Exercise and Pharmacotherapy for Anxiety in Cardiac Patients
Phase: NA
Conditions: Anxiety, Cardiovascular Disease
Sponsor: Duke University

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Exercise and Pharmacotherapy for Anxiety in Cardiac Patients 
NCT02516332 
 

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1. Protocol Title: Exercise and Pharmacotherapy for Anxiety in Cardiac Patients: The UNWIND Study 
 
2. Purpose of the Study: 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 continues to be a need to identify alternative approaches 
for treating anxiety in cardiac patients. We 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 exercise, Lexapro, or placebo on anxiety symptoms and CHD biomarkers among individuals with 
cardiac disease and elevated anxiety. We hypothesize the following: (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. We 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.  
 
3. Background & Significance: Over $100 billion is spent on CHD each year in direct medical costs, 
disability payments, and lost productivity.[1]  Mental illness also is a major health problem in this country, 
with estimated direct costs of $57.5 billion in 2006.[2]  Mental disorders are associated with significant 
impairment of function that may, at times, be worse than that of chronic medical disorders.  Anxiety 
disorders are the most commonly diagnosed forms of mental illness in the U.S. and are responsible for 
one-third of the total expenditures of the federal government for mental illness.[3]  Approximately half of 
those costs are due to the repeated use of health care services since people with anxiety disorders often 
solicit medical evaluation for symptoms that resemble physical illnesses.[4]  Nationally representative 
surveys indicate that as many as 30% of patients will suffer from some kind of anxiety disorder during 
their lifetimes,[5] a figure that has increased significantly over the past 2 decades.  Anxiety symptoms 
have been correlated with the presence of one or more chronic diseases,[6] as well as impaired work 
performance, increased use of medical services, decreased well-being, and lowered functioning.[7, 8]   
Although the actual prevalence of anxiety disorders among cardiac patients is not known, Tully and Cosh 
reported an 11-14% prevalence of generalized anxiety disorder (GAD) across 12 studies (N=3485) and 
a pooled lifetime prevalence of 26%.[9]  Frasure-Smith[10] noted that 5.3% of a sample of 804 patients 
with stable CHD had GAD and 41.4% had elevated anxiety symptoms measured by the Hospital Anxiety 
and Depression Scale-Anxiety (HADS-A).  Thus, anxiety is common in CHD patients.  However, the prior 

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set of reviews raised questions about the significance of anxiety in CHD patients and of the novelty of 
exercise to treat anxiety.  Our team took up this challenge by revisiting and expanding our previous review 
of the relevant literature and conducting new analyses of pilot data from our laboratory, both of which 
proved helpful in further articulating a working conceptual model and providing a rationale for our 
proposed RCT.  
 
Anxiety and CHD Risk.  Findings from a number of prospective epidemiological studies report a 
strong association of anxiety with mortality in healthy individuals [11-13]  and in CHD patients.[10, 14-19]  
Our own studies have shown that elevated scores on the anxiety subscale of the HADS were associated 
with increased risk of mortality after accounting for established risk factors in 934 men and women with 
CHD (Hazard Ratio  HR , 2.27; 95% CI, 1.55 to 3.33, p<.001).[20]  Elevated anxiety symptoms have been 
shown to be associated with a 2-fold increased risk of mortality in CABG patients[16, 18] and in 
outpatients with CHD.[10, 21, 22]  Frasure-Smith and colleagues reported that CHD patients with GAD 
assessed two months following hospital discharge showed a 2.3-fold increased risk of adverse cardiac 
events, and Strik et al.[21] reported a 2.8-fold increased risk of adverse events in acute post-MI patients 
in which anxiety was measured one month following hospital discharge.  Similarly, a 2-fold increased risk 
of adverse events was observed in stable CHD patients[23] and in patients with elevated anxiety during 
annual clinic visits.[24]  Similar to the depression literature,[25] not all studies have found a prognostic 
relationship, especially when anxiety was measured in-hospital following an acute coronary event or 
during diagnostic exercise stress testing.[8, 26-30]  In the proposed study, anxiety symptoms will be 
evaluated outside of the clinic and hospital environment in individuals with stable CHD with high levels of 
anxiety.  
  
Anxiety and depression share high comorbidity.[10, 31, 32]  Findings from several recent 
prospective studies suggest that anxiety predicts increased risk independently of depression, and that 
the presence of both anxiety and depression identifies individuals at greater risk of mortality than those 
with either prognostic factor alone.[20, 33]  We observed a 3-fold increased risk of mortality in CHD 
patients with comorbid anxiety and depression, compared with an approximate 2-fold risk in patients with 
either anxiety or depression alone.[20]  The additive effects of anxiety and depressive symptoms have 
been noted by other investigators,[33, 34] and we will explore this issue in our proposed trial.    
 
Treatment of Anxiety Disorders in Cardiac Patients.  Despite compelling reasons for treating 
anxiety in CHD patients, there have been few trials that have examined the effects of treating anxiety 
symptoms in cardiac patients, and no studies reported the effects of treating anxiety on clinical outcomes.  
Several studies, including the ENRICHD trial, have examined the effects of treating depressed post-MI 
patients,[35] and several pharmacologic studies have examined the effects of SSRIs on depressive 
symptoms and outcomes in cardiac patients.[36-40]  The SADHART-CHF trial found no advantage for 
sertraline over placebo in either reducing depression or in improving clinical outcomes.[40]  The 
SADHART study[36] also reported no differences between CHD patients receiving sertraline compared 
to placebo, although greater reductions in depressive symptoms were observed in the subset of patients 
with more severe depression.   We will consider more severe anxiety (i.e., diagnosed anxiety disorders) 
as a potential moderator of treatment in our proposed RCT.   
Exercise and Anxiety.   The use of aerobic exercise has been widely used in many secondary 
prevention programs[41] and may reduce risk of fatal CHD events.[42]  The mechanisms for this benefit 
remain uncertain, although exercise has been shown to reduce traditional risk factors, such as 
hypertension and hyperlipidemia,[41] attenuate cardiovascular responses to mental stress and reduce 
myocardial ischemia,[43-46] and reduce depressive symptoms in patients with MDD,[47] heart failure,[48] 
and in CHD patients with elevated depressive symptoms.[49]  Epidemiological studies have observed an 
inverse relationship between exercise and anxiety.  In a study of 8,098 adults, Goodwin[50] reported that 
persons who indicated that they exercise “regularly” were at reduced risk for being diagnosed with an 
anxiety disorder compared to their sedentary counterparts.  There have been many exercise trials that 
have reported anxiety as an outcome.  
For example, Wipfli and colleagues[51] found that exercise was associated with an overall effect size of 
0.48, indicating greater reductions in anxiety symptoms compared to no-treatment controls, and Herring 

