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Selective Serotonin Reuptake Inhibitor Use by Patients with Acute Coronary Syndromes
The American Journal of Medicine (2007) 120, 525-530
CLINICAL RESEARCH STUDY
Selective Serotonin Reuptake Inhibitor Use by Patients with Acute Coronary Syndromes Roy C. Ziegelstein, MD,a Jennifer Meuchel, MD,a Thomas J. Kim, MD,a Madiha Latif, MBBS,a William Alvarez, PharmD,b Neela Dasgupta, MD,a Brett D. Thombs, PhDc a
Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, bDepartment of Pharmacy, Johns Hopkins Hospital, cDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Md. ABSTRACT BACKGROUND: Selective serotonin reuptake inhibitors are commonly used to treat anxiety, depression, and other conditions that commonly affect patients with coronary artery disease. Selective serotonin reuptake inhibitors inhibit platelet activation and may, therefore, affect outcomes in patients with acute coronary syndromes. METHODS: A retrospective study was performed of 1254 patients with acute coronary syndromes comparing in-hospital bleeding and cardiac event rates in 158 patients who received a selective serotonin reuptake inhibitor and a propensity score-matched group of patients who did not. All patients were treated with a glycoprotein IIb/IIIa inhibitor and almost all also received aspirin, clopidogrel, and heparin. RESULTS: Patients who received a selective serotonin reuptake inhibitor were significantly more likely to experience any bleeding (37.3% vs 26.6%, OR 1.65, 95% confidence interval (CI), 1.02-2.66, P ⫽.04) and significantly less likely to experience recurrent myocardial ischemia, heart failure, or asymptomatic cardiac enzyme elevation while in the hospital (7.0% vs 13.9%, OR 0.46, 95% CI, 0.22-0.99, P ⫽.04). No differences were observed in death, myocardial infarction during the hospitalization, urgent revascularization, or major bleeding. Bleeding and cardiac events were not affected by antidepressants other than selective serotonin reuptake inhibitors. CONCLUSIONS: Selective serotonin reuptake inhibitor use during a hospitalization for an acute coronary syndrome is associated with reduced rates of recurrent ischemia, heart failure, or cardiac enzyme elevation at the expense of increased bleeding in patients receiving maximal conventional antiplatelet medications and heparin. Clinicians should be aware of this association when treating patients with an acute coronary syndrome. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Acute coronary syndrome; Bleeding; Depression; Myocardial infarction; Selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of anxiety, depression, and other conditions that commonly affect patients with coronary ar-
Requests for reprints should be addressed to Roy C. Ziegelstein, MD, Department of Medicine, B-1-North, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224-2780. E-mail address: [email protected]
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.10.026
tery disease.1 Several lines of evidence suggest that platelet function might be affected by SSRIs. Neurons and platelets are the only cells that express serotonin receptors in the nonactivated state.2 As part of the hemostatic process, activated platelets release serotonin, a key step in platelet aggregation and vasoconstriction. SSRIs reduce the content of serotonin in platelets and inhibit adenosine diphosphateinduced platelet aggregation and dense granule release.3 Serotonin-deficient platelets might not be able to release sufficient serotonin when activated, thereby leading to dysfunctional hemostasis.4
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A recent review identified more than 120 MEDLINEOutcome Measures cited peer-reviewed articles linking SSRI use to bleeding Bleeding events and adverse cardiac events were monitored events.2 Reported bleeding episodes attributed to SSRIs as during the index hospitalization. Information was extracted they are used in clinical practice appear to be uncommon and from the handwritten and electronic medical records and generally mild.5 An association between SSRI use and gastrorecorded on an 8-page data collection form. Responses to intestinal bleeding has been reportthese questions were then used to ed,6-8 particularly with concurrent code whether a bleeding event or use of nonsteroidal anti-inflammaadverse cardiac event occurred. CLINICAL SIGNIFICANCE tory drugs or aspirin. Major bleeding was defined as Three case-control studies9-11 bleeding resulting in death; intracra● Acute coronary syndrome patients who showed that current use of SSRIs nial hemorrhage; retroperitoneal received an SSRI were significantly more was associated with a lower risk bleeding; or bleeding accompanied likely to experience bleeding and less of developing a myocardial infarcby a drop in the hemoglobin conlikely to experience recurrent myocardial tion (MI) when compared to no centration of ⬎3 g/dL.17-19 Minor ischemia, heart failure, or asymptomatic use. On the other hand, 2 other bleeding was defined as overt bleedcardiac enzyme elevation while in the studies showed no relationship being not meeting criteria for major hospital. tween SSRI use and MI,12,13 and bleeding.19 This included any one study found an increased mention of blood loss in the med● Clinicians should be aware of this assorisk.14 The possibility that the efical record or the need for any ciation when treating acute coronary fect of SSRIs on platelets might intervention to treat a puncture syndrome patients. decrease adverse cardiac event site complication that resulted in rates in this setting is suggested by bleeding. Blood loss resulting the finding that treatment with serfrom coronary artery bypass graft traline in depressed patients who had recently experienced surgery was not counted under major or minor bleeding. an acute coronary syndrome reduced platelet and endotheGastrointestinal bleeding included any note of blood in the lial activation even though these patients were already restool or vomitus (ie, melena, hematemesis, hematochezia). ceiving traditional antiplatelet agents.15 No prior study has Any need for endoscopy during the hospitalization was evaluated whether SSRI use by patients who are already documented, and then if this was needed, the endoscopy receiving contemporary acute coronary syndrome therapy report was examined to determine whether bleeding