Medicines Q&As. Medicines Q&As. What is the risk of gastrointestinal bleeding associated with selective serotonin reuptake inhibitors (SSRIs)?

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1 Medicines Q&As Q&A What is the risk of gastrointestinal associated with selective serotonin reuptake inhibitors (SSRIs)? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at Date prepared: 21 January 2013 Background Various reviews and meta-analyses (1-8) have indicated that there is a link between selective serotonin reuptake inhibitor (SSRI) use and gastrointestinal (GI), particularly upper GI (3,4,7,8). An increased risk of has been noted in elderly patients (7), and with the concomitant use of SSRIs and non-steroidal anti-inflammatory drugs (NSAIDs) (2-5,7,8). Serotonin has an important role in the haemostatic response to injury by promoting platelet aggregation (1,9,10). SSRIs inhibit the uptake of serotonin into platelets which might lead to an increased risk of abnormal (1,9,10). The increase in gastric acid secretion caused by SSRIs could also increase the risk of ulcer development and GI (8). Due to reports of, including GI, manufacturers advise caution in patients with a history of disorders and in those taking SSRIs concomitantly with antiplatelets and other drugs that might increase the risk of (11-16). Answer To determine whether SSRIs and venlafaxine (a serotonin and noradrenaline re-uptake inhibitor [SNRI]) are associated with upper GI tract, de Abajo and colleagues (17) conducted a casecontrol study in which details of case and control patients were drawn from a database used by general practitioners in the UK to store clinical information about their patients. Several similar casecontrol studies had been conducted in the past, but this one differed in that as well as aiming to identify subgroups of patients at an increased risk of bleeds with SSRIs, it sought to determine whether acid suppressing agents were effective in minimising this risk. Patients with upper GI tract (n=1321) who had been referred to a hospital or consultant and 10,000 control subjects were matched for age, sex and calendar year of the index date. For cases, the index date was the date of first symptoms or first diagnosis. For controls, a date within the study period was assigned randomly. Patients were defined as current users if their prescribed antidepressants lasted until the index date or were discontinued within 30 days of the index date. Although the three-fold increased risk of upper GI with SSRIs reported in a previous study (1) by the same authors was not seen again, percentages of current users of SSRIs or venlafaxine were found to be higher for case subjects than controls (5.3% versus 3.0% [SSRIs]; adjusted odds ratio [OR] 1.6; 95% confidence interval [CI]: ; and 1.1% versus 0.3% [venlafaxine]; adjusted OR 2.9; 95% CI: ). The odds ratios were adjusted for age, sex, calendar year, smoking status, alcohol intake, antecedents of GI disorder and concomitant use of NSAIDs, systemic corticosteroids, warfarin, low-dose aspirin and other antiplatelet drugs. The risk of upper GI tract was elevated further in patients receiving concomitant NSAIDs (OR 4.8; 95% CI: ) or corticosteroids (OR 4.0; 95% CI: ) (17). these drugs. Another study found that concomitant therapy with a proton-pump inhibitor (PPI) significantly reduced the modest risk of SSRI-related upper GI (OR 0.39; 95% CI: )(18). Before these studies, gastro-protective agents such as H2 receptor antagonists, PPIs or misoprostol had not been shown to reduce the risk of GI bleeds associated with SSRIs alone (4,6) or in combination with NSAIDs (6). Results from cohort and case-control studies with similar objectives and comparable outcomes to those of de Abajo and colleagues (17) are shown in Table 1. The majority of these concluded that SSRIs are associated with an increased risk