Selective serotonin reuptake inhibitor (SSRI) medications have been linked to increased bleeding risk; however, the actual association among warfarin, SSRI exposure, and bleeding risk has not been well-established. We studied the AnTicoagulation and Risk factors In Atrial fibrillation cohort of 13,559 adults with atrial fibrillation, restricted to the 9,186 patients contributing follow-up time while taking warfarin. Exposure to SSRIs and tricyclic antidepressants (TCAs) was assessed from pharmacy database dispensing data. The main outcome was hospitalization for major hemorrhage. Results were adjusted for bleeding risk and time in international normalized ratio range >3. We identified 461 major hemorrhages during 32,888 person-years of follow-up, 45 events during SSRI use, 12 during TCA-only use, and 404 without either medication. Hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years, p <0.001) and did not differ between TCA exposure and no antidepressants (1.30 per 100 person-years on TCAs, p = 0.94). After adjustment for underlying bleeding risk and time in international normalized ratio range >3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk 1.41, 95% confidence interval 1.04 to 1.92, p = 0.03), whereas TCA exposure was not (adjusted relative risk 0.82, 95% confidence interval 0.46 to 1.46, p = 0.50). In conclusion, SSRI exposure was associated with higher major hemorrhage risk in patients taking warfarin, and this risk should be considered when selecting antidepressant treatments in those patients.
Antidepressant medications are commonly used medications, with a prevalence of 10% to 15% use in adults in the United States. Selective serotonin reuptake inhibitors (SSRIs) are considered a first-line pharmacologic therapy for depression and several other conditions and are widely prescribed because of relatively favorable side-effect profiles. However, there is some evidence that SSRIs may increase bleeding risk, particularly upper gastrointestinal hemorrhage. Serotonin plays a role in platelet aggregation, and it has been suggested that SSRIs block platelet reuptake of serotonin and therefore inhibit the ability of platelets to aggregate. Drug information guides warn about a potential interaction between warfarin and SSRIs (Coumadin (R) [Package Insert], Princeton, New Jersey, Bristol-Meyers Squibb, 2011). However, the actual relation among warfarin, SSRI exposure, and bleeding risk has not been well characterized. Previous studies have not controlled for other factors that may influence warfarin-associated bleeding risk and have not accounted for anticoagulation intensity in patients taking concomitant SSRIs and warfarin. To address these issues, we tested the association between SSRI exposure and major hemorrhage events in patients taking warfarin for atrial fibrillation (AF) using data from a large community-based cohort of patients with diagnosed AF.
Methods
The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study is a cohort of 13,559 adults enrolled in Kaiser Permanente Northern California with diagnosed AF from July 1, 1996, to December 31, 1997 and followed up for a median of 6 years. Patients with previous valve repair or replacement, mitral stenosis, perioperative AF that was transient, or recent hyperthyroidism were excluded.
Demographic and clinical data on subjects were obtained from automated clinical databases using condition-specific International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes and disease registries. Coronary artery disease was defined by hospitalization for acute myocardial infarction (ICD-9 code 410.x), unstable angina (ICD-9 code 411.x), or receipt of coronary revascularization (percutaneous coronary intervention or coronary artery bypass surgery). Clinical and laboratory databases were used to calculate an ATRIA bleeding risk score for each patient. The ATRIA bleeding risk index is a validated risk tool based on 5 clinical variables (anemia, severe renal disease, age, previous bleeding, and hypertension) and predicts the likelihood of warfarin-associated major hemorrhage. We did not have information on nonprescription medications such as aspirin or nonsteroidal anti-inflammatory drugs. Exposure to prescription antiplatelet medications (clopidogrel and ticlopidine) was determined from searching the pharmacy database.
The present study focused on the 9,186 patients who were exposed to warfarin during the study period. Longitudinal warfarin exposure was determined using a previously validated algorithm based on serial pharmacy dispensing and outpatient international normalized ratio (INR) measurements. Measurements of the INR were obtained from health plan outpatient laboratory databases. The proportion of time spent within specific INR ranges (<2.0, 2.0 to 3.0, and >3.0) was determined using a modified linear interpolation method.
Exposure to SSRIs was defined as receipt of ≥1 of the following Food and Drug Administration–approved medications during the study period based on information for dispensed prescriptions found in health plan pharmacy databases: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. We also included venlafaxine, a serotonin and norepinephrine inhibitor, because of reported similarities in bleeding effects. Longitudinal exposure, duration, and timing of SSRI exposure were determined by the date of dispensation and number of medication days supplied between serial prescriptions using previously described methods.
We also searched for exposure to tricyclic antidepressants (TCAs), medications that are often used for similar indications as SSRIs but have not been linked to hemorrhage risk. Specifically, we searched for amitriptyline, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine. Longitudinal exposure was assessed in the same way as for SSRIs.
We searched for hospitalizations for incident major hemorrhages occurring while taking warfarin. Primary ICD-9 diagnosis codes for extracranial hemorrhages (gastrointestinal, genitourinary, and retroperitoneal) or primary and secondary diagnoses of intracranial hemorrhage (including intracerebral, subarachnoid, or subdural) were identified from computerized databases based on previously validated algorithms. Medical records for all potential hemorrhagic events then underwent validation through medical chart review using a formal review protocol by a clinical outcomes committee. All events included must have been either during warfarin exposure or within 5 days of preceding warfarin exposure. Major hemorrhages were defined as bleeding events that were fatal, requiring ≥2 units of transfused blood, or hemorrhage into a critical anatomic site (e.g., intracranial, retroperitoneal, or intraocular that impairs vision). Reviewers also collected information about exposure to aspirin in patients presenting with hemorrhage.
