Myocardial Ischemia
Conditions
Keywords
ischemic heart disease, mental stress-induced myocardial ischemia, escitalopram
Brief summary
Depression is commonly seen in patients with cardiovascular disorders. In recent studies it has been shown that mild to moderate depression symptoms were associated with increased likelihood of mental stress-induced myocardial ischemia (MSIMI), which is a risk factor of poor cardiac outcome. In this project, the investigators aim to assess the treatment of mental stress-induced myocardial ischemia in ischemic heart disease patients with mild to moderate depressive symptoms. This study is a six-week double-blind placebo controlled study to examine the effects of escitalopram on mental stress-induced myocardial ischemia. This study will look to show that patients with ischemic heart disease who are treated with escitalopram will exhibit a significant improvement of MSIMI at the end of week 6 compared to patients receiving placebo.
Detailed description
The goals of this project are to investigate the response of mental stress-induced myocardial ischemia (MSIMI) to escitalopram, a selective serotonin reuptake inhibitor (SSRI); to determine whether MSIMI will be reduced by the treatment, and whether the modification of MSIMI is related to improvement of depression symptoms, and/or the reduction of platelet aggregation, and/or the reduction of cardiovascular reactivity. This is a randomized study using escitalopram versus placebo for stable ischemic heart disease patients with MSIMI. This study will also explore the role of platelet activity in occurrence with MSIMI and other characteristics of MSIMI, such as systolic and diastolic function of the left ventricle during mental stress testing as compared to exercise testing. The stress testing will be conducted at the Duke Cardiology Diagnostic Unit Laboratory. Following a 20-minute calibration-rest period, participants will be asked to complete a series of 3 mental stress tasks. There are 3 mental stress tasks to be used for this study, i.e., (1) Mental arithmetic: during this test, patients will be asked to perform a series of serial subtractions beginning at a given number which will be different for each repeated test and will be chosen by the tester from a fixed list of various numbers, with encouragement to perform calculations as quickly as possible; (2) Public speaking with anger recall: during this test, patients will be asked to give a speech on a recent situation in which they experienced anger to an audience of observers (two to three) after 1 minute of preparation. Prior to the speech, subjects are told that their speech will be evaluated on their description of the situation, as to what happened, what they thought, felt, what they did, and what happened as a result. If they run out of things to say, the research tech will prompt them with questions to elicit more content until the three minutes are up; (3) Mirror trace: during this test, patients will be asked to outline, as quickly as possible, a star from its reflection in a mirror. Each task will last 3 minutes and there will be a 6-minute rest period between tasks.
Interventions
DRUGEscitalopram
Dosage will range from 5 mg to 20 mg once a day for the duration of the study (6 weeks). Tablets are in 5 mg or 10 mg form, depending upon the dosage the patient is prescribed.
DRUGPlacebo
Placebo dosage will range from 5 mg to 20 mg once a day for the duration of the study (6 weeks). Tablets are in 5 mg or 10 mg form, depending upon the dosage the patient is prescribed.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Age 21 or greater, less than 90 * Stable ischemic heart disease
Exclusion criteria
* Recent myocardial infarction, coronary artery bypass graft surgery, or other revascularization procedures (less than 3 months ago) * Left ventricular ejection fraction(LVEF) \< 15% measured by echocardiography, radionuclide ventriculography (RNV), or cardiac catheterization * Life threatening arrhythmia or arrhythmia interrupting the interpretation of ischemia * Unable to withdraw from anti-anginal medications during ischemic assessment phase * Unable to perform exercise testing * Pregnancy * Current or previous history of bipolar disorder, cyclothymia, schizophrenia, schizoaffective or schizophreniform disorder, or other psychotic disorders * Active suicidal ideation * Current substance abuse or history of substance abuse in the previous 6 months * Significant cardiac, pulmonary, metabolic, renal, hepatic disease, or malignancy, interfering with patient's participation in this study * Seizure (history and/or present) with/without treatment * Currently taking antidepressants that cannot be discontinued
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Absence of Mental Stress-induced Myocardial Ischemia (MSIMI) During the 3 Mental Stressors | Week 6 | MSIMI is defined by the following: compared to rest, 1) any development of new abnormal wall motion; 2) reduction of LVEF 8% and/or; 3) deviation (depression or elevation) of ST-segment of ECG in 2 or more leads lasting for 3 consecutive beats, occurring during at least one of the 3 mental stress tasks. |
