Exercise and Pharmacotherapy for Anxiety in Cardiac Patients

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02516332
• Collaborator: (none)
• Enrollment: 128
• Location: 1
• Arms: 3
• Duration (Months): 65
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

Coronary heart disease (CHD) is the leading cause of death in the United States; more than 600,000 Americans suffer a fatal cardiac event each year. Traditional CHD risk factors such as high blood pressure, smoking, and elevated cholesterol do not fully account for the timing and occurrence of CHD events and individuals with elevated levels of anxiety appear to have a greater risk of cardiovascular events. The present study will examine the impact of aerobic exercise and Lexapro in the treatment of anxiety and cardiovascular biomarkers among individuals with CHD.

Condition or Disease	Intervention/Treatment	Phase
Anxiety; Cardiovascular Disease	Drug: Lexapro; Drug: Placebo; Behavioral: Supervised Aerobic Exercise	N/A

Detailed Description

Coronary heart disease (CHD) is the leading cause of death in the United States; more than 600,000 Americans suffer a fatal cardiac event each year. Traditional CHD risk factors such as high blood pressure, smoking, and elevated cholesterol do not fully account for the timing and occurrence of CHD events. The term "cardiovascular vulnerable patient" has been used to describe patients susceptible to acute coronary events based upon plaque, blood, or myocardial characteristics. Psychosocial factors also have been shown to be associated with increased adverse health outcomes and increased cardiovascular vulnerability. For example, clinical depression and elevated depressive symptoms are associated with increased morbidity and mortality, and as a result, the American Heart Association has recommended that clinicians should routinely assess depression in CHD patients. Although much research and clinical recommendations have focused on depression, the significance of anxiety has been largely ignored, despite the fact that anxiety disorders are as prevalent as depression in the general population and are associated with similar levels of disability.

Despite the prevalence and prognostic significance of anxiety in CHD populations, there have been few randomized clinical trials (RCTs) specifically targeting anxious CHD patients. Anxiolytic medications, including selective serotonin reuptake inhibitors (SSRIs), have been shown to be effective in treating anxiety. SSRIs have been evaluated for the treatment of clinical depression in cardiac patients, with equivocal results. Surprisingly, to our knowledge, there have been no RCTs examining the efficacy of medications for treating anxiety in CHD patients. Moreover, because many cardiac patients are reluctant to take additional medications and psychotropic medications may not be effective for everyone or may produce unwanted side effects, there continue to be a need to identify alternative approaches for treating anxiety in cardiac patients. The investigators believe that exercise may be one such approach.

The purpose of this study is to evaluate the following hypotheses in a population of CHD patients with elevated symptoms of anxiety. The present study will examine the impact of a 3-month intervention of either exercise, Lexapro, or placebo on anxiety symptoms and CHD biomarkers among individuals with cardiac disease and elevated anxiety. The investigators hypothesize that: (1) Both exercise training and medication will reduce anxiety symptoms to a greater extent than placebo; (2) Exercise training will improve CHD biomarkers of risk including autonomic regulation, vascular endothelial function, and inflammation more than either medication or placebo; and (3) Improvements in CHD biomarkers will be mediated by reductions in symptoms of anxiety. The investigators also will explore potential moderators of treatment (e.g., anxiety diagnoses, CHD severity) as well as the longer-term benefits of treatment by documenting medical events and health care costs over a follow-up period of up to 4 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Exercise and Pharmacotherapy for Anxiety in Cardiac Patients
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: May 1, 2020
• Actual Study Completion Date: May 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Supervised Aerobic Exercise Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges.	Behavioral: Supervised Aerobic Exercise
Experimental: Lexapro Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement.	Drug: Lexapro
Placebo Comparator: Placebo Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro.	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change in Hospital Anxiety and Depression Scale (HADS), Anxiety [Baseline, 3 months]

   The Hospital Anxiety and Depression Scale, Anxiety, is a 7-item subscale with scores ranging from 0-21, with higher scores indicating more anxiety.

Secondary Outcome Measures

1. Change in Heart Rate Variability, SDNN (Msec) [Baseline, 3 months]

   To quantify heart rate variability (HRV), an electrocardiogram was recorded for 24-hours using the 3-channel DigiTrak XT Holter recorder (Philips Healthcare, Andover, Massachusetts). Electrocardiographic data were downloaded and edited using the Philips Zymed Holter analysis software (2010 Plus/1810 series) and HRV was estimated from the standard deviation of the normal-to-normal R-R intervals (SDNN).

2. Change in Baroreflex Sensitivity, ms/mm Hg [Baseline, 3 months]

   To assess baroreflex sensitivity (BRS), beat-by-beat systolic blood pressure (SBP) and heart rate (HR) were collected using the Nexfin noninvasive BP monitor (Bmeye, Amsterdam, Netherlands). BRS was estimated from the magnitude of the transfer function relating R-R interval oscillations to SBP oscillations across the 0.07 to 0.1299 Hz, or low frequency band.