of GI (1,10,17-19,21,), and some found this risk to be potentiated by the concomitant use of NSAIDs (1,10,17,19,20). Others found no significant association between GI and SSRI use (22,23) or no potentiation of this effect with concomitant SSRI and NSAID use (18,24). Comparison of these results is complicated by the fact that the studies differed with regard to adjustment for confounding factors. Studies have shown that, in addition to concomitant medication, alcohol intake (25) and H.pylori status (26) are important to take into account when determining the effects of SSRIs on the risk of GI. Patient age and the degree to which different antidepressants inhibit serotonin reuptake were factors of interest in one observational study in 317,824 elderly patients which looked at upper GI rates. The antidepressants these patients were taking were split into 2 groups: those with low inhibition of serotonin reuptake (e.g. nortriptyline, doxepin, trazodone) and those with high inhibition of serotonin reuptake (e.g. paroxetine, sertraline, fluoxetine) (27). Absolute differences between these antidepressant groups were greatest (and statistically significant) for patients aged 80 and over ( rates for high versus low inhibition: 14.7 per 1000 person years versus 10.6 per 1000 person years; number needed to harm [NNH] =244), and those with previous upper GI ( rates for high versus low inhibition: 40.3 per 1000 person years versus 28.6 per 1000 person years; NNH=85) (27). A recent study, in which the medical records of 36,389 patients were examined, also found the adjusted relative risk for GI bleeds to be higher in patients receiving antidepressants with a higher affinity for the serotonin transporter (relative risk for high versus low-affinity antidepressants = 1.17 (95% CI ). This study was of particular interest because it was restricted to patients with major depressive disorder, thereby reducing the risk of confounding by indication. Patients in this study received monotherapy with a SSRI, serotonin-norepinephrine reuptake inhibitor or other newgeneration antidepressant (28). In a case-control study (19), the risk of upper GI was found to be greatest in patients who had recently (within the last 0-30 days) started SSRI use. This finding is supported by another study, which found that mortality was increased in the 30 days following hospital admission for peptic ulcer in patients who had started SSRIs within 60 days of admission (particularly those over 80 years). In this study, long-term exposure to SSRIs, alone or with NSAIDs did not increase 30-day mortality after peptic ulcer (29). For a rare condition, the OR approximates the relative risk (30). Therefore, in Table 1, some results are reported as an OR and others as relative risk (both versus non-use of the specified medicines), as they appeared in the original papers. Interestingly, de Abajo and colleagues (17) noted that acid suppressing agents protected against GI in patients receiving either serotonin reuptake inhibitors (SRIs [SSRIs or SNRIs]) or both SRIs and NSAIDs (OR 2.0; 95% CI: [SRI only] and OR 9.1; 95% CI: [SRI + NSAID] in non-users of acid suppressors and OR 1.4; 95% CI: [SRI only] and OR 1.1; 95% CI: [SRI + NSAID] in current users of acid suppressors). In context, this would mean that for every 2000 patients receiving an SRI only, or every 250 patients receiving an SRI with an NSAID, without GI protection, one patient would have an upper GI bleed. With GI protection, 5000 or more patients would need to be treated with an SRI or SRI with an NSAID in order for one case to be attributed to

