BMJ 2001;323:655-658 [Abridged] ( 22 September )

Papers

Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study

C van Walraven, assistant professor of medicine a, M M Mamdani, scientist b, P S Wells, associate professor of medicine a, J I Williams, vice president of research c. 

a Clinical Epidemiology Unit, Ottawa Health Research Institute, Ottawa Hospital--- Civic Campus, Ottawa, ON, Canada K1Y 4E9, b Institute for Clinical Evaluative Sciences, Toronto, ON, Canada M4N 3M5, c Toronto Rehabilitation Institute, Toronto, ON, Canada M5G 2A2

Correspondence to: C van Walraven carlv{at}ohri.ca


    Abstract
Top
Abstract
Introduction
Patients and methods
Results
Discussion
References

Objectives: To determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding.
Design: Retrospective cohort study from population based databases.
Setting: Ontario, Canada.
Participants: 317 824 elderly people observed for more than 130 000 person years. The patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper gastrointestinal bleed, or died or the study ended.
Main outcome measure: Admission to hospital for acute upper gastrointestinal bleeding.
Results: Overall, 974 bleeds were observed, with an overall bleeding rate of 7.3 per 1000 person years. After controlling for age or previous gastrointestinal bleeding, the risk of bleeding significantly increased by 10.7% and 9.8%, respectively, with increasing inhibition of serotonin reuptake. Absolute differences in bleeding between antidepressant groups were greatest for octogenarians (low inhibition of serotonin reuptake, 10.6 bleeds/1000 person years v high inhibition of serotonin reuptake, 14.7 bleeds/1000 person years; number needed to harm 244) and those with previous upper gastrointestinal bleeding (low, 28.6 bleeds/1000 person years v high, 40.3 bleeds/1000 person years; number needed to harm 85).
Conclusions: After age or previous upper gastrointestinal bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper gastrointestinal bleeding. These increases are clinically important for elderly patients and those with previous gastrointestinal bleeding.


What is already known on this topic
A case-control study found that the risk of upper gastrointestinal bleeding increases with intake of antidepressants that extensively inhibit serotonin reuptake

The study's validity was questioned because antidepressants were not specifically classified by the extent that they inhibit serotonin reuptake, and absolute differences in bleeding rates between antidepressants were unavailable

What this study adds
The risk of upper gastrointestinal bleeding in elderly and depressed patients increases with antidepressants having the greatest extent of inhibition of serotonin reuptake

This increased risk of bleeding is clinically important for patients with a high risk of bleeding---namely, octogenarians and those with previous upper gastrointestinal bleeding

The extent that an antidepressant inhibits serotonin reuptake should be considered when drugs are required for depression in high risk patients



    Introduction
Top
Abstract
Introduction
Patients and methods
Results
Discussion
References

Serotonin potentiates platelet aggregation.1 Selective serotonin reuptake inhibitors decrease serotonin uptake from the blood by platelets. Because platelets do not synthesise serotonin, these inhibitors decrease the amount of serotonin in platelets.2 Case reports suggest that serotonin reuptake inhibitors are associated with a variety of bleeding events.3-10

The strongest evidence linking the use of selective serotonin reuptake inhibitors with bleeding comes from a case-control study.11 After potential confounders were controlled for, this study found the odds of gastrointestinal bleeding for users of the inhibitors were three times that of the controls. Patients taking tricyclic antidepressants had no increased risk of upper gastrointestinal bleeding.

The study did, however, have potential limitations, which we have addressed in this study.12-15 In particular, the study could not provide the absolute risk of serious bleeding associated with antidepressant use. Clinicians need this information when choosing antidepressants for patients.

We conducted a retrospective cohort study to determine the overall risk of serious upper gastrointestinal bleeding in elderly patients taking antidepressants. We also aimed to determine if this risk varied with the extent of inhibition of serotonin reuptake by antidepressants.


    Patients and methods
Top
Abstract
Introduction
Patients and methods
Results
Discussion
References

Cohort definition
We obtained our data from administrative databases for Ontario, Canada, where services provided by physicians, drugs, and hospital services for patients aged over 65 are provided by a universally funded health programme.

We used a retrospective cohort design that included all residents of Ontario aged over 65 who received a new prescription for any antidepressant (see table A1 on website). Drug use was determined from the Ontario drug benefits database, which records the type of drug, quantity, and date of all prescriptions for all residents aged 65 and over.

