JOURNAL READING

Depression,
antidepressants
and the risk of
cardiovascular
events and death
in older men

Oleh : dr. Ni Putu Tika Pradnyandari

Introduction

– A recent systematic review and meta-analysis reported that people with

depression have 30–87% higher risk of experiencing an ischaemic heart disease
(IHD) event, with depression accounting for 3% of the disability-adjusted life
years associated with IHD.

– Depression increases the risk of incident fatal or non-fatal strokes by 29–63%

– Stroke and IHD remain the leading causes of death in middle-low
to high income countries so that the successful management of
risk factors associated with CVD is expected to lead to a
decrease in both disability and mortality worldwide.

– Large cohor study of 60,746 British primary care patients aged

65–100 years found that, over an average follow up period of 5
years  the use of selective serotonin reuptake inhibitors was
associated with about 15% increase in the risk of myocardial
infarctions, 17% increase in the risk of a stroke or transient
ischaemic attack, and 54% increase in the risk of death.
Different classes of antidepressants could have distinct effects on the
cardiovascular outcomes of people with depression. This may be a particularly
important consideration when managing older adults, given the high prevalence of
cardiovascular morbidity and use of medications in this age group.

This study to investigate the association of depression and antidepressant use with
the risk of incident cardiovascular events and mortality. In particular, we sought to
clarify if exposure to antidepressants had a different impact on CVD risk in people
with and without depression.
 Methods
Study Design
Cohort study of community-dwelling older men living in the metropolitan region of
Perth, Western Australia.

Participants
This study was based on data from 5522 participants who took part in the second wave of assessments of the
Health In Men Study (HIMS). Briefly, we identified 49,801 men aged 65–84 years in 1996 who were living in the
Perth metropolitan region. Of these, 41,000 were alive and eligible for screening, with 19,352 receiving an
invitation to complete a face-to-face assessment. Of those invited, 12,203 attended the first wave of
assessments between 1996 and 1998, with the second wave occurring between 2001 and 2004. The results of
this study are limited to participants of the second wave of HIMS because no information about the use of
medications was retrieved during the first wave of assessments. These men were followed using electronic
health data linkage until death or for up to 12 years (details below).
Study measures

– Cardiovascular events (ischaemic heart and cerebrovascular events) were the

primary outcomes of this investigation. These were ascertained using the
Western Australian Data Linkage System (WADLS). WADLS brings together
hospital morbidity data (inpatient and outpatient), emergency department
contacts, as well as the cancer and death registries.
– The causes leading to the health contacts are recorded, with clinical diagnoses
following the guidelines of the International Classification of Diseases (ICD)
– ICD codes to establish the presence of an ischaemic heart event: ICD-8 and 9
codes 390–398, 402, 404, 410–429, and ICD-10 codes I00-09, I11, I13, I20-29,
I50-51.
– cerebrovascular event: ICD-8 and 9 codes 430–434 and ICD-10 codes I60-64.
– Participants were considered to have prevalent depression if they had the
following recorded diagnoses in WADLS before the start of the follow up period:
296.0 and 300.4 (ICD-8), 296.2, 296.3, 311 and 300.4 (ICD-9), and F32, F33,
F34.1 and F38.10 (ICD-10). Men with a total score of 7 or greater on the 15-item
Geriatric Depression Scale (GDS-15) during the second wave of assessments of
HIMS were also considered prevalent cases of depression.
– participants provided a written list of medications used on a regular basis
(including over the counter).
– All medications were subsequently coded according the Anatomical Therapeutic
Chemical (ATC) Classification system:
– N06AA (non-selective monoamine reuptake inhibitors – cyclic antidepressants)
– N06AB (selective serotonin reuptake inhibitors), N06AF and N06AG (monoamine
oxidase inhibitors)
– N06AX (other antidepressants).
– Antiplatelet medications appeared under the codes A01AD05, B01AC06, N02BA01
and B01AC.
 Statistical analyses
– Statistical software Stata 15.1 (StataCorp LLC, 2018) to manage and analyse the data
– Descriptive statistics summarised categorical variables as count and proportions (%), and continuous
variables as mean, range, and standard deviation of the mean (SD).
– t-tests to compare the age of participants with and without prevalent depression, and reported the t-
statistic, the number of degrees of freedom (df) and p-value.
– Pearson chi-square statistic was employed to compare the distribution of categorical measures among
men with and without depression (yes/no completed high school, prevalent comorbidities and use of
medications).
– We used Cox regression (Breslow method) to investigate the hazard ratio (HR) of a cardiovascular
event during follow up.
– We used age as the time scale in the Cox regression models in order to control as accurately as
possible the effect of age on endpoints. In these models, we split and joined time-span sets according
to the diagnosis of depression, so that men without prevalent depression contributed data as controls
until the time of diagnosis and as cases thereafter.
Result

