BMJ 2001;323:655 ( 22 September )
C van Walraven
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]
|
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 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 This increased risk of bleeding is
clinically important for patients with a high risk of bleedingnamely, 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 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 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
13 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
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
Yet the antidepressant groups comprised drugs with often disparate
inhibition.14
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
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
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
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 ). 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
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 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 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
32
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 ) 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
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 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).
|
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 . 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
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 describes the cohort.
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 1). 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). 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). 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 244that 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). 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 despite
some notable differences between our studies. Firstly, increased
overall illness is associated with both depression18-24 and
gastrointestinal bleeding. 25-27 36 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 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 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
patients26
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). 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 37 Although
drug exposure was measured by prescription only, this method agrees
well with self reported use of drugs.38 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. This problem is common to many studies with admission to
hospital for gastrointestinal bleeding as an outcome. 11 26 27 32 36 37 39 Despite
this potential misclassification bias,40 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 |
|
|
|
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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.