- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02516332
Exercise and Pharmacotherapy for Anxiety in Cardiac Patients
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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North Carolina
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Durham, North Carolina, United States, 27710
- Duke University Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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:
- Dementia, delirium;
- Schizophrenia, Schizoaffective, or other psychotic disorder;
- Psychotic features including any delusions or hallucinations; or
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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.
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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.
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Hospital Anxiety and Depression Scale (HADS), Anxiety
Time Frame: Baseline, 3 months
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The Hospital Anxiety and Depression Scale, Anxiety, is a 7-item subscale with scores ranging from 0-21, with higher scores indicating more anxiety.
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Baseline, 3 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Heart Rate Variability, SDNN (Msec)
Time Frame: Baseline, 3 months
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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).
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Baseline, 3 months
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Change in Baroreflex Sensitivity, ms/mm Hg
Time Frame: Baseline, 3 months
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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.
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Baseline, 3 months
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Change in Vascular Endothelial Function, Percentage of Dilation
Time Frame: Baseline, 3 months
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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.
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Baseline, 3 months
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Change in Inflammation (C-Reactive Protein, ug/ml)
Time Frame: Baseline, 3 months
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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.
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Baseline, 3 months
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Change in Urinary Catecholamines (Epinephrine and Norepinephrine, Unit-weighted Z-score)
Time Frame: Baseline, 3 months
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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.
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Baseline, 3 months
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Change in Lipids - Total Cholesterol, LDL (Low-density Lipoprotein), and HDL (High-density Lipoprotein); mg/dL
Time Frame: Baseline, 3 months
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Lipids were obtained from fasting blood samples and assays were measured enzymatically (LabCorp).
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Baseline, 3 months
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Other Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Change in Hospital Anxiety and Depression Scale, Total Score
Time Frame: 9 months, 15 months
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9 months, 15 months
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Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Blumenthal JA, Smith PJ, Jiang W, Hinderliter A, Watkins LL, Hoffman BM, Kraus WE, Liao L, Davidson J, Sherwood A. Effect of Exercise, Escitalopram, or Placebo on Anxiety in Patients With Coronary Heart Disease: The Understanding the Benefits of Exercise and Escitalopram in Anxious Patients With Coronary Heart Disease (UNWIND) Randomized Clinical Trial. JAMA Psychiatry. 2021 Nov 1;78(11):1270-1278. doi: 10.1001/jamapsychiatry.2021.2236.
- Blumenthal JA, Feger BJ, Smith PJ, Watkins LL, Jiang W, Davidson J, Hoffman BM, Ashworth M, Mabe SK, Babyak MA, Kraus WE, Hinderliter A, Sherwood A. Treatment of anxiety in patients with coronary heart disease: Rationale and design of the UNderstanding the benefits of exercise and escitalopram in anxious patients WIth coroNary heart Disease (UNWIND) randomized clinical trial. Am Heart J. 2016 Jun;176:53-62. doi: 10.1016/j.ahj.2016.03.003. Epub 2016 Mar 12.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Mental Disorders
- Cardiovascular Diseases
- Anxiety Disorders
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Psychotropic Drugs
- Serotonin Uptake Inhibitors
- Neurotransmitter Uptake Inhibitors
- Membrane Transport Modulators
- Serotonin Agents
- Antidepressive Agents
- Antidepressive Agents, Second-Generation
- Citalopram
Other Study ID Numbers
- Pro00064329
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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