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and colleagues[52] reported that exercise was associated with an overall effect size of .29, compared to 
control conditions.  In a review of 8 RCTs of patients with a broad range of anxiety disorders, 
Jayakody[53] noted that exercise seems to be effective as an adjunctive treatment for most anxiety 
disorders, but there were too few studies to provide meaningful conclusions.  In response to the prior 
review, we re-examined the exercise literature and identified only 12 RCTs specifically targeting patients 
with high anxiety, most of which had serious methodological shortcomings, including small sample sizes, 
lack of blinding of assessors, confounding of exercise with other treatments, and no adherence to intent-
to-treat analytic principles.[54]  In one of the few studies of cardiac patients, Lavie and Milani[55] reported 
more than a 69% reduction in anxiety among highly anxious participants in an exercise-based cardiac 
rehabilitation (CR) program; however, there was no control group and exercise was only one component 
of the intervention.  In the one RCT that targeted cardiac patients with elevated anxiety, Oldridge and 
colleagues reported greater reductions in symptoms of anxiety assessed by the STAI and POMS after 8 
weeks of CR compared to community care controls.[56, 57]  However, the CR group also received 
concurrent weekly 90-minute group counseling sessions, including training in progressive relaxation, so 
that the benefits of exercise training could not be determined.  Thus, while results from previous exercise 
studies are encouraging, there remains an important gap in understanding the potential therapeutic 
benefits of exercise, especially among anxious cardiac patients who are vulnerable to adverse cardiac 
events.  
Biomarkers of CHD Risk.  Reliance on "hard" clinical endpoints (MI and death) that occur 
infrequently and require large sample sizes over extended follow-up intervals has proven to be a major 
challenge to furthering our understanding of the optimal ways to treat vulnerable cardiac patients because 
of the obvious logistical and financial obstacles such investigations present.  One solution to this problem 
is to first study intermediate markers of risk in patients who are vulnerable to untoward cardiac events.[58]  
Examination of changes in intermediate endpoints can provide important insights into the mechanisms 
and potential value of clinical interventions and has a number of important advantages over “hard 
endpoints,” in that fewer patients are required to detect treatment effects and changes in cardiac risk can 
be reliably and objectively measured over short follow-up intervals.   Following the guidelines advanced 
by a panel of prominent cardiovascular scientists,[59, 60] we propose to examine intervention effects on 
autonomic, vascular, and inflammatory biomarkers of cardiovascular risk (i.e., "intermediate endpoints") 
in “vulnerable” CHD patients with high anxiety:  
 
Heart rate variability (HRV) is widely recognized as an important index of autonomic regulation of 
the heart and prognostic indicator of risk and will serve as our primary biomarker of interest.  Reduced 
24-hour HRV independently predicts mortality in community samples[61-63] and patients with stable 
CHD,[64] with a recent MI, [65] or with heart failure (HF).[66]   
 
Baroreceptor reflex sensitivity (BRS) is also an index of cardiac regulation by the parasympathetic 
nervous system (PSNS), with experimental models showing that low levels of BRS predict sudden 
cardiac death (SCD) due to ventricular fibrillation.[67]  Anxiety has been linked to reduced PSNS control 
of heart rate in several different populations, including patients with anxiety disorders,[68-72] MDD, [73, 
74] and CHD,[75] as well as healthy volunteers.[76]  Elevated sympathetic nervous system (SNS) activity 
is another pathophysiological aspect of autonomic dysregulation contributing to the development of 
CHD[77] that is thought to contribute to increased cardiovascular risk associated with anxiety.[78, 79] 
      
Although no study has compared the effects of an SSRI with exercise training on HRV in anxious 
cardiac patients, it is well documented that SSRIs that inhibit the reuptake of norepinephrine reduce 
HRV.[80, 81]  Several RCTs have provided evidence that regular exercise improves HRV, as well as 
BRS, in middle-aged and elderly sedentary subjects[82, 83] and patients with CHD.  In the present 
proposal, 24-hour HRV will be our primary biomarker in examining the impact of exercise and anxiolytic 
medication on cardiovascular risk in anxious CHD patients, with SNS activity also assessed in order to 
provide a comprehensive assessment of intervention effects on autonomic regulation. 
      
Endothelial dysfunction plays a vital role in the development, progression, and clinical 
manifestations of atherosclerosis.[84, 85]  It can be assessed non-invasively using standardized vascular 
ultrasound techniques to determine flow-mediated dilatation (FMD) of the brachial artery,[86] has been 

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related to a wide range of CHD risk factors,[87] and has been shown to be prognostic in cardiac patients.  
Impaired FMD has been linked to elevated depression symptoms in stable CHD patients,[88] and to 
elevated anxiety symptoms in CHD patients following a percutaneous coronary intervention.[89]  Several 
studies also have shown that acute mental stress is associated with impaired FMD.[90-92]  There is 
preliminary evidence that exercise may improve endothelial function in CHD patients.  Several cross-
sectional studies have found that self-reported physical activity is associated with preserved endothelial 
function.[93, 94]  Several small interventional studies also have shown that FMD may be improved by 
exercise training in cardiac patients.[95-98] These observations suggest that reducing anxiety symptoms 
may result in improved FMD and that anxious CHD patients randomized to the exercise intervention may 
demonstrate the most marked improvements in FMD.  
 
Inflammation is widely considered to play a central role in the development and progression of 
CHD.  C-reactive protein (CRP), an acute-phase reactant primarily produced in hepatocytes, is a highly 
sensitive marker of underlying systemic inflammation.[99]  An elevated level of CRP is an independent 
risk factor for MI and stroke.[100, 101]  Interleukin-6 (IL-6) is an inflammatory cytokine that may be the 
initial event leading to an increase in CRP levels, and recent meta-analyses indicate that IL-6 may be 
more strongly related than CRP to the promotion of atherosclerosis.[102, 103]  Elevated levels of both 
CRP and IL-6 have been observed in patients with depression,[104-106] but few studies have examined 
the relationship with anxiety.[107]  In a subsample of healthy participants in the ATTICA study, Pitsavos 
et al.[108] observed a significant dose-response relationship between the severity of anxiety symptoms 
and CRP and IL-6.  In a cross-sectional study of 120 stable CHD outpatients, Bankier et al.[109] also 
found GAD to be associated with increased CRP.  In a sample of 682 post-ACS patients, Frasure-Smith 
et al.[110] reported that HRV was correlated with inflammatory markers and suggested that interventions 
targeting regulation of both autonomic control and inflammation may be especially worthwhile.  The 
interventions proposed in this RCT are designed to accomplish this goal.  
 
 Summary.  We propose to examine the effects of exercise and anxiolytic medication on both 
symptoms of anxiety and on "intermediate endpoints" that are associated with adverse outcomes in CHD 
patients.  In this application, we propose a RCT to compare the effects of exercise training and anxiolytic 
medication (escitalopram, Lexapro) to a placebo in anxious patients with CHD.  Patients will be assessed 
on clinical, behavioral, and physiological dimensions at baseline, 3 months (post-treatment), and 6-month 
follow-up.  Additional measures of quality of life also will be obtained along with annual follow-ups to 
document clinical events and medical costs.  The findings from this RCT will have directly translational 
implications for anxiety assessment and management in CHD patients.  
 
4. Design & Procedures: This study will be a single-site, randomized clinical trial of exercise training 
and anxiolytic medication in the treatment of anxiety in anxious CHD patients without MDD as a primary 
diagnosis.  One hundred fifty men and women aged ≥40 years with stable CHD and elevated anxiety 
symptoms (HADS-A scores ≥11) will be randomly assigned to Exercise Training, Medication 
(escitalopram), or Placebo.  Patients will be evaluated for anxiety at baseline, after 3 months of treatment, 
and at 6-month and annual follow-ups.  Three months is ample time to observe cardiovascular 
conditioning effects, even among older cardiac patients, whose responses are often quite variable, and 
is also adequate to assess the efficacy of pharmacologic treatment.  Comprehensive assessments will 
include clinical evaluations of anxiety and measures of intermediate surrogate endpoints, including 
autonomic, vascular, and blood markers of risk.  Following the completion of the 3-month treatment 
program, subjects will undergo a post-intervention repeat assessment.  Patients will then undergo a 6-
month follow-up evaluation for anxiety and CHD risk status and will be followed annually for anxiety and 

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clinical events (see Figure 1).  All assessors will be blinded to patients' treatment group assignment; 
groups receiving a pill will be double-blind.  Following completion of the intervention, participants will be 
advised to contact their referring physicians, if necessary, for further treatment, or they will be referred to 
appropriate mental health care providers.    
 
