US Pharm. 2012;37(11):HS-12-HS-15.
ABSTRACT: Depression occurs in 10% to 20% of post–myocardial
infarction (MI) patients and 15% to 30% of heart failure (HF) patients.
Depression has been associated with an increased risk of morbidity and
mortality in these high-risk populations. Sertraline and citalopram are
first-line antidepressants for post-MI patients; sertraline also has
been proven safe for HF patients. It is unclear whether antidepressants
improve cardiovascular (CV) outcomes. However, patients with improved
depressive symptoms are more likely to be adherent to their cardiac
medications and follow lifestyle modifications to reduce the likelihood
of recurrent CV events. Pharmacists can play a pivotal role in screening
cardiac patients for depression and educating them about their
medications to improve clinical outcomes.
Depression is common in patients with cardiac disease. A study of
more than 30,000 patients revealed an incidence of 9.3% in ambulatory
cardiac patients versus 4.8% in the general population.1 The rate is even higher in the hospital setting, with 15% to 20% of patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision),
criteria for major depressive disorder (MDD) after an acute myocardial
infarction (MI). These patients are at greater risk for mortality than
other patients with cardiovascular (CV) diseases, even after adjustment
for severity of heart disease.2 Patients with depression
after an MI also have a poorer quality of life, increased health and
cardiac complaints, and more disability at 12 months compared with
patients without depression.3 Numerous trials have aimed to
determine which interventions—whether pharmacologic or
nonpharmacologic—are more effective at treating depression in this
Coronary Artery Disease (CAD) and MI
It is important to detect and treat depression in CAD and post-MI
patients, as the risk of a cardiac event doubles within 1 to 2 years
after an MI.2,4 Numerous pathophysiological causes have been
suggested as possible explanations for this correlation, including
higher levels of biomarkers, reduced heart rate variability, impaired
vascular function, increased C-reactive protein levels, and increased
fibrinogen levels.2 In addition, depression is associated
with behaviors that can lead to adverse cardiac outcomes, such as
continued smoking and nonadherence to medications and exercise regimens.5
Several trials have been conducted to determine the safety and
efficacy of antidepressants in post-MI patients. One double-blind study,
SADHART (Sertraline AntiDepressant Heart Attack Randomized Trial),
examined the use of the selective serotonin reuptake inhibitor (SSRI)
sertraline versus placebo in 369 post-MI patients over 24 months. The
use of sertraline had no effect on cardiac function as measured by
change in left ventricular ejection fraction, demonstrating that
sertraline was safe in this population. Sertraline patients who had at
least one previous episode of depression or had more severe MDD derived
more benefit in terms of change in depression ratings. A lower, but
nonsignificant, rate of CV events was seen in the sertraline group.6
A 7-year follow-up of SADHART found that certain characteristics were
associated with long-term mortality in these patients, including
baseline MDD severity and failure of MDD to improve during treatment
with either sertraline or placebo.7
MIND-IT (Myocardial INfarction and Depression-Intervention Trial) was
a randomized, multicenter study that assessed the use of mirtazapine, a
selective noradrenergic reuptake inhibitor, in 331 post-MI patients
over 18 months. Compared with placebo, mirtazapine did not reduce the
rate of long-term depression or adverse CV outcomes.8
CREATE, a randomized, multicenter study, evaluated the use of the
SSRI citalopram, clinical management, and interpersonal therapy (IT)
over 12 weeks in 284 subjects. This was a 2 × 2 factorial trial in that
subjects underwent two randomizations: either IT with clinical
management or clinical management alone, then either citalopram or
placebo. Clinical management consisted of weekly 20- to 25-minute
sessions about depression and medication use. In IT sessions, which took
place immediately after clinical-management meetings, a therapist
discussed interpersonal conflict, life transitions, and social isolation
with subjects. This study found no difference in QTc prolongation
between citalopram patients and placebo subjects. Citalopram
demonstrated superiority over placebo in treating depression, but IT was
not more effective than standard clinical management.9
The randomized ENRICHD (Enhancing Recovery In Coronary Heart Disease
Patients) trial studied the effect of cognitive-behavioral therapy (CBT)
intervention in 2,481 depressed cardiac patients who were treated for 6
months. While there was no difference in event-free survival (defined
as incidence of death or recurrent MI) between treated and placebo
groups at mean follow-up of 29 months, this trial showed that CBT
improved depression and social support.10
A recent study of 4,037 depressed post-MI patients sought to
determine the effect of resistance to antidepressant treatment on
mortality risk. Mean follow-up was 39 months. Although resistance to
treatment increased the mortality risk slightly, the greatest risk was
seen in insufficiently treated patients (defined as failure to receive
12 weeks of continuous antidepressants at therapeutic doses).11
Based on the studies discussed above, sertraline and citalopram are
considered first-line agents for the treatment of depression in post-MI
patients (TABLE 1).2 However, in patients previously
treated with alternative agents for depression, resumption of the
previous agents may be considered if they were clinically effective.
