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Perioperative Inpatient Use of Selective Serotonin Reuptake Inhibitors Is Associated With a Reduced Risk of THA and TKA Revision

Yao, Jie J. BA; Maradit Kremers, Hilal MD, MSc; Kremers, Walter K. PhD; Lewallen, David G. MD; Berry, Daniel J. MD

Clinical Orthopaedics and Related Research®: June 2018 - Volume 476 - Issue 6 - p 1191–1197
doi: 10.1007/s11999.0000000000000098
SYMPOSIUM: 6th INTERNATIONAL CONGRESS OF ARTHROPLASTY REGISTRIES
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Background Depression is common in the general population, and so it is likewise common among patients undergoing THA and TKA. Depression is associated with lower perioperative patient-reported outcomes and an increased risk of postoperative complications. Antidepressants are effective in managing symptoms of depression and may potentially contribute to better functional status and better clinical outcomes after THA and TKA.

Questions/purposes We examined (1) whether perioperative depression is associated with all-cause revisions, revisions for aseptic loosening, revisions without infection, and periprosthetic joint infections (PJIs) in patients undergoing THA and TKA; and (2) whether perioperative antidepressant use reduces the risk of all-cause revisions, revisions for aseptic loosening, aseptic revisions, and PJIs in patients undergoing THA and TKA.

Methods This was a retrospective study of adult patients (≥ 18 years) who underwent 20,112 primary and revision THAs and TKAs from January 1, 2002, through December 31, 2009, at a large US tertiary care hospital. Data on patient and surgery characteristics and outcomes (dates and types of revisions, death) were ascertained through the institutional joint registry. Perioperative antidepressant use was assessed by searching the daily medication administration records beginning at admission and ending at discharge. A diagnosis of depression was present in 4466 (22%), and antidepressants were administered at the time of 5077 (25%) surgical procedures. Multivariable Cox proportional hazard models were used to estimate associations between antidepressant use and the risk of all-cause revisions, revisions for aseptic loosening, aseptic revisions, and PJIs.

Results Depression was associated with an increased risk of all-cause revisions (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.42-2.02; p < 0.001) and PJIs (HR, 2.23; 95% CI, 1.53-3.17; p < 0.001). Overall, perioperative antidepressant use was not associated with the risk of revision or PJI, but selective serotonin reuptake inhibitor (SSRI) users had a lower risk of all-cause revisions (HR, 0.77; 95% CI, 0.61-0.96; p = 0.001) and aseptic revisions (HR, 0.72; 95% CI, 0.56-0.93; p = 0.013).

Conclusions The presence of a depression diagnosis confers an increased risk of revision and PJI among patients undergoing THA and TKA, yet the risk is lower within the subset of patients who received SSRIs during the perioperative period. Future longitudinal studies with detailed antidepressant medication histories are warranted to better understand the potential biologic effects of SSRI on the risk of revision in patients undergoing THA and TKA.

Level of Evidence Level III, therapeutic study.

J. J. Yao, H. Maradit Kremers, D. G. Lewallen, D. J. Berry, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA

W. K. Kremers, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

H. Maradit Kremers, Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA, email: maradit@mayo.edu

One of the authors certifies that he (DGL), or a member of his immediate family, has or may receive payments or benefits, during the study period, an amount of USD 10,000 to USD 100,000, from Zimmer (Warsaw, IN, USA) and Pipeline Biomedical (Cedar Knolls, NJ, USA). One of the authors certifies that he (DJB), or a member of his immediate family, has or may receive payments or benefits, during the study period, an amount of USD 10,000 to USD 100,000, from DePuy (Warsaw, IN, USA).

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Each author certifies that his or her institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.

Received March 26, 2017

Received in revised form June 20, 2017

Accepted November 20, 2017

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Introduction

Patients with chronic pain from arthritis may present with comorbid diagnoses of depression and other mood disorders [8, 19]. In patients with arthritis, depression is associated with more pain and increased functional disability [6, 17, 18, 37, 41]. Of those patients who progress to THA and TKA, almost one-fourth may meet criteria for a major depressive disorder [29]. Additionally, studies suggest that depressed patients who have undergone THA and TKA experience worse functional outcomes [25, 26, 31, 33-35, 40], more surgical complications, increased readmission rates, and even increased in-hospital mortality risk [3, 4, 11, 12, 14, 15, 28]. Although the underlying mechanisms for this phenomenon remain to be established, there is growing interest in identifying strategies to effectively manage perioperative depression in an effort to improve functional and clinical outcomes in patients undergoing arthroplasty.

