General practice Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study

Objective To examine the association between selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Design Population based case-control study. Setting General practices included in the UK general practice research database. Subjects 1651 incident cases of upper gastrointestinal bleeding and 248 cases of ulcer perforation among patients aged 40 to 79 years between April 1993 and September 1997, and 10 000 controls matched for age, sex, and year that the case was identified. Interventions Review of computer profiles for all potential cases, and an internal validation study to confirm the accuracy of the diagnosis on the basis of the computerised information. Main outcome measures Current use of selective serotonin reuptake inhibitors or other antidepressants within 30 days before the index date. Results Current exposure to selective serotonin reuptake inhibitors was identified in 3.1% (52 of 1651) of patients with upper gastrointestinal bleeding but only 1.0% (95 of 10 000) of controls, giving an adjusted rate ratio of 3.0 (95% confidence interval 2.1 to 4.4). This effect measure was not modified by sex, age, dose, or treatment duration. A crude incidence of 1 case per 8000 prescriptions was estimated. A small association was found with non-selective serotonin reuptake inhibitors (relative risk 1.4, 1.1 to 1.9) but not with antidepressants lacking this inhibitory effect. None of the groups of antidepressants was associated with ulcer perforation. The concurrent use of selective serotonin reuptake inhibitors with non-steroidal anti-inflammatory drugs increased the risk of upper gastrointestinal bleeding beyond the sum of their independent effects (15.6, 6.6 to 36.6). A smaller interaction was also found between selective serotonin reuptake inhibitors and low dose aspirin (7.2, 3.1 to 17.1). Conclusions Selective serotonin reuptake inhibitors increase the risk of upper gastrointestinal bleeding. The absolute effect is, however, moderate and about equivalent to low dose ibuprofen. The concurrent use of non-steroidal anti-inflammatory drugs or aspirin with selective serotonin reuptake inhibitors greatly increases the risk of upper gastrointestinal bleeding. Introduction In the past few years several case reports have shown an association between selective serotonin reuptake inhibitors such as fluoxetine and bleeding disorders. Most of the patients had mild bleeding disorders, for example, ecchymoses, purpura, epistaxis, or prolonged bleeding time but several had more serious conditions such as gastrointestinal haemorrhage, genitourinary bleeding, and intracranial haemorrhage. 6 The release of serotonin from platelets has an important role in regulating the haemostatic response to vascular injury. 9 Serotonin is not synthesised in platelets but is taken up from the circulation by serotonin transporters on the platelets, which are similar to those in the human brain. At therapeutic doses fluoxetine and other selective serotonin reuptake inhibitors have consistently been shown to block this reuptake of serotonin by platelets leading to a depletion of serotonin after several weeks of treatment. 12 It is possible that these drugs impair haemostatic function, at least under certain conditions, and thereby increase the risk of bleeding. We tested this hypothesis with data from an ongoing case-control study, which was set up to estimate the risk of ulcer complications from non-steroidal anti-inflammatory drugs. Subjects and methods We studied data from the general practice research database. This database has been described elsewhere. It contains details of patients’ demographics, medical diagnoses, referrals to consultants and hospitals, and prescriptions. The accuracy and completeness of these data have been validated in previous studies. 16 Case definition and ascertainment The source population was all patients aged 40 to 79 years between April 1993 and September 1997, with at least 2 years’ enrolment with their general practitioner. Patients with cancer, oesophageal varices, MalloryWeiss disease, alcoholism, liver disease, or coagulopathies were excluded. We identified incident cases of upper gastrointestinal bleeding or ulcer perforation, and we reviewed the computerised profiles of such Editorial by Li Wan Po División de Farmacoepidemiología y Farmacovigilancia, Agencia Española del Medicamento, 28220 Majadahonda, Madrid, Spain Francisco J de Abajo head Safety Evaluation Unit, División de Farmacoepidemiología y Farmacovigilancia, Agencia Española del Medicamento Dolores Montero head Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain Luis A García Rodríguez director Correspondence to: F J de Abajo [email protected]