2 Table 1. Studies examining the possibility of an association between SSRI use and upper GI. Study and type Number of study participants Current use Risk (odds ratio [OR], relative risk [RR] or other) versus non-use de Abajo FJ and Garcia- Rodriguez LA. Arch Gen Psych 2008;65(7): (17) Nested case-control study Dall M et al. Clin Gastroenterol Hepatol 2009;7: (19) 1321 patients with upper GI / perforation referred to consultant or hospital 10,000 controls 3652 patients with serious upper GI 36,502 controls SRIs (includes SSRIs and venlafaxine) only a : 22 cases, 105 controls NSAID only b : 173 cases, 642 controls NSAID and SRIs: 23 cases, 44 controls SSRIs (current use): 377 cases, 1809 controls SSRI (recent use): 77 cases, 381 controls SSRI (past use): 360 cases, 2484 controls SSRI alone: 40 cases, 326 controls NSAID only: 625 cases, 2635 controls NSAID and SSRI: 99 cases, 183 controls OR, adjusted c (95% CI): SRIs only a :1.8 ( ) SRIs plus NSAIDs: 4.8 ( ) OR (95% CI): with gastro protection: SRIs only a :1.4 ( ) SRIs plus NSAIDs: 1.1 ( ) With no gastro protection/remote use: SRIs only a : 2.0 ( ) SRIs plus NSAIDs: 9.1 ( ) OR, adjusted d (95% CI): SSRIs (current use): 1.70 ( ) SSRIs (recent use): 1.86 ( ) SSRIs (past use): 1.24 ( ) SSRI only: 1.7 ( ) NSAID only: 4.3 ( ) NSAID plus SSRI: 8.0 (4.8-13) NSAID, SSRI plus low-dose Conclusions SSRIs, and venlafaxine, increase the risk of upper GI tract. This risk was increased further by the concomitant use of NSAIDs and SRIs. Acid suppressing agents lowered the risk of upper GI tract associated with SRIs +/- NSAIDs. SSRI use was associated with upper GI. This risk was increased further by the concomitant use of NSAIDs and SSRIs, and further still by adding in low-dose aspirin to treatment with NSAIDs and SSRIs. Among users of SSRIs, the risk of upper GI was found to be highest in those who had recently started

3 Helin-Salmivaara A et al. Eur J Clin Pharmacol 2007;63:403-8 (21) Wessinger S et al. Aliment Pharmacol Ther 2006;23: (20) Targownik LE et al. Am J Gastroenterol 2009;104: (18) Dalton S et al. Arch Intern Med 2003;163:59-64 (10) Population based cohort study 9191 cases with serious upper GI events 41,780 controls 579 cases hospitalised with acute GI haemorrhage 1000 controls 1552 patients with upper GI 68,590 controls Users of antidepressants: 26,005 Control: No antidepressants/ no NSAIDs (numbers not given) SSRI only a : 284 cases, 931 controls NSAID only e :1714 cases, 3089 controls NSAID and SSRI: 157 cases, 159 controls SSRI (included venlafaxine): 111 cases, 136 controls NSAID: 42 cases, 38 controls SSRI only: 62 cases, 1881 controls NSAID only: 263 cases, 5266 controls SSRI and NSAID: 23 cases, 337 controls SSRI and PPI: 6 cases, 369 controls SSRI only a : 55 cases, 17,320 persons SSRI and NSAID only: 17 cases, 4107 persons Other antidepressants only e : 9 cases, 4436 persons OR, adjusted f (95% CI): SSRIs, excluding NSAID users:1.30 ( ) SSRI and NSAID:4.19 ( ) NSAID only:2.83 ( ) OR (95% CI): SSRIs (lower or upper bleeds) 1.5 ( ) p=0.003 SSRIs (lower bleeds): 1.8 ( ) p=0.005 SSRIs (upper bleeds): 1.3 ( ) p=0.281 OR, adjusted g (95% CI): SSRI only: 1.43 ( ) NSAID only: 2.62 ( ) SSRI plus NSAID: 3.17 ( ) SSRI plus PPI: 0.56 ( ) Observed/expected ratio (95% CI) SSRIs only b : 3.6 ( ) Other antidepressants only e :1.7 ( ) SSRI and NSAID:12.2 ( ) Compared with NSAID use alone, the concurrent use of SSRIs and NSAIDs is associated with a moderate excess relative risk of a serious upper GI event. Patients admitted with GI haemorrhage (lower or upper) were more likely to be taking SSRIs than controls. SSRI use was statistically significantly greater among cases of lower GI, but not among those of upper GI. SSRI use was associated with a modest increase in the risk of upper GI. PPIs reduced the risk of SSRIassociated upper GI by approximately 60% (OR, 0.39; 95% CI: ). The risk of developing upper GI in patients using both an SSRI and an NSAID was not increased significantly above that in patients using only an NSAID SSRIs, but not other antidepressants, increased the risk of upper GI, and this effect is potentiated by concurrent use of NSAIDs.