I. Assessment of Anxiety 
  
 
 
Patients will undergo a comprehensive assessment of anxiety.  The primary outcome measure 
will be scores on the Hospital Anxiety and Depression Scale – Anxiety (HADS-A).[111]  The HADS-A is 
a commonly used psychiatric self-report questionnaire designed to identify anxiety and depression 
among patients in nonpsychiatric medical settings,[112] and has been shown to detect independent 
constructs of anxiety and depression.[111, 113, 114]  It has excellent psychometric properties,[111, 113-
117] and has been widely used in outpatient RCTs in patients with clinical anxiety.[118, 119]  Published 
clinical cutoffs[120] are 0-7 (normal), 8-10 (mild), 11-14 (moderate), and 15-21 (severe).  Our eligibility 
criteria will include patients with HADS-A scores ≥8, which represents a more conservative cut-point for 
identifying patients with significant anxiety who are at increased risk for adverse CHD events and who 
may receive greater benefit from treatment. 
 
A clinical psychologist will administer modules from the Structured Clinical Interview for DSM-5 
Disorders (SCID), including the anxiety disorder section, the mood disorder section (to rule out primary 
MDD), the somatization section, and the alcohol abuse and/or dependence section.[121]  The 
psychologist also will administer the 14-item Hamilton Anxiety Rating Scale (HAMA)[122] to obtain a 
clinical rating of anxiety symptom severity. 
Other psychiatric self-report anxiety assessments will include the Anxiety and Depression 
Detector (ADD), the Patient Health Questionnaire 9 item (PHQ-9), the Anxiety Sensitivity Index (ASI), 
and the General Anxiety Disorder 7-item questionnaire (GAD-7). Together, these assessments will afford 
a comprehensive analysis of a patient’s severity of anxiety symptoms and the comorbidity with 
depression. The ADD provides 5 items that effectively and efficiently screen for panic disorder, PTSD, 
social phobia, GAD, and depression.[123] The PHQ-9 is a brief, reliable, and valid measure of depression 
severity.[124] The ASI assesses fear of arousal-related sensations, and we will be using the test to 
assess physical factors of arousal.[125]  The GAD-7 is an efficient screening tool for assessing GAD 
severity.[126]   
  
The 20-item Trait section of the Spielberger Stait-Trait Inventory (STAI) also will be presented to 
the patients to assess anxiety symptoms before treatment. However, to assess ongoing treatment 
response, participants will complete the 20-item State section of the STAI[127] at weekly intervals 
throughout the duration of the 3-month intervention by a clinician who will be blinded to patients’ treatment 
group status.  The STAI will be used to evaluate the process of change and to assess at-risk patients 
(i.e., worsening anxiety) regularly and systematically.  Suicidal potential also will be carefully assessed.  
Contact time will be documented and content limited (to avoid simulating psychotherapy, which would 
seriously confound data interpretation).     
       
Importantly, patients with primary MDD will be excluded from this trial.  However, because 
symptoms of depression are likely to co-occur with anxiety, we also will assess depressive symptoms 
with the Beck Depression Inventory-II (BDI-II).[128]  The BDI-II is a widely used measure of depressive 
symptomatology, consisting of 21 items, each corresponding to a specific category of symptoms and 
attitudes.  It has been shown to be both a reliable and valid measure of depression severity[129] and has 
been used in many major interventional trials of cardiac patients.[35, 130, 131] Item #9 (suicidality) of the 
BDI-II will be used to assess suicidal ideation and administered weekly along with the STAI.  
 
Electronic-based questionnaires (e-questionnaires) will be used for all assessments, both anxiety 
and quality of life, except for interview-based assessments. These e-questionnaires will be delivered 
during participants’ visits to Duke for pre- and post-intervention assessments. A Duke Psychiatry 
computer will be used and secured by Psychiatry Computer Support. The computer log-in will be 
performed and documented by study personnel; the computer will be used only for the survey purpose; 

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the study personnel will remain in the room with the participants while they have computer access; and 
study personnel will document log-off before leaving the room. The computer will be setup such that only 
necessary software will be installed on the computer, and access to other applications and network assets 
will be limited. The software necessary for assessments is Qualtrics, a Duke-approved survey platform.  
 
II.  Intermediate Endpoint Assessments 
 
1. Heart Rate Variability.   For the 24-hour HRV measurement, patients will be instrumented with 
a DigiTrak XT Holter ambulatory ECG monitor (Philips Healthcare, Andover, MA).  Following 
instrumentation, patients will be reminded to engage in their normal pattern of activity and to wear the 
monitor for 24 hours. During that time, if participants experience a high-anxiety event, they will be asked 
to record the event by pressing an event marker button associated with the monitor.  A Laser scanner 
(DelMar Medical, Irvine, California, USA) will be used to scan the recordings using standard Holter 
analysis procedures.  The labeled beat-to-beat file will then be processed using the DelMar time domain 
HRV analysis software and the DelMar enhanced 24-hour spectral heart rate variability analysis software.  
Heart rate variability will be estimated from the standard deviation of all normal R-R intervals (SDNN) and 
from spectral power summed across each of the following bands: high frequency (0.14 to 0.5 Hz), low 
frequency (0.05 to 0.139 Hz), very low frequency (0.003 to 0.049 Hz), and ultra-low frequency (0.000015 
to 0.0029 Hz).  For the purposes of the proposed study, the primary hypotheses will be tested using the 
SDNN measure of HRV, because it is less affected by artifact and nonstationarities found in the 
ambulatory environment and is most strongly predictive of increased risk of mortality.[65]  Certain 
medications may affect HRV through effects on the autonomic nervous system.  Beta-blockers, for 
example, are known to increase the tonic levels of several measures of HRV, such as RSA.  However, 
the primary outcome HRV measure, SDNN, is relatively resistant to the effects of beta-blockade.[132]  
Because sleep apnea may impact HRV, a STOP-BANG sleep apnea questionnaire will be administered.  
2. Baroreflex Sensitivity.  BRS studies will be performed between 0800 and 1000 hours under 
fasting conditions.  In the supine posture, following 5 minutes of quiet rest, 10 minutes of beat-to-beat BP 
data will be collected using the Finometer PRO Model-1 (Finapres Medical System, Amsterdam, the 
Netherlands), and 10 minutes of beat-to-beat R-R interval will be collected from an electrocardiogram 
(ECG) recorded digitally at 1000 Hz.  The Finometer instrument utilizes the vascular unloading technique 
to measure SBP, DBP, and MAP on a beat-to-beat basis, and has been validated against intra-arterial 
measures under various conditions.[133]  Power spectra will be estimated using the Welch 
algorithm.[134]  Power spectra will be derived as the average of 60-second data segments, overlapping 
by half.  BRS will be estimated from the modulus of the cross spectrum of R-R interval and SBP for 
frequencies ranging from 0.070 - 0.129 Hz.  This method produces reliable measures that are comparable 
to estimates of BRS obtained using the invasive phenylephrine injection technique, widely considered to 
be the “gold standard” measurement method.[135] 
3. Vascular Endothelial Function.  Our approach for assessing endothelial function conforms to 
the recently published guidelines for assessment of flow-mediated arterial vasodilatation.[136]   
Longitudinal B-mode ultrasound images of the brachial artery, 4-6 cm proximal to the antecubital crease, 
will be obtained at end-diastole (ECG R-wave gated digital image capture) using a dedicated Acuson 
Aspen ultrasound platform.  All images will be acquired with participants supine, utilizing an 11 MHz linear 
array probe with stereotactic holder in our temperature-controlled clinical research laboratory, by Michael 
Ellis, RDMS, RVT, who has over 15 years of experience performing the standardized image acquisition 
protocols for our ultrasound FMD assessments.  In an unpublished evaluation of 20 healthy men and 
women who underwent our FMD assessment protocol on two consecutive days, repeat FMD values 
showed a correlation of r=0.81, p<.001, a mean absolute difference of 0.64%.  Images will be obtained 
and stored digitally at resting baseline, as well as during and following inflation to 250 mm Hg of an 
occlusion cuff placed around the forearm, 2 cm below the elbow.  All arterial diameter measurements will 
be performed by the same experienced member of the research team (AS), blinded to participant identity 
and treatment condition, using edge detection software (Brachial Analyzer, MIA-LLC, Coralville, IA).  FMD 
response will be assessed from 10-120 seconds post-deflation of the forearm cuff, with peak arterial 

