- Email: [email protected]
Antidepressant Therapy in Patients Undergoing Coronary Artery Bypass Grafting: The MOTIV-CABG Trial
Sidney Chocron, MD, PhD, Pierre Vandel, MD, PhD, Camille Durst, MD, Fr ed eric Laluc, MD, Djamel Kaili, MD, Michael Chocron, PhD, and Joseph-Philippe Etievent, MD Departments of Thoracic and Cardiovascular Surgery and Psychiatry, EA3920, University Hospital Jean Minjoz, Besanc¸on; and Unit of Transversal Research in Psychogenesis and Psychopathology, University of Paris 13, Villetaneuse, France
Background. The efficacy of antidepressant therapy in patients undergoing coronary artery bypass grafting (CABG) is not clearly established. Methods. This double-blind trial was conducted at University Hospital, Besanc¸on, France. Adult CABG patients were randomized (1:1) to receive escitalopram (10 mg daily) or placebo from 2 to 3 weeks before to 6 months after surgery, including 12 months post-surgery follow-up. The primary composite endpoint was the occurrence of mortality or predefined morbidity events. Secondary endpoints included measures of depression, mental and physical health using Beck Depression Inventory Short Form (BDI), and quality of life 36-Item Short Form (SF-36) self assessments. Results. The treated cohort contained 361 patients with mean age 67 years. At 12 months, the proportions of patients with the composite morbidity and mortality endpoint were not different between escitalopram and placebo (110 of 182 [60.4%] vs 108 of 179 [60.3%], p [ 0.984). However, over the 6 months postoperative
period, the BDI and SF-36 Mental Component Summary scores were better overall in the escitalopram group than in the placebo group for all patients (p [ 0.015 and p [ 0.014, respectively) and preoperatively depressed (BDI > 3) patients (p [ 0.002 and p [ 0.005, respectively). Moreover, the SF-36 Pain score was better overall in the escitalopram group than in the placebo group in the preoperatively-depressed subset (p [ 0.026). Conclusions. Antidepressant therapy had no effect on morbidity and mortality events up to 1 year after CABG. However, antidepressant therapy may provide faster improvements to mental health aspects of quality of life and reduce postoperative pain in patients with preoperative depression. Subject to contra-indications, we recommend antidepressant therapy in coronary revascularization patients who are preoperatively depressed.
T
he incidence of depression is high in patients requiring or having undergone coronary artery bypass grafting (CABG). Burker and colleagues [1] showed that 47% of patients waiting for surgery and 61% of patients who have undergone CABG were depressed. The knowledge of the need for an imminent operation also contributes to the perceived physical and psychologic stress [1, 2]. Depression can also occur after surgery in preoperative non-depressed patients [3]. Depression has been associated with a higher risk of morbidity and mortality outcomes after myocardial infarction [4] and subsequent open-heart surgery [5]. For Connerney and colleagues [6], depressed patients are more likely to present complications after heart surgery (odds ratio ¼ 2.3, 95% confidence interval 1.17 to 4.56).
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class approved for generalized anxiety disorder, social anxiety disorder, and obsessive-compulsive disorder. The aim of this study was to compare treatment with escitalopram and placebo on postoperative mortality, morbidity, and quality of life of patients scheduled to undergo CABG. The treatment was started from 14 to 21 days before surgery because the beneficial effects of SSRIs become apparent only after a minimum of 2 weeks on average [7]. Non-depressed patients were also included in the study because depression could occur after surgery [3]. Patients with long-term oral anticoagulation medication were not included because this medication may interact with escitalopram and require more frequent monitoring through coagulation tests.
Accepted for publication Feb 25, 2013.
Patients and Methods
Address correspondence to Dr Chocron, Department of Thoracic and Cardio-Vascular Surgery, EA3920, University Hospital Jean Minjoz, Boulevard Fleming, 25000 Besanc¸on, France; e-mail: sidney.chocron@ univ-fcomte.fr.
Study Design and Organization
Ó 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2013;95:1609–18) Ó 2013 by The Society of Thoracic Surgeons
The MOTIV-CABG study was a single-center, non-stratified, randomized, double-blind, parallel-group, phase 4 trial 0003 4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2013.02.035
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Abbreviations and Acronyms ANCOVA = analysis of covariance BDI = Beck Depression Inventory Short Form CABG = coronary artery bypass grafting ITT = intention to treat MCS = Mental Component Summary OR = odds ratios PCS = Physical Component Summary SF 36 = Short Form (36) Health Survey SSRI = selective serotonin reuptake inhibitor
conducted between January 2006 and February 2012. Eligible subjects were randomized (1:1 ratio) into 2 treatment groups to receive escitalopram (group E) or placebo (group P). The trial was sponsored by H. Lundbeck A/S (Copenhagen, Denmark). A steering committee had final responsibility for the study design, clinical protocol, study oversight, data verification, and analyses. The protocol was approved by the Institutional Review Board, and written informed consent was obtained from all participants. A single committee adjudicated on the mortality and morbidity events.
Participants The trial was conducted at University Hospital, Besanc¸on, France. Eligible subjects were 30 years old or greater, coronary patients with stable angina pectoris, and scheduled to undergo CABG. Exclusion criteria were the following: antidepressant treatment in progress or treatment terminated within 2 months before trial entry; escitalopram contraindication; psychotic disease, severe hepatic disease; long-term anticoagulation treatment; pregnancy; difficulty in understanding French (oral or written); a participation in another concurrent research trial; a requirement of complementary cardiac surgery other than coronary bypass; a high-risk coronary lesion; a requirement of urgent or emergent surgery. Randomized patients were included in the intention-to-treat cohort. Randomized patients who took at least 1 dose of trial medication were included in the “treated cohort.”
Randomization and Treatment Regimens Tablets were contained in packs of 4 boxes that were distinguished from other packs only by the unique treatment number. The content of each pack (either escitalopram [10 mg/tablet] or placebo) was determined from a randomization list built by the manufacturer (and concealed from the investigators) using a randomnumber table with a block size of 20 packs. Escitalopram and placebo tablets were identical in appearance. Patients were allocated consecutive treatment numbers on entering the trial. The blind (kept by the hospital’s pharmacist) was broken for a given patient only in case of their death. All study personnel and patients were blinded to treatment.
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Tablets were taken orally in the morning. One tablet/ day was taken from 14 days to 21 days before surgery up to 6 months after surgery (month 6). As antidepressant therapy has to be stopped progressively, for the 8 days after month 6 half a tablet a day was taken before stopping [8]. The overall compliance of study treatment intake (%) was calculated as (number of tablets dispensed – number of tablets returned) 100/Number of tablets that should have been taken.
Outcome Assessment The primary composite endpoint was assessed in the treated cohort and was the occurrence of a mortality or morbidity event throughout the 12-month postoperative period. Morbidity was defined as 1 or more of the following: (1) cardiac: perioperative myocardial infarction or low cardiac output syndrome; (2) pulmonary: mechanical ventilation support for more than 24 hours, or need for reintubation; (3) neurologic: focal brain injury with permanent or transient deficit, or agitation or confusion for more than 24 hours; (4) renal: need for dialysis when previously not required, or maximum creatinine serum level more than twice preoperative creatinine serum level; (5) acquired atrial fibrillation: paroxysmal or persistent; (6) infectious: pneumonia, sepsis with positive culture, sternal wound infection requiring intravenous antibiotics, surgical debridement, or both; (7) any surgery or invasive procedure necessary to treat a postoperative adverse event associated with the initial cardiac surgery; (8) myocardial infarction; (9) congestive heart failure; (10) rehospitalization for cardiac-related cause; and (11) rehospitalization for noncardiac-related cause. Secondary endpoints included the quantitative measurement of depression and of quality of life using the self-assessment questionnaires at each visit and assessed in the treated cohort and in a subset of patients of the treated cohort scored as being at least mildly depressed at visit 1 (pre-surgery). During each follow-up visit (before and after surgery at months 1, 3, 6, and 12) patients were examined, detailed information was gathered about events that occurred since the previous visit, and patients filled in the self-assessment questionnaires. All patients received a systematic psychiatry consultation during post-surgery hospitalization. If a depression syndrome requiring antidepressant treatment was identified, the patient stopped taking study treatment and was switched to open-label antidepressant treatment.