The analysis was restricted to periods of on-warfarin exposure. Descriptive statistics were used to summarize the patient characteristics during exposure to SSRIs, TCAs, or neither medication. Multivariable Poisson regression models were developed to compare risk of major hemorrhage among different types of exposures (SSRI, TCA, or neither), adjusting for time-varying ATRIA bleeding risk score and INR value. A generalized estimating equations approach was used to adjust for periods in which individual patients could be exposed multiple times to warfarin. We also performed similar analyses examining the rates of hemorrhage on concomitant TCA and warfarin use. Analyses were performed using SAS software, version 9.3 (SAS Institute, Inc., Cary, North Carolina). The institutional review boards at each participating institution approved the study.
Results
A total of 9,186 patients with AF in the cohort took warfarin, with 32,888 person-years of follow-up time on warfarin available for analysis. The median duration of warfarin use was 3.5 years (interquartile range 1.2 to 6.0 years). Clinical characteristics of the patients, weighted by the length of follow-up, are presented in Table 1 . Because patients who underwent anticoagulation therapy could discontinue warfarin and subsequently resume therapy at a later time, individual patients could contribute multiple periods on warfarin; 2,790 patients (30%) had >1 period on warfarin and 709 patients (8%) had >2 periods on warfarin.
| Characteristic | Neither Med | TCA | SSRI |
|---|---|---|---|
| Total follow-up time (person years) | 30,028 | 921 | 1,939 |
| % person-years or mean | |||
| Female sex | 40.7% | 59.1% | 52.7% |
| Diabetes mellitus | 19.9% | 33.8% | 27.6% |
| Congestive heart failure | 36.7% | 45.8% | 43.0% |
| Coronary artery disease | 32.5% | 42.4% | 36.8% |
| History of gastrointestinal bleeding | 6.8% | 9.4% | 10.2% |
| History of intracranial hemorrhage | 0.5% | 1.1% | 1.1% |
| History of other bleeds | 2.7% | 3.7% | 3.2% |
| CHADS 2 stroke risk score | |||
| 0 | 10.7% | 5.4% | 7.4% |
| 1 | 27.6% | 18.0% | 22.5% |
| 2 | 32.5% | 34.3% | 28.6% |
| 3 | 18.4% | 21.6% | 24.4% |
| 4 | 7.3% | 12.8% | 12.2% |
| 5 | 3.0% | 4.9% | 5.9% |
| 6 | 0.6% | 0.3% | 1.9% |
| ATRIA bleeding risk score factors | |||
| Anemia | 11.9% | 16.0% | 18.8% |
| Severe renal disease | 2.9% | 4.4% | 3.9% |
| Age ≥75 years | 53.2% | 54.4% | 55.1% |
| Prior bleeding history | 14.0% | 16.8% | 19.1% |
| Hypertension | 60.8% | 71.0% | 64.5% |
| ATRIA bleeding risk score category | |||
| Low risk (0–3 points) | 38.9% | 33.7% | 32.3% |
| Intermediate risk (4 points) | 44.4% | 42.6% | 42.8% |
| High risk (5–10 points) | 16.7% | 23.7% | 24.9% |
| ATRIA bleeding risk score (mean) | 2.45 | 2.73 | 2.99 |
Among patients on warfarin, 1,743 patients had concomitant use of at least 1 SSRI (1,939 person-years of simultaneous SSRI and warfarin exposure). The SSRIs used were paroxetine (51.6% of SSRI users), fluoxetine (49.4%), sertraline (13.9%), venlafaxine (4.6%), citalopram (3.8%), and fluvoxamine (0.5%).
The INR could be interpolated for 86.3% of the total warfarin-exposed time, and 65.5% of the interpolated person-years was in a therapeutic INR range of 2 to 3. SSRI and TCA exposures were associated with a greater proportion of time spent in INR >3 compared with not being on these agents (12.3% for SSRIs, 11.9% for TCAs, and 10.3% for neither, p <0.001). The mean ATRIA bleeding risk score during periods of SSRI exposure was higher than on no antidepressants (2.99 vs 2.45, p <0.001). A higher mean bleeding risk score was also observed during TCA exposure compared with no antidepressants (2.73 vs 2.45, p <0.001).
We identified 461 validated incident warfarin-associated major hemorrhages during follow-up. Of these events, 45 events occurred during SSRI use (16 intracranial and 29 extracranial), 12 events during TCA-only use (5 intracranial and 7 extracranial), and 404 events during periods in which neither medication was used (165 intracranial and 239 extracranial).
Unadjusted rates of major hemorrhage were higher during periods of SSRI exposure compared with periods when patients were not taking antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years, p <0.001). The rates of hemorrhage for patients taking fluoxetine, paroxetine, and sertraline were similar (2.26, 2.46, and 2.47 per 100 person-years, respectively). In contrast, rates of hemorrhage during TCA-only exposure were not significantly different from rates on no antidepressant use (1.30 per 100 person-years on TCAs vs 1.35 per 100 person-years on none, p = 0.94).
In a multivariable model adjusting for ATRIA bleeding risk score and time in INR range >3, SSRI exposure was significantly associated with an increased risk for major hemorrhage compared with no antidepressants (adjusted rate ratio 1.41, 95% confidence interval 1.04 to 1.92) whereas TCA exposure was not associated with increased hemorrhage risk ( Table 2 ). Essentially the same effects were seen for both intra- and extra-cranial hemorrhages, although the heightened risk with SSRI exposure was not statistically significant in these subgroup analyses.