was with aspirin, clopidogrel, a glycoprotein IIb/IIIa inhibitor, found at the time of the procedure. and heparin, affects the incidence of bleeding or cardiac Prior to chart review, adverse cardiac events were clasevents. sified as “major” or “minor.” Major adverse cardiac events included death, MI during the hospitalization, and/or the need for urgent revascularization.20 Death was defined as METHODS mortality from any cause. An MI during the hospitalization Patient Sample and Data Collection was defined as an episode of typical ischemic chest pain accompanied by new elevation of the MB fraction of creaThis study was approved by the Johns Hopkins Medicine tine phosphokinase with at least one value of 8 ng/mL or Institutional Review Board. All patients who were admitted to more or by a new elevation of the cardiac troponin I of The Johns Hopkins Hospital in Baltimore, Maryland from greater than 3 times the upper limit of normal (in a patient April 1, 2001 through April 30, 2004 with an acute coronary with unstable angina as the admission diagnosis). For a syndrome (ie, a diagnosis of unstable angina or of MI with or patient with an admitting diagnosis of MI, an MI during the without ST-segment elevation) and who were treated with any hospitalization was defined as typical ischemic chest pain glycoprotein IIb/IIIa receptor inhibitor during the hospitalizaand an increase in creatine phosphokinase-MB of at least tion were identified with CView, a Johns Hopkins Health 50% above the previous creatine phosphokinase-MB value System hospital billing software application.16 with a characteristic rising and falling pattern of the creatine Both electronic and handwritten medical records were phosphokinase-MB fraction. In addition to major adverse reviewed. Recorded information included demographics, cardiac events, minor adverse cardiac events were moniadmission diagnosis, antidepressant use, glycoprotein IIb/ tored, including recurrent myocardial ischemia (ischemic IIIa inhibitor agent, medical comorbidities, risk factors for chest pain with new electrocardiographic changes but withcardiovascular disease and bleeding, use of percutaneous out elevation of cardiac biomarkers), new heart failure, and transluminal coronary angioplasty, recurrent angina, MI during the hospitalization, asymptomatic cardiac enzyme asymptomatic cardiac enzyme elevation (as defined above). elevation, bleeding, cardiac death, and total mortality. The Patients were classified hierarchically; if criteria for both data collection form also recorded the use of aspirin, clopimajor and minor adverse cardiac events were met, the padogrel, warfarin, heparin, nonsteroidal anti-inflammatory tient was included only in the major adverse cardiac event drugs, and direct thrombin inhibitors. group.
Ziegelstein et al Table 1
SSRI Use in Acute Coronary Syndromes
527
Baseline Demographic and Clinical Characteristics
Age (Years), Mean ⫾ SD Male Gender, n (%) Myocardial Infarction*, n (%) Hypertension†, n (%) Diabetes Mellitus†, n (%) Hypercholesterolemia†, n (%) Smoking†, n (%) Chronic obstructive pulmonary disease†, n (%) Prior MI†, n (%) Congestive heart failure†, n (%) Left ventricular ejection fraction ⬍35%, n (%) Liver disease, n (%) Renal failure†, n (%) Gastrointestinal bleed†, n (%) Anemia†, n (%) Cancer†, n (%) Bleeding diathesis†, n (%) Depression†, n (%) Non-SSRI antidepressant, n (%)
Pre-Propensity Score Matching
Post-Propensity Score Matching
SSRI (n ⫽ 158)
No SSRI (n ⫽ 1096)
P Value
No SSRI (n ⫽ 158)
P Value
61.4 ⫾ 11.8 90 (57.0) 49 (31.0) 133 (84.2) 66 (41.8) 128 (81.0) 102 (64.6) 31 (19.6) 68 (43.0) 35 (22.2) 26 (17.7) 7 (4.4) 20 (12.7) 9 (5.7) 20 (12.7) 17 (10.8) 2 (1.3) 98 (62.0) 20 (12.7)
63.4 ⫾ 12.0 789 (72.0) 513 (46.8) 825 (75.3) 345 (31.5) 866 (79.0) 623 (56.8) 124 (11.3) 309 (28.2) 143 (13.0) 141 (14.3) 18 (1.6) 81 (7.4) 41 (3.7) 116 (10.6) 123 (11.2) 4 (0.4) 80 (7.3) 80 (7.3)
.06 ⬍.01 ⬍.01 .01 .01 .56 .07 ⬍.01 ⬍.01 ⬍.01 .27 .02 .02 .24 .43 .86 .17 ⬍.01 .02
61.2 ⫾ 12.1 91 (57.6) 55 (34.8) 133 (84.2) 65 (41.1) 127 (80.4) 109 (69.0) 29 (18.4) 64 (40.5) 36 (22.8) 27 (19.1) 5 (3.2) 22 (13.9) 5 (3.2) 24 (15.2) 10 (6.3) 0 (0.0) 18 (11.4) 19 (12.0)
.84 .91 .47 1.00 .91 .89 .40 .77 .65 .89 .75 .56 .74 .27 .52 .16 .50 ⬍.01 .86
SSRI ⫽ selective serotonin reuptake inhibitor; MI ⫽ myocardial infarction. *Admitting diagnosis. †Any history.
Statistical Analysis Statistical significance was defined as a probability value less than .05. Chi-square and Fisher’s exact tests were used to compare categorical variables and 2-tailed t tests to compare continuous demographic and clinical variables between patients who were administered an SSRI at any time during the hospitalization and patients who were not administered an SSRI. Risk for bleeding and major adverse cardiac events was assessed by calculating odds ratios for patients who were administered an SSRI compared to patients not administered an SSRI. To adjust for differences in demographic and clinical characteristics of patients who were administered an SSRI in the hospital and those who were not administered an SSRI, we used a propensity score approach to generate a set of matched cases.21,22 The propensity score is a measure of the likelihood that a patient received an SSRI based on relevant demographic and clinical variables. This approach reduces many covariates to a single variable, the propensity score. Since patients with similar propensity scores have similar characteristics, once matched, the outcome of interest can be compared for patients who received an SSRI versus those who did not receive an SSRI. A stepwise logistic regression approach with P ⱕ.20 as the limit for variable entry was used to model the likelihood that patients received an SSRI based on demographic and clinical variables. A propensity score was generated for each patient, and each patient who received an SSRI during the hospitalization was matched with a patient with the
closest possible propensity score who did not receive an SSRI. The maximum allowable difference between propensity scores for matching was set at 0.1. When 2 or more patients who did not receive an SSRI had an identical propensity score, the match patient was chosen randomly.23 All analyses were performed with SPSS version 13.0 (Chicago, Ill). Data are reported as means ⫹ standard deviation or as odds ratios with 95% confidence intervals (CI).
