Abstract & Commentary
Synopsis: Sertraline contributed to a decrease in platelet activation over and above either aspirin or thienopyridines, and the SSRI "might represent an attractive additional advantage for patients with depression and comorbid coronary artery disease and stroke."
Source: Serebruany VL, et al. Circulation. 2003;108:939-944.
It is well known that clinical depression is common after acute myocardial infarction and unstable angina and is associated with considerably higher mortality. Up to 2- to 5-fold increases in mortality risk have been reported; multiple reports have linked depression in acute coronary syndrome (ACS) patients with decreased survival. A number of observations suggest that depression may be related to enhanced platelet activation as well as endothelial dysfunction. In 2002, the results of SADHART were published.1 This multicenter trial was carried out in the United States and Canada; 356 clinically depressed patients following ACS were randomized to placebo or sertraline for a period of 6 months.
The sertraline (selective serotonin reuptake inhibitor or SSRI) cohort demonstrated a trend toward a reduction in morbidity and mortality without an increase in risk; there was no statistically significant reduction in major end points. Other studies have been reported suggesting that SSRI treatment in post-MI and stroke patients may be beneficial, but as yet, there is no hard evidence that pharmacologic treatment of depression improves survival in these patients. The present report is a substudy assessing platelet and endothelial biomarkers from 5 SADHART outpatient sites. All measurements were made at baseline, 6, and 16 weeks. This subset of 64 patients from SADHART represents 17.5% of the entire study. Assessment of depression was made clinically as well as using validated tools; all patients met DSM-IV criteria for major depression. Platelet biomarkers included platelet factor 4, ß-thromboglobulin, and platelet/endothelial cell adhesion molecule-1 (PECAM-1). P-selectin, vascular cell adhesion molecule-1 (VCAM-1), E-selectin, thromboxane B2, and prostacyclin were also measured using meticulous techniques in highly standardized and experienced laboratories. The primary end point of the substudy was a change in components of platelet function at week 6 compared to baseline, as well as week 16.
Results
The 64 post-ACS patients in the platelet substudy were generally similar to the other 305 SADHART patients, although there were some minor inequities in a variety of clinical end points. The biomarker data support a role for sertraline in modulating several measurements of platelet function. Placebo and sertraline patients experienced a decrease in platelet markers over the 4-month period, but the reductions were for the most part greater in the SSRI cohort. For instance, decreases from baseline were statistically significant in 12 of 16 measurements in the sertraline group compared to only 8 of 16 in the placebo group. Using a repeated-measures ANOVA, sertraline was superior to placebo regarding measurements of platelet activation (eg, ßTG at 6 and 16 weeks and at 16 weeks for P-selectin). "Biomarker changes were numerically greater on drug than placebo in 14 of the 16 observations."
Serebruany et al conclude that sertraline was associated with reductions in platelets/endothelial activation, which may reflect a beneficial component resulting in increased survival in depressed patients, as suggested but not proven by the main SADHART study and other trials. Serebruany et al suggest that the platelet effects of SSRIs may represent an independent therapeutic modality other than treatment of depression and that these effects might be applicable to nondepressed patients with coronary artery disease. They suggest, "SSRIs might represent an attractive class of dual agents for treating depression, as well as protecting patients from secondary vascular events by simultaneously inhibiting platelet activation." They emphasize the considerable increase in mortality in depressed patients with ACS, which may be present in as many as 40% of individuals, a minority of which develop major depression. In the Cardiac Arrhythmia Pilot Study in post-AMI patients with ventricular arrhythmias, the depressed patients had up to a 20-fold increased mortality from cardiac arrest at 1 year.
Other studies in depressed patients have shown alterations in platelet function, as well as increases in serotonin 5HT receptor binding sites on the platelet surface. Several abnormalities in depressed subjects have been reported relating to platelet serotonin receptors; elevated ß-TG and PF4 have been documented as well as a variety of other serotonin abnormalities. Serebruany et al conclude that the sertraline-related platelet alterations in this small cohort, particularly decreases in BTG and E-selectin, may represent significant evidence of improved platelet function. PECAM-1 and VCAM-1 did not change significantly.
Serebruany et al suggest that the results may indicate that some SSRI effects are directed at the platelet level rather than the brain. No single biomarker appears to be indicative of SSRI action. Multiple markers of platelet activation increase immediately after an ACS and decrease over time. Most of the patients in this study were on aspirin or a thienopyridine; thus, if sertraline did induce a significant effect on platelet activation, it would be in addition to the platelet anti-aggregatory affects of aspirin and clopidogrel and presumably with a different mechanism. Serebruany et al are convinced that "excessive transcardiac accumulation of serotonin" is an adverse phenomenon and that activated platelets resulting in local release of serotonin may be associated with vasoconstriction and recurrent cycles of platelet aggregation. Animal models would appear to support a protective effect of serotonin receptor antagonists. Serebruany et al conclude that sertraline contributed to a decrease in platelet activation over and above either aspirin or thienopyridines and that the SSRI "might represent an attractive additional advantage for patients with depression and comorbid coronary artery disease and stroke."
Comment by Jonathan Abrams, MD
Careful scrutiny of the biomarker data in this platelet substudy of SADHART does confirm that sertraline diminishes platelet biomarkers more than placebo at 16 weeks, although some of the differences are not statistically significant. Many comparisons are not significant at a single time point, although sertraline vs placebo across all weeks was found to be effective in reducing ß-TG (P = .005) and E-selectin (P = .013). All other markers were not different from placebo when compared across the entire 16 weeks of the study. It is difficult to know whether these data reflect random noise, differences in platelet activation, or a clinically relevant finding that sertraline does contribute to a decreased risk of coronary and cerebral vascular disease.
The results of SADHART as well as other antidepressant trials have been disappointing, and at the present time a uniform approach cannot be advocated in post-MI individuals who are depressed. The EnrichD trial of counseling failed to decrease mortality in depressed patients. Nevertheless, counseling or psychotherapy, as well as careful selection of an antidepressant agent, particularly an SSRI, clearly are indicated in the substantial number of patients who develop clinical depression. However, one problem is the rapid turnover of ACS subjects in the hospital environment, often with an invasive cardiologist caring for the patients during the short-term hospitalization. This may decrease the likelihood of detection of depression unless carefully sought by trained personnel, particularly during the hospital setting. Depressed patients often have psychomotor slowing and may be more likely to be noncompliant with medications, exercise, and diet; it is not surprising that mortality rates are higher, although it is unlikely that major depression in the present era carries the enormous risk when compared to many years ago before the advent of IIb/IIIa receptor blockers, clopidogrel, and routine treatment with statins, ACE inhibitors, and beta blockers. In addition, there is evidence that depression may be related to immune abnormalities as well as endothelial dysfunction.
The SADHART investigators are to be congratulated on the meticulous approach they took to the issue of platelet function. However, the actual number of individuals studied is quiet small, reflecting less than 20% of the entire SADHART population. One cannot make definitive conclusions about the SSRI-platelet hypothesis until large trial results are available.
Dr. Abrams, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque, is on the Editorial Board of Clinical Cardiology Alert.
Reference
1. Sertraline AntiDepressant Heart Attack Randomized Trial. JAMA. 2002;288:701-709.
Sertraline contributed to a decrease in platelet activation over and above either aspirin or thienopyridines, and the SSRI might represent an attractive additional advantage for patients with depression and comorbid coronary artery disease and stroke.
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