Self-Assessment Questionnaires Depression symptoms were measured using the Beck Depression Inventory (BDI) Short Form self-assessment questionnaire [9]. The BDI scores were qualified as follows: 0 to 3, no depression; 4 to 7, mild depression; 8 to 15, moderate depression; 16 and above, severe depression. Quality of life was measured using the French version [10] of the Short Form (SF)-36 selfassessment questionnaire and quantified (on a scale from 0 to 100 with higher scores indicating better health)
CHOCRON ET AL ANTIDEPRESSANT THERAPY IN CABG PATIENTS
in 8 domains of health: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Two summary scores were calculated to summarize the patient’s physical (the Physical Component Summary score [PCS]) and mental state of health (Mental Component Summary score [MCS]) [11].
Surgical Technique Coronary artery bypass grafting was performed on all patients by using only both mammary arteries. No saphenous vein graft or other conduit was used. Completion of coronary revascularization was performed using sequential anastomosis.
Sample Size Under the assumption that 50% of patients would have a primary endpoint event, 182 patients per group were required to detect 15% fewer events in one group compared with the other, with a 2-sided 5% significance level (alpha risk) and a 90% statistical power (10% beta risk).
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Statistical Analysis: Analyses of the Primary Composite Endpoint Differences between the 2 treatment groups of the frequency of the composite endpoint or the individual event were identified using a c2 test. Additional comparisons were performed according to demographic and baseline characteristics using c2 or Fisher exact tests (categoric variables) and the Student t test or MannWhitney test (continuous variables) as appropriate. The p values less than 0.05 were used to indicate statistical significance.
Statistical Analyses: Analyses of Self-Assessment Questionnaire Scores Differences within a treatment group of self-assessment questionnaire scores were identified using a paired Student t test or the Wilcoxon signed rank test, as appropriate. For each patient and for each questionnaire depression or health domain, the preoperative score was considered as baseline score, and changes in the score from baseline were calculated by subtracting the baseline score from the scores at month 1, 3, 6, or 12. Differences
Assessed for eligibility (n=595)
Excluded (n=227) Not meeting inclusion criteria (n=150) Declined to participate (n=77)
Randomized: ITT cohort (n=368)
Allocated to treatment: Placebo (n=183) Received allocated treatment (n=179) Did not receive allocated treatment (n=4) Withdrawal of consent (n=4)
Allocated to treatment: Escitalopram (n=185) Received allocated treatment (n=182) Did not receive allocated treatment (n=3) Withdrawal of consent (n=3)
Completed the study up to Month 12 (n=175) Study termination or early withdrawal (n=4)
Completed the study up to Month 12 (n=178) Study termination or early withdrawal (n= 4)
Discontinued treatment (n= 33) Stop period: Between pre op and intervention (n= 2) Between intervention and Month 1 (n=22) Between Month 1 and Month 3 (n= 8) Between Month 3 and Month 6 (n=1)
Discontinued treatment (n=47) Stop period: Between pre op and intervention (n=14) Between intervention and Month 1 (n=22) Between Month 1 and Month 3 (n= 8) Between Month 3 and Month 6 (n=3)
Analysed: Treated Cohort (n=179) Subgroups: Patients who have a BDI Score > 3 (n=68) Patients who have a BDI Score 3 (n=106)
Analysed: Treated Cohort (n=182) Subgroups: Patients who have a BDI Score > 3 (n=74) Patients who have a BDI Score 3 (n=107)
Fig 1. Study flowchart by treatment group. (BDI Beck Depression Inventory Short Form; ITT intention to treat.)
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Table 1. Global Characteristics by Treatment Group; Treated Cohort Characteristics Demographic characteristics: Age (years) Mean SD Body mass index (kg/m2) Mean SD Sex ratio Women/men Academic level Elementary Intermediary Higher Social group (former employment) Farmers Employers and own account Workers Higher managerial and professional occupations Intermediate occupations Lower managerial and professional occupations Supervisory and technical workers Work status Active Retired Sick leave Disabled Unemployed Risk factors and preoperative characteristics Hypertension Hyperlipidemia Smoking history Overweight Family history of coronary artery disease Previous myocardial infarction Previous stroke Extracardiac arteriopathy Diabetes COPD Creatinine clearance (mL/minute) Mean SD Angina CCS class None/I/II III/IV Ejection fraction class <0.30 [0.30; 0.50] >0.50 Logistic EuroSCORE (%) Operative and postoperative characteristics One vessel disease Two vessel disease Three vessel disease Number of anastomoses Off pump surgery 24 hour bleeding (mL)
Total (N
361)
Placebo (N
179)
Escitalopram (N
182)
p Valuea
67.1 8.9
66.7 8.9
67.4 9.0
0.449
27.6 4.1
27.7 4.1
27.5 4.2
0.635
0.16
0.17
0.15
0.713
136 (42.6%) 141 (44.2%) 42 (13.2%)
79 (48.8%) 62 (38.3%) 21 (13.0%)
57 (36.3%) 79 (50.3%) 21 (13.4%)
0.063
21 37 34 43 84 125
(6.0%) (10.5%) (9.7%) (12.2%) (23.9%) (35.2%)
9 22 16 19 45 61
(5.1%) (12.5%) (9.1%) (10.8%) (25.6%) (34.5%)
12 15 18 24 39 64
(6.8%) (8.5%) (10.2%) (13.6%) (22.2%) (36.4%)
0.794
56 286 6 4 7
(15.6%) (79.7%) (1.7%) (1.1%) (1.9%)
28 141 2 3 5
(15.6%) (78.8%) (1.1%) (1.7%) (2.8%)
28 145 4 1 2
(15.6%) (80.6%) (2.2%) (0.6%) (1.1%)
0.602
233 252 37 89 131 88 24 27 126 13
(64.7%) (70.0%) (10.3%) (24.7%) (36.4%) (24.4%) (6.7%) (7.8%) (35.2%) (3.6%)
119 129 17 43 67 44 14 10 63 7
(66.5%) (72.1%) (9.5%) (24.0%) (37.4%) (24.6%) (7.9%) (5.8%) (35.2%) (3.9%)
114 123 20 46 64 44 10 17 63 6
(63.0%) (68.0%) (11.0%) (25.4%) (35.4%) (24.2%) (5.5%) (9.7%) (35.2%) (3.3%)
0.488 0.395 0.628 0.760 0.683 0.929 0.367 0.185 1.000 0.762
81.6 28.0
80.9 26.2
82.4 29.9
0.628
327 (93.7%) 22 (6.3%)
162 (93.6%) 11 (6.4%)
165 (93.8%) 11 (6.3%)
0.967
9 (2.6%) 88 (25.4%) 249 (72.0%) 3.1 2.1
5 (2.9%) 46 (26.7%) 121 (70.3%) 3.1 2.0
4 (2.3%) 42 (24.1%) 128 (73.6%) 3.1 2.2
0.790
0.904
35 (9.7%) 104 (28.8%) 208 (57.6%) 2.94 0.93 134 (37.2%) 508.3 194.5
13 (7.3%) 52 (29.1%) 104 (58.1%) 3.02 0.91 58 (32.4%) 508.0 181.3
22 (12.1%) 52 (28.6%) 104 (57.1%) 2.86 0.96 76 (42.0%) 508.7 207.2
0.121 0.920 0.854 0.115 0.060 0.971 (Continued)
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Table 1. Continued Characteristics
Total (N
Transfusions Troponin I level at hour 6 Duration of assisted ventilation (hours) a
361)
98 (27.1%) 5.885 5.211 9.11 15.99
Placebo (N
179)
46 (25.7%) 6.186 5.675 9.47 16.54
Escitalopram (N 52 (28.6%) 5.583 4.695 8.75 15.44
182)
p Valuea 0.539 0.269 0.684
Comparison between treatment groups: c2 test or Fisher exact test for categoric variables; Student t-test or Mann-Whitney test for continuous variables.
