Our cohort included 27 058 patients. More than half were taking ASA alone, and about 3% were taking an SSRI in combination with antiplatelet therapy at discharge (, ).
Selection of patients for the study. ASA = acetylsalicylic acid, SSRI = selective serotonin reuptake inhibitor.
Table 1: Characteristics of patients discharged from hospital with antiplatelet therapy following acute myocardial infarction between January 1998 and March 2007, by antiplatelet therapy at discharge and receipt of selective serotinin reuptake inhibitor (SSRI) (more ...)
Compared with patients who were taking ASA alone, those taking ASA and an SSRI were more likely to be older, to have renal failure, to have taken antihypertensive agents or anti-depressants in the year before the index admission, and to be taking a corticosteroid (). Compared with patients taking dual antiplatelet therapy (ASA and clopidogrel), those taking dual antiplatelet therapy and an SSRI were more likely to be older, to have taken antihyperglycemic medications or antidepressants in the year before the index admission, and to have anemia or another hematologic disease ().
Patient characteristics associated with the use of antiplatelet medications and selective serotonin reuptake inhibitors (SSRIs)
Risk of bleeding associated with exposure to study drugs
The periods included in the analyses totalled 80 991 patient-years, during which 1070 episodes of bleeding occurred ().
Crude rate of bleeding episodes per 100 patient-years, by antiplatelet therapy at discharge and receipt of selective serotinin reuptake inhibitor (SSRI)
After adjustment for baseline patient characteristics, we found that the use of an SSRI combined with any form of antiplatelet therapy was associated with an increased risk of bleeding compared with ASA use alone (ASA and SSRI: HR 1.42, 95% CI 1.08–1.87; ASA, clopidogrel and SSRI: HR 2.35, 95% CI 1.61–3.42) (). The combination of clopidogrel and an SSRI appeared to have an increased risk of bleeding compared with clopidogrel alone, but the confidence interval was too wide for firm conclusions (HR 1.54, 95% CI 0.70–3.39). The combination of SSRl with dual antiplatelet therapy increased the risk of bleeding compared with dual antiplatelet therapy alone (HR 1.57, 95% CI 1.07–2.32). The risk of bleeding associated with clopidogrel use was similar to that associated with ASA alone (HR 1.15, 95% CI 0.87–1.51). The combined use of clopidogrel and ASA increased the risk of bleeding beyond that of ASA alone by 49% (HR 1.49, 95% CI 1.28–1.75) ().
Figure 2: Association between exposure to medications under study and risk of bleeding among patients taking antiplatelet therapy following acute myocardial infarction (Cox regression model with time-dependent exposure). The model was adjusted for patient characteristics (more ...)
Risk of bleeding associated with other patient characteristics
Patient characteristics that were independently associated with an increased risk of bleeding were age, cancer, renal failure, congestive heart failure, anemia or other hematologic disease, use of anticoagulants or corticosteroids at discharge, prior use of antihyperglycemic or anti-hypertensive agents, history of peptic ulcer disease, history of bleeding other than gastrointestinal bleeding and prior visit to gastroenterologist (). Women and patients who underwent percutaneous transluminal coronary angioplasty appeared to be at lower risk of bleeding.
Figure 3: Patient characteristics associated with the risk of bleeding during follow-up (Cox regression model with time-dependent exposure). The model was adjusted for exposure to study drugs as presented in , and for use of antidepressants other than selective (more ...)
When we restricted the outcome to gastrointestinal bleeding, the results were similar to those of the main analysis (ASA and SSRI v. ASA alone: HR 1.50, 95% CI 1.05–2.15; ASA, clopidogrel and SSRI v. ASA alone: HR 3.11, 95% CI 2.00–4.85). When we assessed the risk of bleeding by SSRI affinity, the increased risk of bleeding associated with the use of high-affinity SSRIs compared with ASA alone was not significant (ASA and high-affinity SSRI v. ASA alone: 34 events; HR 1.29, 95% CI 0.90–1.84; and ASA, clopidogrel and high-affinity SSRI v. ASA alone: 11 events; HR 1.56, 95% CI 0.85–2.86. When we assessed intermediate-affinity SSRIs compared with ASA alone, the increased risk of bleeding was significant (ASA and intermediate-affinity SSRI: 27 events; HR 1.48, 95% CI 1.00–2.18; and ASA, clopidogrel and intermediate-affinity SSRI: 20 events; HR 3.02, 95% CI 1.92–4.75). When we compared the combined use of intermediate-affinity SSRIs and single or dual antiplatelet therapy with the combined use of high-affinity SSRIs and single or dual antiplatelet therapy, we found no statistically significant difference in the associated risk of bleeding.