RESULTS Sample Characteristics A total of 1254 patients were admitted with an acute coronary syndrome and received a glycoprotein IIb/IIIa inhibitor during the study period. Baseline demographic and clinical characteristics of the patients are shown in Table 1. The mean age of the sample was 63.1 ⫾ 12.0 years (range, 26 to 92), and 70.1% were male. Over half of the patients were admitted with unstable angina pectoris (55.2%), 26.6% were admitted with non-ST segment elevation MI, and 18.2% with ST segment elevation MI. Most patients had hypertension (76.4%) and a history of smoking (57.8%). Almost all patients underwent percutaneous transluminal coronary angioplasty (98.6%). Approximately 1 of every 7 patients (14.2%) had a history of depression. A total of 158 patients (12.6%) were administered an SSRI during the hospitalization. Compared to patients who were not administered an SSRI, patients who received an SSRI during the hospitalization were sig-
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Table 2
Antiplatelet and Anticoagulant Medications during Hospitalization Pre-Propensity Score Matching
Post-Propensity Score Matching
Medication
SSRI (n⫽158)
No SSRI (n⫽1096)
P Value
No SSRI (n ⫽ 158)
P Value
Abciximab, n (%) Eptifibatide, n (%) Tirofiban, n (%) Aspirin, n (%) Clopidogrel, n (%) Nonsteroidal anti-inflammatory drug, n (%) Warfarin, n (%) Unfractionated heparin, n (%) Low molecular weight heparin, n (%) Lepirudin, n (%)
8 150 1 156 151 4 20 153 23 1
75 1027 6 1087 1063 44 106 1080 149 6
.40 .55 .99 .58 .34 .51 .24 .12 .74 .99
14 144 2 157 148 6 15 157 17 0
.19 .19 .99 .99 .45 .52 .37 .21 .31 .99
(5.1) (94.9) (0.6) (98.7) (95.6) (2.5) (12.7) (96.8) (14.6) (0.6)
(6.8) (93.7) (0.5) (99.2) (97.0) (4.0) (9.7) (98.5) (13.6) (0.5)
(8.9) (91.1) (1.3) (99.4) (93.7) (3.8) (9.5) (99.4) (10.8) (0.0)
SSRI ⫽ selective serotonin reuptake inhibitor.
nificantly more likely to be female; to have been admitted with unstable angina pectoris; to have had a prior MI; and to have had a history of hypertension, diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, renal failure, or liver disease. The majority of patients (62%) administered an SSRI during the hospitalization had a history of depression, whereas less than 10% of patients not administered an SSRI had a history of depression. Patients receiving an SSRI during the hospitalization were more likely to also be receiving another, non-SSRI, antidepressant than patients not receiving an SSRI (12.7 vs 7.3%, P ⫽.02). The propensity score model included 11 predictor variables (age, gender, admission diagnosis of MI, congestive heart failure, chronic obstructive pulmonary disease, prior MI, history of hypertension, history of smoking, history of renal failure, liver disease, and non-SSRI anti-depressant use) and 5 interactions (age ⫻ prior MI, age ⫻ chronic obstructive pulmonary disease, gender ⫻ chronic obstructive pulmonary disease, gender ⫻ history of hypertension, gender ⫻ history of smoking). The c-statistic for the propensity score model was 0.72, indicating adequate discrimination. Collinearity analysis showed that the variables included in the propensity score were not highly correlated; the highest bivariate correlation between any two variables was 0.22. All 158 patients who were administered an SSRI were successfully matched: 46 on 5 or more digits of the propensity score, 27 on 4 digits, 47 on 3 digits, 20 on 2 digits, and 18 on 1 digit. After propensity score matching, the only significant difference between the SSRI and nonSSRI patients was that patients administered an SSRI were more likely to have a history of depression (Table 1). As shown in Table 2, almost all matched patients received aspirin (99.1%), clopidogrel (94.6%), and intravenous unfractionated heparin (98.3%) as standard therapy; 99.2% received either unfractionated or low molecular weight heparin. There were no significant differences between the patients administered an SSRI and those who were not, with respect to medications administered during
the hospitalization that are known to affect bleeding or thrombosis risk. These medications included aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs, warfarin, unfractionated heparin, low molecular weight heparin, glycoprotein IIb/IIIa inhibitors, or direct thrombin inhibitors. Similarly, there were no significant differences in the administration of these medications during the hospitalization after propensity score matching. The frequency of percutaneous transluminal coronary angioplasty was essentially the same among those administered an SSRI (156 of 158, 98.7%) and those who did not receive an SSRI (154 of 158, 97.5%, P ⫽ .68). Of the 158 patients who were administered an SSRI, sertraline was administered to 75 (47.5%), fluoxetine to 42 (26.6%), paroxetine to 26 (16.5%), escitalopram to 8 (5.1%), and citalopram to 7 (4.4%). In addition, 100 patients were administered a non-SSRI antidepressant; 46 received buproprion, 22 trazadone, 15 amitriptylline, 9 venlafaxine, and 15 either doxepine, imipramine, mirtazapine, nefazodone, or nortriptylline (7 patients were administered two non-SSRI antidepressants). Twenty patients who received an SSRI also received a non-SSRI antidepressant.