For patients with depression who have undergone arthroplasty, antidepressant use may potentially contribute to better pain management, faster functional recovery, and better clinical outcomes. Despite the potential beneficial effects of antidepressant use, specific antidepressants are known to be associated with lower bone mineral density and increased risk of fractures [13, 16, 30] and may thereby exert negative effects on bone-implant osseointegration and increase the risk of aseptic loosening. Additionally, antidepressants may have immunomodulatory effects and may contribute to increased risk of surgical site infections [7]. The most widely prescribed and first-line class of antidepressants is selective serotonin reuptake inhibitors (SSRIs) [5, 20]. Given the risk of drug interactions and withdrawal-related complications, perioperative SSRIs require cautious management and avoidance of rapid interruption, reduction, or discontinuation [2, 32]. Previous investigation of perioperative inpatient SSRI safety during THA and TKA admissions has focused largely on bleeding risk and transfusion requirements [22, 38]. Although prior research has evaluated the association between the diagnosis of depression and other psychiatric disorders on functional outcomes [25, 31] and the risk of complications and revisions [4, 14, 15], we are unaware of previous studies examining the potential effects of antidepressant use on long-term risk of revisions.

We examined (1) whether perioperative depression is associated with all-cause revisions, revisions for aseptic loosening, aseptic revisions, and periprosthetic joint infections (PJIs) in patients undergoing THA and TKA; and (2) whether perioperative antidepressant use reduces the risk of all-cause revisions, revisions for aseptic loosening, aseptic revisions, and PJIs in patients undergoing THA and TKA.

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Patients and Methods

We performed a retrospective study using our institutional joint registry from 2002 to 2009.

We identified a retrospective cohort of 20,112 primary and revision THAs and TKAs performed at our institution between January 1, 2002, and December 31, 2009. Patients who had declined research authorization for use of their medical records in research were excluded. This study was approved by the institutional review board. The cohort comprised 9666 THAs and 10,446 TKAs (Table 1). Of the 9666 THAs, 8319 (86%) were performed with an uncemented acetabular component. Of the 10,446 TKAs, only 250 (2.4%) were performed with an uncemented tibial and/or femoral component. Twenty percent of the surgical procedures were revisions. Mean age of the entire cohort was 66 (± 12) years and 9137 (45%) were men.

Table 1

Table 1

Demographic and clinical characteristics and outcome data were obtained from the institutional joint registry and associated electronic medical records. Data elements included patient age, sex, body mass index (BMI), comorbidities, American Society of Anesthesiologists (ASA) class, surgery date, surgical indication, surgical procedure, surgical procedure duration, complications, subsequent revision procedures, and deaths. All patients were followed (either through a visit to the Mayo Clinic or by mail communication from local orthopaedists) at regular intervals at least twice during the first postoperative year; at 2, 5, 7, and 10 years; and at 5-year intervals thereafter. Completeness of followup remained high. For example, of all the procedures with the potential for at least 7 years of followup (that is, procedures in patients who had not died or had revision before 7 years), 90% were followed up for at least 5 years. Four different outcomes (not mutually exclusive) were examined: revision surgery for any reason (any component exchange, including liner exchange and secondary patellar resurfacing), revision surgery for aseptic loosening, aseptic revisions (ie, all aseptic revisions including revisions for dislocation, instability, periprosthetic fracture), and PJI. PJIs were limited to events during the first year after surgery and fulfilled the Infectious Diseases Society of America criteria [24]. PJIs did not include superficial surgical site infections. Comorbidities were defined based on administrative data from the hospitalization time window (ie, beginning at admission and ending at discharge) and using the Elixhauser comorbidity measure codes [9].

Three different methods were used for ascertainment of depression: (1) administrative data from the hospital episode using International Classification of Diseases, 9th Revision codes 296.2, 296.3, 296.5, 300.4, 301.12, 309.x, and 311; (2) a medical diagnosis of depression during the 1-year period before and 30-day period after surgery; and (3) a natural language processing-based search of keywords in the electronic health records during the 1-year period before and 30-day period after surgery. A total of 1284 (6%) procedures contained an administrative record of depression, 2666 (13%) additional surgical procedures contained a medical diagnosis of depression during the 1-year period before and 30 days after surgery, and an additional 516 (3%) surgical procedures were identified through natural language processing methods, for a total of 4466 (22%) surgical procedures involving patients classified as having depression. Patients with depression were younger (mean age, 65 versus 67 years), more likely to be women (68% versus 51%), more likely to be current smokers, had higher average BMI, and higher ASA scores of 3 to 4 than those patients without depression. Despite the younger age, they also had a higher prevalence of many of the Elixhauser comorbidities such as hypertension and diabetes mellitus (Table 1).