3. Change in Vascular Endothelial Function, Percentage of Dilation [Baseline, 3 months]

   Endothelial function, assessed by Flow-Mediated Dilation (FMD), was determined from longitudinal B-mode ultrasound images of the brachial artery. Images were obtained using an Acuson (Mountain View, California) Aspen ultrasound platform with an 11-MHz linear-array transducer after 10 min of supine relaxation and during reactive hyperemia, induced by the inflation of a forearm pneumatic occlusion cuff to suprasystolic pressure (about 200 mm Hg) and subsequent deflation after 5 min. FMD was defined as the maximum percentage change in arterial diameter relative to resting baseline from 10 to 120 s after deflation of the occlusion cuff.

4. Change in Inflammation (C-Reactive Protein, ug/ml) [Baseline, 3 months]

   High-sensitivity C-reactive protein was quantified by ELISA (LabCorp). Values >10 mg/L were truncated at 10 to account for acute inflammatory processes that may have skewed the distribution of this blood marker.

5. Change in Urinary Catecholamines (Epinephrine and Norepinephrine, Unit-weighted Z-score) [Baseline, 3 months]

   Urinary catecholamines, an index of sympathetic nervous system (SNS) activity, served as a biomarker of anxiety. Urinary concentrations of epinephrine (EPI) and norepinephrine (NE) were determined by high-pressure liquid chromatography (HPLC) with electrochemical detection (LabCorp). A composite 24-hr catecholamines z-score is presented. The z-score is the raw score minus the population mean, divided by the population standard deviation. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.

6. Change in Lipids - Total Cholesterol, LDL (Low-density Lipoprotein), and HDL (High-density Lipoprotein); mg/dL [Baseline, 3 months]

   Lipids were obtained from fasting blood samples and assays were measured enzymatically (LabCorp).

Other Outcome Measures

1. Change in Hospital Anxiety and Depression Scale, Total Score [9 months, 15 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women with documented CHD (i.e., a prior MI, coronary revascularization procedure, or >70% stenosis in at least one coronary artery)

• Age > 39 years

• Patients also will have an anxiety symptom severity score of at least 8 on the Hospital Anxiety and Depression-Anxiety scale (HADS-A) or a DSM-5 diagnosis of an Anxiety Disorder, such as General Anxiety, Social Anxiety, or Panic Disorder.

The study team plans to actively recruit women and minorities, with at least 50% women and 25% minorities.

Exclusion Criteria:

• An MI or coronary revascularization procedure (i.e., CABG or percutaneous coronary intervention) within the last 3 months

• Unstable angina

• Severe left ventricular dysfunction (ejection fraction <30%) or decompensated heart failure

• Unrevascularized left main coronary artery stenosis >50%

• Complete Pacemaker dependence

• Resting BP >200/120 mm Hg

• Conditions that would preclude randomization to either the drug (e.g., prolonged QT interval, known allergy to or intolerance of escitalopram) or exercise (e.g., musculoskeletal problems or abnormal cardiac response to exercise)

• Patients with a primary psychiatric diagnosis other than Anxiety Disorder will be excluded, including patients with PTSD, OCD, or any of the following DSM-5 diagnoses:

1. Dementia, delirium;

2. Schizophrenia, Schizoaffective, or other psychotic disorder;

3. Psychotic features including any delusions or hallucinations; or

4. Current alcohol or other substance abuse disorder.

• Similarly, patients who pose an acute suicide or homicide risk or who, during the course of the study, would likely require treatment with additional psychopharmacologic agents will not be enrolled.

• Patients will also be excluded if they are taking other medications that would preclude assignment to either drug or exercise conditions (e.g., clonidine, dicumarol, anticonvulsants, and MAO inhibitors) or are taking herbal supplements with purported mood effects (e.g., St. John's Wort, valerian, ginkgo).

• Patients already engaged in regular exercise (at least 30 minutes >1x/week) will not be enrolled.

• Finally, pregnant women will be excluded from participation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 16, 2018

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02516332
• Other Study ID Numbers: Pro00064329
• First Posted: Aug 5, 2015
• Last Update Posted: Jun 11, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Cardiovascular Diseases; Anxiety Disorders; Citalopram

Study Results

Participant Flow

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Period Title: Overall Study
STARTED	52	53	23
COMPLETED	50	52	21
NOT COMPLETED	2	1	2

Baseline Characteristics

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo	Total
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo	Total of all reporting groups
Overall Participants	52	53	23	128
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.2 (10.1)	63.9 (8.6)	65.2 (10.8)	64.6 (9.6)
Sex: Female, Male (Count of Participants)
Female	17 32.7%	14 26.4%	6 26.1%	37 28.9%
Male	35 67.3%	39 73.6%	17 73.9%	91 71.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.9%	0 0%	0 0%	1 0.8%
Not Hispanic or Latino	51 98.1%	53 100%	23 100%	127 99.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.9%	4 7.5%	0 0%	5 3.9%
Asian	2 3.8%	0 0%	0 0%	2 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	8 15.4%	12 22.6%	5 21.7%	25 19.5%
White	40 76.9%	36 67.9%	18 78.3%	94 73.4%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.9%	1 1.9%	0 0%	2 1.6%
Region of Enrollment (Count of Participants)
United States	52 100%	53 100%	23 100%	128 100%