| Percentage of Participants With Overall Mental Stress-induced Myocardial Ischemia (MSIMI) | week 6 | MSIMI is defined by the following: compared to rest, 1) any development of new abnormal wall motion; 2) reduction of LVEF 8% and/or; 3) deviation (depression or elevation) of ST-segment of ECG in 2 or more leads lasting for 3 consecutive beats, occurring during at least one of the 3 mental stress tasks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mental Stress Induced Change of Diastolic Blood Pressure | Baseline, week 6 | Blood pressure will be measured the last 3 minutes of the 20 minute calibration period (resting), every minute during the 3 minutes mental stress testing, the last 3 minutes of the 6 minute rest periods between mental stress testing, and every minute during and after the physical stress testing with an automatic oscillometric blood pressure monitor (Quinton Electronics). Mental Stress Induced Change of Diastolic Blood Pressure will be calculated by taking the mean of the mental stress Diastolic blood pressure measurements minus the resting Diastolic blood pressure. End point values adjusted for baseline values age and sex. |
| Percentage of Participants With Adverse Events | Baseline to week 6 | — |
| Beck Depression Inventory | 6 week | The Beck Depression Inventory II (BDI-II) is a 21 question, self-administered measure of depressive symptoms. Score range, 0 to 63 (higher score=greater severity of depressive symptoms). End point values adjusted for baseline values age and sex. |
| Mental Stress Induced Change in Heart Rate | baseline, 6 weeks | A standard 12-lead Electrocardiograph (ECG) will be recorded at 1-minute intervals during the last 3 minutes of each rest period, the 3 minutes of the mental stress testing, and during exercise testing. Heart rate will be determined from the ECGs. Mental Stress Induced Change in heart rate will be calculated by taking the mean of the mental stress heart rate measurements minus the resting heart rate measurements. End point values adjusted for baseline values age and sex. |
| 5HTT, Serotonin Transporter Protein | week 6 | End point values adjusted for baseline values age and sex. |
| Platelet Serotonin Binding Affinity Kd_100 | 6 weeks | End point values adjusted for baseline values age and sex. |
| Cook-Medley Hostility (Ho) Scale | 6 weeks | Score ranges: hostility, 0 to 27 (higher score=greater levels of hostility)/ End point values adjusted for baseline values age and sex. |
| Cook-Medley Hostility (Ho) Hostile Affect Sub-scale | 6 weeks | hostile affect, 0 to 5 (higher score=greater levels of hostile affect). End point values adjusted for baseline values age and sex. |
| Spielberger State-Trait Anxiety Inventory Scales (STAI) | 6 weeks | STAI measures anxiety. The questionnaire asks the patients how they feel and allows them to respond on a frequency scale that ranges from 1(not at all) to 4(almost always/very much so). Scores range from 20-80 and the higher the score the greater the anxiety level. This applies to both the Trait and State scales. End point values adjusted for baseline values age and sex. |
| Exercise Stressed-induced Myocardial Ischemia (ESIMI) | 6 week | End point values adjusted for baseline values age and sex. |
| Perceived Stress Scale | 6 weeks | Score range, 10 to 50 (higher score = greater levels of perceived stress). End point values adjusted for baseline values age and sex. |
| Mental Stress Induced Change of Systolic Blood Pressure | Baseline, week 6 | Blood pressure will be measured the last 3 minutes of the 20 minute calibration period (resting), every minute during the 3 minutes mental stress testing, the last 3 minutes of the 6 minute rest periods between mental stress testing, and every minute during and after the physical stress testing with an automatic oscillometric blood pressure monitor (Quinton Electronics). Mental Stress Induced Change of Systolic Blood Pressure will be calculated by taking the mean of the mental stress systolic blood pressure measurements minus the resting Systolic blood pressure. End point values adjusted for baseline values age and sex. |
Countries
United States
Participant flow
Recruitment details
We screened all patients with Coronary Heart Disease (CHD) who visited Duke cardiology clinics. Patients 21 years or older were eligible to participate if they had CHD, as documented by angiographic findings of coronary artery stenosis of 70% or greater, history of MI, or history of cardiac revascularization.
Pre-assignment details
25527 underwent initial screening. 22833 excluded due to reasons including no CHD, atrial fibrillation/arrhythmia, psychiatric disorder, and LVEF less than 30%. 2294 did not provide consent. 65 excluded due to medical conditions. 203 excluded due to no MSIMI or inability to undergo mental stress testing. 5 more declined to undergo randomization.