COPD ¼ chronic obstructive pulmonary disease; system for cardiac operative risk evaluation.
CCS ¼ Canadian Cardiovascular Society grading of angina pectoris;
between groups in the changes in scores from baseline were identified using repeated measure analyses of covariance, including treatment group and time as factors, time by treatment interaction and preoperative
scores as a covariate. The repeated measure pattern of the data was taken into account by means of an autoregressive correlation structure. Both time-by-treatment interactions over the 6-month period and differences
Months from Baseline 0
3
1
6
Adjusted Mean Change from Baseline in BDI Score
0.00 P-value global treatment effect = 0.015
-0.50 -1.00 -1.50 -2.00
-2.50 -3.00 -3.50
Placebo -4.00
Escitalopram
A
Months from Baseline 0
3
1
Adjusted Mean Change from Baseline in BDI Score
0.00 P-value global treatment effect = 0.002
-0.50 -1.00 -1.50 -2.00
-2.50 -3.00 -3.50 Placebo -4.00
B
Escitalopram
EuroSCORE ¼ European
6
Fig 2. Change from baseline in Beck Depression Inventory (BDI) score by period (1, 3, and 6 months) and treatment group. (A) Treated cohort; (B) Patients with a preopera tive BDI > 3. Values presented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treatment and visit as factors, treatment by visit interaction, and baseline score as covariate. A negative change shows an improvement. Error bars indicate standard errors. (* indicates p values < 0.05 for treatment group difference; : placebo; C escitalopram.)
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Fig 3. Change from baseline in Short Form (SF) 36 Physical Component Summary (PCS) score by period (1, 3, and 6 months) and treatment group; (A) Treated cohort; (B) Patients with a preoperative Beck Depression Inventory > 3. Values presented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treatment and visit as factors, treatment by visit interaction, and baseline score as covariate. A positive change shows an improvement. Error bars indicate standard errors. (* indicates p values < 0.05 for treatment group difference; : placebo; C escitalopram.)
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P-value global treatment effect = 0.947
8.00 7.00 Placebo
6.00
Escitalopram 5.00 4.00 3.00 2.00 1.00 0.00 -1.00
0
1
3
6
Months from Baseline
-2.00
-3.00 -4.00 -5.00
P-value global treatment effect = 0.111
8.00 7.00 Adjusted Mean Change from Baseline in SF-36 PCS
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Adjusted Mean Change from Baseline in SF-36 PCS
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Placebo
6.00
Escitalopram
5.00 4.00 3.00 2.00 1.00 0.00 -1.00
0
-2.00
1
3
6
Months from Baseline
-3.00 -4.00 -5.00
between treatment groups at month 1, 3, and 6 were estimated to assess the dynamic of the treatment effect through time. The same analyses were also performed over the entire 12-month follow-up period. All statistical tests were carried out at the 2-sided 5% significance level. Statistical analyses were performed using SAS version 9.2 software (SAS Institute, Cary, NC).
Results Subject Disposition and Demography In total, 595 patients were screened at the pre-surgery visit (Fig 1). Of these, 368 patients were randomized into group E (escitalopram) and group P (placebo). The treated cohort (361 patients) contained 182 patients in group E and 179 in group P. The overall compliance of study treatment intake was similar between the 2
treatment groups (group P: 96.1% 20.6%; group E: 93.9% 23.0%, p ¼ 0.219). All preoperative and operative characteristics of treated cohort patients were balanced between the 2 groups (Table 1).
Effect of Treatment on Composite and Individual Mortality and Morbidity Events By postoperative month 12, the proportions of patients with the composite endpoint of morbidity and mortality events were not different between group E and group P (110 of 182 [60%] vs 108 of 179 [60%], respectively; p ¼ 0.984). No patient died within 30 days after surgery. One patient did die in hospital. Of the 5 patients who died outside hospital, 2 died of cardiac-related causes, and 3 of noncardiac-related causes. Three patients died in each treatment group. No differences were identified between treatment groups for each of the events that defined the
CHOCRON ET AL ANTIDEPRESSANT THERAPY IN CABG PATIENTS
composite endpoint (data not shown). Acquired atrial fibrillation was the most frequently reported event (29% in group E, 34% in group P).
Effect of Treatment on Depression and Quality of Life Self Assessments BDI. The preoperative (baseline) mean BDI scores in all patients were 3.7 in both groups (p ¼ 0.929). During the postoperative 6-month treatment period, mean decreases in BDI scores from baseline were greater overall in group E than in group P (p ¼ 0.015), suggesting a better improvement in group E than in group P during this period (Fig 2A). Also at months 1 and 6, the adjusted mean changes in BDI scores from baseline were lower in group E than in group P (p ¼ 0.049, and p ¼ 0.021, respectively) suggesting that in group E compared with
Adjusted Mean Change from Baseline in SF-36 MCS
14.00
group P, depression status is notably better at months 1 and 6, and that the postoperative improvement in depression symptoms is more rapid. SF-36. No differences were observed in preoperative (baseline) mean scores between groups for the SF-36 individual health domain scores or for the SF-36 MCS or PCS scores in all patients. In each group, mean SF-36 component or summary scores were typically higher than the respective mean baseline scores from month 3 to month 6 (Figs 3A; 4A; 5A). Over the postoperative treatment period, the mean increases in scores from baseline were greater overall in group E than in group P for 2 SF-36 domains; mental health (p ¼ 0.004) and social functioning (p ¼ 0.028), and for the MCS score (p ¼ 0.014). At month 1 and 6, the mean changes in mental health and MCS scores from baseline were higher in
Fig 4. Change from baseline in Short form (SF) 36 Mental Component Summary (MCS) score by period (1, 3, and 6 months) and treatment group; (A) treated cohort and (B) patients with a preoperative Beck Depression Inventory > 3. Values presented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treat ment and visit as factors, treatment by visit interaction and baseline score as covariate. A positive change shows an improvement. Error bars indicate standard errors. (* indi cates p values < 0.05 for treatment group difference; : placebo; C escitalopram.)
P-value global treatment effect = 0.014
12.00
10.00
8.00
6.00
4.00 Placebo
2.00
Escitalopram 0.00 0
A
1
Adjusted Mean Change from Baseline in SF-36 MCS
14.00
3 Months from Baseline
6
P-value global treatment effect = 0.005
12.00
10.00
8.00
6.00
4.00 Placebo 2.00
Escitalopram
0.00
B
0
1
3 Months from Baseline
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Fig 5. Change from baseline in Short Form (SF) 36 domain scores by period (1, 3, and 6 months) and treatment group; (A) treated cohort and (B) patients with a preoperative Beck Depression Inventory > 3. Values pre sented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treatment and visit as factors, treatment by visit interaction, and baseline score as covariate. A positive change shows an improvement. Error bars indicate standard errors. (* indicates p values < 0.05 and ** indicates p values < 0.01 for treatment group difference.)