Outcome Measures

1. Primary Outcome

Title	Change in Hospital Anxiety and Depression Scale (HADS), Anxiety
Description	The Hospital Anxiety and Depression Scale, Anxiety, is a 7-item subscale with scores ranging from 0-21, with higher scores indicating more anxiety.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Measure Participants	52	53	23
Least Squares Mean (95% Confidence Interval) [score on a scale]	-3.9	-5.7	-3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supervised Aerobic Exercise, Lexapro, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supervised Aerobic Exercise, Lexapro, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Change in Heart Rate Variability, SDNN (Msec)
Description	To quantify heart rate variability (HRV), an electrocardiogram was recorded for 24-hours using the 3-channel DigiTrak XT Holter recorder (Philips Healthcare, Andover, Massachusetts). Electrocardiographic data were downloaded and edited using the Philips Zymed Holter analysis software (2010 Plus/1810 series) and HRV was estimated from the standard deviation of the normal-to-normal R-R intervals (SDNN).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Measure Participants	52	53	23
Least Squares Mean (95% Confidence Interval) [msec]	-0.3	-8.7	-1.1

3. Secondary Outcome

Title	Change in Baroreflex Sensitivity, ms/mm Hg
Description	To assess baroreflex sensitivity (BRS), beat-by-beat systolic blood pressure (SBP) and heart rate (HR) were collected using the Nexfin noninvasive BP monitor (Bmeye, Amsterdam, Netherlands). BRS was estimated from the magnitude of the transfer function relating R-R interval oscillations to SBP oscillations across the 0.07 to 0.1299 Hz, or low frequency band.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Measure Participants	52	53	23
Least Squares Mean (95% Confidence Interval) [ms/mm Hg]	1.2	1.3	1.5

4. Secondary Outcome

Title	Change in Vascular Endothelial Function, Percentage of Dilation
Description	Endothelial function, assessed by Flow-Mediated Dilation (FMD), was determined from longitudinal B-mode ultrasound images of the brachial artery. Images were obtained using an Acuson (Mountain View, California) Aspen ultrasound platform with an 11-MHz linear-array transducer after 10 min of supine relaxation and during reactive hyperemia, induced by the inflation of a forearm pneumatic occlusion cuff to suprasystolic pressure (about 200 mm Hg) and subsequent deflation after 5 min. FMD was defined as the maximum percentage change in arterial diameter relative to resting baseline from 10 to 120 s after deflation of the occlusion cuff.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Measure Participants	52	53	23
Least Squares Mean (95% Confidence Interval) [percentage of dilation]	0.7	0.5	0.5

5. Secondary Outcome

Title	Change in Inflammation (C-Reactive Protein, ug/ml)
Description	High-sensitivity C-reactive protein was quantified by ELISA (LabCorp). Values >10 mg/L were truncated at 10 to account for acute inflammatory processes that may have skewed the distribution of this blood marker.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Measure Participants	52	53	23
Least Squares Mean (95% Confidence Interval) [ug/ml]	-0.2	0.1	-0.3

6. Secondary Outcome

Title	Change in Urinary Catecholamines (Epinephrine and Norepinephrine, Unit-weighted Z-score)
Description	Urinary catecholamines, an index of sympathetic nervous system (SNS) activity, served as a biomarker of anxiety. Urinary concentrations of epinephrine (EPI) and norepinephrine (NE) were determined by high-pressure liquid chromatography (HPLC) with electrochemical detection (LabCorp). A composite 24-hr catecholamines z-score is presented. The z-score is the raw score minus the population mean, divided by the population standard deviation. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Measure Participants	52	53	23
Least Squares Mean (95% Confidence Interval) [z-score]	0.05	-0.24	0.36

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supervised Aerobic Exercise, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Regression, Linear
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supervised Aerobic Exercise, Lexapro
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	Regression, Linear
	Comments

7. Secondary Outcome

Title	Change in Lipids - Total Cholesterol, LDL (Low-density Lipoprotein), and HDL (High-density Lipoprotein); mg/dL
Description	Lipids were obtained from fasting blood samples and assays were measured enzymatically (LabCorp).
Time Frame	Baseline, 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supervised Aerobic Exercise	Lexapro	Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerobic Exercise	Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro	Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
Measure Participants	52	53	23
Total Cholesterol	-28.2	-15.3	-31.6
LDL	-18.6	-9.8	-19.3
HDL	6.3	3.4	7.2

8. Other Pre-specified Outcome

Title	Change in Hospital Anxiety and Depression Scale, Total Score
Time Frame	9 months, 15 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Baseline to 3 months
Arm/Group Title	Supervised Aerobic Exercise		Lexapro		Placebo
Arm/Group Description	Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges. Supervised Aerboic Exercise		Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement. Lexapro		Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro. Placebo
All Cause Mortality
	Supervised Aerobic Exercise		Lexapro		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/53 (0%)		0/23 (0%)
Serious Adverse Events
	Supervised Aerobic Exercise		Lexapro		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/53 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Supervised Aerobic Exercise		Lexapro		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/53 (0%)		0/23 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.