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European Journal of Heart Failure 2003 5(4):517-521; doi:10.1016/S1388-9842(03)00005-9
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© 2003 European Society of Cardiology

Selective serotonin reuptake inhibitors yield additional antiplatelet protection in patients with congestive heart failure treated with antecedent aspirin

V.L. Serebruanya, A.H. Glassmanb, A.I. Malinina, D. Atarc, D.C. Saned, B.R. Oshrinea, J.J. Fergusone and C.M. O'Connorf

a Sinai Center for Thrombosis Research, Johns Hopkins University 2401 West Belvedere Avenue, Schapiro Research Building-R 202 Baltimore, MD 21215, USA
b Columbia University New York, NY, USA
c Frederiksberg Hospital Copenhagen, Denmark
d Wake Forest University School of Medicine Winston-Salem, NC, USA
e Texas Heart Institute Houston, TX, USA
f Duke Clinical Research Institute Durham, NC, USA

* Corresponding author. Tel.: +1-410-601-5266; fax: +1-410-601-9061 E-mail address: heartdrug{at}aol.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Clinical depression has been identified as an independent risk factor for increased mortality in patients with coronary artery disease. Enhanced platelet activity has been suggested as the mechanism responsible for this adverse association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelets in patients undergoing coronary stenting. We sought to determine whether concomitant therapy with SSRIs would yield additional anti-platelet benefit in patients with congestive heart failure (CHF) already treated with antecedent aspirin. A total of 88 patients with left ventricular ejection fraction (LVEF) <40% or CHF symptoms in the setting of preserved systolic function and NYHA Class II–IV were analyzed. Of these, 23 patients (26%) were chronic SSRI users (SSRI+), and 65 patients were free from SSRI therapy (SSRI–). All patients received aspirin (325 mg) for at least 1 month prior to platelet studies. Platelets were assessed by aggregometry, flow cytometry and a rapid analyzer. The SSRI+ group exhibited a substantial decrease in platelet activity when compared with SSRI– patients, as manifested by a significant reduction in ADP- (P=0.001), and collagen-induced (P=0.02) aggregation, and the expression of PECAM-1 (P=0.03), GPIb (P=0.03), GP IIb/IIIa antigen (P=0.02) and GP IIb/IIIa activity with PAC-1 antibody (P=0.04) and P-selectin (P=0.02). Therapy with SSRIs also resulted in the reduced formation of platelet–leukocyte microparticles (P=0.01). Epinephrine-induced aggregation in plasma, collagen-induced whole blood aggregation, closure time and expression of vitronectin receptor, CD63, CD107a, CD107b and CD151 did not differ between groups. In patients with CHF already on aspirin, SSRI therapy was associated with further inhibition of platelet function. This observation may help to explain some of the clinical benefits associated with SSRI therapy. Further clinical trials may help to elucidate the potential outcome benefits of SSRIs in other potential thrombotic circumstances.

Key Words: Congestive heart failure • Platelets • Selective serotonin reuptake inhibitors (SSRIs)

Received June 11, 2002; Revised October 24, 2002; Accepted December 17, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The pathophysiology of congestive heart failure (CHF) is complex and much of our comprehension revolves strictly around the neurohormonal and mechanical mechanisms involved. It has been suggested that CHF is associated with altered hemostasis in general and platelets in particular, but whether a prothrombotic state contributes to the pathogenesis and progression of the disease is still controversial [1,2]. Thromboembolism is a critical and relatively common complication of CHF. Small observational studies have suggested that pulmonary thromboembolism and stroke are common in patients with dilated cardiomyopathy [3,4]. The annual risk of stroke is increased to 4% in patients with severe CHF [5].

Depression has been identified as an independent risk factor for adverse vascular clinical outcomes in patients after acute coronary events and ischemic stroke. Selective serotonin reuptake inhibitors (SSRIs) are established first-line medications for treatment of major depression. The modulation of platelet activity has been suggested as a potential mechanism responsible for the reduction of cardiovascular mortality in major depression following therapy with SSRIs [6–8]. However, the potential mortality benefits of SSRIs could also be related to the antidepressant properties per se and improved quality of life, rather than to direct platelet inhibition. The effect of SSRI therapy on platelet characteristics in patients with CHF already treated with aspirin has never been explored. The present study examines the effect of SSRI therapy on platelet function in CHF patients already on aspirin therapy, utilizing a variety of techniques, including conventional aggregometry in plasma and whole blood, expression of major surface receptors by flow cytometry and quantitative platelet function.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
The study was performed in the outpatient cardiology clinics in the Baltimore metropolitan area. Written informed consent was obtained from all patients. The study population consisted of 88 outpatients with documented evidence of CHF, defined as LVEF <40%, or CHF symptoms in the setting of preserved systolic function and NYHA class II–IV symptoms. A total of 23 patients (26%) were on chronic SSRI therapy (SSRI+ group); 65 patients were not on SSRI therapy (SSRI– group) and served as internal controls. All patients had been treated with aspirin (375 mg/day) for at least 1 month prior to the platelet studies. Patients on an antithrombotic agent other than aspirin were excluded. Patients with a history of bleeding diathesis, acute myocardial infarction within 1 month, stroke within 3 months, drug or alcohol abuse, prothrombin time greater than 1.5-fold control, platelet count <100 000/mm [3], hematocrit <25% or creatinine >4.0 mg/dl were also excluded from the study.