Patient observation
We began our surveillance on 1 July 1992. Patients entered the cohort on the date they were first prescribed an antidepressant (see table A1 on website). Patients were grouped by the affinity of the antidepressant for the transporter responsible for serotonin reuptake. This affinity was categorised before the analysis as low, intermediate, or high, on the basis of the drug's dissociation constant.16

Observation ended when exposure to the drug, as defined by the duration of the prescription, ended. Observation also ended when patients were admitted to hospital with upper gastrointestinal bleeding, or died or the study ended. Admissions to hospital with the primary diagnosis of upper gastrointestinal bleeding were identified from the discharge abstract database, which records all admissions to Ontario hospitals. We identified upper gastrointestinal bleeds by using a series of ICD-9 (international classification of diseases, 9th revision) codes that have been shown to have a positive predictive value of 86% for upper gastrointestinal bleeds.17 Patient deaths were identified from the Registered Patient Database, which records all deaths for residents of Ontario, including those occurring out of the province. Our study ended 1 April 1998.

Potential confounders
We controlled for factors that are associated with upper gastrointestinal bleeding, including age, sex, previous upper gastrointestinal bleeding, and diabetes. 18 19 Confounding drugs included non-steroidal anti-inflammatory drugs, acetylsalicylic acid, glucocorticoids, anticoagulants, H2 blockers, and proton pump inhibitors. We considered that patients were exposed to these drugs if they were prescribed within 30 days of the end of observation. Capture of non-steroidal anti-inflammatory drugs and acetylsalicylic acid that can be acquired without prescription is likely to be incomplete.

Finally, given the long duration of our study and the potential for changes in patient care over that time, we thought it necessary to control for year of study entry. To do this we stratified the analysis by year of entry to the study.


    Results
Top
Abstract
Introduction
Patients and methods
Results
Discussion
References

During the study period, 383 911 of 1 798 382 (21.3%) elderly patients were prescribed antidepressants. Of these, 317 824 (82.8%) started their drug during the study period and were included. They were observed for 132 812 person years, during which time there were 974 admissions to hospital for upper gastrointestinal bleeding. Patients entering the study in later years were much more likely to be prescribed antidepressants with greater inhibition of serotonin reuptake.

The overall risk of upper gastrointestinal bleeding was 7.3 per 1000 person years (table). The risk of upper gastrointestinal bleeding was significantly associated with each confounder. This was especially so with increasing age and previous upper gastrointestinal bleeding.


                              
View this table:
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Rates of gastrointestinal bleeding per 1000 person years of observation in antidepressant groups by serotonin reuptake inhibition. Values in brackets are 95% confidence intervals

The risk of upper gastrointestinal bleeding increased slightly with inhibition of serotonin reuptake, rising from 6.6 bleeds per 1000 person years for antidepressants with the lowest inhibition to 7.9 bleeds per 1000 person years in the highest group (table). This trend did not reach significance.

However, significant increases in upper gastrointestinal bleeding with increasing inhibition were seen after controlling for variables strongly associated with upper gastrointestinal bleeding (table). When we controlled for age, the risk of bleeding increased by 10.7% for each higher inhibition group. For octogenarians, bleeding rates increased from 10.6 per 1000 person years in the lowest group to 14.7 per 1000 person years in the highest group. This corresponded with a number needed to harm of 244---that is, one extra upper gastrointestinal bleed would be expected when 244 patients were treated with an antidepressant from the high rather than the low serotonin reuptake inhibitors. When we controlled for previous upper gastrointestinal bleeding, bleeding risk increased by 9.8%. For patients with a history of active peptic ulcer disease, bleeding rates increased from 28.6 per 1000 person years in the lowest group to 40.3 per 1000 person years in the highest group. This corresponded with a number needed to harm of 85. Finally, we also found a period effect. When we controlled for the year of study entry, the relative risk of upper gastrointestinal bleeding increased significantly by 10.7% with increasing inhibition of serotonin reuptake.


    Discussion
Top
Abstract
Introduction
Patients and methods
Results
Discussion
References

We found a trend towards an increased risk of upper gastrointestinal bleeding for patients taking antidepressants with greater inhibition of serotonin reuptake. This association was significant when we controlled for age or previous upper gastrointestinal bleeding. We believe that the increased bleeding rates are clinically important for octogenarians or patients with previous upper gastrointestinal bleeding and should be considered when selecting antidepressants. For most patients, however, such precautions are probably unnecessary.

Our conclusions are similar to those of de Ajabo et al11 and corroborate them in a distinct patient population using a different study design. We believe that this strengthens the association between inhibition of serotonin reuptake by antidepressants and gastrointestinal bleeding.