Adverse Cardiac Events and Bleeding Adverse cardiac event rates and bleeding outcomes for matched patients are summarized in Table 3. A total of 15 patients died during the index hospitalization (1.2%). Major and minor adverse cardiac events occurred in 86 patients (6.9%) and 163 patients (13.0%), respectively. A total of 98 patients experienced major bleeding (7.8%), 287 minor bleeding (22.9%), and 34 gastrointestinal bleeding (2.7%). Any bleeding occurred in 396 patients (31.6%). Patients who received an SSRI during the hospitalization were significantly more likely to experience any bleeding episode compared to those who did not receive an SSRI (37.3% vs 26.6%, OR 1.65, 95% CI, 1.02-2.66, P ⫽.04). This was due principally to an increase in the risk of minor bleeding (27.2% vs 18.4%, OR 1.66, 95% CI, 0.98-2.84, P ⫽.06). Of note, the bleeding rates observed in this study population are
Ziegelstein et al Table 3
SSRI Use in Acute Coronary Syndromes
529
Adverse Cardiovascular and Bleeding Events During Hospitalization
Event
No SSRI After Matching (n ⫽ 158)
SSRI (n⫽158)
Odds Ratio (95% Confidence Interval)
P Value
Major Adverse Cardiac Events Minor Adverse Cardiac Events Major Bleeding Minor Bleeding Gastrointestinal Bleeding Any Bleeding
10 22 13 29 2 42
12 11 11 43 5 59
1.22 0.46 0.84 1.66 2.55 1.65
.66 .04 .67 .06 .25 .04
(6.3%) (13.9%) (8.2%) (18.4%) (1.3%) (26.6%)
(7.6%) (7.0%) (7.0%) (27.2%) (3.2%) (37.3%)
(0.51-2.90) (0.22-0.99) (0.36-1.92) (0.98-2.84) (0.49-13.34) (1.02-2.66)
SSRI ⫽ selective serotonin reuptake inhibitor. Patients who experienced both a major and a minor adverse cardiac event were only counted as having had a major adverse cardiac event (see text for definitions). A bleeding event was only counted once in the total if a person had more than one type (see text for definitions).
similar to those reported among patients with an acute coronary syndrome receiving conventional antiplatelet therapy and heparin.19,24 Patients who received an SSRI during the hospitalization were significantly less likely to experience a minor adverse cardiac event (ie, recurrent myocardial ischemia, heart failure or asymptomatic cardiac enzyme elevation) than individuals who did not receive an SSRI (7.0% vs 13.9%, OR 0.46, 95% CI, 0.22-0.99, P ⫽.04). In the SSRI group, there were 5 patients with recurrent myocardial ischemia, 1 with heart failure, and 5 with asymptomatic cardiac enzyme elevation. Among those who did not receive an SSRI, there were 11 patients with recurrent myocardial ischemia (P ⫽.12 vs SSRI group), 1 with heart failure (P ⫽1.0), and 10 with asymptomatic cardiac enzyme elevation (P ⫽.19 vs SSRI group). The likelihood of major adverse cardiac events did not differ between groups that did or did not receive an SSRI (7.6% vs 6.3%, P ⫽.66). All analyses were repeated for patients who were administered a non-SSRI antidepressant. The degree of balancing of demographic and clinical characteristics through propensity score matching was comparable to the SSRI analysis (not shown). There were 5 major adverse cardiac events among the 100 patients administered a non-SSRI antidepressant and 5 among matched controls. Compared to matched patients, however, patients who were administered a non-SSRI antidepressant during the hospitalization tended, albeit non-significantly, to experience more minor adverse cardiac events (14.0% vs 7.0%, OR 2.16, P ⫽.11) compared to those patients who did not receive a non-SSRI antidepressant. Non-SSRI antidepressant use was not associated with bleeding (OR 1.04, P ⫽.89) or, individually, with major (OR 1.09, P ⫽.84), minor (OR 0.95, P ⫽.87), or gastrointestinal (OR 0.59, P ⫽.72) bleeding. Results for the SSRI and non-SSRI antidepressant analyses did not change substantively when the 20 patients who used both types of antidepressants were excluded from analyses.
DISCUSSION This is the first study to examine the association of SSRI use during hospitalization for an acute coronary syndrome with bleeding episodes and adverse cardiac events. The major
finding of this study was that patients who received an SSRI during the hospitalization were significantly more likely to experience a bleeding episode and significantly less likely to experience recurrent myocardial ischemia, heart failure, or asymptomatic cardiac enzyme elevation while in the hospital. The effects of SSRI use were observed in patients already receiving contemporary standard therapy for an acute coronary syndrome, including aspirin, clopidogrel, heparin, and a glycoprotein IIb/IIIa inhibitor. SSRI use has been associated with an increased risk of upper gastrointestinal bleeding in population-based studies,6,7,25 especially in elderly patients, in those with a history of gastrointestinal bleeding,25 or in patients concurrently administered nonsteroidal anti-inflammatory drugs or aspirin.6-8 The association between SSRI use and gastrointestinal bleeding and the increased risk when used concurrently with nonsteroidal anti-inflammatory drugs, aspirin, or drugs that affect coagulation is noted in the prescribing information available to consumers for all major SSRI antidepressants.26-30 The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART)31 found that the incidence of major adverse cardiac events was lower, although not significantly so, among patients hospitalized for an acute coronary syndrome with major depression who were randomized to receive sertraline than in those who received placebo (relative risk [RR] 0.77, 95% CI, 0.51-1.16). Of note, exposure to SSRIs in SADHART occurred on average more than a month after the acute coronary syndrome. A secondary analysis of the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial32 showed that the risk of death or recurrent MI was significantly lower in the 301 patients taking an SSRI to treat depression than in the 1388 depressed patients not receiving an antidepressant. In ENRICHD, patients were enrolled within 28 days of the index MI, and SSRIs were prescribed a minimum of 5 weeks after beginning cognitive behavior therapy. Although our results are consistent with these studies, several limitations should be considered in interpreting these findings. In particular, the results are observational and from a retrospective chart review; the number of patients who received an SSRI and the numbers of bleeding
530 events and adverse cardiac events were relatively small; and the period of exposure to SSRIs is not known. In summary, this retrospective study shows that SSRI use during a hospitalization for an acute coronary syndrome is associated with reduced cardiac events at the expense of increased bleeding in patients already receiving therapy with conventional antiplatelet medications and heparin. The effect of SSRIs in depressed patients with an acute coronary syndrome should be examined in a randomized, prospective controlled trial with a larger number of patients.
ACKNOWLEDGMENT RCZ, JM, and TK were supported by the Miller Family Scholar Program.