– The cohort consisted of 5522 men aged 77.3 ± 3.7 years (range: 70–88 years). Four
hundred and forty-three (8.0%) of them had prevalent depression because they had
either a recorded clinical diagnosis in WADLS (n = 374) or scored 7 or more on the
GDS-15 at the time of assessment (n = 355; 69 men did not complete the GDS-15)
– Men with depression were on average 0.6 years older than men without depression
(t = 3.42, p < 0.001), but a similar proportion in both groups reported having
completed high school.
– Compared with men without depression, a higher proportion of men with
depression had a recorded diagnosis of diabetes, ischaemic heart disease, stroke,
chronic respiratory diseases, digestive and renal diseases, and dementia.
– Three-hundred and sixty-five (6.6%) men were using an antidepressant and
more men with than without depression were using antidepressants of all
classes.
– As a group, SSRIs were the most commonly used group of antidepressants (4.1%
among all participants). Sixteen (0.3%) men were using 2 antidepressants
simultaneously and one was using 3.
– Participants were followed until death or for up to 12 years (average = 8.4 ± 3.0
years). The adjusted HR of a cardiovascular event (coronary heart disease event
or stroke) was 1.52 (95%CI = 1.20, 1.93) for men using an antidepressant and
1.50 (95%CI = 1.21, 1.86) for men with depression.
Result
– The HR of the interaction between having depression and using an antidepressant was 0.51
(95%CI = 0.30, 0.87), suggesting that the interaction was multiplicative rather than additive
(Fig. 1).
– Incident cases of depression were used as controls until the date of the episode of depression
and as cases thereafter.
– All analyses were adjusted for age, use of antiplatelet agents and prevalent diabetes,
hypertension, ischaemic heart disease, stroke, chronic respiratory diseases, dementia, and
diseases of the digestive and renal systems, as well as use of antiplatelet therapy.
– This statistical adjustment for other measured factors relied solely on information available at
study entry. The E-value for the interaction between use of antidepressant and depression of
cardiovascular risk was 0.26 (95%CI = 0.16, 0.64), suggesting the effect of unmeasured factors
would have to be very large to account for the results that we observed.
– We also completed a series of post hoc analyses to determine if the interaction
between depression and antidepressant use on future cardiovascular events
was due to cardiac or cerebrovascular events – the adjusted HR of the
interaction was, respectively, 0.52 (95%CI = 0.27, 1.01) and 0.40 (95%CI = 0.21,
0.76) (Fig. 2).
– In addition, we examined whether the interaction between cardiovascular
events and antidepressants varied according to the type of medication used:
cyclic antidepressants (HR = 0.65, 95%CI = 0.30, 1.41), selective serotonin
reuptake inhibitors (HR = 0.59, 95%CI = 0.25, 1.39) and other antidepressants
(HR = 0.51, 95%CI = 0.20, 1.32)
– Fig. 3 shows the survival of men with and without depression according to whether
or not they were using antidepressants.
– Both antidepressant use and depression were associated with increased mortality
hazard (HR = 1.41, 95%CI = 1.20, 1.67 and HR = 1.41, 95%CI = 1.22, 1.64,
respectively), but men with depression using antidepressants had comparatively
lower mortality hazard (HR for the interaction = 0.46, 95%CI = 0.33, 0.65).
– For this reason, we repeated the analyses investigating the interaction between
antidepressant use and depression on the risk of cardiovascular events using death
as a competing risk. Both depression (SHR = 1.34, 95%CI = 1.08, 1.66) and
antidepressant use (SHR = 1.39, 95%CI = 1.09, 1.77) continued to be associated with
increased risk of cardiovascular events, but the interaction term failed to reach
statistical significance (SHR = 0.68, 95%CI = 0.40, 1.15; p = 0.151).
Discussion

