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Hemostasis and Thrombosis: Original Clinical Research Report

Selective Serotonin Reuptake Inhibitors and Serotonin–Norepinephrine Reuptake Inhibitors Are Not Associated With Bleeding or Transfusion in Cardiac Surgical Patients

Smith, Mark M. MD*; Smith, Bradford B. MD*; Lahr, Brian D. MS; Nuttall, Gregory A. MD*; Mauermann, William J. MD*; Weister, Timothy J. MSN, RN; Dearani, Joseph A. MD§; Barbara, David W. MD*

Author Information
doi: 10.1213/ANE.0000000000002668

Abstract

KEY POINTS

  • Question: Does the use of selective serotonin reuptake inhibitor (SSRI)/serotonin–norepinephrine reuptake inhibitor (SNRI) medications increase the risk of bleeding and transfusion in patients undergoing cardiac surgery?
  • Findings: The use of SSRI/SNRIs did not increase the risk of bleeding or transfusion in patients undergoing cardiac surgery when compared to matched controls.
  • Meaning: Interruption of SSRI/SNRIs before cardiac surgery is not warranted and may risk worsening patients’ psychiatric condition.

Psychiatric diseases are common in the United States, with the prevalence of anxiety, impulse control disorders, and mood disorders such as depression >20%.1 Additionally, the prevalence of depression among patients with cardiac disease is thought to be 2–3 times higher than the general population.2 Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are among the most widely prescribed medications in the United States. These drugs are often first-line agents in the treatment of depression but are also utilized in the treatment of generalized anxiety disorder, panic disorder, posttraumatic stress disorder, and obsessive-compulsive disorder among others.3 Use of SSRI/SNRIs alters platelet activation and aggregation leading to some degree of hemostatic impairment.4–8 Patients undergoing cardiac surgery are at an elevated risk of bleeding, with >50% of patients receiving perioperative transfusion.9–11 It is well appreciated that cardiac surgical patients necessitating perioperative transfusion are at increased risk of morbidity and mortality.12,13 Previous studies examining the relationship between SSRI/SNRIs and perioperative bleeding, transfusion, morbidity, and mortality in surgical patients have produced mixed results.14–22 The authors hypothesize that similar to other surgical cohorts, patients taking SSRI/SNRI medications and undergoing cardiac surgery would have a higher incidence of bleeding and hence allogenic blood transfusions and associated complications. The aim of this study was to evaluate the risk of perioperative bleeding, transfusion, morbidity, and mortality in patients undergoing cardiac operations taking SSRI/SNRIs compared with propensity-matched controls.

METHODS

This study was approved by the Mayo Foundation Institutional Review Board, and all patients consented to the use of their records for research purposes. A computerized search of the electronic medical records database along with the Society of Thoracic Surgery (STS) database was conducted. All patients ≥18 years of age who underwent cardiac surgery with the use of cardiopulmonary bypass (CPB) at our institution between January 1, 2004, and December 31, 2014, were identified. Only patients who preoperatively consented to the use of their medical records for research were included.

All patients with a history of inherited or acquired coagulation disorders were excluded. Patients taking anticoagulants other than aspirin, unfractionated heparin, or low molecular weight heparin within 30 days of the operation were excluded. Remaining patients were grouped into those taking SSRI/SNRIs (subjects) or not taking SSRI/SNRIs (controls) according to their intake medication reconciliation before cardiac surgery. All SSRI/SNRIs commercially available during the study period were included. To facilitate observational treatment comparisons, subgroups of successfully matched pairs of patients taking SSRI/SNRI and controls were derived and used to analyze outcomes. Perioperative antifibrinolytic administration, laboratory values, CPB time, transfusion data, chest tube output quantity, and intensive care unit (ICU) and hospital length of stay (LOS) were collected from the medical record and STS database. During the study period, use of an institutional laboratory–based transfusion algorithm was standard care.23 The STS database was utilized to identify postoperative complications occurring during the hospitalization for surgery for the following: renal failure, reoperation for bleeding, stroke or transient ischemic accident, prolonged mechanical ventilation, perioperative myocardial infarction (MI), and 30-day mortality. The STS database definition for each above complication is listed in Supplemental Digital Content, Appendix, http://links.lww.com/AA/C140.

The primary outcomes for the study include incidence of allogenic blood product transfusion during the intraoperative, postoperative, and entire perioperative time periods, along with bleeding in the postoperative period defined by chest tube output and reoperation for bleeding. Secondary outcomes include postoperative complications (renal failure, stroke or transient ischemic accident, prolonged mechanical ventilation, and perioperative MI), ICU LOS, hospital LOS, and 30-day mortality.