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram Escitalopram: Dosage will range from 5 mg to 20 mg once a day for the duration of the study (6 weeks). Tablets are in 5 mg or 10 mg form, depending upon the dosage the patient is prescribed. | 64 |
| Placebo Placebo: Placebo dosage will range from 5 mg to 20 mg once a day for the duration of the study (6 weeks). Tablets are in 5 mg or 10 mg form, depending upon the dosage the patient is prescribed. | 63 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Did not receive medication (declined) | 2 | 5 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Escitalopram | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 9.3 | 61.4 years STANDARD_DEVIATION 11.5 | 64.0 years STANDARD_DEVIATION 10.7 |
| History of Depression | 11 participants | 10 participants | 21 participants |
| Sex: Female, Male Female | 11 Participants | 15 Participants | 26 Participants |
| Sex: Female, Male Male | 53 Participants | 48 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 64 | 28 / 63 |
| serious Total, serious adverse events | 3 / 64 | 1 / 63 |
Outcome results
Primary
Percentage of Participants With an Absence of Mental Stress-induced Myocardial Ischemia (MSIMI) During the 3 Mental Stressors
MSIMI is defined by the following: compared to rest, 1) any development of new abnormal wall motion; 2) reduction of LVEF 8% and/or; 3) deviation (depression or elevation) of ST-segment of ECG in 2 or more leads lasting for 3 consecutive beats, occurring during at least one of the 3 mental stress tasks.
Time frame: Week 6
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Percentage of Participants With an Absence of Mental Stress-induced Myocardial Ischemia (MSIMI) During the 3 Mental Stressors | 34.2 percentage of participants |
| Placebo | Percentage of Participants With an Absence of Mental Stress-induced Myocardial Ischemia (MSIMI) During the 3 Mental Stressors | 17.5 percentage of participants |
Primary
Percentage of Participants With Overall Mental Stress-induced Myocardial Ischemia (MSIMI)
MSIMI is defined by the following: compared to rest, 1) any development of new abnormal wall motion; 2) reduction of LVEF 8% and/or; 3) deviation (depression or elevation) of ST-segment of ECG in 2 or more leads lasting for 3 consecutive beats, occurring during at least one of the 3 mental stress tasks.
Time frame: week 6
Population: Subjects who completed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Percentage of Participants With Overall Mental Stress-induced Myocardial Ischemia (MSIMI) | 66.1 percentage of participants |
| Placebo | Percentage of Participants With Overall Mental Stress-induced Myocardial Ischemia (MSIMI) | 83.9 percentage of participants |
Secondary
5HTT, Serotonin Transporter Protein
End point values adjusted for baseline values age and sex.
Time frame: week 6
Population: ITT, 29 subjects excluded from analysis due to missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | 5HTT, Serotonin Transporter Protein | 139.7 fmol/mg |
| Placebo | 5HTT, Serotonin Transporter Protein | 160.4 fmol/mg |
Secondary
Beck Depression Inventory
The Beck Depression Inventory II (BDI-II) is a 21 question, self-administered measure of depressive symptoms. Score range, 0 to 63 (higher score=greater severity of depressive symptoms). End point values adjusted for baseline values age and sex.
Time frame: 6 week
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Beck Depression Inventory | 7.4 units on a scale |
| Placebo | Beck Depression Inventory | 7.0 units on a scale |
Secondary
Cook-Medley Hostility (Ho) Hostile Affect Sub-scale
hostile affect, 0 to 5 (higher score=greater levels of hostile affect). End point values adjusted for baseline values age and sex.
Time frame: 6 weeks
Population: ITT, 1 subject excluded from analysis due to missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Cook-Medley Hostility (Ho) Hostile Affect Sub-scale | 1.6 units on a scale |
| Placebo | Cook-Medley Hostility (Ho) Hostile Affect Sub-scale | 1.8 units on a scale |
Secondary
Cook-Medley Hostility (Ho) Scale
Score ranges: hostility, 0 to 27 (higher score=greater levels of hostility)/ End point values adjusted for baseline values age and sex.
Time frame: 6 weeks
Population: ITT, 1 subject excluded from analysis due to missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Cook-Medley Hostility (Ho) Scale | 9.9 units on a scale |
| Placebo | Cook-Medley Hostility (Ho) Scale | 10.3 units on a scale |
Secondary
Exercise Stressed-induced Myocardial Ischemia (ESIMI)
End point values adjusted for baseline values age and sex.