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30 25 0.028
20
0.004
15 10 5 0 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 -5 -10 -15 -20
Physical Functioning
RolePhysical
Bodily Pain
General Health Placebo
Vitality
Social Functioning
RoleEmotional
Mental Health
Escitalopram
30
Adjusted Mean Change from Baseline in SF-36 Domain Scores
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Adjusted Mean Change from Baseline in SF-36 Domain Scores
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0.013 25
0.002
0.011
20
0.026
15 10 5 0 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 -5 -10 -15 -20
Physical Functioning
RolePhysical
group E than in group P (p < 0.05). These data suggest a better improvement in these health domains in group E than in group P during this period (Figs 4A; 5A).
All Scores in BDI Greater Than 3 Subset A total of 142 patients out of 361 (39%) had preoperative BDI scores greater than 3 (Fig 1). In this subset, in groups E and P, the preoperative mean BDI scores were 6.6 and 7.2, respectively, and not different (p ¼ 0.315). In each group, mean BDI scores were lower than the respective mean baseline scores from month 1 (p < 0.05) (Fig 2B). Over the postoperative 6-month treatment period, the mean decreases in BDI scores from baseline were greater overall in group E than in group P (p ¼ 0.002) (Fig 2B). At month 1 and 6, the mean changes in BDI scores were lower in group E than in group P (p ¼ 0.017 and
Bodily Pain
General Health Placebo
Vitality
Social Functioning
RoleEmotional
Mental Health
Escitalopram
p ¼ 0.011, respectively) (Fig 2B). No differences were observed in preoperative (baseline) SF-36 mean scores between groups in the BDI greater than 3 subset. However, over the postoperative 6-month treatment period, the mean increases in scores from baseline were greater overall in group E than in group P for 4 SF-36 domains; vitality (p ¼ 0.011), mental health (p ¼ 0.002), social functioning (p ¼ 0.013), and bodily pain (p ¼ 0.026) (Fig 5B), and for the MCS score (p ¼ 0.005) (Fig 4B), but not for the PCS score (p ¼ 0.111) (Fig 3B). At months 1 and 6 the mean changes in SF-36 MCS scores from baseline were higher in group E than in group P (p ¼ 0.008 and p ¼ 0.019, respectively) (Fig 4B). In contrast, in the subset of patients with a preoperative BDI score 3 or less, there were no significant differences between groups in changes in BDI scores or for any of the
changes in SF-36 domain or summary scores (data not shown). Therefore, this suggested that improvements in mental health and bodily pain outcomes mainly occurred in the BDI greater than 3 subset.
Harms Side effects were reported by 23 (12.6%) patients in group E and 8 patients (4.5%) in group P (p ¼ 0.006). In group E, patients reported diarrhea (n ¼ 7), constipation (n ¼ 3), nausea (n ¼ 3), shivering (n ¼ 3), somnolence (n ¼ 2), tingling of extremities (n ¼ 2), dizziness (n ¼ 2), and attention concentration difficulty (n ¼ 1). In group P, patients reported nausea (n ¼ 1), constipation (n ¼ 2), diarrhea (n ¼ 1), sleep disorder (n ¼ 1), heartburn (n ¼ 2), and aggravated anxiety (n ¼ 1). All these side effects were transient. Of the 23 patients in group E, 4 stopped their medication. Of the 8 patients in group P, 2 stopped their medication. No other serious side effects were reported.
Comment Antidepressant treatment of major depressive disorder usually takes 2 to 4 weeks before any significant improvement appears [12]. This was checked by the psychiatrist consultation during postoperative hospitalization. Once a person positively responds to an antidepressant, this depression treatment should be continued for 4 to 9 months, according to the American College of Physicians guidelines [12]; we therefore chose to treat the patients during 6 months. The escitalopram treatment regime had no effect on the composite measure of morbidity and mortality events after CABG surgery, or on frequency of these individual morbidity and mortality events in the 12-month postoperative period. However, escitalopram in this study improved depression status and mental health aspects of quality of life during the 6-month postoperative treatment period, principally in a subset of patients who were at least mildly depressed (BDI > 3) at the time of the preoperative visit. In patients treated with escitalopram, higher improvements were observed by postoperative month 1, suggesting that their depression symptoms and mental health improved more rapidly than those of placebo patients. Also, in the BDI greater than 3 subset, escitalopram ameliorated the sensation of bodily pain during treatment. No unexpected safety concerns were identified with escitalopram treatment [13]. No significant differences were identified at month 12 between changes in scores from baseline in the analysis of the entire treated cohort or the BDI greater than 3 subset, suggesting that the better improvements in depression status, mental health, and bodily pain outcomes subsided after escitalopram treatment ended soon after month 6 (data not shown). This study differs from other examinations of SSRI treatment in cardiac patients in that it has used a randomized design with a placebo control group and systematic follow-up to assess physical and mental health. The SSRI treatment of depressed cardiac patients has been
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typically examined in observational studies suggesting that treatment reduced mortality and morbidity. Therefore, the observation in this study that antidepressant treatment had no effect on morbidity and mortality suggests that if depression is a predictor of worse postoperative morbidity and mortality then an underlying factor may affect mental health together with these physical outcomes. However, no such factor was identified in this study even though a large array of demographic and baseline characteristics were analyzed. The SSRIs have a better safety profile with regard to the cardiovascular system [14] than tricyclic agents and monoamine oxidase inhibitors [15]. There was no evidence that escitalopram treatment increased bleeding or in-hospital mortality, in line with what was observed in another study [13]. Although there was a higher frequency of side effects in group E compared with group P unrelated to the composite endpoints, there was no evidence from the SF-36 self-assessments of relatively worse physical health outcomes in group E compared with group P. The prevalence of preoperative depression identified in this study (39% with BDI > 3) is in line with estimates made elsewhere for patients scheduled for heart surgery; such as 27% to 47% [1, 3]. Although the escitalopram therapy has no effect on postoperative morbidity or mortality up to 1 year after CABG, this study suggested that SSRI antidepressant therapy provided faster improvements of mental health aspects of quality of life and reduced postoperative pain in patients who are at least mildly depressed before surgery. Depressed patients were easily identified with the BDI questionnaire at the preoperative visit. Moreover, the beneficial effects of escitalopram were principally observed during treatment, suggesting that the patient’s depression should be reevaluated regularly to assess the appropriate dose and duration. Subject to contraindications, we recommend antidepressant therapy in surgical coronary revascularization patients with a preoperative BDI greater than 3. This study was funded by H. Lundbeck A/S, Copenhagen, Denmark; MOTIV CABG study. We thank, Sylvie di Nicola (Inferential) for the statistical anal yses, Matthew Morgan (MG Science Communications) for scientific writing and editorial support, and Gaye Siliman for the data management. ClinicalTrials.gov number, NCT00243477 (http://clinicaltrials.gov/ct2/show/NCT00243477).
References 1. Burker EJ, Blumenthal JA, Feldman M, et al. Depression in male and female undergoing cardiac surgery. Br J Clin Psy chol 1995;34(Pt 1):119 28. 2. Stoll C, Schelling G, Goetz AE, et al. Health related quality of life and post traumatic stress disorder in patients after cardiac surgery and intensive care treatment. J Thorac Car diovasc Surg 2000;120:505 12. 3. Pirraglia PA, Peterson JC, Williams Russo P, Gorkin L, Charlson ME. Depressive symptomatology in coronary artery bypass graft surgery patients. Int J Geriatr Psychiatry 1999;14:668 80.