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diameter quantified using polynomial curve fitting, and FMD thereby defined as the maximum percent 
change in arterial diameter relative to pre-inflation resting baseline.  As others have reported, using this 
rigorous standardization of FMD methodology, our FMD assessments will be obtained with optimal 
reproducibility, reflected in a coefficient of variation of approximately 10% or less.[137-139]  Peak 
hyperemic flow and shear stress will be derived by standard formulae based upon Doppler velocity 
measurements during the first 10 seconds following deflation of the occlusion cuff.[140],[141]  In 
participants for whom there is no contraindication (e.g., history of migraine), we also will assess brachial 
artery response to the administration of 0.4 mg sublingual glyceryl trinitrate (GTN), which is the standard 
approach to confirming vascular endothelial specificity of FMD findings.[86]   
4. Measures of chronic inflammation.  Plasma inflammatory biomarkers will be measured by 
ELISA using commercially available kits.  We will examine C-Reactive Protein (hsCRP) using a high-
sensitivity assay obtained from American Diagnostica, Inc. (Stamford, CT).  We will also measure 
interleukin-6 (IL-6), an inflammatory cytokine that promotes myocardial hypertrophy and may be elevated 
prior to increases in CRP levels.  On the day of blood work, we will ask participants to hold off taking 
nonsteroidal anti-inflammatory medications (including aspirin) and antihistamines until after their morning 
(0700-0800 hours) blood draw.  
5. Urinary catecholamines.  Patients will be asked to collect urine over a 24-hour period, with 
samples kept cold by storage in a portable cooler.  Samples will be assayed for norepinephrine, 
epinephrine, creatinine, sodium, and potassium.  Catecholamine levels will be expressed as urine 
concentration (µg/ml) per urine concentration of creatinine (mg/ml), yielding norepinephrine and 
epinephrine values in units of µg per mg creatinine for each sample.  This provides catecholamine 
excretion indices that are corrected for individual differences in body size and urine volume.[142]  In prior 
studies, urinary catecholamine data have proven informative, with low subject burden and excellent 
compliance.[78, 143, 144]  As in these prior studies, excellent compliance with urine collection is achieved 
by emphasizing to participants the importance of a complete 24-hour collection and by providing detailed 
instructions on how this can be achieved.  The completeness of 24-hour urine collections will be assessed 
by ascertaining whether 24-hour urinary creatinine excretion falls within boundaries based upon body 
size, race and gender.[145]  Incomplete collections will be repeated.  
6. Lipids.  Total cholesterol, HDL- and LDL-cholesterol, VLDL-cholesterol, and triglycerides will 
be assayed from fasting blood samples drawn between 0700 and 0800 hours. 
7. Metabolic blood analyses. Other blood components to be analyzed include a metabolic panel, 
insulin, and HbA1c. 
8. Blood biomarker analyses. Participant blood that remains following the aforementioned blood 
analyses may be banked for potential future analyses examining blood biomarkers, such as proteins or 
metabolites, related to the interplay of exercise, anxiety, and cardiac disease. Importantly, the ability to 
bank participants’ extra blood is at the discretion of the participants. During the consenting process, 
participants will be explicitly informed about this optional sub-study, their ability to choose whether or not 
their blood may be saved, and that their choice does not influence their participation or treatment in the 
study. Participants will consent by initialing a specific section of the consent form detailing the storage 
and use of their blood.  
 
 III. Assessment of Aerobic Capacity   
 
 
Graded treadmill exercise testing will be conducted at baseline and at the conclusion of treatment 
using a protocol developed at Duke and Wake Forest Universities.[146]  Subjects will exercise to 
exhaustion or other standard endpoints (e.g., chest pain, ST-segment depression, etc.) under continuous 
electrocardiographic monitoring.  Expired gases will be analyzed continuously by a Parvo Medics True 
One measurement system (Parvo Medics, Sandy, Utah).  Peak VO2 will serve as the primary measure 
of aerobic capacity.  
 
To obtain a measure of participants’ average daily physical activity, participants’ will be asked to 
wear an ActigraphTM activity watch for 7 continuous days. The ActigraphTM GT9X Link features a validated 
3-axis accelerometer, and the accompanying software allows for examination of physical activity 

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characteristics and sleep patterns. 
 
 
  
 
IV.  Assessment of Quality of Life 
     
 
The proposed interventions may not only reduce anxiety, but also impact a number of other areas 
of functioning that are considered to reflect “quality of life.”  We propose to use a questionnaire battery 
that includes a measure of general health,[147] resilience,[148] perceived stress,[149] optimism,[150] 
self-efficacy, and perceived social support.[151, 152]  These are clearly exploratory measures and are 
peripheral to our main hypotheses.  However, this information is of interest and can be obtained at 
minimal additional cost. Further, to obtain a more complete picture of patients’ health, we also will use 
the Godin Leisure-Time Exercise questionnaire[153] to evaluate exercise habits, the Pittsburgh sleep 
questionnaire[154] to examine sleep patterns, which may affect anxiety and HRV, the Morisky Medication 
Adherence Scale[155] and Medication Adherence Behavior Evaluation to identify medication adherence, 
and a fat-related diet habits questionnaire[156] to examine nutrition habits. 
 
V. Post-treatment Assessments at 3-Months and at 9-Months (Six-month follow-up) 
 
At the conclusion of the 3-month intervention (post-treatment), or at the time a participant may 
drop out of the study (or in the rare instance of requiring additional or different anxiolytic treatment outside 
of our protocol), patients will complete the same clinical, biomarker, and psychometric test battery that 
they completed at baseline.  At the 6-month follow-up, we will assess anxiety, patients' exercise habits, 
any psychiatric treatment, psychopharmacologic medications, aerobic fitness using a 6-minute walk test, 
and cardiac status, including revascularization procedures and CHD events.  This will be a naturalistic 
follow-up that we have used in previous trials,[157, 158] which will allow us to determine patients’ anxiety 
status 6 months after the conclusion of study-related treatment, along with changes in health habits and 
measures of quality of life.   Figure 2 presents an expanded view of the assessment schedule and design 
of the study.  For clinical events, we carefully will document cardiac-related hospitalizations and 

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emergency room visits, revascularizations, and any deaths for up to 4 years post-treatment.  
 
