleeding in patients co-prescribed SSRIs with DOACs when compared to SSRIs not concomitantly prescribed.
Our results align with an analysis from the ROCKET AF trial [39] which found no significant increase in the risk of major bleeding among patients assigned to warfarin or rivaroxaban anticoagulant therapy while also taking SSRIs. Similarly, a study using the Austrian health insurance database [40] reported that co-medication of SSRIs with DOACs or vitamin K antagonists (VKAs) has no substantial impact on major bleeding events compared to cotreatment with other antidepressants. Another study using the national health insurance database from Taiwan [41] found that the combination of DOACs and SSRIs was associated with an increased risk of intracerebral hemorrhage (ICH). However, the overall risk of major bleeding, including ICH, gastrointestinal bleeding, and other types of bleeding, was not elevated. Our results are also consistent with a study from the Mayo Clinic [42], suggesting that DOAC-treated patients co-prescribed with SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs) exhibited a lower risk of any bleeding, with no significant association with major bleeding events.
Conversely, some studies have reported conflicting results, indicating an increased risk of bleeding among patients concomitantly taking DOACs and SSRIs [22,35,36,37,38]. We acknowledge that differences in study designs, data sources, sample sizes, and variations in defining major bleeding events could account for the discrepancies. For instance, many studies reporting an increased risk of bleeding utilized a nested case–control design. Additionally, while most studies utilize large population-based databases, regional demographic differences and prescribing practices could contribute to variations in results. Notably, our study spans a relatively long duration (2013–2023), covering the most recent data among all comparable sources. Furthermore, the definition of bleeding events in our study was refined by integrating ICD codes from multiple sources while excluding unrelated bleeding events (e.g., traumatic hemorrhage).
Additionally, the high usage of proton pump inhibitors (PPIs) in our study population may have influenced the results. The prescription of PPIs alongside DOACs is recommended due to the increased risk of upper gastrointestinal bleeding [56]. The high proportion of PPIs use in our cohort suggested a growing trend and increased awareness regarding the use of PPIs to prevent GI bleeding (gastrointestinal bleeding) among patients prescribing with DOACs. Other reasons may be, for example, that we did not include information on the ‘duration of time’ for the use of both medications concomitantly prescribed, nor drug–drug interactions with other medications such as antiplatelets (e.g., clopidogrel).
Our study has several strengths. We utilized electronic health records from a large academic medical center, reflecting DOAC and SSRI prescriptions in a real-world setting. Next, we performed a sensitivity test using the Fine and Gray model. This is important, since death is a strong competing risk for major bleeding events, particularly among elderly DOAC users. In addition, as mentioned above, the definition of bleeding events in our study was refined and excluded unrelated bleeding events, making our classification more specific. Furthermore, our study covers a relatively long period, incorporating the most up-to-date data among comparable sources. Nonetheless, several limitations warrant further consideration. First, our results relied on pre-existing records, which may have been misclassified or under-reported, potentially leading to biases. Second, although we applied inverse probability of treatment weighting to the covariates available in our data, we could not include any confounders which were not present in our data. For this reason, some unmeasured confounders may not be balanced between the two groups due to the limitations of what variables were available in our data. Third, capturing over-the-counter medications such as NSAIDs and aspirin in our data set was challenging. Lastly, the actual medication adherence of the patients remains unknown.

5. Conclusions

In conclusion, our study found no evidence to support an increased risk of major bleeding among patients with concomitant use of SSRIs and DOACs. These findings provide a different perspective regarding the safe use of SSRIs with DOACs in patients with NVAF. However, healthcare providers should be mindful to evaluate each patient’s medical condition before prescribing these medications.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/pharma4010006/s1: Table S1: Definitions and codes of major bleeding events; Table S2: Detailed medication selection list; Table S3: Balance assessment between groups before and after IPTW; Figure S1. Standardized mean differences between groups before and after IPTW; Table S4. The proportion of the different types of SSRIs; Table S5. Hazard ratio of individual SSRIs.

Author Contributions

Conceptualization, S.-Y.Y., T.E.M., W.H. and P.T.K.; methodology, S.-Y.Y. and T.E.M. and W.H. and P.T.K.; software, S.-Y.Y. and T.E.M. and W.H.; validation, S.-Y.Y., T.E.M. and W.H.; formal analysis, S.-Y.Y., T.E.M. and W.H.; investigation, S.-Y.Y.; resources, W.H.; data curation, S.-Y.Y. and W.H.; writing—original draft preparation, S.-Y.Y.; writing—review and editing, W.H., P.T.K. and T.E.M.; visualization, S.-Y.Y.; supervision, W.H.; project administration, S.-Y.Y. and W.H.; funding acquisition, W.H. All authors have read and agreed to the published version of the manuscript.