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CLINICAL RESEARCH STUDY
Selective Serotonin Reuptake Inhibitor Use by Patients with Acute Coronary Syndromes Roy C. Ziegelstein, MD,a Jennifer Meuchel, MD,a Thomas J. Kim, MD,a Madiha Latif, MBBS,a William Alvarez, PharmD,b Neela Dasgupta, MD,a Brett D. Thombs, PhDc a
Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, bDepartment of Pharmacy, Johns Hopkins Hospital, cDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Md. ABSTRACT BACKGROUND: Selective serotonin reuptake inhibitors are commonly used to treat anxiety, depression, and other conditions that commonly affect patients with coronary artery disease. Selective serotonin reuptake inhibitors inhibit platelet activation and may, therefore, affect outcomes in patients with acute coronary syndromes. METHODS: A retrospective study was performed of 1254 patients with acute coronary syndromes comparing in-hospital bleeding and cardiac event rates in 158 patients who received a selective serotonin reuptake inhibitor and a propensity score-matched group of patients who did not. All patients were treated with a glycoprotein IIb/IIIa inhibitor and almost all also received aspirin, clopidogrel, and heparin. RESULTS: Patients who received a selective serotonin reuptake inhibitor were significantly more likely to experience any bleeding (37.3% vs 26.6%, OR 1.65, 95% confidence interval (CI), 1.02-2.66, P ⫽.04) and significantly less likely to experience recurrent myocardial ischemia, heart failure, or asymptomatic cardiac enzyme elevation while in the hospital (7.0% vs 13.9%, OR 0.46, 95% CI, 0.22-0.99, P ⫽.04). No differences were observed in death, myocardial infarction during the hospitalization, urgent revascularization, or major bleeding. Bleeding and cardiac events were not affected by antidepressants other than selective serotonin reuptake inhibitors. CONCLUSIONS: Selective serotonin reuptake inhibitor use during a hospitalization for an acute coronary syndrome is associated with reduced rates of recurrent ischemia, heart failure, or cardiac enzyme elevation at the expense of increased bleeding in patients receiving maximal conventional antiplatelet medications and heparin. Clinicians should be aware of this association when treating patients with an acute coronary syndrome. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Acute coronary syndrome; Bleeding; Depression; Myocardial infarction; Selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of anxiety, depression, and other conditions that commonly affect patients with coronary ar-
Requests for reprints should be addressed to Roy C. Ziegelstein, MD, Department of Medicine, B-1-North, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224-2780. E-mail address: [email protected]
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.10.026
tery disease.1 Several lines of evidence suggest that platelet function might be affected by SSRIs. Neurons and platelets are the only cells that express serotonin receptors in the nonactivated state.2 As part of the hemostatic process, activated platelets release serotonin, a key step in platelet aggregation and vasoconstriction. SSRIs reduce the content of serotonin in platelets and inhibit adenosine diphosphateinduced platelet aggregation and dense granule release.3 Serotonin-deficient platelets might not be able to release sufficient serotonin when activated, thereby leading to dysfunctional hemostasis.4
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A recent review identified more than 120 MEDLINEOutcome Measures cited peer-reviewed articles linking SSRI use to bleeding Bleeding events and adverse cardiac events were monitored events.2 Reported bleeding episodes attributed to SSRIs as during the index hospitalization. Information was extracted they are used in clinical practice appear to be uncommon and from the handwritten and electronic medical records and generally mild.5 An association between SSRI use and gastrorecorded on an 8-page data collection form. Responses to intestinal bleeding has been reportthese questions were then used to ed,6-8 particularly with concurrent code whether a bleeding event or use of nonsteroidal anti-inflammaadverse cardiac event occurred. CLINICAL SIGNIFICANCE tory drugs or aspirin. Major bleeding was defined as Three case-control studies9-11 bleeding resulting in death; intracra● Acute coronary syndrome patients who showed that current use of SSRIs nial hemorrhage; retroperitoneal received an SSRI were significantly more was associated with a lower risk bleeding; or bleeding accompanied likely to experience bleeding and less of developing a myocardial infarcby a drop in the hemoglobin conlikely to experience recurrent myocardial tion (MI) when compared to no centration of ⬎3 g/dL.17-19 Minor ischemia, heart failure, or asymptomatic use. On the other hand, 2 other bleeding was defined as overt bleedcardiac enzyme elevation while in the studies showed no relationship being not meeting criteria for major hospital. tween SSRI use and MI,12,13 and bleeding.19 This included any one study found an increased mention of blood loss in the med● Clinicians should be aware of this assorisk.14 The possibility that the efical record or the need for any ciation when treating acute coronary fect of SSRIs on platelets might intervention to treat a puncture syndrome patients. decrease adverse cardiac event site complication that resulted in rates in this setting is suggested by bleeding. Blood loss resulting the finding that treatment with serfrom coronary artery bypass graft traline in depressed patients who had recently experienced surgery was not counted under major or minor bleeding. an acute coronary syndrome reduced platelet and endotheGastrointestinal bleeding included any note of blood in the lial activation even though these patients were already restool or vomitus (ie, melena, hematemesis, hematochezia). ceiving traditional antiplatelet agents.15 No prior study has Any need for endoscopy during the hospitalization was evaluated whether SSRI use by patients who are already documented, and then if this was needed, the endoscopy receiving contemporary acute coronary syndrome therapy report was examined to determine whether bleeding was with aspirin, clopidogrel, a glycoprotein IIb/IIIa inhibitor, found