Exposure to antidepressants (irrespective of depression diagnosis) was ascertained using daily inpatient medication administration records in the hospital electronic medical records. Any patient who had at least one antidepressant administered during the period of time between hospital admission and discharge was considered to be exposed to antidepressants. Antidepressants were classified as SSRIs and non-SSRI antidepressants. SSRIs included citalopram hydrobromide, escitalopram oxalate, fluoxetine hydrochloride, paroxetine hydrochloride, sertraline hydrochloride, fluvoxamine maleate, and other combinations containing recognized SSRIs, ie, fluoxetine/olanzapine. Patients received at least one dose of perioperative antidepressant in 5077 (25%) surgical procedures, and 2186 (11%) involved SSRI use (Table 1). In 650 (3%) surgical procedures, patients received both an SSRI and another antidepressant. Of the 5077 surgical procedures in patients who were using antidepressants, only 3353 procedures were associated with either an administrative record or a medical record of depression. Conversely, there were 1113 surgical procedures with either an administrative record or a medical record of depression but no documented antidepressant use during hospitalization. In 15,646 surgical procedures in patients without a diagnosis of depression, 1724 (11%) procedures involved perioperative antidepressant use (Table 1). During a mean 6-year followup of 20,112 procedures, we observed 1082 all-cause revisions, 293 revisions for aseptic loosening, 822 aseptic revisions, and 191 PJIs.

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Statistical Analysis

Multivariable Cox proportional hazard models were used to estimate associations between depression and our selected endpoints and associations between antidepressant or SSRI use and these outcomes. We examined the risk of four outcomes (ie, all-cause revision, revision for aseptic loosening, aseptic revision, PJI) separately in patients with a diagnosis of depression and patients without a diagnosis of depression. These models were stratified by THA and TKA status and adjusted for age, sex, and surgery type (primary versus revision). Data are reported as hazard ratios (HRs) with 95% confidence intervals (CIs).

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Results

Depression and the Risk of Revision and PJI

After controlling for potentially confounding variables of sex, age, and type of surgery, depression was associated with an increased overall risk of subsequent revision arthroplasty (HR, 1.73; 95% CI, 1.42-2.02; p < 0.0001) regardless of surgical indication. Patients with depression were also more likely to undergo revisions without infection (HR, 1.78; 95% CI, 1.48-2.13; p < 0.001) or PJIs during the first year of surgery (HR, 2.23; 95% CI, 1.53-3.17; p < 0.001). These estimates remained unchanged on further adjustment for the presence of prior procedures on the same joint, ASA score, obesity, and the Elixhauser comorbidities.

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Antidepressant Use and the Risk of Revision and PJI

Analyses of the risk of our four arthroplasty outcomes associated with antidepressant and SSRI use were performed separately in 4466 surgical procedures in patients with depression diagnoses and 15,646 procedures in patients without any documentation of depression (Table 2). Within the depression cohort of 4466 procedures, there was no association between overall antidepressant use and the risk of revision, revision for aseptic loosening, aseptic revision, or PJI. Similarly, within the no-depression cohort of 15,646 procedures, there was no association between overall antidepressant use and the risk of revision, revision for aseptic loosening, aseptic revision, or PJI. In contrast, the patients using SSRI experienced a lower risk of subsequent revision arthroplasty for any indication (HR, 0.77; 95% CI, 0.61-0.96) or for aseptic revisions (HR, 0.72; 95% CI, 0.56-0.93). The reduced risk of revision among patients using SSRI persisted after further adjustment for potential confounders. After controlling for sex, age, and type of surgery, presence of prior surgical procedures on the same joint, ASA score, obesity, and the Elixhauser comorbidities, SSRI use was still associated with a reduced risk of revision arthroplasty for any indication (HR, 0.76; 95% CI, 0.61-0.95) and aseptic revisions (HR, 0.72; 95% CI, 0.55-0.93). Within the no-depression cohort of 15,646 procedures, we observed an excess risk of PJI, but this finding was based on only three infections in 69 patients using SSRIs.

Table 2

Table 2

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Discussion

Using a large single-institution cohort of 20,112 THAs and TKAs, we examined the risk of revision for any reason and aseptic loosening as well as the risk of revision for aseptic indications and PJI in patients with depression and those who received perioperative antidepressants during their hospitalization. Our findings related to a higher risk of infections and revisions among patients with depression extend the findings of prior studies [3, 4, 11, 12, 14, 15, 26, 28], yet the reduced long-term risk of revision among patients receiving SSRIs is a novel observation and deserves further investigation.