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4. Meijer A, Conradi HJ, Bos EH, Thombs BD, van Melle JP, de Jonge P. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis of 25 years of research. Gen Hosp Psychiatry 2011;33:203–16. 5. Frasure-Smith N, Lesp erance F, Talajic M. Depression following myocardial infarction: impact on 6 months survival. JAMA 1993;270:1819–25. 6. Connerney I, Shapiro PA, McLaughlin JS, Bagiella E, Sloan RP. Relation between depression after coronary artery bypass surgery and 12-month outcome: a prospective study. Lancet 2001;358:1766–71. 7. Pignay-Demaria V, Lesperance F, Demaria RG, FrasureSmith N, Perrault LP. Depression and anxiety and outcomes of coronary artery bypass surgery. Ann Thorac Surg 2003;75: 314–21. 8. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World J Biol Psychiatry 2007;8:67–104. 9. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty five years of evaluation. Clin Psychol Rev 1988;8:77–100.
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10. Lepl ege A, Mesbah M, Marquis P. Preliminary analysis of the psychometric properties of the French version of an international questionnaire measuring the quality of life: the MOS SF-36 (version 1.1). [Article in French] Rev Epidemiol Sante Publique 1995;43:371–9. 11. Ware JE, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczeck A. Comparison of methods for the scoring and statistical analysis of SF36 health profile and summary measures. Med Care 1995;33(Suppl 4):AS264–79. 12. Qaseem A, Snow V, Denberg TD, Forciea MA, Owens DK. Using Second-Generation Antidepressants to Treat Depressive Disorders: A Clinical Practice Guideline from the American College of Physicians. Ann Intern Med 2008;149: 725–33. 13. Xiong GL, Jiang W, Clare RM, et al. Safety of selective serotonin reuptake inhibitor use prior to coronary artery bypass grafting. Clin Cardiol 2010;33:E94–8. 14. Roose SP, Laghrissi-Thode F, Kennedy JS, et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998;279:287–91. 15. Lesp erance F, Frasure-Smith N. Depression in patients with cardiac disease: a practical review. J Psychosom Res 2000;48: 379–91.
Background. The efficacy of antidepressant therapy in patients undergoing coronary artery bypass grafting (CABG) is not clearly established. Methods. This double-blind trial was conducted at University Hospital, Besanc¸on, France. Adult CABG patients were randomized (1:1) to receive escitalopram (10 mg daily) or placebo from 2 to 3 weeks before to 6 months after surgery, including 12 months post-surgery follow-up. The primary composite endpoint was the occurrence of mortality or predefined morbidity events. Secondary endpoints included measures of depression, mental and physical health using Beck Depression Inventory Short Form (BDI), and quality of life 36-Item Short Form (SF-36) self assessments. Results. The treated cohort contained 361 patients with mean age 67 years. At 12 months, the proportions of patients with the composite morbidity and mortality endpoint were not different between escitalopram and placebo (110 of 182 [60.4%] vs 108 of 179 [60.3%], p [ 0.984). However, over the 6 months postoperative
period, the BDI and SF-36 Mental Component Summary scores were better overall in the escitalopram group than in the placebo group for all patients (p [ 0.015 and p [ 0.014, respectively) and preoperatively depressed (BDI > 3) patients (p [ 0.002 and p [ 0.005, respectively). Moreover, the SF-36 Pain score was better overall in the escitalopram group than in the placebo group in the preoperatively-depressed subset (p [ 0.026). Conclusions. Antidepressant therapy had no effect on morbidity and mortality events up to 1 year after CABG. However, antidepressant therapy may provide faster improvements to mental health aspects of quality of life and reduce postoperative pain in patients with preoperative depression. Subject to contra-indications, we recommend antidepressant therapy in coronary revascularization patients who are preoperatively depressed.
T
he incidence of depression is high in patients requiring or having undergone coronary artery bypass grafting (CABG). Burker and colleagues [1] showed that 47% of patients waiting for surgery and 61% of patients who have undergone CABG were depressed. The knowledge of the need for an imminent operation also contributes to the perceived physical and psychologic stress [1, 2]. Depression can also occur after surgery in preoperative non-depressed patients [3]. Depression has been associated with a higher risk of morbidity and mortality outcomes after myocardial infarction [4] and subsequent open-heart surgery [5]. For Connerney and colleagues [6], depressed patients are more likely to present complications after heart surgery (odds ratio ¼ 2.3, 95% confidence interval 1.17 to 4.56).
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class approved for generalized anxiety disorder, social anxiety disorder, and obsessive-compulsive disorder. The aim of this study was to compare treatment with escitalopram and placebo on postoperative mortality, morbidity, and quality of life of patients scheduled to undergo CABG. The treatment was started from 14 to 21 days before surgery because the beneficial effects of SSRIs become apparent only after a minimum of 2 weeks on average [7]. Non-depressed patients were also included in the study because depression could occur after surgery [3]. Patients with long-term oral anticoagulation medication were not included because this medication may interact with escitalopram and require more frequent monitoring through coagulation tests.
Accepted for publication Feb 25, 2013.
Patients and Methods
Address correspondence to Dr Chocron, Department of Thoracic and Cardio-Vascular Surgery, EA3920, University Hospital Jean Minjoz, Boulevard Fleming, 25000 Besanc¸on, France; e-mail: sidney.chocron@ univ-fcomte.fr.
Study Design and Organization
Ó 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2013;95:1609–18) Ó 2013 by The Society of Thoracic Surgeons
The MOTIV-CABG study was a single-center, non-stratified, randomized, double-blind, parallel-group, phase 4 trial 0003 4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2013.02.035
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Abbreviations and Acronyms ANCOVA = analysis of covariance BDI = Beck Depression Inventory Short Form CABG = coronary artery bypass grafting ITT = intention to treat MCS = Mental Component Summary OR = odds ratios PCS = Physical Component Summary SF 36 = Short Form (36) Health Survey SSRI = selective serotonin reuptake inhibitor
conducted between January 2006 and February 2012. Eligible subjects were randomized (1:1 ratio) into 2 treatment groups to receive escitalopram (group E) or placebo (group P). The trial was sponsored by H. Lundbeck A/S (Copenhagen, Denmark). A steering committee had final responsibility for the study design, clinical protocol, study oversight, data verification, and analyses. The protocol was approved by the Institutional Review Board, and written informed consent was obtained from all participants. A single committee adjudicated on the mortality and morbidity events.
Participants The trial was conducted at University Hospital, Besanc¸on, France. Eligible subjects were 30 years old or greater, coronary patients with stable angina pectoris, and scheduled to undergo CABG. Exclusion criteria were the following: antidepressant treatment in progress or treatment terminated within 2 months before trial entry; escitalopram contraindication; psychotic disease, severe hepatic disease; long-term anticoagulation treatment; pregnancy; difficulty in understanding French (oral or written); a participation in another concurrent research trial; a requirement of complementary cardiac surgery other than coronary bypass; a high-risk coronary lesion; a requirement of urgent or emergent surgery. Randomized patients were included in the intention-to-treat cohort. Randomized patients who took at least 1 dose of trial medication were included in the “treated cohort.”
Randomization and Treatment Regimens Tablets were contained in packs of 4 boxes that were distinguished from other packs only by the unique treatment number. The content of each pack (either escitalopram [10 mg/tablet] or placebo) was determined from a randomization list built by the manufacturer (and concealed from the investigators) using a randomnumber table with a block size of 20 packs. Escitalopram and placebo tablets were identical in appearance. Patients were allocated consecutive treatment numbers on entering the trial. The blind (kept by the hospital’s pharmacist) was broken for a given patient only in case of their death. All study personnel and patients were blinded to treatment.
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Tablets were taken orally in the morning. One tablet/ day was taken from 14 days to 21 days before surgery up to 6 months after surgery (month 6). As antidepressant therapy has to be stopped progressively, for the 8 days after month 6 half a tablet a day was taken before stopping [8]. The overall compliance of study treatment intake (%) was calculated as (number of tablets dispensed – number of tablets returned) 100/Number of tablets that should have been taken.