Both pre-treatment and post-treatment (3 month) assessments will be performed in the same 
sequence over 3-4 visits. Following a phone screen, participants will arrive for Visit 1 under normal 
physiologic conditions (i.e. not fasted and having taken all medications) for an orientation and consenting 
process. If participants consent to the study, then they will perform the battery of anxiety and quality of 
life assessments and the physical. For Visit 2, participants will arrive fasted and bring in their 
medication(s). Blood will be taken followed by HRV and BRS measurements and Holter monitor set-up. 
After these fasted-required procedures are performed, we will provide food for the participants so they 
can take their medicine. Then, the Actigraph will be initialized and put on participants’ wrists, and they 
will be given a urine cup to take home. For Visit 3, participants will arrive under normal physiologic 
conditions except for taking aspirin, NSAIDs, or other medication that will impact vascular dynamics. 
Participants will return the Holter monitor, Actigraph, and urine cup. Lab procedures will include tests for 
vascular endothelial function, consisting of forearm-mediated dilation, and aerobic capacity, consisting of 
the exercise treadmill test. Based on the participants’ schedules and time limitations, they may choose 
to combine Visit 2 and Visit 3. On Visit 4, participants will arrive under normal physiologic conditions. 
Participants will be randomized. If randomization is to a pill group, participants will immediately visit Dr. 
Wei. If randomization is to exercise training, participants will immediately meet with a staff exercise 
physiologist to discuss exercise prescription and exercise site location.   
 
VI. Annual Follow up for Clinical Events 
 
 
 
 Medical outcomes will be tracked.  Our main medical outcome is combined all-cause mortality 
and CHD hospitalizations, emergency department visits, and unscheduled physician office visits because 
of worsening angina.  The study staff will collect these data via medical records review, which will be 
coordinated by Dr. Alan Hinderliter at UNC.  We have conducted these types of follow-up assessments 
in our prior work.[159, 160]  Based upon unpublished data from our UPBEAT trial, it is estimated that 
there will be a 30% annual event rate in this vulnerable population of anxious CHD patients.   
 
5. Selection of Subjects: This will be an outpatient study of 150 cardiac patients with stable CHD and 
elevated symptoms of anxiety. We anticipate consenting 300 patients in order to reach our goal of 150 
randomized. To accomplish our recruitment and treatment goals, we have established a referral network 
of community hospitals including Duke University Medical Center, the Durham Veterans Affairs (VA) 
Hospital, Duke Raleigh Hospital, Alamance Regional Hospital, WakeMed Health and Hospitals, and the 
UNC Health Care system in Chapel Hill.  Patients will be recruited through a variety of sources including 
IRB-approved advertising, such as brochures, flyers, e-mail messaging, posters, television, radio, and 
internet, like researchmatch.org. Additional recruitment aids include self-referral and referral from 
physicians, psychologists, and other mental health care professionals. We also my mail letters to 
participants of our previous studies, including but not limited to ENHANCED (Pro00015896), UPBEAT 
(Pro00011980), and REMIT (Pro00009555), that inform the patients about the opportunity of this study; 
these letters first would be IRB approved through the previous studies protocol and then through this 
study’s protocol before being mailed. Further, potential participants may be identified by reviewing 
records from Duke Cardiopulmonary Rehabilitation and UNC Cardiopulmonary Rehabilitation and Duke 
Echocardiography Laboratory. Further still, potential participants may be pre-screened through Maestro 
Care; upon identifying potential participants, we first would contact the physicians of the potential 
participants to acquire their consent to inform their patients about the study. This approach effectively 
serves to avoid “cold calling” participants. Following agreement by the physicians and a positive 
acknowledgement by their respective patients, we would inform the patients about the study. Finally, 
following physician consent, we may identify potential participants by reviewing physician records and 
meet the identified patients in the clinic; this meeting would take place after the patient’s physician 
introduces the study and gains the patient’s acknowledgement to receive more study information, and 
the meeting purpose would be to describe the study and, if the patient is interested, present a short 
consent form to the patient that is directed to taking the 2-item GAD questionnaire to determine anxiety 

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symptom severity and, thus, study eligibility. This is a racially and socioeconomically diverse region, 
which will be reflected in our sample of anxious CHD patients. Patients from Duke, UNC, and outside 
hospitals will be considered for participation. Non-Duke patients will be provided with Duke’s Notice of 
Privacy Practices.  
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 ≥40 years will be 
selected for study.  Patients also will have an anxiety symptom severity score of ≥8 on the HADS-A; a 
subgroup of patients will also have a DSM-5 diagnosis of an Anxiety Disorder.  A modified GAD diagnosis 
will be used, wherein the GAD criteria include a minimum of 1 month of worry and at least 2 of the 
associated symptoms listed in DSM-V. Patients diagnosed with MDD may be included provided a) they 
have an anxiety diagnosis (e.g., generalized anxiety disorder, panic disorder, social anxiety disorder); b) 
their BDI-II total score is < 30; c) their response to BDI-II item #9 (suicidality) is 0 or 1; and d) the 
psychiatric interview determines that the patient is at minimal suicide risk.For patients included that meet 
these criteria, suicidality will be assessed weekly throughout the duration of the trial as noted in Section 
13 (Data and Safety Monitoring). We plan to actively recruit women and minorities, with at least 50% 
women and 25% minorities.    
Exclusion criteria.  Medical exclusions will include an MI or coronary revascularization procedure 
(i.e., CABG or percutaneous coronary intervention) within the last 3 months, unstable angina, severe left 
ventricular dysfunction or decompensated heart failure (i.e., left ventricular ejection fraction <30% AND 
New York Heart Association functional classification of III or IV), unrevascularized left main coronary 
artery stenosis >50%, pacemaker dependence, resting BP >200/120 mm Hg, and 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 MDD, 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.  Further, patients with active 
suicidal ideation at screening and/or a history of a suicide attempt requiring inpatient admission will not 
be enrolled into the trial. To determine the risk for suicide, which would meet our exclusion criteria, any 
patient with a history of inpatient admission for MDD documented in the medical record will be excluded. 
Second, selection of BDI-II response choice 2 (“I would like to kill myself”) or 3 (“I would kill myself if I 
had the chance”) to BDI-II item 9 would be excluded. 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. 
 
 
I. Screening procedures 
 
    
1.  Psychiatric Screen.  All potential candidates will be screened using the ADD[123] and the 
PHQ-9. The ADD is a 5-item instrument that has been used to detect anxiety (and depression) in medical 
settings and is an effective screening tool for anxiety disorders (e.g., panic disorder, social phobia, and 
GAD).  It is a good overall measure of distress and is likely to reflect a diagnosis of at least one of these 
conditions or at least significantly elevated levels of anxiety.  Patients must obtain a score of >1; the ADD 
is correlated with the Overall Anxiety Severity and Impairment Scale (OASIS),[161] which also has been 
used to detect the presence of significant anxiety. The PHQ-9 is a brief, reliable, and valid measure of 
depression severity (J Gen Intern Med. 2001; 16:606-613), which will be used to examine the comorbidity 
between anxiety and depression in patients.  
      
2.  Medical Screen.  Each participant will receive a screening physical examination.  Blood 
pressure (BP) will be determined by standard sphygmomanometry.  Subjects will undergo routine blood 

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tests including creatinine, electrolytes, liver function tests, complete blood count, B12, insulin, and thyroid 
profile, which will be performed by phlebotomy-trained study staff.  If subjects are found to have any 
significant medical illness during the medical screen that would contraindicate safe participation in this 
study, they will be excluded.  Because older cardiac patients are likely to have at least one additional 
chronic disease, the presence of a comorbid medical condition is not, in itself, a reason for exclusion.  
Smoking and alcohol use also will be documented at screening, as well as during follow-up. 
 
