Depression—not the use of antidepressants—is associated with increased mortality in patients with heart failure, according to a new study in the Archives of Internal Medicine.1
Christopher O’Connor, MD, and colleagues in the department of medicine collaborated with faculty of psychiatry and behavioral sciences and the Aging Center at Duke University Medical Center in Durham, NC, to investigate a purported increased risk of myocardial infarction (MI) and death in patients with heart disease who take antidepressants.
This association has not been limited to tricyclic antidepressants (TCAs), which exert pharmacological properties of type 1A antiarrhythmics and are linked to increased mortality in patients with arrhythmias.2 Although the use of TCAs has declined because of a less favorable adverse-effect profile relative to newer agents such as SSRIs, O’Connor and colleagues point out that the safety of SSRI antidepressants in patients with heart diseases remains in question.
“Although the efficacy of antidepressant therapy for depression is generally well recognized, the safety of these medications in ischemic heart disease and HF [heart failure] has been challenged,” they note. Citing findings from the Cardiac Arrhythmia Suppression Trial (CAST),3 they caution that “a medication that demonstrates great efficacy may have an unsuitable safety profile.”
The possibility that SSRIs could pose a risk in heart disease has emerged from some reports, including a recent case-control population study in the United Kingdom that was cited by O’Connor and colleagues. That study could not distinguish between SSRIs and TCAs in terms of increased risk of MI after starting antidepressant therapy.4
In a separate study from Duke University, investigators who analyzed a database from patients with cardiovascular disease found that those patients who received coronary artery bypass grafts appeared to be at higher risk for mortality and rehospitalization if exposed to an SSRI.5
Assessing risk in 1000 patients
Few studies investigating this risk with antidepressants have accounted for the depression status of patients, according to O’Connor and colleagues. In their assessment of long-term deaths in patients admitted to the cardiology service at Duke with heart failure, these investigators prospectively measured depression status with the Beck Depression Inventory (BDI). Depressive illness was defined as a BDI score of 10 or more. The BDI was employed as the more common screen for depression than, for example, the Hamilton Depression Rating Scale, which is more often used to gauge change in depressive symptoms in clinical trials.
Between 1997 and 2003, 1006 patients 18 years or older were monitored for heart failure. These patients had an ejection function of 35% or less; 62% of the patients had ischemic heart disease.
Using inpatient pharmacy records and discharge summaries, patients were categorized according to whether they received an SSRI, a TCA, a combination, another antidepressant type, or no antidepressant. Of 162 patients receiving antidepressants, 129 (79.6%) received SSRIs. The groups receiving other types of antidepressants (7.4% TCAs, 7.4% other) were too small to analyze for association with survival.
The average duration of follow-up was 971 days, during which 429 patients died. As expected, these patients were older and had been admitted for worsening heart failure. Higher death rates were associated with ischemic causes of heart failure rather than with non-ischemic cardiac disease. Most of the deaths were attributed to cardiovascular causes (94.4%), regardless of whether patients had received an antidepressant. Antidepressant use correlated well with the severity of depressive illness: patients with more severe depression were more likely to have received antidepressants.
Higher rates of death were observed with patients taking antidepressants. After adjustment for depression, however, the investigators reported, “neither antidepressant use nor use of SSRIs only was associated with reduced survival. Nonetheless, depression remained associated with reduced survival.”
The investigators noted that while they had found an association of depression rather than antidepressants with increased risk of death in patients with heart failure, the risk with depression did not appear to be significantly attenuated by use of antidepressants. They also noted, however, that others have reported that antidepressant treatment, specifically with SSRIs, can improve outcomes for patients with heart disease and depression.6 In addition, they described limitations of the study: they noted that it was observational and therefore made causality difficult to infer.
This study did not definitively separate antidepressant use from increased mortality in patients who have heart failure. However, O’Connor and colleagues suggest that their findings support the need for randomized clinical trials “that are adequately powered to evaluate whether the use of SSRIs and/or other antidepressants may reduce mortality and other cardiac outcomes without raising safety concerns among depressed cardiac patients.”