Time frame: 6 week
Population: ITT, 7 subject excluded from analysis due to missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Exercise Stressed-induced Myocardial Ischemia (ESIMI) | 45.8 percentage of change |
| Placebo | Exercise Stressed-induced Myocardial Ischemia (ESIMI) | 52.5 percentage of change |
Secondary
Mental Stress Induced Change in Heart Rate
A standard 12-lead Electrocardiograph (ECG) will be recorded at 1-minute intervals during the last 3 minutes of each rest period, the 3 minutes of the mental stress testing, and during exercise testing. Heart rate will be determined from the ECGs. Mental Stress Induced Change in heart rate will be calculated by taking the mean of the mental stress heart rate measurements minus the resting heart rate measurements. End point values adjusted for baseline values age and sex.
Time frame: baseline, 6 weeks
Population: ITT, 10 subjects excluded from analysis due to missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Mental Stress Induced Change in Heart Rate | 6.34 beats/minute |
| Placebo | Mental Stress Induced Change in Heart Rate | 9.1 beats/minute |
Secondary
Mental Stress Induced Change of Diastolic Blood Pressure
Blood pressure will be measured the last 3 minutes of the 20 minute calibration period (resting), every minute during the 3 minutes mental stress testing, the last 3 minutes of the 6 minute rest periods between mental stress testing, and every minute during and after the physical stress testing with an automatic oscillometric blood pressure monitor (Quinton Electronics). Mental Stress Induced Change of Diastolic Blood Pressure will be calculated by taking the mean of the mental stress Diastolic blood pressure measurements minus the resting Diastolic blood pressure. End point values adjusted for baseline values age and sex.
Time frame: Baseline, week 6
Population: ITT, 9 subjects excluded from the analysis due to missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Mental Stress Induced Change of Diastolic Blood Pressure | 11.4 mm Hg |
| Placebo | Mental Stress Induced Change of Diastolic Blood Pressure | 12.2 mm Hg |
Secondary
Mental Stress Induced Change of Systolic Blood Pressure
Blood pressure will be measured the last 3 minutes of the 20 minute calibration period (resting), every minute during the 3 minutes mental stress testing, the last 3 minutes of the 6 minute rest periods between mental stress testing, and every minute during and after the physical stress testing with an automatic oscillometric blood pressure monitor (Quinton Electronics). Mental Stress Induced Change of Systolic Blood Pressure will be calculated by taking the mean of the mental stress systolic blood pressure measurements minus the resting Systolic blood pressure. End point values adjusted for baseline values age and sex.
Time frame: Baseline, week 6
Population: ITT, 9 subjects excluded from analysis due to missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Mental Stress Induced Change of Systolic Blood Pressure | 19.3 mm Hg |
| Placebo | Mental Stress Induced Change of Systolic Blood Pressure | 23.6 mm Hg |
Secondary
Perceived Stress Scale
Score range, 10 to 50 (higher score = greater levels of perceived stress). End point values adjusted for baseline values age and sex.
Time frame: 6 weeks
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Perceived Stress Scale | 21.4 units on a scale |
| Placebo | Perceived Stress Scale | 21.8 units on a scale |
Secondary
Percentage of Participants With Adverse Events
Time frame: Baseline to week 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escitalopram | Percentage of Participants With Adverse Events | 71.9 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events | 44.4 percentage of participants |
Secondary
Platelet Serotonin Binding Affinity Kd_100
End point values adjusted for baseline values age and sex.
Time frame: 6 weeks
Population: ITT, 27 subjects were excluded from analysis due to missing data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Escitalopram | Platelet Serotonin Binding Affinity Kd_100 | 4202.4 nM |
| Placebo | Platelet Serotonin Binding Affinity Kd_100 | 210.1 nM |
Secondary
Spielberger State-Trait Anxiety Inventory Scales (STAI)
STAI measures anxiety. The questionnaire asks the patients how they feel and allows them to respond on a frequency scale that ranges from 1(not at all) to 4(almost always/very much so). Scores range from 20-80 and the higher the score the greater the anxiety level. This applies to both the Trait and State scales. End point values adjusted for baseline values age and sex.
Time frame: 6 weeks
Population: ITT
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Escitalopram | Spielberger State-Trait Anxiety Inventory Scales (STAI) | Trait | 31.2 units on a scale |
| Escitalopram | Spielberger State-Trait Anxiety Inventory Scales (STAI) | State | 27.9 units on a scale |
| Placebo | Spielberger State-Trait Anxiety Inventory Scales (STAI) | Trait | 32.0 units on a scale |
| Placebo | Spielberger State-Trait Anxiety Inventory Scales (STAI) | State | 29.5 units on a scale |