4 de Abajo FJ et al. Br Med J 1999;319: (1) Population based casecontrol study Dunn NR et al. Br Med J2000;320: (22) Population based cohort study Vidal X et al. Drug Safety 2008;(312): (23) Tata LJ et al. Aliment Pharmacol Ther 2005;22: (24) 1651 cases of upper GI 248 cases of ulcer perforation 10,000 controls SSRIs: 237,609 patient months of exposure Comparator drugs (moclobemide and salmeterol): 205,431 patient months of exposure 2813 cases of upper GI 7193 matched controls 11,261 cases with upper GI 53,156 controls NSAIDs only e : 295 cases, 652 controls SSRIs only a : 38 cases, 93 controls NSAIDs & SSRIs: 16 cases, 9 controls SSRIs i : 103 cases Comparator drug: 72 cases High affinity SRI j (not necessarily alone): 84 cases, 160 controls NSAID and high affinity SRI: 41 cases, 26 controls SSRI only a : 253 cases, 522 controls NSAID only b : 1871 cases, 4700 controls SSRI and NSAID:92 cases, 168 controls RR, adjusted h (95% CI): SSRIs only a : 2.6 ( ) SSRI and NSAID:15.6 ( ) Rate ratio (95% CI) versus comparator group: 1.24 ( ) OR, adjusted k (95% CI): High-affinity SRIs: 1.24 ( ) High-affinity SRI and NSAID: 8.32 ( ) NSAIDs without high-affinity SRI: 7.82 ( ) Analysis within the SSRI group: SSRIs (>70 years):1.57 ( ) SSRIs (<70 years):1.04 ( ) OR (95% CI): SSRI only a : 2.63 ( ) SSRI and NSAID: 2.93 ( ) NSAID only b : 2.19 ( ) SSRIs moderately increase the risk of upper GI. Concurrent use of NSAIDs and SSRIs greatly increases the risk of upper GI. Found no evidence to suggest that SSRIs are more likely to cause GI than comparator drugs. No significant association was found between use of SRIs and risk of upper GI. The OR among concurrent users of a high-affinity SRI and an NSAID did not differ from that of users of NSAIDs alone. The risk of GI with SSRI use was slightly increased in patients aged over 70 compared to those aged under 70. The risk of GI is not substantially increased when NSAIDs and SSRIs are prescribed together when compared to alone.

5 a. No other antidepressants or NSAIDs used. b. No antidepressants used. c. Adjusted for smoking status, alcohol intake, antecedents of GI disorder, and concomitant use of other medications associated with upper GI tract (NSAIDs, systemic corticosteroids, warfarin, low-dose aspirin and other antiplatelet drugs). d. Adjusted for use of aspirin and PPIs, alcohol abuse, cerebral ischemia, stroke, use of warfarin, clopidogrel, dipyridamole, and corticosteroids, prior Helicobacter eradication, peptic ulcer, upper GI bleed and cirrhosis. e. No SSRIs used. f. Adjusted for year of birth, sex, hospital catchment area, diabetes mellitus, rheumatoid arthritis, coronary artery disease, hypertension, asthma, cardiac insufficiency, use of H2 antagonist, PPI or plain misoprostol in the period extending from five years to 90 days prior to the index date (as a proxy for past GI morbidity). Also, use of H2 antagonist, plain misoprostol, PPI, warfarin, clopidogrel, oral or inhaled glucocorticoid or tramadol in the 90-day period immediately prior to the index date as well as any in-patient period lasting at least 7 days, in-patient period for an injury and a hospitalisation for hip or knee arthroplasty. g. Adjusted for specific medical comorbidities, use of other medications believed to affect the risk of upper GI complications, and history of GI disease. h. Adjusted for sex, age, year, antecedents of upper GI disorders, smoking status, and use of aspirin, anticoagulants, or steroids. i. Fluvoxamine, fluoxetine, paroxetine, sertraline and included nefazodone (SNRI). j. Included fluoxetine, paroxetine, sertraline and clomipramine, but not fluvoxamine, citalopram or venlafaxine. k. Adjusted for history of peptic ulcer, dyspepsia, upper GI, diabetes mellitus, smoking habit, alcohol consumption and use of antacids, PPIs, sucralfate, nitrates, systemic NSAIDs, topical NSAIDs, analgesics, antiplatelet drugs, dihydropyridine calcium antagonists and HMG Co-A reductase inhibitors in the week before the GI symptoms started.