at the time of the procedure. and heparin, affects the incidence of bleeding or cardiac Prior to chart review, adverse cardiac events were clasevents. sified as “major” or “minor.” Major adverse cardiac events included death, MI during the hospitalization, and/or the need for urgent revascularization.20 Death was defined as METHODS mortality from any cause. An MI during the hospitalization Patient Sample and Data Collection was defined as an episode of typical ischemic chest pain accompanied by new elevation of the MB fraction of creaThis study was approved by the Johns Hopkins Medicine tine phosphokinase with at least one value of 8 ng/mL or Institutional Review Board. All patients who were admitted to more or by a new elevation of the cardiac troponin I of The Johns Hopkins Hospital in Baltimore, Maryland from greater than 3 times the upper limit of normal (in a patient April 1, 2001 through April 30, 2004 with an acute coronary with unstable angina as the admission diagnosis). For a syndrome (ie, a diagnosis of unstable angina or of MI with or patient with an admitting diagnosis of MI, an MI during the without ST-segment elevation) and who were treated with any hospitalization was defined as typical ischemic chest pain glycoprotein IIb/IIIa receptor inhibitor during the hospitalizaand an increase in creatine phosphokinase-MB of at least tion were identified with CView, a Johns Hopkins Health 50% above the previous creatine phosphokinase-MB value System hospital billing software application.16 with a characteristic rising and falling pattern of the creatine Both electronic and handwritten medical records were phosphokinase-MB fraction. In addition to major adverse reviewed. Recorded information included demographics, cardiac events, minor adverse cardiac events were moniadmission diagnosis, antidepressant use, glycoprotein IIb/ tored, including recurrent myocardial ischemia (ischemic IIIa inhibitor agent, medical comorbidities, risk factors for chest pain with new electrocardiographic changes but withcardiovascular disease and bleeding, use of percutaneous out elevation of cardiac biomarkers), new heart failure, and transluminal coronary angioplasty, recurrent angina, MI during the hospitalization, asymptomatic cardiac enzyme asymptomatic cardiac enzyme elevation (as defined above). elevation, bleeding, cardiac death, and total mortality. The Patients were classified hierarchically; if criteria for both data collection form also recorded the use of aspirin, clopimajor and minor adverse cardiac events were met, the padogrel, warfarin, heparin, nonsteroidal anti-inflammatory tient was included only in the major adverse cardiac event drugs, and direct thrombin inhibitors. group.
Ziegelstein et al Table 1
SSRI Use in Acute Coronary Syndromes
527
Baseline Demographic and Clinical Characteristics
Age (Years), Mean ⫾ SD Male Gender, n (%) Myocardial Infarction*, n (%) Hypertension†, n (%) Diabetes Mellitus†, n (%) Hypercholesterolemia†, n (%) Smoking†, n (%) Chronic obstructive pulmonary disease†, n (%) Prior MI†, n (%) Congestive heart failure†, n (%) Left ventricular ejection fraction ⬍35%, n (%) Liver disease, n (%) Renal failure†, n (%) Gastrointestinal bleed†, n (%) Anemia†, n (%) Cancer†, n (%) Bleeding diathesis†, n (%) Depression†, n (%) Non-SSRI antidepressant, n (%)
Pre-Propensity Score Matching
Post-Propensity Score Matching
SSRI (n ⫽ 158)
No SSRI (n ⫽ 1096)
P Value
No SSRI (n ⫽ 158)
P Value
61.4 ⫾ 11.8 90 (57.0) 49 (31.0) 133 (84.2) 66 (41.8) 128 (81.0) 102 (64.6) 31 (19.6) 68 (43.0) 35 (22.2) 26 (17.7) 7 (4.4) 20 (12.7) 9 (5.7) 20 (12.7) 17 (10.8) 2 (1.3) 98 (62.0) 20 (12.7)
63.4 ⫾ 12.0 789 (72.0) 513 (46.8) 825 (75.3) 345 (31.5) 866 (79.0) 623 (56.8) 124 (11.3) 309 (28.2) 143 (13.0) 141 (14.3) 18 (1.6) 81 (7.4) 41 (3.7) 116 (10.6) 123 (11.2) 4 (0.4) 80 (7.3) 80 (7.3)
.06 ⬍.01 ⬍.01 .01 .01 .56 .07 ⬍.01 ⬍.01 ⬍.01 .27 .02 .02 .24 .43 .86 .17 ⬍.01 .02
61.2 ⫾ 12.1 91 (57.6) 55 (34.8) 133 (84.2) 65 (41.1) 127 (80.4) 109 (69.0) 29 (18.4) 64 (40.5) 36 (22.8) 27 (19.1) 5 (3.2) 22 (13.9) 5 (3.2) 24 (15.2) 10 (6.3) 0 (0.0) 18 (11.4) 19 (12.0)
.84 .91 .47 1.00 .91 .89 .40 .77 .65 .89 .75 .56 .74 .27 .52 .16 .50 ⬍.01 .86
SSRI ⫽ selective serotonin reuptake inhibitor; MI ⫽ myocardial infarction. *Admitting diagnosis. †Any history.
Statistical Analysis Statistical significance was defined as a probability value less than .05. Chi-square and Fisher’s exact tests were used to compare categorical variables and 2-tailed t tests to compare continuous demographic and clinical variables between patients who were administered an SSRI at any time during the hospitalization and patients who were not administered an SSRI. Risk for bleeding and major adverse cardiac events was assessed by calculating odds ratios for patients who were administered an SSRI compared to patients not administered an SSRI. To adjust for differences in demographic and clinical characteristics of patients who were administered an SSRI in the hospital and those who were not administered an SSRI, we used a propensity score approach to generate a set of matched cases.21,22 The propensity score is a measure of the likelihood that a patient received an SSRI based on relevant demographic and clinical variables. This approach reduces many covariates to a single variable, the propensity score. Since patients with similar propensity scores have similar characteristics, once matched, the outcome of interest can be compared for patients who received an SSRI versus those who did not receive an SSRI. A stepwise logistic regression approach with P ⱕ.20 as the limit for variable entry was used to model the likelihood that patients received an SSRI based on demographic and clinical variables. A propensity score was generated for each patient, and each patient who received an SSRI during the hospitalization was matched with a patient with the
closest possible propensity score who did not receive an SSRI. The maximum allowable difference between propensity scores for matching was set at 0.1. When 2 or more patients who did not receive an SSRI had an identical propensity score, the match patient was chosen randomly.23 All analyses were performed with SPSS version 13.0 (Chicago, Ill). Data are reported as means ⫹ standard deviation or as odds ratios with 95% confidence intervals (CI).
