BMJ 2001;323:655 ( 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 [log in to unmask] <mailto:[log in to unmask]>



  Abstract
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
Serotonin potentiates platelet aggregation. 1
<http://bmj.com/cgi/content/full/323/7314/#B1>  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 <http://bmj.com/cgi/content/full/323/7314/#B2>
Case reports suggest that serotonin reuptake inhibitors are associated with
a variety of bleeding events. 3-10
<http://bmj.com/cgi/content/full/323/7314/#B3>
The strongest evidence linking the use of selective serotonin reuptake
inhibitors with bleeding comes from a case-control study. 11
<http://bmj.com/cgi/content/full/323/7314/#B11>  The authors identified 1651
incident cases of upper gastrointestinal bleeding or ulcer perforation from
a high quality clinical database and randomly selected 10 000 controls
matched by age, sex, and time. 12
<http://bmj.com/cgi/content/full/323/7314/#B12>  13
<http://bmj.com/cgi/content/full/323/7314/#B13>  Drug records were reviewed
to determine if the participants had been exposed to selective serotonin
reuptake inhibitors or other antidepressants. After potential confounders
were controlled for, 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. 14-17
<http://bmj.com/cgi/content/full/323/7314/#B14>  Firstly, if the
hypothesised pathophysiology of bleeding involved the inhibition of
serotonin reuptake, the extent of this inhibition should correlate with the
risk of bleeding and determine how these drugs were grouped. 14
<http://bmj.com/cgi/content/full/323/7314/#B14>  Yet the antidepressant
groups comprised drugs with often disparate inhibition. 14
<http://bmj.com/cgi/content/full/323/7314/#B14>  Secondly, the association
between the inhibitors and gastrointestinal bleeding could have been due to
confounding. This is because patients with depression generally are sicker
than those without. 18-24 <http://bmj.com/cgi/content/full/323/7314/#B18>
Patients who are sicker are more likely to experience gastrointestinal
bleeding because such bleeding has been associated with factors that
contribute to overall disease burden, including increased age, decreased
physical activity, heart failure, diabetes, and annual number of hospital
admissions. 25-27 <http://bmj.com/cgi/content/full/323/7314/#B25>  Thirdly,
as only 131 bleeds were recorded in the antidepressant group, there were
relatively wide confidence intervals for bleeding risks. Fourthly, serotonin
plays a minor part in the haemostatic process. It is a comparatively weak
agonist for platelet aggregation because its stimulation of platelet
receptors induces change only in platelet shape and not the platelet
secretory processes key to platelet activation. 28
<http://bmj.com/cgi/content/full/323/7314/#B28>  Finally, the study could
not provide the absolute risk of serious bleeding associated with
antidepressant use. Clinicians need this information when choosing
antidepressants for patients.
To address these issues, 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
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.
The databases are anonymous and linked by unique identifiers for patients
that are common to all databases.
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 in Appendix <http://bmj.com/cgi/content/full/323/7314/#Appendix> ).
Age was determined from the registered patient database, which contains
basic personal information on all residents of Ontario. 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. Because regulations stipulate that prescriptions should not exceed
three months, we reviewed all drug claims between 1 April 1992 and 1 July
1992 to ensure that study patients were not receiving an antidepressant. We
also excluded those without a valid health insurance plan number.
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). 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. 29 <http://bmj.com/cgi/content/full/323/7314/#B29>
Observation ended when exposure to the drug, as defined by the duration of
the prescription, ended. Prescription duration equalled drug quantity (from
the Ddug benefits database) divided by the daily intake of drug recommended
by the manufacturer. 30 <http://bmj.com/cgi/content/full/323/7314/#B30>
Drug exposure was considered to have continued as long as a subsequent
prescription for the antidepressant, or others in the same group, was filled
within 30 days of the prescription's duration. For example, assume that we
calculated a prescription to end on 1 January. Exposure to the drug
continued beyond that date only if the patient filled a subsequent
prescription for that antidepressant, or another in the same group, by 30
January. Otherwise exposure ended on 1 January.
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. This database records all
admissions to Ontario hospitals, and major diagnoses are classified by using
ICD-9 (international classification of diseases 9th revision) codes. By
using a database similar to the discharge abstract database, one study found
that the ICD-9 codes 533 (complicated gastric ulcer), 532 (uncomplicated
duodenal ulcer), 533 (complicated peptic ulcer), 578.0 (haematemesis), 579.0
(melaena), and 578.9 (unspecified intestinal bleeding) had a positive
predictive value of 86% for upper gastrointestinal bleeds. 31
<http://bmj.com/cgi/content/full/323/7314/#B31>  We used these codes to
identify upper gastrointestinal bleeds in our study. 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. These included age and sex. We considered medical conditions,
including previous upper gastrointestinal bleeding and diabetes. 27
<http://bmj.com/cgi/content/full/323/7314/#B27>  32
<http://bmj.com/cgi/content/full/323/7314/#B32>  Patients were classified
with gastrointestinal bleeding if the discharge abstract database indicated
that they were admitted to hospital with a primary diagnosis of upper
gastrointestinal bleeding (see table A2 in the Appendix
<http://bmj.com/cgi/content/full/323/7314/#Appendix> ) before entering the
study. Patients were classified with diabetes if the Ontario drug benefits
database indicated that they were prescribed oral hypoglycaemics or insulin
before the end of observation. 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. From 1996, elderly patients had to pay the first
$100 of their prescriptions. Therefore 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.
Analysis
To adjust for varying observation times, we calculated the density of
incidence of upper gastrointestinal bleeding for each group. We compared
rates between strata by using relative rates and 95% confidence intervals.
33 <http://bmj.com/cgi/content/full/323/7314/#B33>  Notable differences
between groups were expressed as the number needed to harm. We calculated
this as the reciprocal of the differences between the bleeding rates of the
two groups, expressed as proportions.
To test for trend in bleeding rates across groups for serotonin reuptake
inhibition after controlling for potential confounders, we used a weighted
linear regression method. 34 <http://bmj.com/cgi/content/full/323/7314/#B34>
In this analysis the bleeding rates based on larger numbers of cases are
given more weight. The stratified analysis models the natural log of
bleeding rates as a linear function of serotonin reuptake inhibition (see
table A1) within each strata of the confounding variable, and then combines
the equations to derive an overall estimate of the common coefficient for
the inhibition group. One minus the antilog of the common coefficient for
the inhibition group expresses the relative change in bleeding rates for
each group with higher inhibition of serotonin reuptake. This analysis
assumes that the effect of inhibition is the same within each strata. This
was an appropriate assumption after inspection of the rates within each
strata (table 1 <http://bmj.com/cgi/content/full/323/7314/#T1> ).