2.2. Samples
Blood samples were obtained with a 19-gauge needle by direct venipuncture and drawn into two 7-ml vacutainer tubes, at room temperature, containing 3.8% trisodium citrate. The vacutainer tube was filled to capacity and gently inverted three–five times to ensure complete mixing of the anticoagulant.

2.3. Platelet aggregation
2.3.1. Platelet-rich plasma: optical aggregometry
The blood–citrate mixture was centrifuged at 1200xg for 2.5 min. The resulting platelet-rich plasma (PRP) was kept at room temperature for use within 1 h. The platelet count was determined in the PRP sample and adjusted to 3.5x108 /ml with homologous platelet-poor plasma. Platelets were stimulated with 5 µmol ADP, 1 µg/ml collagen or 750 µmol arachidonic acid (Chronolog, Hawerton, PA) and aggregation was assessed as previously described [9] using a Chronolog Lumi aggregometer (model 560-Ca) with the AGGROLINK software package. Aggregation was expressed as the maximal percentage change in light transmittance from baseline, using platelet-poor plasma as a reference. Curves were analyzed according to international standards.

2.3.2. Whole blood: impedance aggregometry
Whole-blood aggregation was determined using a Chronolog device. The whole blood–citrate mixture was diluted 1:1 with 0.5 ml of phosphate-buffered saline and gently swirled. The sample was allowed to warm to 37 °C for 5 min, then transferred to the assay well. The electrode was then placed in the cuvette and the sample stimulated with 1 µg/ml collagen. The change in electrical impedance was recorded as previously described [10].

2.4. Platelet function analyzer
Using the Dade Behring (Miami, FL) platelet function analyzer (PF-100TM) instrument, the blood–citrate mixture was aspirated under a constant negative pressure and contacted an ADP and collagen-coated membrane. The blood then passed through an aperture that induces high shear and simulates primary hemostastis after injury to a small blood vessel under flow conditions. The time to aperture occlusion (the closure time inversely related to the degree of shear-induced platelet activation [11]) was recorded in seconds.

2.5. Whole-blood flow cytometry
The surface expression of platelet receptors was determined by flow cytometry using the following monoclonal antibodies: CD 41 antigen (GP IIb/IIIa, {alpha}IIβ3) CD 42b (GP Ib), CD 62p (P-selectin) (DAKO Corporation, Carpenteria, CA), CD 51/CD 61 ({alpha}vβ3, or vitronectin receptor), CD 31 (platelet/endothelial cell adhesion molecule [PECAM]-1), CD 107a (LAMP-1), CD 107b (LAMP-2), CD 63 (LIMP or LAMP-3), CD 151 (PETA-3), and GPIIb/IIIa activity with PAC-1 (PharMingen, San Diego, CA). Formation of platelet–leukocyte microparticles was assessed by dual labeling with pan-platelet marker (CD151), and then with CD14, the macrophage receptor for endotoxin lipopolysaccharides. The blood–citrate mixture (50 µl) was diluted with 450 µl of Tris-buffered saline (10 mmol/l Tris, 0.15 mol/l sodium chloride) and mixed by inverting an Eppendorf tube gently two times. The corresponding antibody was then added (5 µl) and incubated at room temperature for 30 min. After incubation, 400 µl of 2% buffered paraformaldehyde was added for fixation. The samples were analyzed on a Becton Dickinson FACScan flow cytometer set up to measure fluorescent light scatter as previously described [12]. All parameters were collected using four-decade logarithmic amplification. The data were collected in list mode files and then analyzed. P-selectin was expressed as the percentage of positive cells, as previously described [13]. Other antigens were expressed as log mean fluorescence intensity.

2.6. Statistical analysis
Comparisons between SSRI+ and SSRI– groups were made using the t-test with Bonferroni correction. Data are expressed as mean±S.D., and differences were considered significant at a P<0.05. Differences between individual flow cytometric histograms were assessed using the Smirnov–Kolmogorov test incorporated in the CELLQUESTTM software.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Clinical characteristics
The demographics and clinical characteristics of the 88 patients, stratified by SSRI use, are shown in Table 1.