RESULTS Sample Characteristics A total of 1254 patients were admitted with an acute coronary syndrome and received a glycoprotein IIb/IIIa inhibitor during the study period. Baseline demographic and clinical characteristics of the patients are shown in Table 1. The mean age of the sample was 63.1 ⫾ 12.0 years (range, 26 to 92), and 70.1% were male. Over half of the patients were admitted with unstable angina pectoris (55.2%), 26.6% were admitted with non-ST segment elevation MI, and 18.2% with ST segment elevation MI. Most patients had hypertension (76.4%) and a history of smoking (57.8%). Almost all patients underwent percutaneous transluminal coronary angioplasty (98.6%). Approximately 1 of every 7 patients (14.2%) had a history of depression. A total of 158 patients (12.6%) were administered an SSRI during the hospitalization. Compared to patients who were not administered an SSRI, patients who received an SSRI during the hospitalization were sig-
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Table 2
Antiplatelet and Anticoagulant Medications during Hospitalization Pre-Propensity Score Matching
Post-Propensity Score Matching
Medication
SSRI (n⫽158)
No SSRI (n⫽1096)
P Value
No SSRI (n ⫽ 158)
P Value
Abciximab, n (%) Eptifibatide, n (%) Tirofiban, n (%) Aspirin, n (%) Clopidogrel, n (%) Nonsteroidal anti-inflammatory drug, n (%) Warfarin, n (%) Unfractionated heparin, n (%) Low molecular weight heparin, n (%) Lepirudin, n (%)
8 150 1 156 151 4 20 153 23 1
75 1027 6 1087 1063 44 106 1080 149 6
.40 .55 .99 .58 .34 .51 .24 .12 .74 .99
14 144 2 157 148 6 15 157 17 0
.19 .19 .99 .99 .45 .52 .37 .21 .31 .99
(5.1) (94.9) (0.6) (98.7) (95.6) (2.5) (12.7) (96.8) (14.6) (0.6)
(6.8) (93.7) (0.5) (99.2) (97.0) (4.0) (9.7) (98.5) (13.6) (0.5)
(8.9) (91.1) (1.3) (99.4) (93.7) (3.8) (9.5) (99.4) (10.8) (0.0)
SSRI ⫽ selective serotonin reuptake inhibitor.
nificantly more likely to be female; to have been admitted with unstable angina pectoris; to have had a prior MI; and to have had a history of hypertension, diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, renal failure, or liver disease. The majority of patients (62%) administered an SSRI during the hospitalization had a history of depression, whereas less than 10% of patients not administered an SSRI had a history of depression. Patients receiving an SSRI during the hospitalization were more likely to also be receiving another, non-SSRI, antidepressant than patients not receiving an SSRI (12.7 vs 7.3%, P ⫽.02). The propensity score model included 11 predictor variables (age, gender, admission diagnosis of MI, congestive heart failure, chronic obstructive pulmonary disease, prior MI, history of hypertension, history of smoking, history of renal failure, liver disease, and non-SSRI anti-depressant use) and 5 interactions (age ⫻ prior MI, age ⫻ chronic obstructive pulmonary disease, gender ⫻ chronic obstructive pulmonary disease, gender ⫻ history of hypertension, gender ⫻ history of smoking). The c-statistic for the propensity score model was 0.72, indicating adequate discrimination. Collinearity analysis showed that the variables included in the propensity score were not highly correlated; the highest bivariate correlation between any two variables was 0.22. All 158 patients who were administered an SSRI were successfully matched: 46 on 5 or more digits of the propensity score, 27 on 4 digits, 47 on 3 digits, 20 on 2 digits, and 18 on 1 digit. After propensity score matching, the only significant difference between the SSRI and nonSSRI patients was that patients administered an SSRI were more likely to have a history of depression (Table 1). As shown in Table 2, almost all matched patients received aspirin (99.1%), clopidogrel (94.6%), and intravenous unfractionated heparin (98.3%) as standard therapy; 99.2% received either unfractionated or low molecular weight heparin. There were no significant differences between the patients administered an SSRI and those who were not, with respect to medications administered during
the hospitalization that are known to affect bleeding or thrombosis risk. These medications included aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs, warfarin, unfractionated heparin, low molecular weight heparin, glycoprotein IIb/IIIa inhibitors, or direct thrombin inhibitors. Similarly, there were no significant differences in the administration of these medications during the hospitalization after propensity score matching. The frequency of percutaneous transluminal coronary angioplasty was essentially the same among those administered an SSRI (156 of 158, 98.7%) and those who did not receive an SSRI (154 of 158, 97.5%, P ⫽ .68). Of the 158 patients who were administered an SSRI, sertraline was administered to 75 (47.5%), fluoxetine to 42 (26.6%), paroxetine to 26 (16.5%), escitalopram to 8 (5.1%), and citalopram to 7 (4.4%). In addition, 100 patients were administered a non-SSRI antidepressant; 46 received buproprion, 22 trazadone, 15 amitriptylline, 9 venlafaxine, and 15 either doxepine, imipramine, mirtazapine, nefazodone, or nortriptylline (7 patients were administered two non-SSRI antidepressants). Twenty patients who received an SSRI also received a non-SSRI antidepressant.