– The results of this study indicate that both depression and antidepressant use
increase the 12-year risk of cardiovascular events among older men.
– They also suggest that the use of antidepressants decreases the risk of
cardiovascular events among older men with depression, but not among those
without.
– This pattern of associations could not be ascribed to confounding or to a
particular class of antidepressant medications, nor was it specifically associated
with cardiac or cerebrovascular events, although the association with
cerebrovascular events was more robust.
– After considering the strengths and limitations of our study, we would argue that our results are
compelling and generalisable to older men living in the community.
– If that is the case, how could findings be explained?
– Depression has been associated with hazardous lifestyle practices and physiological changes that increase the
risk of cardiovascular events, including decreased heart-rate variability, elevated basal levels of catecholamines
and inflammatory markers, as well as endothelial and platelet dysfunction
– The use of antidepressants has traditionally been associated with increased cardiovascular risk but evidence
from clinical trials suggests that they can improve the clinical outcomes of people at risk of cardiovascular
event.
– Antidepressants, and selective serotonin inhibitors in particular, decrease the functionality of platelets over
time by blocking the serotonin reuptake transporter, which in turn hinders their function and reduces platelet
aggregation. Like antiplatelet agents (e.g., aspirin) this could contribute to reduce the risk of future
cardiovascular events . The results from the FOCUS trial are consistent with this hypothesis as they showed a
reduced trend in the incidence of cardiovascular events among stroke survivors treated with fluoxetine for 6
months (20 mg daily) compared with placebo . Although this could explain why antidepressants reduce the
risk of myocardial infarction and strokes, it cannot adequately account for the finding of increased risk among
antidepressant consumers who do not have depression.
– Antidepressants are often prescribed for the management of conditions other than depression,
such as chronic pain and anxiety disorders. This might explain why 5% of our older men without
a recorded diagnosis of depression were using these medications.
– Anxiety disorders have been associated with increased risk of myocardial infarction and strokes,
although it is difficult to conceive how the use of antidepressants would lead to cardiovascular
benefits among older adults with depression but not with other mental health disorders.
– One might speculate that depression, unlike other conditions, is associated with specific
physiological changes that increase the risk of cardiovascular events that can be reversed with
treatment, although what these unique physiological anomalies might be remains unclear.
– Our analyses also showed that the cardiovascular effects of different classes of antidepressants
are largely similar (e.g., cyclic antidepressants or selective serotonin reuptake inhibitors), which
seems to imply that response to treatment may be more important than the class of
antidepressant medication used. However, our study had limited power to investigate these
associations.
– Depression is associated with an increase in the risk of cardiovascular events, with 3% of
ischaemic heart disease disability-adjusted life years being attributable to depression.
– Nonetheless, the merit of using antidepressants to manage depressive episodes in later life has
been questioned because of their potential risk to further increase the risk of myocardial
infarction and stroke, although not all studies have associated their use with increased harm.
– Our results indicate that the risk of cardiovascular events decreases when antidepressants are
used to manage depression.
– We would suggest that the most economical explanation for these findings is that depression
increases the risk of cardiovascular events and that remission of symptoms decreases risk,
regardless the type of treatment received. In contrast, anxiety disorders have a more protracted,
and possibly unremitting, course in later life even when treated, which might explain the
increased risk of cardiovascular events among our older participants without depression using
antidepressants
– Taken together, the results arising from this large prospective study suggest that
depression increases the risk of cardiovascular events in later life and that the
use of antidepressants reduces this risk.
– The supposed cardiovascular benefit associated with the use of antidepressants
is limited to people with depression, which suggests that their effect on the risk
of cardiovascular events may be driven by their ability to lead to clinical
improvements in mood.
– If that is the case, clinicians should remain confident about offering treatment
with antidepressants to their older patients with depression.
THANKYOU