Outcome Assessment The primary composite endpoint was assessed in the treated cohort and was the occurrence of a mortality or morbidity event throughout the 12-month postoperative period. Morbidity was defined as 1 or more of the following: (1) cardiac: perioperative myocardial infarction or low cardiac output syndrome; (2) pulmonary: mechanical ventilation support for more than 24 hours, or need for reintubation; (3) neurologic: focal brain injury with permanent or transient deficit, or agitation or confusion for more than 24 hours; (4) renal: need for dialysis when previously not required, or maximum creatinine serum level more than twice preoperative creatinine serum level; (5) acquired atrial fibrillation: paroxysmal or persistent; (6) infectious: pneumonia, sepsis with positive culture, sternal wound infection requiring intravenous antibiotics, surgical debridement, or both; (7) any surgery or invasive procedure necessary to treat a postoperative adverse event associated with the initial cardiac surgery; (8) myocardial infarction; (9) congestive heart failure; (10) rehospitalization for cardiac-related cause; and (11) rehospitalization for noncardiac-related cause. Secondary endpoints included the quantitative measurement of depression and of quality of life using the self-assessment questionnaires at each visit and assessed in the treated cohort and in a subset of patients of the treated cohort scored as being at least mildly depressed at visit 1 (pre-surgery). During each follow-up visit (before and after surgery at months 1, 3, 6, and 12) patients were examined, detailed information was gathered about events that occurred since the previous visit, and patients filled in the self-assessment questionnaires. All patients received a systematic psychiatry consultation during post-surgery hospitalization. If a depression syndrome requiring antidepressant treatment was identified, the patient stopped taking study treatment and was switched to open-label antidepressant treatment.
Self-Assessment Questionnaires Depression symptoms were measured using the Beck Depression Inventory (BDI) Short Form self-assessment questionnaire [9]. The BDI scores were qualified as follows: 0 to 3, no depression; 4 to 7, mild depression; 8 to 15, moderate depression; 16 and above, severe depression. Quality of life was measured using the French version [10] of the Short Form (SF)-36 selfassessment questionnaire and quantified (on a scale from 0 to 100 with higher scores indicating better health)
CHOCRON ET AL ANTIDEPRESSANT THERAPY IN CABG PATIENTS
in 8 domains of health: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Two summary scores were calculated to summarize the patient’s physical (the Physical Component Summary score [PCS]) and mental state of health (Mental Component Summary score [MCS]) [11].
Surgical Technique Coronary artery bypass grafting was performed on all patients by using only both mammary arteries. No saphenous vein graft or other conduit was used. Completion of coronary revascularization was performed using sequential anastomosis.
Sample Size Under the assumption that 50% of patients would have a primary endpoint event, 182 patients per group were required to detect 15% fewer events in one group compared with the other, with a 2-sided 5% significance level (alpha risk) and a 90% statistical power (10% beta risk).
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Statistical Analysis: Analyses of the Primary Composite Endpoint Differences between the 2 treatment groups of the frequency of the composite endpoint or the individual event were identified using a c2 test. Additional comparisons were performed according to demographic and baseline characteristics using c2 or Fisher exact tests (categoric variables) and the Student t test or MannWhitney test (continuous variables) as appropriate. The p values less than 0.05 were used to indicate statistical significance.
Statistical Analyses: Analyses of Self-Assessment Questionnaire Scores Differences within a treatment group of self-assessment questionnaire scores were identified using a paired Student t test or the Wilcoxon signed rank test, as appropriate. For each patient and for each questionnaire depression or health domain, the preoperative score was considered as baseline score, and changes in the score from baseline were calculated by subtracting the baseline score from the scores at month 1, 3, 6, or 12. Differences
Assessed for eligibility (n=595)
Excluded (n=227) Not meeting inclusion criteria (n=150) Declined to participate (n=77)
Randomized: ITT cohort (n=368)
Allocated to treatment: Placebo (n=183) Received allocated treatment (n=179) Did not receive allocated treatment (n=4) Withdrawal of consent (n=4)
Allocated to treatment: Escitalopram (n=185) Received allocated treatment (n=182) Did not receive allocated treatment (n=3) Withdrawal of consent (n=3)
Completed the study up to Month 12 (n=175) Study termination or early withdrawal (n=4)
Completed the study up to Month 12 (n=178) Study termination or early withdrawal (n= 4)
Discontinued treatment (n= 33) Stop period: Between pre op and intervention (n= 2) Between intervention and Month 1 (n=22) Between Month 1 and Month 3 (n= 8) Between Month 3 and Month 6 (n=1)
Discontinued treatment (n=47) Stop period: Between pre op and intervention (n=14) Between intervention and Month 1 (n=22) Between Month 1 and Month 3 (n= 8) Between Month 3 and Month 6 (n=3)
Analysed: Treated Cohort (n=179) Subgroups: Patients who have a BDI Score > 3 (n=68) Patients who have a BDI Score 3 (n=106)
Analysed: Treated Cohort (n=182) Subgroups: Patients who have a BDI Score > 3 (n=74) Patients who have a BDI Score 3 (n=107)
Fig 1. Study flowchart by treatment group. (BDI Beck Depression Inventory Short Form; ITT intention to treat.)
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Table 1. Global Characteristics by Treatment Group; Treated Cohort Characteristics Demographic characteristics: Age (years) Mean SD Body mass index (kg/m2) Mean SD Sex ratio Women/men Academic level Elementary Intermediary Higher Social group (former employment) Farmers Employers and own account Workers Higher managerial and professional occupations Intermediate occupations Lower managerial and professional occupations Supervisory and technical workers Work status Active Retired Sick leave Disabled Unemployed Risk factors and preoperative characteristics Hypertension Hyperlipidemia Smoking history Overweight Family history of coronary artery disease Previous myocardial infarction Previous stroke Extracardiac arteriopathy Diabetes COPD Creatinine clearance (mL/minute) Mean SD Angina CCS class None/I/II III/IV Ejection fraction class <0.30 [0.30; 0.50] >0.50 Logistic EuroSCORE (%) Operative and postoperative characteristics One vessel disease Two vessel disease Three vessel disease Number of anastomoses Off pump surgery 24 hour bleeding (mL)
Total (N
361)
Placebo (N
179)
Escitalopram (N
182)
p Valuea
67.1 8.9
66.7 8.9
67.4 9.0
0.449
27.6 4.1
27.7 4.1
27.5 4.2
0.635
0.16
0.17
0.15
0.713
136 (42.6%) 141 (44.2%) 42 (13.2%)
79 (48.8%) 62 (38.3%) 21 (13.0%)
57 (36.3%) 79 (50.3%) 21 (13.4%)
0.063
21 37 34 43 84 125
(6.0%) (10.5%) (9.7%) (12.2%) (23.9%) (35.2%)
9 22 16 19 45 61
(5.1%) (12.5%) (9.1%) (10.8%) (25.6%) (34.5%)
12 15 18 24 39 64
(6.8%) (8.5%) (10.2%) (13.6%) (22.2%) (36.4%)
0.794
56 286 6 4 7
(15.6%) (79.7%) (1.7%) (1.1%) (1.9%)
28 141 2 3 5
(15.6%) (78.8%) (1.1%) (1.7%) (2.8%)
28 145 4 1 2
(15.6%) (80.6%) (2.2%) (0.6%) (1.1%)
0.602
233 252 37 89 131 88 24 27 126 13
(64.7%) (70.0%) (10.3%) (24.7%) (36.4%) (24.4%) (6.7%) (7.8%) (35.2%) (3.6%)
119 129 17 43 67 44 14 10 63 7
(66.5%) (72.1%) (9.5%) (24.0%) (37.4%) (24.6%) (7.9%) (5.8%) (35.2%) (3.9%)
114 123 20 46 64 44 10 17 63 6
(63.0%) (68.0%) (11.0%) (25.4%) (35.4%) (24.2%) (5.5%) (9.7%) (35.2%) (3.3%)
0.488 0.395 0.628 0.760 0.683 0.929 0.367 0.185 1.000 0.762
81.6 28.0
80.9 26.2
82.4 29.9
0.628
327 (93.7%) 22 (6.3%)
162 (93.6%) 11 (6.4%)
165 (93.8%) 11 (6.3%)
0.967
9 (2.6%) 88 (25.4%) 249 (72.0%) 3.1 2.1
5 (2.9%) 46 (26.7%) 121 (70.3%) 3.1 2.0
4 (2.3%) 42 (24.1%) 128 (73.6%) 3.1 2.2
0.790
0.904
35 (9.7%) 104 (28.8%) 208 (57.6%) 2.94 0.93 134 (37.2%) 508.3 194.5
13 (7.3%) 52 (29.1%) 104 (58.1%) 3.02 0.91 58 (32.4%) 508.0 181.3
22 (12.1%) 52 (28.6%) 104 (57.1%) 2.86 0.96 76 (42.0%) 508.7 207.2
0.121 0.920 0.854 0.115 0.060 0.971 (Continued)
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Table 1. Continued Characteristics
Total (N
Transfusions Troponin I level at hour 6 Duration of assisted ventilation (hours) a
361)
98 (27.1%) 5.885 5.211 9.11 15.99
Placebo (N
179)
46 (25.7%) 6.186 5.675 9.47 16.54
Escitalopram (N 52 (28.6%) 5.583 4.695 8.75 15.44
182)
p Valuea 0.539 0.269 0.684
Comparison between treatment groups: c2 test or Fisher exact test for categoric variables; Student t-test or Mann-Whitney test for continuous variables.