6. Subject Recruitment and Compensation: One hundred fifty anxious CHD patients (approximately 
50% women and 25% minority) will be recruited from the North Carolina Piedmont region. Because 
children are unlikely to suffer a cardiac event, and age (and CHD risk factors) is strongly related to our 
intermediate endpoints, children will not be included in our proposed investigation. The catchment area 
from which we draw our research subjects encompasses the counties of Durham (pop. 192,566; 50% 
minority), Orange (pop. 104,186; 25% minority), Chatham (pop. 42,985; 21% minority), Alamance (pop. 
115,278; 20% minority), and Wake (pop. 518,206; 23% minority). We believe that recruitment from this 
geographic area will allow us to enroll sufficient minorities and patients from diverse socioeconomic 
backgrounds. It also should be noted that approximately 4,000 patients with suspected CHD are 
catheterized each year at Duke, with 70% (2,800 patients) having stenoses of >75% in at least 1 artery. 
At the Durham VA, 600 patients are catheterized annually, with 90% having CHD. More than 1,200 
patients undergo cardiac catheterizations at UNC, and more than 2,000 patients with stable CHD are in 
the UNC Health Care Network. Thus, there is an ample recruitment base for potential patients for this 
study. 
In addition to receiving free evaluations and treatment programs, subjects will be compensated 
with $125 for completing the study. And as a token of our appreciation for participation, and as a method 
of promoting participant engagement in the trial, we will send birthday and holiday cards to participants.  
 
7. Consent Process: Informed consent will be obtained during interviews between potential subjects 
and a member of the investigational team familiar with all aspects of the project. 
 
8. Subject’s Capacity to Give Legally Effective Consent: Subjects who are <18 years of age or with 
diminished capacity will be excluded.  
 
9. Study Interventions: 
 
 
Randomization:  All eligible subjects will be randomly assigned to one of the 3 treatment 
conditions.  Randomization will occur after each subject has completed the assessment protocol and will 
adhere to standard procedures for randomized clinical trials.[162]  We will employ a conditional 
randomization procedure wherein equal proportion of participants with anxiety disorders will be assigned 
to the respective treatment groups.  We also will stratify by gender (male/female), history of myocardial 
infarction (yes/no), and age (<60/>60).  Our anticipated sample size is 150 patients, wherein 
randomization will include 60 patients to Exercise Training, 60 patients to Medication, and 30 patients to 
Placebo. We anticipate needing to consent 300 patients in order to reach our sample size goal.  
 
  
1. 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 
treadmill 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. Weekly 
supervised exercise sessions may take place at one of four sites chosen by the patient: Duke 
Cardiopulmonary Rehabilitation at Croasdaile, WakeMed Health and Hospitals, UNC Wellness Center at 
Meadowmont, and Alamance Regional Medical Center. Although depending on the geographic location 
of participants, other sites may be recruited for participation.   

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At UNC Wellness Center at Meadowmont, Dr. Hinderliter will oversee recruitment and exercise 
interventions, provide active consultation and collaboration in all aspects of the study, and contribute to 
data analysis and manuscript writing, while Dr. Miller will assist with recruitment and oversee participation 
of subjects. Both investigators will have access to Duke PHI. At WakeMed, Beth Drossman and staff will 
work in their normal capacity to supervise patient exercise. At Alamance Regional Hospital, now owned 
by Cone Health, Jamie Athas will work in her normal capacity to supervise patient exercise.  
   
 
 
2/3. Medication/placebo.  Treatment in the medication and placebo pill arms will be supervised 
by Dr. Wei Jiang.  Drug dispensing will be performed by licensed pharmacists at the Duke Investigational 
Drug Services, who have extensive experience in clinical trials.  The pharmacists will maintain the blind 
and will dispense enough medication/placebo to last until the next visit.  Each bottle will have a label 
displaying the dose and the subject ID number of the patient who is to receive the medication/placebo.  
We will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of 
anxiety, in 5 mg capsules or matched placebo.  Medication will be dispensed as capsules of escitalopram 
or placebo in individually coded bottles.  A new bottle of medications will be dispensed at each medication 
dispensing visit to study staff.  Medication will be taken once daily in the morning but can be switched to 
once daily in the evening if deemed necessary.  Medication adherence will be assessed using pill count 
at each study visit. Medication adherence, defined as the percentage of days on which the medication 
was taken, will be compared between the two pill arms to determine whether group differences in HADS-
A scores could be attributed to differences in medication adherence.  
 
Patients will see Dr. Jiang (who will be blinded to pill condition) at week 0 (baseline), week 1, 
week 2, week 4, week 8, and week 12 with phone consultations at weeks 3 and 6.  Patients will be 
contacted weekly by telephone between regularly scheduled visits to take the STAI-State.  Dr. Jiang will 
make all medication adjustments based primarily upon STAI scores and safety/tolerability/side-effect 
assessments.  Patients will be randomly assigned to receive escitalopram (5 mg/d) or placebo.  
Depending on symptoms, daily escitalopram (or placebo) 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.  At 
week 4, if patients show no change or only minimal improvement, they will receive up to a maximum daily 
dose of 20 mg or placebo equivalent.  The dose can be reduced in the event of side effects.   Dr. Jiang 
is an experienced clinical investigator in pharmacological RCTs and will serve as the treating psychiatrist 
for this trial.  In all cases, the treating physician will use supportive measures to help manage medication 
side effects.  In cases of severe side effects or patient discomfort, the physician may elect to decrease 
the medication dosage at any time or permit unscheduled visits during the study.  At each medication 
dispensing visit, the patient will see the treating physician, who will prescribe the medication, and the 
study coordinator, who will order the medication, which will be signed off by the treating physician. The 
signed order will be released to and filled by the on-site investigational pharmacy.  The pharmacy will 
dispense enough medication to last to the next expected dispensing visit plus a 5-day window. Patients 
will be instructed to use their previous bottle of medication before opening and using the newest provided 
bottle(s). The pharmacy will be responsible for medication storage and verifying expiration, maintaining 
the blind, storing codes in a sealed envelope accessible at emergencies, and for dispensing medication.  
 
Patients and raters will be kept blinded to drug therapy assignments both during the treatment 
phase (3 months) and until the patient has completed the post-treatment assessments.  Dr. Jiang, who 
will perform the ongoing medication monitoring and safety ratings, will be blinded until the completion of 
the trial.  Limited use of sleep medications, but not other anxiolytic agents, will be permitted (see Human 
Subjects).  
 