Exceptions would be tricyclic antidepressants and monoamine oxidase
inhibitors, which are not recommended in cardiac patients because of the
increased risk of cardiac events.12
Heart Failure (HF)
While less extensively studied than therapy for depression in the
post-MI population, the treatment of patients with depression and HF is
an area of increasing interest because of significant morbidity and
mortality rates in the more than 5 million U.S. patients with HF. The
incidence of clinical depression in HF patients ranges from 19.3% to
33.6% based upon diagnostic interview versus questionnaires, and from
11% in New York Heart Association class I patients to 42% in class IV
patients.13 In a meta-analysis, depression in HF patients was
associated with increased morbidity and mortality, higher utilization
of health care resources, and increased rates of hospitalization.13
A registry review of 13,708 patients with CAD revealed that those who develop depression are at greater risk for HF.14
However, this review also found that treatment of depression with
antidepressants did not affect HF progression. Another review
demonstrated that, in 204 HF outpatients, symptoms of depression were
significantly associated with increased risk of death and
hospitalization for CV causes after HF disease severity, ejection
fraction, age, and use of medications were controlled for.15
Surprisingly, patients treated with antidepressants (mainly SSRIs) had
an increased risk of hospitalization or death from a CV cause.
These conflicting results were addressed in SADHART-CHF (Congestive
Heart Failure). This randomized, double-blind trial investigated the use
of sertraline 50 to 200 mg per day versus placebo in 469 HF patients
for 12 weeks. All patients received supportive care from nurses. Similar
to findings in SADHART’s post-MI patients, sertraline appeared to be
safe for use in the HF population, as there was no difference in serious
adverse effects between treated and placebo patients. However, there
was no difference in reduction of depression or adverse CV outcomes.16 Therefore, this trial suggests that there is no added benefit to giving sertraline in addition to supportive care.
Although evidence concerning the benefits of using antidepressants to
treat depression in HF patients is weak and conflicting, it is clear
that depression in this population increases morbidity and mortality. As
with the post-MI population, depression in HF patients is likely
associated with behaviors that can lead to a deterioration of their CV
disease state, including nonadherence to medications, smoking, and
physical inactivity. Therefore, it is important to identify these
behaviors and provide support and reinforcement through secondary
prevention measures until further research determines the optimal
treatment of depression in HF patients.
Screening for Depression
The significant effect of depression on disease progression in
cardiac patients led the American Heart Association (AHA) to release
screening recommendations for patients with coronary heart disease.2 The AHA’s recommendations include the Patient Health Questionnaire (PHQ)-2 and PHQ-9 (TABLE 2).17,18
Consisting of two questions, the PHQ-2 is a simple initial screening
tool for depression. A patient with a positive response to one or both
questions should take the PHQ-9 (nine questions), with physician
follow-up if the PHQ-9 score is high.2 Furthermore, the AHA
recommends that patients with cardiac disease be routinely screened for
depression, whether in the physician’s office, clinic, hospital, or
cardiac rehabilitation center.
Opponents of the AHA recommendation for routine screening cite the
lack of evidence that routine screening for depression in cardiac
patients leads to improved CV outcomes.19 It has been
hypothesized that, although routine screening will result in increased
diagnosis of depression, there may not be a difference in outcomes,
owing to inadequate antidepressant dosing or duration of treatment.20
One approach to this problem is to utilize a collaborative-care
depression-management program for depressed cardiac patients. A recent
prospective study of this type of program in cardiac inpatients had a
social-work care manager develop individualized treatment
recommendations, contact the patient’s primary care physician to discuss
recommendations, and educate the patient about depression. Patients who
received care through the collaborative program were significantly more
likely to receive adequate depression treatment compared with patients
who were not in the program.21 However, further research is needed to determine whether this result would translate to improved CV outcomes.
Pharmacists are in a unique position to provide education and support
to cardiac patients experiencing depression. Inadequately treated
patients are at increased risk for poorer CV outcomes, so it is
essential that pharmacists be involved in their care. There are multiple
ways in which the pharmacist can accomplish this. In a community
setting, the pharmacist can determine trends in medication adherence,
provide counseling on antidepressants, and offer support as needed.
Because the pharmacist sees patients on a regular basis, he or she can
advise the patient and the physician if more specialized care is needed
for a worsening of disease state. In a clinic or hospital setting, the
pharmacist can help screen for depression, ensure appropriate medication
dosing, and educate the patient and family members. These interventions
can potentially increase adherence and improve depressive symptoms.
Although antidepressants have not been proven to reduce adverse CV
outcomes, patients with an improvement in depression will likely be more
adherent to their cardiac medications and reduce secondary risk
factors. As a health care provider who has the potential to communicate
with patients on a regular basis to assess adherence, the pharmacist can
significantly impact the care of high-risk cardiac patients
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