COPD ¼ chronic obstructive pulmonary disease; system for cardiac operative risk evaluation.
CCS ¼ Canadian Cardiovascular Society grading of angina pectoris;
between groups in the changes in scores from baseline were identified using repeated measure analyses of covariance, including treatment group and time as factors, time by treatment interaction and preoperative
scores as a covariate. The repeated measure pattern of the data was taken into account by means of an autoregressive correlation structure. Both time-by-treatment interactions over the 6-month period and differences
Months from Baseline 0
3
1
6
Adjusted Mean Change from Baseline in BDI Score
0.00 P-value global treatment effect = 0.015
-0.50 -1.00 -1.50 -2.00
-2.50 -3.00 -3.50
Placebo -4.00
Escitalopram
A
Months from Baseline 0
3
1
Adjusted Mean Change from Baseline in BDI Score
0.00 P-value global treatment effect = 0.002
-0.50 -1.00 -1.50 -2.00
-2.50 -3.00 -3.50 Placebo -4.00
B
Escitalopram
EuroSCORE ¼ European
6
Fig 2. Change from baseline in Beck Depression Inventory (BDI) score by period (1, 3, and 6 months) and treatment group. (A) Treated cohort; (B) Patients with a preopera tive BDI > 3. Values presented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treatment and visit as factors, treatment by visit interaction, and baseline score as covariate. A negative change shows an improvement. Error bars indicate standard errors. (* indicates p values < 0.05 for treatment group difference; : placebo; C escitalopram.)
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Fig 3. Change from baseline in Short Form (SF) 36 Physical Component Summary (PCS) score by period (1, 3, and 6 months) and treatment group; (A) Treated cohort; (B) Patients with a preoperative Beck Depression Inventory > 3. Values presented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treatment and visit as factors, treatment by visit interaction, and baseline score as covariate. A positive change shows an improvement. Error bars indicate standard errors. (* indicates p values < 0.05 for treatment group difference; : placebo; C escitalopram.)
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P-value global treatment effect = 0.947
8.00 7.00 Placebo
6.00
Escitalopram 5.00 4.00 3.00 2.00 1.00 0.00 -1.00
0
1
3
6
Months from Baseline
-2.00
-3.00 -4.00 -5.00
P-value global treatment effect = 0.111
8.00 7.00 Adjusted Mean Change from Baseline in SF-36 PCS
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Adjusted Mean Change from Baseline in SF-36 PCS
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Placebo
6.00
Escitalopram
5.00 4.00 3.00 2.00 1.00 0.00 -1.00
0
-2.00
1
3
6
Months from Baseline
-3.00 -4.00 -5.00
between treatment groups at month 1, 3, and 6 were estimated to assess the dynamic of the treatment effect through time. The same analyses were also performed over the entire 12-month follow-up period. All statistical tests were carried out at the 2-sided 5% significance level. Statistical analyses were performed using SAS version 9.2 software (SAS Institute, Cary, NC).
Results Subject Disposition and Demography In total, 595 patients were screened at the pre-surgery visit (Fig 1). Of these, 368 patients were randomized into group E (escitalopram) and group P (placebo). The treated cohort (361 patients) contained 182 patients in group E and 179 in group P. The overall compliance of study treatment intake was similar between the 2
treatment groups (group P: 96.1% 20.6%; group E: 93.9% 23.0%, p ¼ 0.219). All preoperative and operative characteristics of treated cohort patients were balanced between the 2 groups (Table 1).
Effect of Treatment on Composite and Individual Mortality and Morbidity Events By postoperative month 12, the proportions of patients with the composite endpoint of morbidity and mortality events were not different between group E and group P (110 of 182 [60%] vs 108 of 179 [60%], respectively; p ¼ 0.984). No patient died within 30 days after surgery. One patient did die in hospital. Of the 5 patients who died outside hospital, 2 died of cardiac-related causes, and 3 of noncardiac-related causes. Three patients died in each treatment group. No differences were identified between treatment groups for each of the events that defined the
CHOCRON ET AL ANTIDEPRESSANT THERAPY IN CABG PATIENTS
composite endpoint (data not shown). Acquired atrial fibrillation was the most frequently reported event (29% in group E, 34% in group P).
Effect of Treatment on Depression and Quality of Life Self Assessments BDI. The preoperative (baseline) mean BDI scores in all patients were 3.7 in both groups (p ¼ 0.929). During the postoperative 6-month treatment period, mean decreases in BDI scores from baseline were greater overall in group E than in group P (p ¼ 0.015), suggesting a better improvement in group E than in group P during this period (Fig 2A). Also at months 1 and 6, the adjusted mean changes in BDI scores from baseline were lower in group E than in group P (p ¼ 0.049, and p ¼ 0.021, respectively) suggesting that in group E compared with
Adjusted Mean Change from Baseline in SF-36 MCS
14.00
group P, depression status is notably better at months 1 and 6, and that the postoperative improvement in depression symptoms is more rapid. SF-36. No differences were observed in preoperative (baseline) mean scores between groups for the SF-36 individual health domain scores or for the SF-36 MCS or PCS scores in all patients. In each group, mean SF-36 component or summary scores were typically higher than the respective mean baseline scores from month 3 to month 6 (Figs 3A; 4A; 5A). Over the postoperative treatment period, the mean increases in scores from baseline were greater overall in group E than in group P for 2 SF-36 domains; mental health (p ¼ 0.004) and social functioning (p ¼ 0.028), and for the MCS score (p ¼ 0.014). At month 1 and 6, the mean changes in mental health and MCS scores from baseline were higher in
Fig 4. Change from baseline in Short form (SF) 36 Mental Component Summary (MCS) score by period (1, 3, and 6 months) and treatment group; (A) treated cohort and (B) patients with a preoperative Beck Depression Inventory > 3. Values presented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treat ment and visit as factors, treatment by visit interaction and baseline score as covariate. A positive change shows an improvement. Error bars indicate standard errors. (* indi cates p values < 0.05 for treatment group difference; : placebo; C escitalopram.)