Descriptive statistics were reported as absolute number (percentage) or median (25th and 75th percentiles) as appropriate. Comparisons of demographic, preoperative, and operative measures between SSRI- and SNRI-treated and untreated groups were performed using Pearson χ2 test for categorical variables and the Wilcoxon rank sum test for continuous variables. To minimize baseline differences and confounding influences in the comparison of clinical outcomes, we performed propensity score matching of treated and untreated patients. The propensity score was based on the predicted log odds of receiving SSRI/SNRI treatment, as estimated from a flexible additive logistic regression model using the following covariates: age, gender, year of operation, operative type, prior cardiac operation, perfusion time, and preoperative measurements of hemoglobin and platelets.24,25 A greedy, nearest-neighbor–matching algorithm (caliper width equal to 0.1 of the standard deviation) was used to form statistically well-balanced groups, which was demonstrated through formal comparisons and standardized differences on each individual covariate. Comparisons of clinical outcomes between propensity-matched groups were assessed by fitting logistic regression models for binary outcomes (eg, 30-day complications and mortality) and normal linear regression models for continuous outcomes (eg, blood transfusion, laboratory measurements), and using generalized estimating equations to account for correlated data within the same matched pair. For continuous outcomes that were strongly skewed toward large values, data were transformed to natural logarithmic scale before this analysis to satisfy the linear model assumptions. Relative effects from the models were reported as odds ratio (OR) for binary outcome variables and as mean difference for continuous outcome variables, except skewed continuous variables that were presented as ratio of geometric means (fold change). To correct for multiple comparisons among all study outcomes that were analyzed, P values were adjusted according to the method described by Benjamini and Hochberg.26 Because preoperative international normalized ratio (INR) was frequently unavailable and thus not included in the propensity score model, we performed a sensitivity analysis to account for potential imbalance by refitting the outcome models to adjust for preoperative INR in the subset with available measurements (propensity score was included as an additional covariate). All analyses were performed in SAS software version 9.4 (SAS Institute, Inc, Cary, NC).

RESULTS

During the study period, 20,613 adult patients underwent cardiac surgery with CPB at our institution, of which 12,921 met initial study criteria (Figure). A total of 1453 patients were identified as taking SSRI/SNRIs at the time of cardiac surgery (Table 1). Compared to the overall group not taking SSRI/SNRIs, the SSRI/SNRI group was significantly younger, with a markedly higher percentage of females and a slightly higher percentage with prior cardiac surgery. The 2 groups also differed with respect to the type and year of operation, and preoperative hemoglobin and platelet levels. Propensity score matching identified 1417 pairs of SSRI/SNRI patients and matched controls that were alike at the time of surgery, with no significant differences in the baseline characteristics detailed in Table 2. Standardized differences were small for observed baseline covariates after propensity score matching (range from 0.006 to 0.053), validating the comparability of the 2 groups.

Table 1.
Table 1.:
Comparison of Baseline Characteristics in Preliminary Cohort
Table 2.
Table 2.:
Comparison of Baseline Characteristics Among Propensity-Matched Pairs
Figure.
Figure.:
Patient selection CONSORT flow diagram. CONSORT indicates Consolidated Standards of Reporting Trials; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Among matched pairs, post-CPB and ICU admission hemoglobin, INR, activated partial thromboplastin time (aPTT), and fibrinogen values did not differ significantly (Table 3). Perioperative transfusion and blood loss data are presented in Table 4, with perioperative outcome-related data in Table 5. Transfusion rates across all time points and blood product type were not significantly different between groups, with the overall perioperative transfusion rate for SSRI/SNRI patients 66.5% vs 64.9% for matched controls (OR [95% confidence interval], 1.07 [0.92–1.25]; P = .697). Between SSRI/SNRI patients and matched controls, there was no significant difference in postoperative chest tube output (median, 750.0 vs 750.0 mL; 0.99 [0.95–1.03]-fold change; P = .860) or reoperation for bleeding (2.8% vs 2.5%; OR, 1.08 [0.69–1.72]; P = .892).

Table 3.
Table 3.:
Comparison of Perioperative Laboratory Data Among Propensity-Matched Pairs
Table 4.
Table 4.:
Comparison of Perioperative Transfusion Data Among Propensity-Matched Pairs
Table 5.
Table 5.:
Comparison of Postoperative Outcomes Among Propensity-Matched Pairs

Patients in the SSRI/SNRI group had a higher incidence of prolonged mechanical ventilation (13.1% vs 8.6%; OR, 1.61 [1.26–2.05]; P = .002), longer ICU LOS (median, 25.5 vs 23.8 hours; 1.20 [1.13–1.28]-fold change; P < .001), and longer hospital LOS (median, 6.0 vs 5.0 days; 1.09 [1.05–1.13]-fold change; P < .001). The 30-day mortality did not significantly differ between SSRI/SNRI patients and matched controls (1.5% vs 2.3%; OR, 0.65 [0.37–1.14]; P = .411). Remaining postoperative outcomes did not significantly differ between groups.