10. Risk / Benefit Assessment: Potential risks and minimizing potential risks: Procedures for protecting 
subjects against potential risks include the careful screening procedure outlined in the application, weekly 
anxiety monitoring of all patients by a trained clinical psychologist, and the attendance of qualified 
personnel at all exercise testing and training sessions. The treatment duration is sufficiently brief (3 
months) to permit a placebo-controlled trial and yet is of adequate duration to produce therapeutic 

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benefits.  
The favorable efficacy profile with low incidence of side effects has led to SSRIs being the most 
frequently prescribed class of medications for treating anxiety disorders. After consultation with a number 
of experts in the psychopharmacological treatment of anxiety disorders, including our collaborator, Dr. 
Jonathan Davidson, we ultimately selected the FDA-approved SSRI anxiolytic agent escitalopram for this 
study, because it is among the more selective serotonin re-uptake inhibitors, has an optimal profile for 
safety and effectiveness in the treatment of anxiety disorders, and it has been used safely in cardiac 
patients in a variety of studies. 
Escitalopram also has been investigated across a range of anxiety disorders and has been found 
to be safe for elderly persons with CHD and central nervous system (CNS) disorders (e.g. dementia, 
stroke). Multiple studies have demonstrated that SSRIs are effective in improving various anxiety 
symptoms in animal models and individuals who do not have formally diagnosed anxiety disorders based 
on DSM criteria. The effects of escitalopram on GAD and other anxiety disorders have been well-
demonstrated in a variety of RCTs. Owing to multiple metabolic degrading pathways, the clinically 
relevant interactions of escitalopram with other drugs are minimal, which is especially important for our 
proposed study, since these cardiac patients are likely to be on multiple cardiac medications. Compared 
with other anxiolytic medications, escitalopram is generally better tolerated, its onset of action is relatively 
fast, it requires no dose adjustment in renal dysfunction and older age, and its use may have cost–
effective and cost–utility advantages. Therefore, we believe that escitalopram is the optimal choice as a 
safe and effective first-line option in the management of patients with high anxiety and with anxiety 
disorders. It should be noted that we also considered other medications, including different classes of 
medications for which anxiety is an indication (e.g., benzodiazepines), but rejected the use of medications 
such as diazepam because of potential adverse side effects (e.g., falls, cognitive impairment) and 
because such medications are addictive and promote drug dependence. Because of the relatively short 
(i.e., 12-weeks) intervention, patients randomized to placebo will have limited exposure to a “treatment” 
that may have minimal benefit. Moreover, only 30 patients (20%) will actually receive the placebo pill. 
The fact that 80% of patients will receive an active treatment (exercise or escitalopram) should also 
facilitate patient recruitment into the trial. 
The value of treating subclinical anxiety disorders with SSRIs also was carefully considered by 
our research team. In view of the growing evidence that elevated anxiety, and not simply the diagnosis 
of an anxiety disorder, is associated with impaired quality of life and increased CHD risk,[11, 12, 163] we 
believe that treating cardiac patients with elevated symptoms of anxiety is justified. Escitalopram is 
considered the first line of psychotropic medications for treating elevated anxiety symptoms and not just 
for treating an anxiety disorder, and it is regarded as one of the safest and most widely prescribed 
anxiolytic medications in the US.  The risks of receiving escitalopram include common side effects such 
as nausea, insomnia, headache, tremor, diarrhea, nervousness, dry mouth, increased sweating, and 
sexual dysfunction. Less common side effects include rash, bruising, agitation, and hyponatremia. We 
are also aware of recent FDA alerts regarding the possibility of SSRIs being associated with worsening 
of suicidal ideation, agitation, and depression, and we plan to include these warnings in the informed 
consent, and all patients will be counseled by the study psychiatrist about these potential risks. 
Importantly, we will exclude patients with a primary diagnosis of MDD, with active suicidal ideation, or 
who are judged to not be appropriate candidates for escitalopram or placebo therapy (e.g., prior non-
responders, psychotic depression, active suicidal ideation, severe agitation, etc.). If such adverse events 
should develop during the course of the study, we will refer them for appropriate care immediately. We 
estimate that less than 10% of the patients may drop out due to such side effects.  
 
11. Costs to the Subject: Subjects will not incur any costs related to study-related assessments or 
interventions.  
 
12. Data Management and Statistical Considerations 
 

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Data Analytic Approach.  The basic analytic strategy is a linear model carried out in the MPlus 
modeling software,[164] with treatment group contrasts as factors, and ethnicity, age, gender, and pre-
treatment measure of the outcome variable as the adjustment covariables. The intent-to-treat principle 
(ITT) will be followed in all models, using full information maximum likelihood available in MPlus to 
manage missing data.  For the case of the primary outcome, HADS-A, the model will include post-
treatment HADS-A score as the response, with the predictors including two planned contrast variables 
representing 1) the two active treatments (exercise and escitalopram) vs. placebo and 2) exercise vs. 
escitalopram, with ethnicity, gender, age, and pre-treatment level of the HADS-A as the adjustment 
covariables. The contrast tests among treatment groups will be examined directly, i.e., no omnibus or 
“gateway” test will be required before interpreting them.  In support of the HADS-A outcome, we also will 
compare the pattern of weekly changes in the STAI scores over time using a repeated measures model 
with Proc Mixed in SAS (SAS Institute, Cary, NC).  The primary biomarker outcome, HRV, will be 
evaluated similarly.   It is possible that a small number of participants may require off-protocol 
psychotropic medication during the course of the trial.  These participants will be included in the ITT 
analysis and will not be replaced. We also will perform a sensitivity analysis with change in medication 
included as an adjustment variable in the statistical model.  Finally, we will compare the treatments on 
the number of clinical events using a generalized linear model with the appropriate distributional form 
(e.g., negative binomial), using the same contrasts and covariates as in the linear model described above. 
 
  We also will examine treatment effects for a number of additional supportive outcome measures 
(e.g., BDI-II, QoL, inflammatory markers, BRS, urinary catecholamines, etc.).  Significant treatment 
effects for these variables will help us interpret our primary outcomes and may inform further study and 
clinical application.  For example, if the additional quality of life variables or CHD biomarker measures 
are also responsive to exercise treatment, it may indicate that exercise has a more global salutary effect 
above and beyond reducing anxiety.  Despite their importance, we recognize that conducting these 
additional comparisons raises the potential for an inflated Type I error rate.  We will therefore note in 
publications that these additional analyses represent exploratory analyses.  We shall otherwise carry 
these analyses out using the same modeling approach as we do for the primary treatment analyses, 
attending in particular to the distribution of the residuals for each model and modifying our approach 
accordingly.  The above models can be easily extended to include the 6-month follow-up measurement 
occasion. 
      
Prior to conducting these analyses, preliminary examination of the assumptions of the model will 
be conducted to examine the homogeneity of regression assumption.  This assumption requires that the 
relationship between treatment and the response variable be homogeneous for each level of the 
adjustment covariables.  Should the data indicate that this assumption is violated, we will model the 
corresponding multiplicative (interaction) term(s).  In addition to assessing the adequacy of the model 
with respect to the homogeneity of slopes assumption, we also will evaluate the model for violations of 
heteroscedasticity of errors and non-linearity using standard graphical methods.  Should these 
assumptions be violated, appropriate transformations (e.g., Box-Cox method) will be made.  All analyses 
of treatment effects for secondary hypotheses concerning continuous or binary variables will be 
conducted using the modeling capabilities available in MPlus. 
In addition to treatment effects, we also will test the hypothesis that pre- to post-treatment change 
in HADS-A scores will mediate the improvements in intermediate CHD biomarkers.  M-Plus allows a 
direct, formal test of this hypothesis via path analysis modeling.  For example, a model will be specified 
so that both active treatment groups will be contrasted against the placebo arm, with a variable 
representing the change in anxiety intervening between the treatment contrast variables and post-
treatment HRV (with the covariates, pre-treatment HRV, age, ethnicity, and gender).  Mediation is tested 
by examining the product of the two component path coefficients (treatment ->mediator->outcome) and 
its standard error, which yields the point estimate of the mediated effect along with the statistical 
significance of treatment on post-treatment biomarker (e.g., HRV) via change in HADS-A.[165]  We also 
will explore possible treatment-specific mediators (e.g., change in VO2 mediating change in HRV for the 
Exercise group).  In addition to the above tests, we will examine the impact of dropout on the estimates 

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of treatment effects using mixture modeling available in MPlus.  Specifically, we will examine the primary 
outcomes using Rubin’s Complier-Average Causal Effect Estimation (CACE) model,[166] which 
estimates the effect of treatment for all participants who adhere to the protocol irrespective of treatment 
group assignment.  We will explore possible moderators of the treatment effect using interaction terms.  
Specifically, we will examine the possible moderating effects of gender, race, patient expectations, and 
initial severity of anxiety (e.g., DSM-5 diagnosis for an anxiety disorder); if sufficient numbers, we also 
plan to explore individual diagnoses by adding treatment interaction terms for these variables 
simultaneously with the primary model, and using a pooled test of the terms to determine whether the 
individual terms should be interpreted.  Participants who voluntarily drop out of treatment or who are 
unable to complete our protocol will not be replaced but will undergo follow-up assessment.    
  