P-value global treatment effect = 0.014
12.00
10.00
8.00
6.00
4.00 Placebo
2.00
Escitalopram 0.00 0
A
1
Adjusted Mean Change from Baseline in SF-36 MCS
14.00
3 Months from Baseline
6
P-value global treatment effect = 0.005
12.00
10.00
8.00
6.00
4.00 Placebo 2.00
Escitalopram
0.00
B
0
1
3 Months from Baseline
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Fig 5. Change from baseline in Short Form (SF) 36 domain scores by period (1, 3, and 6 months) and treatment group; (A) treated cohort and (B) patients with a preoperative Beck Depression Inventory > 3. Values pre sented are adjusted mean change in score from baseline from a repeated measure analysis of covariance on changes in scores with treatment and visit as factors, treatment by visit interaction, and baseline score as covariate. A positive change shows an improvement. Error bars indicate standard errors. (* indicates p values < 0.05 and ** indicates p values < 0.01 for treatment group difference.)
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30 25 0.028
20
0.004
15 10 5 0 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 -5 -10 -15 -20
Physical Functioning
RolePhysical
Bodily Pain
General Health Placebo
Vitality
Social Functioning
RoleEmotional
Mental Health
Escitalopram
30
Adjusted Mean Change from Baseline in SF-36 Domain Scores
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Adjusted Mean Change from Baseline in SF-36 Domain Scores
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0.013 25
0.002
0.011
20
0.026
15 10 5 0 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 M1 M3 M6 -5 -10 -15 -20
Physical Functioning
RolePhysical
group E than in group P (p < 0.05). These data suggest a better improvement in these health domains in group E than in group P during this period (Figs 4A; 5A).
All Scores in BDI Greater Than 3 Subset A total of 142 patients out of 361 (39%) had preoperative BDI scores greater than 3 (Fig 1). In this subset, in groups E and P, the preoperative mean BDI scores were 6.6 and 7.2, respectively, and not different (p ¼ 0.315). In each group, mean BDI scores were lower than the respective mean baseline scores from month 1 (p < 0.05) (Fig 2B). Over the postoperative 6-month treatment period, the mean decreases in BDI scores from baseline were greater overall in group E than in group P (p ¼ 0.002) (Fig 2B). At month 1 and 6, the mean changes in BDI scores were lower in group E than in group P (p ¼ 0.017 and
Bodily Pain
General Health Placebo
Vitality
Social Functioning
RoleEmotional
Mental Health
Escitalopram
p ¼ 0.011, respectively) (Fig 2B). No differences were observed in preoperative (baseline) SF-36 mean scores between groups in the BDI greater than 3 subset. However, over the postoperative 6-month treatment period, the mean increases in scores from baseline were greater overall in group E than in group P for 4 SF-36 domains; vitality (p ¼ 0.011), mental health (p ¼ 0.002), social functioning (p ¼ 0.013), and bodily pain (p ¼ 0.026) (Fig 5B), and for the MCS score (p ¼ 0.005) (Fig 4B), but not for the PCS score (p ¼ 0.111) (Fig 3B). At months 1 and 6 the mean changes in SF-36 MCS scores from baseline were higher in group E than in group P (p ¼ 0.008 and p ¼ 0.019, respectively) (Fig 4B). In contrast, in the subset of patients with a preoperative BDI score 3 or less, there were no significant differences between groups in changes in BDI scores or for any of the
changes in SF-36 domain or summary scores (data not shown). Therefore, this suggested that improvements in mental health and bodily pain outcomes mainly occurred in the BDI greater than 3 subset.
Harms Side effects were reported by 23 (12.6%) patients in group E and 8 patients (4.5%) in group P (p ¼ 0.006). In group E, patients reported diarrhea (n ¼ 7), constipation (n ¼ 3), nausea (n ¼ 3), shivering (n ¼ 3), somnolence (n ¼ 2), tingling of extremities (n ¼ 2), dizziness (n ¼ 2), and attention concentration difficulty (n ¼ 1). In group P, patients reported nausea (n ¼ 1), constipation (n ¼ 2), diarrhea (n ¼ 1), sleep disorder (n ¼ 1), heartburn (n ¼ 2), and aggravated anxiety (n ¼ 1). All these side effects were transient. Of the 23 patients in group E, 4 stopped their medication. Of the 8 patients in group P, 2 stopped their medication. No other serious side effects were reported.
Comment Antidepressant treatment of major depressive disorder usually takes 2 to 4 weeks before any significant improvement appears [12]. This was checked by the psychiatrist consultation during postoperative hospitalization. Once a person positively responds to an antidepressant, this depression treatment should be continued for 4 to 9 months, according to the American College of Physicians guidelines [12]; we therefore chose to treat the patients during 6 months. The escitalopram treatment regime had no effect on the composite measure of morbidity and mortality events after CABG surgery, or on frequency of these individual morbidity and mortality events in the 12-month postoperative period. However, escitalopram in this study improved depression status and mental health aspects of quality of life during the 6-month postoperative treatment period, principally in a subset of patients who were at least mildly depressed (BDI > 3) at the time of the preoperative visit. In patients treated with escitalopram, higher improvements were observed by postoperative month 1, suggesting that their depression symptoms and mental health improved more rapidly than those of placebo patients. Also, in the BDI greater than 3 subset, escitalopram ameliorated the sensation of bodily pain during treatment. No unexpected safety concerns were identified with escitalopram treatment [13]. No significant differences were identified at month 12 between changes in scores from baseline in the analysis of the entire treated cohort or the BDI greater than 3 subset, suggesting that the better improvements in depression status, mental health, and bodily pain outcomes subsided after escitalopram treatment ended soon after month 6 (data not shown). This study differs from other examinations of SSRI treatment in cardiac patients in that it has used a randomized design with a placebo control group and systematic follow-up to assess physical and mental health. The SSRI treatment of depressed cardiac patients has been
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typically examined in observational studies suggesting that treatment reduced mortality and morbidity. Therefore, the observation in this study that antidepressant treatment had no effect on morbidity and mortality suggests that if depression is a predictor of worse postoperative morbidity and mortality then an underlying factor may affect mental health together with these physical outcomes. However, no such factor was identified in this study even though a large array of demographic and baseline characteristics were analyzed. The SSRIs have a better safety profile with regard to the cardiovascular system [14] than tricyclic agents and monoamine oxidase inhibitors [15]. There was no evidence that escitalopram treatment increased bleeding or in-hospital mortality, in line with what was observed in another study [13]. Although there was a higher frequency of side effects in group E compared with group P unrelated to the composite endpoints, there was no evidence from the SF-36 self-assessments of relatively worse physical health outcomes in group E compared with group P. The prevalence of preoperative depression identified in this study (39% with BDI > 3) is in line with estimates made elsewhere for patients scheduled for heart surgery; such as 27% to 47% [1, 3]. Although the escitalopram therapy has no effect on postoperative morbidity or mortality up to 1 year after CABG, this study suggested that SSRI antidepressant therapy provided faster improvements of mental health aspects of quality of life and reduced postoperative pain in patients who are at least mildly depressed before surgery. Depressed patients were easily identified with the BDI questionnaire at the preoperative visit. Moreover, the beneficial effects of escitalopram were principally observed during treatment, suggesting that the patient’s depression should be reevaluated regularly to assess the appropriate dose and duration. Subject to contraindications, we recommend antidepressant therapy in surgical coronary revascularization patients with a preoperative BDI greater than 3. This study was funded by H. Lundbeck A/S, Copenhagen, Denmark; MOTIV CABG study. We thank, Sylvie di Nicola (Inferential) for the statistical anal yses, Matthew Morgan (MG Science Communications) for scientific writing and editorial support, and Gaye Siliman for the data management. ClinicalTrials.gov number, NCT00243477 (http://clinicaltrials.gov/ct2/show/NCT00243477).
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