Antifibrinolytic use was similar between SSRI/SNRI patients and matched controls (79.8% vs 81.3%; P = .319). During the early study period, aprotinin use was similar between SSRI/SNRI patients and matched controls (3.1% vs 3.3%; P = .749), as were lysine analogues in the later study period (76.8% vs 78.0%; P = .445).

Missing data contained in these analyses were due to changes in the STS data collection, limited availability of laboratory tests in specific subsets of patients, or institutional practice changes for ordering such tests. For example, preoperative fibrinogen testing is not routinely performed at our institution. Prothrombin time/INR and aPTT are often not ordered preoperatively unless patients are taking anticoagulants. The propensity model did not include preoperative levels of INR or aPTT due to extensive missing data, though no group differences were found in those with available data either before or after matching. In addition, we examined the sensitivity of our analysis to potential INR imbalances by fitting INR-adjusted outcome models on the available subset, and we noted that these findings result in the same conclusions. Incomplete laboratory data after CPB or on ICU admission were largely attributable to lack of routine laboratory testing in patients without evidence of clinical bleeding during the early study period. In contrast, data collection of perioperative MI in the STS database was discontinued near the end of the study period and resulted in some missing data for this outcome.

DISCUSSION

The main finding of this study was that SSRI/SNRI use was not associated with increased perioperative bleeding, blood transfusion, or mortality after cardiac surgery. To our knowledge, this is the largest propensity-matched study specifically evaluating SSRI/SNRI use and the association with bleeding, transfusion, and adverse outcomes in patients undergoing cardiac surgery. Additionally, this study includes both SSRI and SNRI medications in addition to all types of cardiac procedures requiring CPB, more closely assimilating common surgical practice.

Serotonin is produced by gastrointestinal enterochromaffin cells and released to the plasma where it is taken up by platelets via the serotonin transporter (5-HTT) and stored in granules.4–8,27 Platelet activation and aggregation are dependent on serotonin along with other mediators such as histamine, thromboxane A2, and adenosine diphosphate.4–8,27 SSRIs inhibit 5-HTT on platelets, leading to reduced serotonin concentrations within platelets that impair platelet activation, aggregation, and ultimately to some degree hemostasis.4–8,27 The mechanism behind SNRI alterations in hemostasis is thought to mirror those of SSRI medications, though the inhibition on the 5-HTT may be less effective.

Prior research has established a clear association between SSRI use and increased risk of gastrointestinal and intracranial bleeding.28–30 Additionally, studies of surgical patients undergoing orthopedic, spine, and breast surgery have reported increased risk of bleeding and transfusion.31–36 Previous retrospective studies evaluating SSRI/SNRI use and perioperative outcomes specifically within the cardiac surgical population have produced mixed results. The findings of our study suggest a lack of association between SSRI/SNRIs and bleeding or transfusion after cardiac surgery. Such findings are consistent with other similar yet smaller retrospective studies in cardiac surgical patients. Andreasen et al14 found no clear association between preoperative SSRIs and risk for transfusion, reoperation, or mortality after coronary artery bypass grafting (CABG) surgery. Kim et al16 reported that after propensity matching, there was no association between SSRIs and bleeding, in-hospital mortality, or 30-day readmission. Similar to these studies, Xiong et al15 found no association with major bleeding events but did note that among those requiring transfusion, SSRI patients received a higher transfusion volume.17 A recent prospective cohort study, however, found a significantly higher rate of hemostatic transfusion products (fresh frozen plasma, cryoprecipitate, platelets) but not red blood cell among 32 SSRI users undergoing cardiac surgery, yet the small number of patients in the SSRI group may limit interpretation of these findings.22 Tully et al18 reported that 105 patients taking SSRI/SNRIs who underwent CABG surgery had an increased risk of postoperative complications (renal failure, prolonged mechanical ventilation) but not bleeding. Xiong et al15 reported higher postoperative mortality and readmission after CABG in 246 patients taking SSRIs.