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  		Table 1 Clinical characteristics of CHF patients dependent on SSRI use

 
Age and gender were evenly distributed, and the majority of patients in both groups were African Americans. Tobacco use, underlying angina, incidence of peripheral vascular disease, prior history of cardiac surgery, systemic hypertension and hyperlipidemia were common in both groups. There were significantly more patients with a history of myocardial infarction, and a higher prevalence of diabetes in the SSRI+ group. The etiology of CHF, NYHA class and ejection fraction was similar between groups. The distribution of concomitant medications was fairly even between groups, except for a slightly higher use of glycosides in the SSRI– patients and more common use of statins in the SSRI+ group. The selection of SSRI agent was spread fairly equally among the four leading agents (fluoxetine, paroxetine, citalopram and sertraline).

3.2. Platelet data
Platelet function data are summarized in Table 2.


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  		Table 2 Platelet characteristics dependent on SSRI use

 
Most of the tests showed inhibition of platelet function in CHF patients receiving SSRIs when compared with the SSRI– group. These differences reached statistical significance for ADP- and collagen-induced aggregation, PECAM-1, GPIb, GP IIb/IIIa antigen and GPIIb/IIIa activity with PAC-1 antibody, and P-selectin expression. Formation of the platelet–leukocyte conjugates was also significantly reduced in the SSRI+ group. Other tests showed trends suggesting platelet inhibition, but these did not achieve statistical significance.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The data from the present study show that treatment with SSRIs is associated with significant inhibition of platelet function in patients with heart failure already receiving aspirin. This finding may, at least in part, explain why SSRI therapy may be associated with a survival benefit in patients not only after acute coronary events, but also in the heart failure population. The ability of SSRIs to yield additional antiplatelet protection in patients already treated with antecedent aspirin may represent a safe and attractive alternative to the limited options we have at present for long-term mild platelet inhibition.

A number of investigators have linked the mortality benefits of SSRIs with their antidepressant properties [14], regulation of sympathetic [15] and parasympathetic [16] balance, and modulation of vascular tone via dopamine [17] and norepinephrine [18] blockade. Prior data from our laboratory have suggested that SSRIs or/and their metabolites exhibit potent antiplatelet activity in both in vitro [19] and ex vivo clinical scenarios in patients undergoing coronary stenting [20]. Platelet inhibition by SSRIs may represent an independent avenue of pharmacological effects responsible for the ultimate success of these drugs in patients not only with depression after acute vascular thrombotic events, but also in other disease states, such as heart failure.

The present data suggest that chronic SSRI therapy is associated with inhibition of various indices of platelet aggregation and activation, including conventional and whole-blood aggregometry, rapid platelet assay and whole-blood flow cytometry. While these differences appeared to be present over a broad range of assays, they did not achieve statistical significance for all markers. This is possibly a function of the fact that no single assay or test truly reflects all aspects of platelet function. These differences also appeared evident with all of the SSRIs included in our study. Moreover, in our study there were certain patients in the SSRI-receiving group who exhibited high platelet function, but, overall, platelet inhibition was prevalent. Considering the relatively large study population, we believe that our findings document an antiplatelet effect of SSRIs above that achieved with aspirin in CHF patients. We do not have enough evidence at this time to speculate on the mechanisms responsible for such associations. However, it appears that SSRIs may modulate platelets by an independent pathway different from glycoprotein IIb/IIIa inhibitors and aspirin. It would appear that SSRIs do not produce platelet inhibition via the established mechanisms; this points to the possible existence of independent pathways possibly related to serotonin metabolism, which may play a role in platelet function other than as a pure mediator of platelet activation.

It should also be noted that antiplatelet properties of SSRI were present in CHF patients receiving aspirin. Considering the existing controversy regarding the high prevalence of aspirin resistance and unfavorable interactions with ACE inhibitors in the CHF population, SSRIs may represent an attractive alternative or addition to other anti-platelet drugs that are being combined with aspirin, such as thicropyridives and dipyridanote. Finally, diabetes is a potential confounder; the SSRI group exhibited nearly twice the incidence of diabetes. Therefore, our results may be even more striking after taking this into account. We were also not able to design the study considering power calculations for the sample size and different SSRIs used. These data represent a secondary analysis of the baseline platelet characteristics for the screen failures, and patients enrolled in the Plavix Use for Treatment of Congestive Heart Failure (PLUTO-CHF) Trial [21]. However, the SSRI+ group in our study is relatively small, and an attempt to distinguish differences between SSRIs on platelet function or triage patients dependent on diabetes would be too speculative.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In patients with CHF already on aspirin, SSRI therapy was associated with further inhibition of platelet function. This observation may help to explain some of the clinical benefits associated with SSRI therapy. Future strategies of more potent anti-platelet therapy should consider the potential anti-platelet effect of SSRIs. Further clinical trials may help to elucidate the potential outcome benefits of SSRIs in other potential thrombotic conditions, including not only CHF, but acute coronary syndromes as well.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

