An interventional study of Lexapro and Placebo in Anxiety and Cardiovascular Disease, sponsored by Duke University. Completed at 1 site in United States. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2021-06-11.
Sponsored by Duke University · Not applicable, Interventional, and Treatment
Coronary heart disease (CHD) is the leading cause of death in the United States; more than 600,000 Americans suffer a fatal cardiac event each year. Traditional CHD risk factors such as high blood pressure, smoking, and elevated cholesterol do not fully account for the timing and occurrence of CHD events and individuals with elevated levels of anxiety appear to have a greater risk of cardiovascular events. The present study will examine the impact of aerobic exercise and Lexapro in the treatment of anxiety and cardiovascular biomarkers among individuals with CHD.
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.
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This study's enrollment of 128 is above the median of 100 across 2,738 interventional studies indexed under Cardiovascular Diseases.
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Of its 194 completed or terminated interventional studies of FDA-regulated products, 159 (82%) have results posted.
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The study team plans to actively recruit women and minorities, with at least 50% women and 25% minorities.
Exclusion Criteria:
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:
Patients will exercise three times per week, under medical supervision, at a level of 70-85% of their VO2peak as determined at the time of their baseline exercise stress test. Patients' exercise will consist of 10 minutes of gradual warm-up exercises followed by 35 minutes of continuous walking, biking, or jogging, and 5 minutes of cool down exercises for a total a 50 minutes per session. Patients will be instructed to monitor their radial pulses and will be checked at least three times per session to ensure that they are within their prescribed exercise training ranges.
Behavioral: Supervised Aerobic Exercise
Treatment in the medication will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service. The investigators will use the SSRI escitalopram (Lexapro), which has received FDA approval for the treatment of anxiety, in 5 mg capsules. Medication will be dispensed as capsules of escitalopram in individually coded bottles. Medication adherence will be assessed using pill count at each study visit. Patients will visit face-to-face with a study psychiatrist at week 0 (baseline), week 1, week 2, week 4, week 8, and week 12 with phone encounters at weeks 3 and 6. The psychiatrist will make all medication adjustments based primarily upon Spielberger Anxiety Scores. Depending on symptoms, daily escitalopram doses will be titrated to 10 mg after week 2 and to 15 mg or placebo equivalent at week 3 if patients show no change or only minimal improvement.
Drug: Lexapro
Treatment in the medication and placebo pill arms will be supervised by a study psychiatrist. Drug dispensing will be done by licensed pharmacists at the Duke Investigational Pharmacy Service, who have extensive experience in clinical trials. Medication will be taken once daily in the morning but can be switched to once daily in the evening if deemed necessary. Placebo medication administration will follow the same protocol as outlined for Lexapro.
Drug: Placebo
Change in Hospital Anxiety and Depression Scale (HADS), Anxiety
The Hospital Anxiety and Depression Scale, Anxiety, is a 7-item subscale with scores ranging from 0-21, with higher scores indicating more anxiety.
Time frame: Baseline, 3 months
Change in Heart Rate Variability, SDNN (Msec)
To quantify heart rate variability (HRV), an electrocardiogram was recorded for 24-hours using the 3-channel DigiTrak XT Holter recorder (Philips Healthcare, Andover, Massachusetts). Electrocardiographic data were downloaded and edited using the Philips Zymed Holter analysis software (2010 Plus/1810 series) and HRV was estimated from the standard deviation of the normal-to-normal R-R intervals (SDNN).
Time frame: Baseline, 3 months
Change in Baroreflex Sensitivity, ms/mm Hg
To assess baroreflex sensitivity (BRS), beat-by-beat systolic blood pressure (SBP) and heart rate (HR) were collected using the Nexfin noninvasive BP monitor (Bmeye, Amsterdam, Netherlands). BRS was estimated from the magnitude of the transfer function relating R-R interval oscillations to SBP oscillations across the 0.07 to 0.1299 Hz, or low frequency band.
Time frame: Baseline, 3 months
Change in Vascular Endothelial Function, Percentage of Dilation
Endothelial function, assessed by Flow-Mediated Dilation (FMD), was determined from longitudinal B-mode ultrasound images of the brachial artery. Images were obtained using an Acuson (Mountain View, California) Aspen ultrasound platform with an 11-MHz linear-array transducer after 10 min of supine relaxation and during reactive hyperemia, induced by the inflation of a forearm pneumatic occlusion cuff to suprasystolic pressure (about 200 mm Hg) and subsequent deflation after 5 min. FMD was defined as the maximum percentage change in arterial diameter relative to resting baseline from 10 to 120 s after deflation of the occlusion cuff.
Time frame: Baseline, 3 months
Change in Inflammation (C-Reactive Protein, ug/ml)
High-sensitivity C-reactive protein was quantified by ELISA (LabCorp). Values \>10 mg/L were truncated at 10 to account for acute inflammatory processes that may have skewed the distribution of this blood marker.