Funding

The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR002014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Institutional Review Board Statement

The study was approved by the Penn State Office of Research Protections (STUDY00021114).

Informed Consent Statement

Not applicable.

Data Availability Statement

Derived data supporting the findings of this study are available from Penn State Health Electronic Health Records (EHRs), under the PCORnet, on request.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
DOACsDirect oral anticoagulants
VKAVitamin K antagonist
SSRIsSelective serotonin reuptake inhibitors
NVAFNonvalvular atrial fibrillation
DDIsDrug–drug interactions
PKPharmacokinetic
PDPharmacodynamic
P-gpP-glycoprotein
NSAIDsNon-steroidal anti-inflammatory analgesics
ACEIsAngiotensin-converting-enzyme inhibitors
ARBsAngiotensin receptor blockers
SNRIsSerotonin-norepinephrine reuptake inhibitors
PPIsProton pump inhibitors
GIGastrointestinal
HRsHazard ratios
CIsConfidence intervals
SDsStandard deviations
PS Propensity score
AHAAmerican Heart Association
FDAFood and Drug Administration

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Pharmacoepidemiology 04 00006 g001
Figure 1. Study cohort selection.
Figure 1. Study cohort selection.
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Figure 2. The association of major bleeding risk with SSRIs among NVAF patients taking DOACs, adjusted by inverse probability of treatment weighting using the propensity score (age, congestive heart failure, hypertension, diabetes, peripheral vascular disorders, renal disease, hepatic disease, stroke/transient ischemic attack, vascular disease, bleeding history, excess alcohol use, concomitant use of aspirin or NSAIDs, CHA2DS2-VASc score, HAS-BLED scores, ACEI, ARB, beta-blocker, calcium channel blocker, diuretic, statin, proton pump inhibitor).
Figure 2. The association of major bleeding risk with SSRIs among NVAF patients taking DOACs, adjusted by inverse probability of treatment weighting using the propensity score (age, congestive heart failure, hypertension, diabetes, peripheral vascular disorders, renal disease, hepatic disease, stroke/transient ischemic attack, vascular disease, bleeding history, excess alcohol use, concomitant use of aspirin or NSAIDs, CHA2DS2-VASc score, HAS-BLED scores, ACEI, ARB, beta-blocker, calcium channel blocker, diuretic, statin, proton pump inhibitor).
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Figure 3. The association of major bleeding risk with SSRIs among NVAF patients taking individual DOACs. Edoxaban was not included in stratified analysis because the sample size (n = 7) was too small.
Figure 3. The association of major bleeding risk with SSRIs among NVAF patients taking individual DOACs. Edoxaban was not included in stratified analysis because the sample size (n = 7) was too small.
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Table 1. Baseline characteristics of NVAF patients prescribed with DOACs with or without SSRIs prescription.
Table 1. Baseline characteristics of NVAF patients prescribed with DOACs with or without SSRIs prescription.
CharacteristicTotal
(n = 8657)		With SSRI
(n = 2649)		Without SSRI
(n = 6008)		p Value
Age (Years, SD)70.26 (11.95)70.02 (12.26)70.37 (11.81)0.2105
Sex, Female3444 (39.78%)1342 (50.66%)2102 (34.99%)<0.0001
DOAC 0.6147
Apixaban5337 (61.65%)1607 (60.66%)3730 (62.08%)-
Rivaroxaban2712 (31.33%)856 (32.31%)1856 (30.89%)-
Dabigatran601 (6.94%)184 (6.95%)417 (6.94%)-
Edoxaban7 (0.08%)2 (0.08%)5 (0.08%)-
Race, White 7770 (89.75%)2414 (91.13%)5356 (89.15%)0.0051