Adverse Cardiac Events and Bleeding Adverse cardiac event rates and bleeding outcomes for matched patients are summarized in Table 3. A total of 15 patients died during the index hospitalization (1.2%). Major and minor adverse cardiac events occurred in 86 patients (6.9%) and 163 patients (13.0%), respectively. A total of 98 patients experienced major bleeding (7.8%), 287 minor bleeding (22.9%), and 34 gastrointestinal bleeding (2.7%). Any bleeding occurred in 396 patients (31.6%). Patients who received an SSRI during the hospitalization were significantly more likely to experience any bleeding episode compared to those who did not receive an SSRI (37.3% vs 26.6%, OR 1.65, 95% CI, 1.02-2.66, P ⫽.04). This was due principally to an increase in the risk of minor bleeding (27.2% vs 18.4%, OR 1.66, 95% CI, 0.98-2.84, P ⫽.06). Of note, the bleeding rates observed in this study population are
Ziegelstein et al Table 3
SSRI Use in Acute Coronary Syndromes
529
Adverse Cardiovascular and Bleeding Events During Hospitalization
Event
No SSRI After Matching (n ⫽ 158)
SSRI (n⫽158)
Odds Ratio (95% Confidence Interval)
P Value
Major Adverse Cardiac Events Minor Adverse Cardiac Events Major Bleeding Minor Bleeding Gastrointestinal Bleeding Any Bleeding
10 22 13 29 2 42
12 11 11 43 5 59
1.22 0.46 0.84 1.66 2.55 1.65
.66 .04 .67 .06 .25 .04
(6.3%) (13.9%) (8.2%) (18.4%) (1.3%) (26.6%)
(7.6%) (7.0%) (7.0%) (27.2%) (3.2%) (37.3%)
(0.51-2.90) (0.22-0.99) (0.36-1.92) (0.98-2.84) (0.49-13.34) (1.02-2.66)
SSRI ⫽ selective serotonin reuptake inhibitor. Patients who experienced both a major and a minor adverse cardiac event were only counted as having had a major adverse cardiac event (see text for definitions). A bleeding event was only counted once in the total if a person had more than one type (see text for definitions).
similar to those reported among patients with an acute coronary syndrome receiving conventional antiplatelet therapy and heparin.19,24 Patients who received an SSRI during the hospitalization were significantly less likely to experience a minor adverse cardiac event (ie, recurrent myocardial ischemia, heart failure or asymptomatic cardiac enzyme elevation) than individuals who did not receive an SSRI (7.0% vs 13.9%, OR 0.46, 95% CI, 0.22-0.99, P ⫽.04). In the SSRI group, there were 5 patients with recurrent myocardial ischemia, 1 with heart failure, and 5 with asymptomatic cardiac enzyme elevation. Among those who did not receive an SSRI, there were 11 patients with recurrent myocardial ischemia (P ⫽.12 vs SSRI group), 1 with heart failure (P ⫽1.0), and 10 with asymptomatic cardiac enzyme elevation (P ⫽.19 vs SSRI group). The likelihood of major adverse cardiac events did not differ between groups that did or did not receive an SSRI (7.6% vs 6.3%, P ⫽.66). All analyses were repeated for patients who were administered a non-SSRI antidepressant. The degree of balancing of demographic and clinical characteristics through propensity score matching was comparable to the SSRI analysis (not shown). There were 5 major adverse cardiac events among the 100 patients administered a non-SSRI antidepressant and 5 among matched controls. Compared to matched patients, however, patients who were administered a non-SSRI antidepressant during the hospitalization tended, albeit non-significantly, to experience more minor adverse cardiac events (14.0% vs 7.0%, OR 2.16, P ⫽.11) compared to those patients who did not receive a non-SSRI antidepressant. Non-SSRI antidepressant use was not associated with bleeding (OR 1.04, P ⫽.89) or, individually, with major (OR 1.09, P ⫽.84), minor (OR 0.95, P ⫽.87), or gastrointestinal (OR 0.59, P ⫽.72) bleeding. Results for the SSRI and non-SSRI antidepressant analyses did not change substantively when the 20 patients who used both types of antidepressants were excluded from analyses.
DISCUSSION This is the first study to examine the association of SSRI use during hospitalization for an acute coronary syndrome with bleeding episodes and adverse cardiac events. The major
finding of this study was that patients who received an SSRI during the hospitalization were significantly more likely to experience a bleeding episode and significantly less likely to experience recurrent myocardial ischemia, heart failure, or asymptomatic cardiac enzyme elevation while in the hospital. The effects of SSRI use were observed in patients already receiving contemporary standard therapy for an acute coronary syndrome, including aspirin, clopidogrel, heparin, and a glycoprotein IIb/IIIa inhibitor. SSRI use has been associated with an increased risk of upper gastrointestinal bleeding in population-based studies,6,7,25 especially in elderly patients, in those with a history of gastrointestinal bleeding,25 or in patients concurrently administered nonsteroidal anti-inflammatory drugs or aspirin.6-8 The association between SSRI use and gastrointestinal bleeding and the increased risk when used concurrently with nonsteroidal anti-inflammatory drugs, aspirin, or drugs that affect coagulation is noted in the prescribing information available to consumers for all major SSRI antidepressants.26-30 The Sertraline Antidepressant Heart Attack Randomized Trial (SADHART)31 found that the incidence of major adverse cardiac events was lower, although not significantly so, among patients hospitalized for an acute coronary syndrome with major depression who were randomized to receive sertraline than in those who received placebo (relative risk [RR] 0.77, 95% CI, 0.51-1.16). Of note, exposure to SSRIs in SADHART occurred on average more than a month after the acute coronary syndrome. A secondary analysis of the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial32 showed that the risk of death or recurrent MI was significantly lower in the 301 patients taking an SSRI to treat depression than in the 1388 depressed patients not receiving an antidepressant. In ENRICHD, patients were enrolled within 28 days of the index MI, and SSRIs were prescribed a minimum of 5 weeks after beginning cognitive behavior therapy. Although our results are consistent with these studies, several limitations should be considered in interpreting these findings. In particular, the results are observational and from a retrospective chart review; the number of patients who received an SSRI and the numbers of bleeding
530 events and adverse cardiac events were relatively small; and the period of exposure to SSRIs is not known. In summary, this retrospective study shows that SSRI use during a hospitalization for an acute coronary syndrome is associated with reduced cardiac events at the expense of increased bleeding in patients already receiving therapy with conventional antiplatelet medications and heparin. The effect of SSRIs in depressed patients with an acute coronary syndrome should be examined in a randomized, prospective controlled trial with a larger number of patients.
ACKNOWLEDGMENT RCZ, JM, and TK were supported by the Miller Family Scholar Program.
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