Time frame: Baseline, 3 months
Change in Urinary Catecholamines (Epinephrine and Norepinephrine, Unit-weighted Z-score)
Urinary catecholamines, an index of sympathetic nervous system (SNS) activity, served as a biomarker of anxiety. Urinary concentrations of epinephrine (EPI) and norepinephrine (NE) were determined by high-pressure liquid chromatography (HPLC) with electrochemical detection (LabCorp). A composite 24-hr catecholamines z-score is presented. The z-score is the raw score minus the population mean, divided by the population standard deviation. A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time frame: Baseline, 3 months
Change in Lipids - Total Cholesterol, LDL (Low-density Lipoprotein), and HDL (High-density Lipoprotein); mg/dL
Lipids were obtained from fasting blood samples and assays were measured enzymatically (LabCorp).
Time frame: Baseline, 3 months
Change in Hospital Anxiety and Depression Scale, Total Score
Time frame: 9 months, 15 months
| Milestone | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Started | 52 | 53 | 23 |
| Completed | 50 | 52 | 21 |
| Not completed | 2 | 1 | 2 |
| Withdrew: Withdrawal by subject | 2 | 1 | 2 |
The Hospital Anxiety and Depression Scale, Anxiety, is a 7-item subscale with scores ranging from 0-21, with higher scores indicating more anxiety.
| score on a scale | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Change in Hospital Anxiety and Depression Scale (HADS), Anxiety | -3.9 (-4.6 to -3.2) | -5.7 (-6.4 to -5.0) | -3.5 (-4.6 to -2.5) |
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).
| msec | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Change in Heart Rate Variability, SDNN (Msec) | -0.3 (-22.5 to 22.0) | -8.7 (-31.4 to 13.9) | -1.1 (-37.1 to 35.0) |
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.
| ms/mm Hg | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Change in Baroreflex Sensitivity, ms/mm Hg | 1.2 (-7.0 to 9.4) | 1.3 (-4.9 to 7.4) | 1.5 (-10.6 to 13.6) |
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.
| percentage of dilation | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Change in Vascular Endothelial Function, Percentage of Dilation | 0.7 (-0.2 to 1.5) | 0.5 (-0.4 to 1.3) | 0.5 (-0.8 to 1.8) |
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.
| ug/ml | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Change in Inflammation (C-Reactive Protein, ug/ml) | -0.2 (-3.0 to 2.5) | 0.1 (-2.0 to 2.2) | -0.3 (-4.0 to 3.4) |
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.
| z-score | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Change in Urinary Catecholamines (Epinephrine and Norepinephrine, Unit-weighted Z-score) | 0.05 (-0.2 to 0.3) | -0.24 (-0.4 to 0.0) | 0.36 (0.0 to 0.7) |
Lipids were obtained from fasting blood samples and assays were measured enzymatically (LabCorp).
| mg/dL | Supervised Aerobic Exercise | Lexapro | Placebo |
|---|---|---|---|
| Total Cholesterol | -28.2 (-67.3 to 10.8) | -15.3 (-50.6 to 20.0) | -31.6 (-90.2 to 27.1) |
| LDL | -18.6 (-46.3 to 9.2) | -9.8 (-33.5 to 13.9) | -19.3 (-59.9 to 21.4) |
| HDL | 6.3 (-4.4 to 16.9) | 3.4 (-5.5 to 12.4) | 7.2 (-8.3 to 22.7) |
Results for this outcome have not been posted.
Collected over Baseline to 3 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Supervised Aerobic Exercise | 0/52 (0%) | 0/52 (0%) | 0/52 (0%) |
| Lexapro | 0/53 (0%) | 0/53 (0%) | 0/53 (0%) |
| Placebo | 0/23 (0%) | 0/23 (0%) | 0/23 (0%) |
| Age, Continuous(years) | Supervised Aerobic Exercise | Lexapro | Placebo | Total |
|---|---|---|---|---|
| Mean | 65.2 ± 10.1 | 63.9 ± 8.6 | 65.2 ± 10.8 | 64.6 ± 9.6 |
| Sex: Female, Male(Participants) | Supervised Aerobic Exercise | Lexapro | Placebo | Total |
|---|---|---|---|---|
| Female | 17 | 14 | 6 | 37 |
| Male | 35 | 39 | 17 | 91 |
| Ethnicity (NIH/OMB)(Participants) | Supervised Aerobic Exercise | Lexapro | Placebo | Total |
|---|---|---|---|---|
| Hispanic or Latino | 1 | 0 | 0 | 1 |
| Not Hispanic or Latino | 51 | 53 | 23 | 127 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Supervised Aerobic Exercise | Lexapro | Placebo | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 1 | 4 | 0 | 5 |
| Asian | 2 | 0 | 0 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 8 | 12 | 5 | 25 |
| White | 40 | 36 | 18 | 94 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 1 | 1 | 0 | 2 |
| Region of Enrollment(Participants) | Supervised Aerobic Exercise | Lexapro | Placebo | Total |
|---|---|---|---|---|
| United States | 52 | 53 | 23 | 128 |
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