Smoking Status <0.0001
Current Smoker620 (7.16%)262 (9.89%)358 (5.96%)
Former Smoker4019 (46.42%)1240 (46.81%)2779 (46.25%)
Never Smoked3807 (43.98%)1096 (41.37%)2711 (45.12%)
Unknown Smoking Status211 (2.44%)51 (1.93%)160 (2.66%)
Excess alcohol use354 (4.09%)158 (5.96%)196 (3.26%)<0.0001
Comorbidities
Congestive Heart Failure3507 (40.51%)1188 (44.85%)2319 (38.60%)<0.0001
Hypertension7346 (84.86%)2334 (88.11%)5012 (83.42%)<0.0001
Diabetes 3188 (36.83%)1095 (41.34%)2093 (34.84%)<0.0001
Peripheral Vascular Disorders2700 (31.19%)922 (34.81%)1778 (29.59%)<0.0001
Renal Disease2467 (28.50%)827 (31.22%)1640 (27.30%)0.0002
Hepatic Disease1374 (15.87%)498 (18.80%)876 (14.58%)<0.0001
Stroke/Transient Ischemic Attack 2166 (25.02%)848 (32.01%)1318 (21.94%)<0.0001
Vascular Disease3811 (44.02%)1295 (48.89%)2516 (41.88%)<0.0001
Bleeding History or Predisposition39 (0.45%)13 (0.49%)26 (0.43%)0.7104
Comedication
Aspirin or NSAIDs6138 (70.90%)1976 (74.59%)4162 (69.27%)<0.0001
ACEIs4205 (48.57%)1382 (52.17%)2823 (46.99%)<0.0001
ARBs2909 (33.60%)903 (34.09%)2006 (33.39%)0.5254
Beta-Blockers5962 (68.87%)1852 (69.91%)4110 (68.41%)0.1636
Calcium Channel Blockers4907 (56.68%)1629 (61.49%)3278 (54.56%)<0.0001
Diuretics6182 (71.41%)1992 (75.20%)4190 (69.74%)<0.0001
Statins6352 (73.37%)2070 (78.14%)4282 (71.27%)<0.0001
Proton Pump Inhibitors5449 (62.94%)1907 (71.99%)3542 (58.95%)<0.0001
CHA2DS2-VASc Score3.77 (1.76)4.12 (1.75)3.62 (1.75)<0.0001
HAS-BLED Score2.98 (1.27)3.19 (1.27)2.88 (1.26)<0.0001
NSAIDs denotes non-steroidal anti-inflammatory drugs; ACEIs refers to angiotensin-converting-enzyme inhibitors; ARBs denotes angiotensin receptor blockers.
Table 2. Incidence rate of major bleeding events among NVAF patients prescribed with DOACs with or without SSRIs prescription.
Table 2. Incidence rate of major bleeding events among NVAF patients prescribed with DOACs with or without SSRIs prescription.
ExposureNo. of EventPerson-YearsIncidence Rate per 1000 Person-Years
All DOAC Patients
 With SSRIs29810,119.4129.45
 Without SSRIs73421,300.2634.46
Apixaban Patients
 With SSRIs1534751.1032.20
 Without SSRIs3659875.3736.96
Rivaroxaban Patients
 With SSRIs1164268.6627.17
 Without SSRIs2988973.2033.21
Dabigatran Patients
 With SSRIs291087.3626.67
 Without SSRIs712421.4729.32
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Yao, S.-Y.; Kocis, P.T.; Murphy, T.E.; Hwang, W. Evaluating Major Bleeding Risks with Concomitant Use of Direct Oral Anticoagulants and Selective Serotonin Reuptake Inhibitors in Nonvalvular Atrial Fibrillation Patients. Pharmacoepidemiology 2025, 4, 6. https://doi.org/10.3390/pharma4010006

AMA Style

Yao S-Y, Kocis PT, Murphy TE, Hwang W. Evaluating Major Bleeding Risks with Concomitant Use of Direct Oral Anticoagulants and Selective Serotonin Reuptake Inhibitors in Nonvalvular Atrial Fibrillation Patients. Pharmacoepidemiology. 2025; 4(1):6. https://doi.org/10.3390/pharma4010006

Chicago/Turabian Style

Yao, Shu-Yu, Paul T. Kocis, Terrence E. Murphy, and Wenke Hwang. 2025. "Evaluating Major Bleeding Risks with Concomitant Use of Direct Oral Anticoagulants and Selective Serotonin Reuptake Inhibitors in Nonvalvular Atrial Fibrillation Patients" Pharmacoepidemiology 4, no. 1: 6. https://doi.org/10.3390/pharma4010006

APA Style

Yao, S.-Y., Kocis, P. T., Murphy, T. E., & Hwang, W. (2025). Evaluating Major Bleeding Risks with Concomitant Use of Direct Oral Anticoagulants and Selective Serotonin Reuptake Inhibitors in Nonvalvular Atrial Fibrillation Patients. Pharmacoepidemiology, 4(1), 6. https://doi.org/10.3390/pharma4010006

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