6 Summary The results from most, but not all observational studies suggest that there is an associa the use of SSRIs and GI bleeds. One study indicated that patients taking SSRIs have a increased risk of developing a GI bleed compared to patients not taking SSRIs and who factors for GI. However, recent studies have found the risk to be more modes comparison of the results of studies on SSRI use and GI is complicated by the confounding factors taken into account differ in each case. Some studies have found th SSRIs with concomitant NSAIDs to increase the risk of GI bleed further. Being over the having a previous history of GI may also add to the risk of GI with SS is some evidence that the risk of GI is higher in patients who have just started If an SSRI is required in a patient at high risk of a GI bleed then the use of a gastro-pro could be considered. Studies have shown the use of acid suppressing drugs, e.g. PPIs protective against GI bleeds in patients receiving single-therapy SSRI or combined NSA treatment. Limitations Studies that have looked at the risk of GI bleeds in SSRI users have differed with respe outcomes and the confounding factors taken into account.

7 References 1. de Abajo FJ, Garcia Rodriguez LA, Montero D. Association between select reuptake inhibitors and upper gastrointestinal : population based c study. Br Med J 1999;319: Mort JR, Aparasu RR, Baer RK. Interaction between selective serotonin re inhibitors and nonsteroidal anti-inflammatory drugs: review of the literature 2006;26(9): Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal due between selective serotonin uptake inhibitors and non-steroidal anti-inflam Aliment Pharmacol Ther 2008;27: Yuan Y, Tsoi K, Hunt RH. Selective serotonin reuptake inhibitors and risk o : confusion or confounding? Am J Med 2006;119: Turner MS, May DB, Arthur RR et al. Clinical impact of selective serotonin inhibitors therapy with risks. J Intern Med 2007;261: Paton C, Ferrier IN. SSRIs and gastrointestinal. Br Med J 2005;33 7. de Abajo FJ, Montero D, Garcia Rodriguez LA et al. Antidepressants and r gastrointestinal. 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8 Quality Assurance Prepared by Alex Bailey, Information Scientist, Welsh Medicines Information Centre Date Prepared 21 January 2013 Checked by Fiona Woods, Director, Welsh Medicines Information Centre Date of check 21 January 2013 Search strategy Embase (exp Serotonin Uptake Inhibitor/ae, to [Adverse Drug Reaction, Drug Toxicity] AND exp Gastrointestinal Hemorrhage/) limited to human and english language Medline (exp Serotonin Uptake Inhibitors/ae, to [Adverse Effects, Toxicity] AND exp Gastrointestinal Hemorrhage/) limited to human IDIS Drug(s): ("antidepressants-ssris " and Descriptors: "side ef digestive 78" AND All fields: ) Micromedex (Searched under individual SSRI names in DrugDex and Martindale, also checked Drug Consults) EMC (Searched under individual SSRI names) In-house database/ resources (SSRI and bleed*) NeLM (ssri* AND bleed*; selective serotonin reuptake, ssri, gastrointestinal bleed*) ( ) Pharmline (for previous version) serotonin reuptake inhibitors AND haemorrhagegastrointestinal Meyler s Side Effects of Drugs (15th ed) selective serotonin re-uptake inhibitors Stockley s (online) ssris warfarin