Octogenarians and patients with previous upper gastrointestinal bleeding are at especially high risk from antidepressants with high inhibition of serotonin reuptake.20 It is possible that increased bioavailability of selective serotonin reuptake inhibitors in elderly patients results in a stronger antiplatelet effect at the same dose, thereby increasing the risk of gastrointestinal bleeding. These findings might also be a function of particular vulnerability to gastrointestinal bleeding in elderly patients21 and those with previous upper gastrointestinal bleeding, thereby allowing the antiplatelet effect of the antidepressant to become apparent. These factors would explain why the association between bleeding risk and inhibition of serotonin reuptake was seen only after these strong confounders were controlled for.

Two factors could explain why upper gastrointestinal bleeding was associated with inhibition of serotonin reuptake after the year of study entry was controlled for (table). Firstly, the number of octogenarians who were prescribed antidepressants with high inhibition increased from 892 in 1992 to 11 179 in 1997. Secondly, the use of upper endoscopy in elderly patients increased noticeably during the study. Therefore major changes during the study in the bleeding risk of patients taking selective serotonin reuptake inhibitors and the use of an important technology to diagnose upper gastrointestinal bleeds may explain the cohort effect in our base analysis.

We believe that our study is valid and provides new information that is useful to clinicians. It is population based and includes a large number of participants. This increased the precision of point estimates for bleeding rates and allowed us to limit the analysis to patients taking antidepressants. It also allowed us to measure absolute differences in bleeding risks, which are essential for determining clinical relevance. The validity of our methods to calculate bleeding rates is supported by our rates being similar to those in two other cohort studies. 21 22 Although drug exposure was measured by prescription only, this method agrees well with self reported use of drugs.23 Our study outcome of admission to hospital with upper gastrointestinal bleeding was explicitly determined by using diagnostic codes that are highly indicative of such bleeding.

Our results potentially have two minor limitations. Firstly, although we controlled for important confounders, we did not control for all of the factors that de Ajabo et al considered, such as smoking or "antecedents of upper gastrointestinal disorders." Because the independent risks of bleeding associated with these factors were not provided,11 we are unsure of the importance of their control when studying upper gastrointestinal bleeding. Secondly, we considered only upper gastrointestinal bleeds that resulted in admission to hospital. We may therefore have missed those patients whose bleed resulted in death before admission to hospital or that did not require admission. Despite this potential misclassification bias,24 we found a significant association between the inhibition of serotonin reuptake and gastrointestinal bleeding when important confounders were controlled for.

    Acknowledgments

We thank Dr George Wells and Dr Peter Austin for statistical advice. CvW was an Arthur Bond scholar of the Physicians' Services Foundation and is an Ontario Ministry of Health career scientist. PSW is a scientist of the Medical Research Council.

Contributors: CvW conceived the study; he will act as guarantor for the paper. CvW, MMM, PSW, and JIW contributed to the design, analysis, and interpretation of the data. CvW drafted the paper, and all investigators helped revise the paper.

    Footnotes

Funding: None.

Competing interests: None declared.

The full version of the article appears on the BMJ's website


    References
Top
Abstract
Introduction
Patients and methods
Results
Discussion
References

1. Li N, Wallen NH, Ladjevardi M, Hjemdahl P. Effects of serotonin on platelet activation in whole blood. Blood Coagulation Fibrinolysis 1997; 8: 517-523[Medline].
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16. Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997; 340: 249-258[Medline].
17. Raiford DS, Gutthann SP, Rodriguez LAG. Positive predictive value of ICD-9 codes in the identification of cases of complicated peptic ulcer disease in the Saskatchewan hospital automated database. Epidemiology 1996; 7: 101-104[Medline].
18. Weil J, Langman MJ, Wainwright P, Lawson DH, Rawlins M, Logan RF, et al. Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs. Gut 2000; 46: 27-31[Abstract/Full Text].
19. Garcia RL, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769-772[Medline].
20. Blatchford O, Davidson LA, Murray WR, Blatchford M, Pell J. Acute upper gastrointestinal haemorrhage in west of Scotland: case ascertainment study. BMJ 1997; 315: 510-514[Abstract/Full Text].
21. Pahor M, Guralnik JM, Salive ME, Chrischilles EA, Brown SL, Wallace RB. Physical activity and risk of severe gastrointestinal hemorrhage in older persons. JAMA 1994; 272: 595-599[Medline].
22. Pahor M, Guralnik JM, Furberg CD, Carbonin P, Havlik R. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996; 347: 1061-1065[Medline].
23. Grymonpre RE, Didur CD, Montgomery PR, Sitar DS. Pill count, self-report, and pharmacy claims data to measure medication adherence in the elderly. Ann Pharmacother 1998; 32: 749-754[Medline].
24. Hennekens CH, Buring JE. Cohort studies. In: Mayrent SL, ed. Epidemiology in medicine. Boston: Little, Brown, 1987:153-177.

(Accepted 10 May 2001)

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