View this table:
[in this window] <http://bmj.com/cgi/content/full/323/7314/655/T1>
[in a new window] <http://bmj.com/cgi/content-nw/full/323/7314/655/T1>

Table 1. Rates of gastrointestinal bleeding per 1000 person years of
observation in antidepressant groups by serotonin reuptake inhibition.
Values in brackets are 95% confidence intervals
We repeated the analysis with proportional hazards modelling (SAS, version
6.12). This modelled observation time as a function of the inhibition group
and the covariates listed in table 1
<http://bmj.com/cgi/content/full/323/7314/#T1>  . As in the original
analysis, observation began when patients started antidepressants and
finished when they stopped treatment, or died, the study ended, or they had
an upper gastrointestinal bleed. To test for the assumption of
proportionality, we recreated the model with an interaction term between
time and each of the covariates in the model. 35
<http://bmj.com/cgi/content/full/323/7314/#B35>  Due to computational
rigours of this latter analysis, we conducted it on a randomly selected
subset of the dataset that contained 30% of the original cohort. We tested
the assumption of proportionality independently for each covariate.




  Results
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. Table 2
<http://bmj.com/cgi/content/full/323/7314/#T2>  describes the cohort.
Patients entering the study in later years were much more likely to be
prescribed antidepressants with greater inhibition of serotonin reuptake.



View this table:
[in this window] <http://bmj.com/cgi/content/full/323/7314/655/T2>
[in a new window] <http://bmj.com/cgi/content-nw/full/323/7314/655/T2>

Table 2. Description of cohort and antidepressant groups by serotonin
reuptake inhibition. Values are numbers (percentages) of patients unless
stated otherwise
The overall risk of upper gastrointestinal bleeding was 7.3 per 1000 person
years (table 1 <http://bmj.com/cgi/content/full/323/7314/#T1> ). The risk of
upper gastrointestinal bleeding was significantly associated with each
confounder. This was especially so with increasing age and previous upper
gastrointestinal bleeding.
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 1
<http://bmj.com/cgi/content/full/323/7314/#T1> ). 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 1
<http://bmj.com/cgi/content/full/323/7314/#T1> ). 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.
Proportional hazards modelling gave similar results (see table A2). After
all potential confounders were controlled for, increasing inhibition of
serotonin reuptake was associated with a significantly increased risk of
upper gastrointestinal bleeding (risk ratio 1.1, 1.02 to 1.19). The two
analyses yielded similar results because six of the univariate relative
risks lay within the 95% confidence intervals of corresponding estimates in
the multivariate Cox model (table 2
<http://bmj.com/cgi/content/full/323/7314/#T2> ). In this analysis there is
no period effect. Of all covariates in the final model (see table A2), only
anticoagulation had a significant interaction with time. We kept the Cox
model because this interaction was of borderline significance (P=0.03) and
the point estimate was of questionable clinical significance (risk ratio
1.001).