A recent meta-analysis across a wide scope of surgical subspecialties and procedures reported increased transfusion rates and higher mortality among serotonergic antidepressant patients who underwent CABG operations.21 Additionally, a large retrospective study across 375 medical centers established that SSRI use preoperatively was associated with a higher risk of in-hospital mortality, bleeding, and 30-day readmission rates.19

Antifibrinolytic therapy is commonly used and known to reduce the rate of major bleeding and transfusion in cardiac surgical patients.37 The use of antifibrinolytic therapy in other surgical subspecialties outside of cardiac, orthopedic, and trauma surgery is uncommon. In this study, 79.8% of patients taking SSRI/SNRIs were treated perioperatively with either aprotinin or lysine analogue antifibrinolytic therapy. Given the weak platelet inhibition induced by SSRI/SNRI medications, it is possible that antifibrinolytic therapy may have contributed to the lack of significant bleeding and transfusion in this study population.

With regard to perioperative outcome data in our study, there was an association between SSRI/SNRIs and prolonged mechanical ventilation (P = .002) and longer ICU/hospital LOS (both P < .001). Tully et al18 presented similar findings in 105 SSRI/SNRI users undergoing CABG surgery for prolonged mechanical ventilation (P = .04), ICU LOS (P = .02), hospital LOS (P = .07), in addition to a higher incidence of renal failure, which our study did not find. The increased ICU and hospital LOS may be explained by the higher incidence of prolonged mechanical ventilation in the SSRI/SNRI group. Anxiety and/or depression for which we can assume is higher in the SSRI/SNRI group is independently associated with worse prognosis after cardiac surgery.18,38 Additionally, affective disorders are associated with comorbidities such as diabetes, hypertension, and smoking, all of which are linked to higher rates for prolonged mechanical ventilation and increased LOS in CABG surgery patients.39,40 It follows that though causality cannot be established with this retrospective study, we hypothesize that the association between SSRI/SNRI use and prolonged mechanical ventilation and increased ICU/hospital LOS is more likely related to the patients’ underlying psychiatric illnesses and associated comorbidities and not pharmacologic effects of SSRI/SNRIs.

The limitations to this study include all those inherent to a retrospective study including charting inaccuracies and incomplete data. The primary outcomes of blood transfusion and reoperation for bleeding along with the secondary postoperative outcomes were retrospectively recorded into the STS database. The STS database records postoperative complications only until hospital discharge; thus, if patients had complications such as stroke or MI within 30 days but after discharge, the rate of such may be underreported. Additionally, as our institution is largely a referral center with patients postdischarge care transitioned to facilities where they reside, complications may not be captured within our medical records database. As described above, affective disorders such as anxiety have been associated with worse outcomes after cardiac surgery. The true incidence of such disorders in each arm of this study is unknown. While the authors hypothesize that the association between SSRI/SNRI use and prolonged mechanical ventilation and increased ICU/hospital LOS is likely related to the patients’ underlying psychiatric illnesses and associated comorbidities, these findings could be the result of changes in clinical decision making that is difficult to discern via retrospective analysis.

CONCLUSIONS

In this study, SSRI/SNRI use was not associated with a clinically significant alteration of hemostasis and risk for bleeding, transfusion, or mortality after cardiac surgery. While there was prolonged mechanical ventilation and increased ICU/hospital LOS in the SSRI/SNRI group, it is unclear if this finding is the result of such medications or rather associated with the underlying psychiatric condition for which they are prescribed. With regard to perioperative management of SSRI/SNRIs in patients undergoing cardiac surgery, interruption in drug therapy to reduce the risk of bleeding and transfusion appears to be unwarranted and may risk destabilization of patients’ psychiatric condition.

DISCLOSURES

Name: Mark M. Smith, MD.

Contribution: This author helped in all aspects and helped approve the final manuscript.

Conflicts of Interest: M. M. Smith is the archival author.

Name: Bradford B. Smith, MD.

Contribution: This author helped in all aspects.

Conflicts of Interest: None.

Name: Brian D. Lahr, MS.

Contribution: This author helped in all aspects.

Conflicts of Interest: None.

Name: Gregory A. Nuttall, MD.

Contribution: This author helped in all aspects.

Conflicts of Interest: None.

Name: William J. Mauermann, MD.

Contribution: W. J. Mauermann helped analyze the data and prepare the manuscript.

Conflicts of Interest: None.

Name: Timothy J. Weister, MSN, RN.

Contribution: This author helped collect the data.

Conflicts of Interest: None.

Name: Joseph A. Dearani, MD.

Contribution: J. A. Dearani helped prepare the manuscript.

Conflicts of Interest: None.

Name: David W. Barbara, MD.

Contribution: This author helped in all aspects.

Conflicts of Interest: None.

This manuscript was handled by: Roman M. Sniecinski, MD.

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