Power Analysis.   Our study is powered with a focus on the primary hypothesis test: the treatment 
effect on anxiety as measured by HADS-A scores.  We estimated power and sample size under the 
following assumptions: an alpha of .05, a linear model with age, gender, ethnicity, and baseline HADS-A 
score as covariates, a conservative estimate of the R-squared of .20 for the full model predicting post-
treatment HADS-A, a 15% attrition rate, and two planned contrasts: active treatment vs. placebo and 
exercise vs. escitalopram.  The comparison of primary interest will be active treatments vs. placebo.  We 
estimate that a sample size of 150 (127 after attrition) will yield .80 power to detect at least a .45 SD 
difference between the active treatments and Placebo.  In the general linear model, the exercise vs. 
escitalopram test will be only slightly less powered in being able to detect a .50 SD difference.  In 
response to a previous reviewer comment, we believe that achieving this effect size is feasible.  For 
example, in individuals with high anxiety sensitivity, Broman-Fulks[167] reported a .61 SD difference 
between exercisers and controls.  We also re-examined data from a subset of highly anxious patients 
(STAI>45; N=32) participating in our recently completed UPBEAT study[49] and found an effect size of 
.85 SDs on the STAI for both active treatments vs. placebo controls. We note that our power estimates 
are conservative in that the R-squared for the model is likely to be greater than .20 and dropout may be 
lower than 15%. With respect to the secondary outcome of HRV, our prior work showed that the R-
squared between the baseline covariates and HRV was .73, greatly increasing the power of the tests of 
treatment on HRV.  For the test of exercise vs. escitalopram on HRV, our primary CHD biomarker of 
interest, we will have a power of .80 to detect a .25 SD effect at alpha of .05.  Finally, for our ancillary 
outcomes, including FMD, lipids, urinary catecholamines, and inflammatory markers, we have sufficient 
pilot data for FMD, which we use as an exemplar for power estimates: our earlier work showed that for 
FMD, the multiple R-squared between the baseline covariates (age, gender, ethnicity, and baseline FMD) 
and FMD was .50.  Thus, we will have a power of .80 to detect a .34 SD effect for FMD with an alpha of 
.05.  We estimate the power for the secondary analysis of treatment on time-to-clinical-event, assuming 
an event rate of 50% in the placebo group (based on unpublished data from our prior work[49]), 42 
months for patient accrual, median follow-up time of 30 months and alpha =.05, is .80 to detect a reduction 
in event rate of 50% between both treatment groups and placebo, as well as .80 to detect a reduction in 
event rate of 56% between either intervention group individually and placebo.  Unpublished data from 
our recently completed ENHANCED trial[168] revealed a 54% reduction in major adverse cardiac events 
among patients participating in CR compared to a matched control group of patients who did not 
participate in exercise-based CR.  
 
13. Data and Safety Monitoring: Study participants will be closely monitored for side effects, level of 
anxiety, and suicide risk. All patients will receive a weekly phone call to assess their state of anxiety using 
the STAI-State instrument. For patients who have a secondary diagnosis of MDD, BDI-II item #9 will be 
administered along with the 20-item STAI; patients who score >1 on the item #9 of the BDI-II or who are 
judged to be at increased risk for suicidality will be evaluated by our study psychiatrist and referred for 
further treatment. For patients with a secondary diagnosis of MDD, suicidality will be assessed at each 
visit and by interim telephone contacts as needed. Subjects may experience no response to treatment or 
a worsening of symptoms; however, all subjects will be carefully monitored and withdrawn from the study 
if their symptoms worsen. If patients become suicidal, they will be evaluated by the treating psychiatrist 

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and appropriate referral or admission procedures will be initiated, such as to their referring physician or 
to the Duke Outpatient Affective Disorders Program, the Duke Psychology Clinic, or a local mental health 
center. Our study coordinator will contact the patient within 24 hours to make sure that he or she followed 
through with the referral. Furthermore, at the conclusion of the interventions, patients will be followed 
bimonthly via telephone and referred to their local physicians for further treatment, if necessary, or to the 
Outpatient Treatment Program at Duke University Medical Center or to the Duke Psychology Clinic.  
The Duke University Psychiatry Outpatient Clinic is staffed by Duke psychiatrists and 
psychologists who treat varying levels of severity of anxiety. The Duke University Psychology Clinic is 
staffed by the Duke clinical psychology faculty, postdoctoral fellows trained specifically in the treatment 
of anxiety disorders, and advanced clinical graduate students who see patients on a sliding fee schedule 
and who function under the supervision of licensed psychologists. We believe that these facilities, in 
addition to private practitioners in the community, can serve as appropriate referral sources for patients 
needing further treatment. We believe that careful monitoring of all patients entered into our protocol and 
tracking of all participants following the completion of the interventions will minimize risk to study 
participants. The study personnel, including physicians, psychologists, the study coordinator, and the 
physician's assistant, have the training and experience to provide the necessary safeguards for 
participation. 
The study clinicians all have extensive experience in the treatment of anxiety disorders. The study 
psychiatrist (Dr. Wei Jiang) has served as a PI or co-PI on a number of clinical trials including many 
patients with CHD (e.g., REMIT, SADHART, MIIT, SADHART-CHF). Finally, we will organize a Data 
Safety and Monitoring Board consisting of a cardiologist (Dr. David Sheps, University of Florida), 
psychiatrist (Dr. Leo Pozuelo, Cleveland Clinic), and biostatistician (Dr. Diane Catellier, RTI).  
At screening, if a patient is excluded on the basis of his or her suicide risk, study staff will contact 
the study psychiatrist (Wei Jiang, MD) and the study PI (James Blumenthal, PhD) to develop an 
appropriate safety plan, including referral for psychiatric care. The participant’s primary care physician, 
with patient consent and approval, also will be notified. Also at screening, patients will be informed of the 
potential side effects of SSRIs and the risks/benefits. Participants are required to inform the research 
team of any medication changes as prescribed by their medical providers. 
Management of Worsening Depression or Active Suicidal Ideation:  In addition to weekly 
assessments, participants are advised to contact the study team should they believe their symptoms 
become worse or they develop active suicidal ideation. An interim visit or phone contact with Dr. Jiang 
may be required. Patients who report suicidal ideation will be immediately evaluated by Dr. Jiang, the 
study psychiatrist. Patients who present with acute and active suicidal ideation will be terminated from 
the study and referred for further psychiatric care as needed.  
 
14. Privacy, Data Storage, and Confidentiality: All participant data will be kept in locked offices and 
electronic data in password-protected folders on the shared drive that are only accessible to key 
personnel. 
 

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