  Discussion
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 al, 11
<http://bmj.com/cgi/content/full/323/7314/#B11>  despite some notable
differences between our studies. Firstly, increased overall illness is
associated with both depression 18-24
<http://bmj.com/cgi/content/full/323/7314/#B18>  and gastrointestinal
bleeding. 25-27 <http://bmj.com/cgi/content/full/323/7314/#B25>  36
<http://bmj.com/cgi/content/full/323/7314/#B36>  The large size of our study
allowed us to remove potential confounding from this association by
restricting the analysis to patients taking antidepressants. Secondly, our
study contained a different collection of drugs because it included
venlaflaxine, nefazodone, and bupropion but not dothiepin, citalopram,
lofepramine, and mianserin. Additionally, as has been suggested, 14
<http://bmj.com/cgi/content/full/323/7314/#B14>  we categorised
antidepressants on the basis of their inhibition of serotonin reuptake
rather than their structure. Finally, our study took place in a different
healthcare system with an older patient population. Our findings corroborate
those of de Ajabo et al 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. 25 <http://bmj.com/cgi/content/full/323/7314/#B25>  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 patients 26
<http://bmj.com/cgi/content/full/323/7314/#B26>  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 1 <http://bmj.com/cgi/content/full/323/7314/#T1> ).
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. Whereas rates for upper endoscopy for patients aged between 65
and 70 years in Ontario decreased from 28.3 per 1000 population in 1992 to
23.7 per 1000 in 1998, rates for octogenarians increased from 23.7 to 30.4
per 1000 during the same period. 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. No cohort effect
was, however, found in our multivariate proportional hazards model (see
table A2).
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. 26
<http://bmj.com/cgi/content/full/323/7314/#B26>  37
<http://bmj.com/cgi/content/full/323/7314/#B37>  Although drug exposure was
measured by prescription only, this method agrees well with self reported
use of drugs. 38 <http://bmj.com/cgi/content/full/323/7314/#B38>  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
<http://bmj.com/cgi/content/full/323/7314/#B11>  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. This problem is common to many studies with admission to hospital
for gastrointestinal bleeding as an outcome. 11
<http://bmj.com/cgi/content/full/323/7314/#B11>  26
<http://bmj.com/cgi/content/full/323/7314/#B26>  27
<http://bmj.com/cgi/content/full/323/7314/#B27>  32
<http://bmj.com/cgi/content/full/323/7314/#B32>  36
<http://bmj.com/cgi/content/full/323/7314/#B36>  37
<http://bmj.com/cgi/content/full/323/7314/#B37>  39
<http://bmj.com/cgi/content/full/323/7314/#B39>  Despite this potential
misclassification bias, 40 <http://bmj.com/cgi/content/full/323/7314/#B40>
we found a significant association between the inhibition of serotonin
reuptake and gastrointestinal bleeding when important confounders were
controlled for.
Depressed patients have a higher risk of gastrointestinal bleeding when
taking antidepressants with higher inhibition of serotonin reuptake. For
high risk patients, such as octogenarians and those with previous
gastrointestinal bleeding, we believe that the differences are clinically
important and should be considered when antidepressants are selected.
Further study is required to determine if serotonin blockade increases the
risk of gastrointestinal bleeding as well as the risk of other clinical
bleeds in other patient populations. In contrast, it needs to be determined
whether the antiplatelet effects of antidepressants are beneficial for
patients at high risk of thromboembolic disorders.



  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.



  Appendix



View this table:
[in this window] <http://bmj.com/cgi/content/full/323/7314/655/TA1>
[in a new window] <http://bmj.com/cgi/content-nw/full/323/7314/655/TA1>

Table A1. Antidepressants available in Ontario drug benefit programme and
their categorisation on basis of drug's affinity for serotonin transporter.
From Tatsumi et al 29 <http://bmj.com/cgi/content/full/323/7314/#B29>



View this table:
[in this window] <http://bmj.com/cgi/content/full/323/7314/655/TA2>
[in a new window] <http://bmj.com/cgi/content-nw/full/323/7314/655/TA2>

Table A2. Results of multivariate proportional hazards regression



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(Accepted 10 May 2001)


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.