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 high-risk population.
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 experiencing depression.
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