  1. Sbarouni E., Bradshaw A., Andreotti F., et al. Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J (1994) 127:607–612.[CrossRef][Web of Science][Medline]
  2. Gibbs C.R., Blann A.D., Watson R.D., et al. Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy. Circulation (2001) 103:1746–1751.[Abstract/Free Full Text]
  3. Nixon J.V. Left ventricular mural thrombus. Arch Internal Med (1983) 143:1567–1571.[Abstract/Free Full Text]
  4. Kyrle P.A., Korninger C., Gossinger H., et al. Prevention of arterial and pulmonary embolism by oral anticoagulants in patients with dilated cardiomyopathy. Thromb Hemost (1985) 54:521–523.[Web of Science][Medline]
  5. Brown A., Cleland J.G.F. Influence of concomitant disease on patterns of hospitalisation in patients with heart failure discharged from Scottish hospitals in 1995. Eur Heart J (1998) 19:1063–1069.[Abstract/Free Full Text]
  6. Glassman A.H., Shapiro P.A. Depression and the course of coronary artery disease. Am J Psychiatry (1998) 155:4–11.[Abstract/Free Full Text]
  7. Nair G.V., Gurbel P.A., O'Connor C.M., et al. Depression, coronary events, platelet inhibition, and serotonin reuptake inhibitors. Editorial. Am J Cardiol (1999) 84:321–323.[CrossRef][Web of Science][Medline]
  8. Sauer W.H., Berlin J.A., Kimmel S.E. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation (2001) 104:1894–1898.[Abstract/Free Full Text]
  9. Ruggeri Z.M. New insights into the mechanisms of platelet adhesion and aggregation. Semin Hematol (1994) 31:229–239.[Web of Science][Medline]
  10. Abbate R., Favilla S., Boddi M., et al. Factors influencing platelet aggregation in the whole blood. Am J Clin Pathol (1986) 86:91–96.[Web of Science][Medline]
  11. Kundu S.K., Heilman E.J., Sio R., et al. Characterization of an in vitro platelet function analyzer, PFA-100TM. Clin Appl Thromb Hemost (1996) 2:241–249.[Abstract/Free Full Text]
  12. Ault K.A. Flow cytometric measurement of platelet function and reticulated platelets. Ann NY Acad Sci (1993) 677:293–308.[Web of Science][Medline]
  13. Serebruany V.L., Kereiakes D.J., Dalesandro M.R., et al. Model of flow cytometer markedly affects platelet-bound P-selectin expression in patients with chest pain. Are we comparing apples with oranges? Thromb Res (1999) 96:51–56.[CrossRef][Web of Science][Medline]
  14. Shapiro P.A., Lesperance F., Frasure-Smith N., et al. An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction. Am Heart J (1999) 137:1100–1106.[CrossRef][Web of Science][Medline]
  15. Glue P. SSRI and sympathomimetic interaction. Br J Psychiatry (1996) 168:653.[Medline]
  16. Cohen H., Kotler M., Matar M., et al. Normalization of heart rate variability in post-traumatic stress disorder patients following fluoxetine treatment: preliminary results. Isr Med Assoc J (2000) 2:296–301.[Web of Science][Medline]
  17. Healy E., McKeon P. Dopaminergic sensitivity and prediction of antidepressant response. J Psychopharmacol (2000) 14:152–156.[Abstract/Free Full Text]
  18. Montgomery S.A. New developments in the treatment of depression. J Clin Psychiatry (1999) 60(Suppl_14):10–15.
  19. Serebruany V.L., Gurbel P.A., O'Connor C.M. Platelet inhibition by sertraline and N-desmethylsertraline: a possible missing link between depression, coronary events, and mortality benefits of selective serotonin reuptake inhibitors. Pharm Res. (2001) 43:453–462.[CrossRef][Web of Science]
  20. Serebruany V.L., O'Connor C.M., Gurbel P.A. Effect of selective serotonin reuptake inhibitors on platelets in patients with coronary artery disease. Am J Cardiol (2001) 87:1398–1400.[CrossRef][Web of Science][Medline]
  21. Serebruany VL, Malinin AI, Jerome SD, et al. Effects of clopidogrel and aspirin combination versus aspirin alone on platelet aggregation and major receptor expression in patients with heart failure. The Plavix Use for Treatment of Congestive Heart Failure (PLUTO-CHF) Trial. Am Heart J (in press).

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