Exercise and Pharmacotherapy for Anxiety in Cardiac Patients

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.

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.