Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction

Background:

Patients prescribed antiplatelet treatment to prevent recurrent acute myocardial infarction are often also given a selective serotonin reuptake inhibitor (SSRI) to treat coexisting depression. Use of either treatment may increase the risk of bleeding. We assessed the risk of bleeding among patients taking both medications following acute myocardial infarction.

Methods:

We conducted a retrospective cohort study using hospital discharge abstracts, physician billing information, medication reimbursement claims and demographic data from provincial health services administrative databases. We included patients 50 years of age or older who were discharged from hospital with antiplatelet therapy following acute myocardial infarction between January 1998 and March 2007. Patients were followed until admission to hospital due to a bleeding episode, admission to hospital due to recurrent acute myocardial infarction, death or the end of the study period.

Results:

The 27 058 patients in the cohort received the following medications at discharge: acetylsalicylic acid (ASA) (n = 14 426); clopidogrel (n = 2467), ASA and clopidogrel (n = 9475); ASA and an SSRI (n = 406); ASA, clopidogrel and an SSRI (n = 239); or clopidogrel and an SSRI (n = 45). Compared with ASA use alone, the combined use of an SSRI with antiplatelet therapy was associated with an increased risk of bleeding (ASA and SSRI: hazard ratio HR] 1.42, 95% confidence interval CI] 1.08–1.87; ASA, clopidogrel and SSRI: HR 2.35, 95% CI 1.61–3.42). Compared with dual antiplatelet therapy alone (ASA and clopidogrel), combined use of an SSRI and dual antiplatelet therapy was associated with an increased risk of bleeding (HR 1.57, 95% CI 1.07–2.32).

Interpretation:

Patients taking an SSRI together with ASA or dual antiplatelet therapy following acute myocardial infarction were at increased risk of bleeding.Antiplatelet agents such as acetylsalicylic acid (ASA) and clopidogrel are a mainstay of therapy following acute myocardial infarction. These agents are effective in reducing the risk of recurrent acute myocardial infarction and other cardiovascular events, with the potential for additive benefit when used in combination.^1–3 The risk of bleeding associated with their use, however, is of concern.^4–6 This risk may be increased further by the frequent concomitant use of other medications associated with an increased risk of bleeding, such as anticoagulant therapy⁷ and selective serotonin reuptake inhibitors (SSRIs).Up to 20% of patients with cardiovascular disease experience depression and are most often prescribed an SSRI.^8–13 The vast majority of these patients also use antiplatelet therapy. The risk of bleeding associated with combining SSRI therapy with single or dual antiplatelet therapy is uncertain. Two large clinical trials that examined SSRI use following acute myocardial infarction did not specifically report on the risk of bleeding,^14,15 and earlier studies suggested no increase in risk associated with SSRI therapy combined with single-agent antiplatelet therapy.^16,17SSRI use itself has been associated with an increased risk of bleeding, particularly during the first month of use.¹⁸ The inhibition of serotonin transporters by SSRIs is thought to be responsible for the risk of bleeding.¹⁹ Platelets release serotonin at sites of bleeding and vascular damage; however, they do not synthesize serotonin and instead acquire it from the blood and store it.^19,20 By this mechanism, SSRIs may also worsen the bleeding caused by ASA and clopidogrel.^19,20 Inhibition of cytochrome P450 by certain SSRIs has also been associated with increased risk of drug interaction causing bleeding;²¹ however, data on this issue are scarce.We examined the risk of bleeding associated with the use of SSRIs when combined with single and dual antiplatelet therapy among patients following acute myocardial infarction.