Analyses investigating the risk of bleeding associated with antidepressants other than SSRIs did not reveal any increased risk. The results of the main analysis did not change significantly when we excluded patients who had any bleeding episode in the year before the index admission, or when we excluded patients who used clopidogrel, a proton pump inhibitor and either fluoxetine or sertraline. Removal of anticoagulant use from the model or adjusting for Charlson Comorbidity Index scores did not alter the results significantly either.
Patients taking an SSRI together with ASA or dual antiplatelet therapy following acute myocardial infarction were at increased risk of bleeding. Our findings showed that the use of ASA or clopidogrel alone was associated with a similar risk of bleeding. Compared with ASA alone, the combined use of an SSRI and ASA was associated with a 42% increase in risk, and the combined use of clopidogrel and ASA was associated with a 49% increase in risk. The addition of an SSRI to dual antiplatelet therapy (ASA and clopidogrel) increased the risk by 57% compared with dual antiplatelet therapy alone. The risk of bleeding among patients taking clopidogrel and an SSRI was higher than that among patients taken clopidogrel alone, although the number of patients using this combination was not large enough to confirm the finding. These results did not vary by SSRI affinity or when we removed patients using drugs that may interact with clopidogrel (proton pump inhibitors, sertraline and fluoxetine).
As found in a previous study,31
age was an independent risk factor for bleeding necessitating hospital admission. Other independent risk factors were cancer, renal failure, congestive heart failure, anemia or other hematologic disease, history of peptic ulcer disease, prior use of antihypertensive agents or antihyperglycemic agents, use of anticoagulants or corticosteroids at discharge, visit to gastroenterologist in prior year and bleeding other than gastrointestinal bleeding or hemorrhagic stroke in prior year. Women appeared to have a decreased risk of bleeding, as did patients who underwent angioplasty during the index admission.
The crude rates of bleeding associated with ASA use and with clopidogrel and ASA use in our study were lower than the rates of bleeding found in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study (2.7% among those taking placebo and ASA, and 3.7% among those taking clopidogrel and ASA for at most 12 months, which implies that the rates per 100 patient-years would be even higher).32
This is surprising when one considers that the CURE study excluded patients at high risk of bleeding. The long follow-up of our study and perhaps the noncompliance of patients with the prescription regimen may have had an impact on the low event rate. If indeed the rate of bleeding is more pronounced during the first month of treatment, as some studies have suggested,18
then a follow-up period stretching over several years would likely dilute this effect.
Some previous studies have reported an increased risk of bleeding associated with SSRIs with higher affinity to serotonin.25
In contrast, we found similar risks of bleeding for SSRIs of high and intermediate affinity, which suggests that affinity to serotonin did not play an important role in the drug interactions of SSRIs and antiplatelet agents. Inhibition of cytochrome P450 by certain SSRIs has also been associated with increased risk of drug interactions causing bleeding;21
however, this hypothesis could not be verified in our study because of the limited number of patients using combinations involving these SSRIs.
Our study has several limitations. First, its design is observational in nature. Selection bias is a major issue in such studies because patients’ physicians determine treatment after myocardial infarction based on the risk–benefit ratio of the medications for these patients. Although our model adjusted for patient characteristics at baseline, some selection bias may have remained because of possible differences in unmeasured characteristics, such as patient frailty. If this were true, it would have biased the results toward a lower effect.
Second, because antiplatelet therapy is recommended for use in all patients following acute myocardial infarction unless contraindicated because of a high risk of adverse events, we did not include patients who were not using antiplatelet therapy.
Third, it may be that patients at increased risk of bleeding are more likely to have depression and require antidepressant therapy. Although our model adjusted for patient risk factors, residual bias may have remained.
Fourth, we depended on physician billing information to ascertain the patients’ history of bleeding episodes in the year before the index admission. Minor bleeds often resolve on their own, and some physicians may not have included the diagnosis code on the bill for some episodes of bleeding before the index admission. If such patients were not prescribed dual antiplatelet therapy because of their increased risk of bleeding, misclassification might have biased our results toward a lower effect of dual antiplatelet therapy.
Fifth, we did not account for the potential use of over-the-counter ASA. However, because we included only patients who were taking prescribed antiplatelet therapy, these patients likely did not use over-the-counter ASA because they had financial incentives to use the prescribed medication.
Finally, our analysis established only that patients filled their prescriptions, not that they took their medications. Our inability to confirm compliance with the prescribed treatment regimens is a potential source of bias.
Use of an SSRI with any form of antiplatelet therapy (ASA or clopidogrel, or both) was associated with an increased risk of bleeding among patients following acute myocardial infarction, beyond the risk associated with the antiplatelet therapy alone. Ultimately, clinicians must weigh the benefits of SSRI therapy against the risk of bleeding in patients with major depression following acute myocardial infarction. Clinicians should exercise caution when prescribing SSRIs to their patients with major depression following acute myocardial infarction. The potential for drug interactions must be evaluated to guide the choice of medication.