There are some potential limitations to this study. First, this cohort was assembled retrospectively at a large tertiary care hospital and may not be representative of all patients undergoing arthroplasty in the United States as a result of differences in demographics, ethnicity, socioeconomic status, and healthcare access. Second, although we made every effort to identify patients with depression using administrative codes, medical diagnoses, and free text of the electronic medical records, underascertainment of depression is a potential concern. Indeed, the administrative codes from the hospital episode captured only one-fourth of patients with depression (6% prevalence) in our cohort, whereas medical diagnoses and free-text search over a wider time window resulted in a depression prevalence of 22%. This wider definition not only improved ascertainment of depression, but also avoided changes in coding practices over time and is more consistent with prior research [29]. Nevertheless, we recognize that the medical history of the referral patients in our institution is still limited. Third, we did not have access to longitudinal medication histories. Although inpatient medication administration records are a reliable and accurate way of identifying antidepressant exposure during hospitalization, we do not have detailed longitudinal information about the duration and intensity of antidepressant use both before and after surgery. Although unlikely, some patients may have discontinued SSRI therapy during hospitalization and were classified as nonusers in our study. We believe that the SSRI administration during hospitalization probably reflects chronic use, but we have no evidence to confirm this. Similarly, some patients may have been diagnosed with depression and started therapy months or years after surgery. Finally, this is an observational study and we are unable to attribute causality in regard to the effectiveness of SSRI in reducing revision risk. Future studies with longitudinal SSRI exposure data are warranted to replicate our observations and investigate the potential causative mechanisms for the protective benefit of SSRI in regard to risk of revision in THA and TKA.

A diagnosis of depression was associated with a doubling of the HR for PJI in addition to an increased risk of revision arthroplasty. This finding is consistent with prior studies [3, 4, 11, 12, 14, 15, 26, 28] and may be the result of immune changes associated with depression or the adverse effect of comorbidities associated with depression [10, 27]. The myriad of comorbidities associated with depression is impressive in both the range and severity of conditions including cancer, diabetes, and inflammatory arthritis [36]. Depression is also known to impair overall health status to a substantially greater degree than angina, arthritis, asthma, or diabetes [21]. We observed a similar pattern in our study with a high comorbidity burden in patients with depression. Therefore, associated immune changes and/or comorbid physical illnesses may potentially underlie the increased risk of PJI and increased risk of revision arthroplasty in depressed patients who have undergone arthroplasty.

The prevalence of perioperative antidepressant use was 75% among patients with a diagnosis of depression. Because antidepressant exposure was determined by medication administration records, we are reasonably confident regarding the validity of antidepressant use. The unsurprising disparity between antidepressant use and depression diagnosis in this cohort (ie, antidepressant use without a depression diagnosis) possibly reflects the wide range of indications (eg, anxiety disorders, sleep disorders) beyond depression [39]. Population-based studies suggest that roughly 57% antidepressant prescriptions are for indications other than depression [1]. In our cohort, 1290 (75%) of the 1724 patients who received antidepressants without a diagnosis of depression had a documented history of anxiety and sleep disorders in their medical records (based on a natural language processing-based search), suggesting that antidepressant use in this cohort was possibly for anxiety and sleep disorders.

An unexpected finding of our study is the association with a reduced risk of revision among patients who received SSRIs during hospitalization. Given the adverse effects of depression in patients undergoing arthroplasty, it is plausible that effective management of depression with antidepressants may potentially mitigate these adverse effects. We speculate that this observation may be the result of (1) better management of depression and other mood disorders in patients using SSRIs; or (2) true biologic effects of SSRIs. It is plausible that continued antidepressant use is associated with better symptom management and less pain in patients undergoing arthroplasty. However, the lower risk of revision in our study is confined only to those using SSRI and not all those who use antidepressants. Therefore, better management of depression may not be the sole reason for the observed findings. Laboratory evidence is currently lacking, but SSRIs may potentially have beneficial biologic effects on the bone and implant interface, thereby reducing the risk of revision, but there is currently no evidence to support this mechanism either. On the contrary, a large body of studies has established the negative effects of SSRIs on bone mineral density and the increased risk of fractures [13, 16, 30]. Because SSRIs have a negative effect on bone health, some investigators have argued that they may have a negative effect on implant osseointegration [42]. This is contrary to our findings, although in the majority of the TKA cases, the interface of the implant was cemented, potentially negating such an effect. Another potential mechanism is through immunomodulatory effects of SSRIs [7]. Unfortunately, without detailed, longitudinal SSRI use histories, we were unable to further examine the causality of the reduced risk of revision among those using SSRIs.

To our knowledge, this is the first published investigation reporting the effects of antidepressant use on revision risk and PJI in total joint arthroplasty. Our findings suggest that SSRI use during hospital admission for THA and TKA is associated with a reduction in revision risk. The reasons for this finding are unknown but may potentially include patient selection or true biologic effects. In the meantime, perioperative SSRIs have been implicated in serious adverse effects (ie, bleeding) and some authors have even suggested discontinuing their use during the perioperative period [23]. Nevertheless, unless indicated otherwise, our findings support the continuation of SSRIs in the perioperative period for patients undergoing THA and TKA. Importantly, depression and psychiatric comorbidity and antidepressant medications are rarely considered during the perioperative evaluation of risk factors among arthroplasty candidates. Studies such as ours raise awareness to better recognize and manage these comorbidities in patients undergoing arthroplasty.

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