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

Abstract

Importance: Anxiety is common among patients with coronary heart disease (CHD) and is associated with worse health outcomes; however, effective treatment for anxiety in patients with CHD is uncertain.

Objective: To determine whether exercise and escitalopram are better than placebo in reducing symptoms of anxiety as measured by the Hospital Anxiety and Depression-Anxiety Subscale (HADS-A) and in improving CHD risk biomarkers.

Design, setting, and participants: This randomized clinical trial was conducted between January 2016 and May 2020 in a tertiary care teaching hospital in the US and included 128 outpatients with stable CHD and a diagnosed anxiety disorder or a HADS-A score of 8 or higher who were older than 40 years, sedentary, and not currently receiving mental health treatment.

Interventions: Twelve weeks of aerobic exercise 3 times per week at an intensity of 70% to 85% heart rate reserve, escitalopram (up to 20 mg per day), or placebo pill equivalent.

Main outcomes and measures: The primary outcome was HADS-A score. CHD biomarkers included heart rate variability, baroreflex sensitivity, and flow-mediated dilation, along with 24-hour urinary catecholamines.

Results: The study included 128 participants. The mean (SD) age was 64.6 (9.6) years, and 37 participants (29%) were women. Participants randomized to the exercise group and escitalopram group reported greater reductions in HADS-A (exercise, -4.0; 95% CI, -4.7 to -3.2; escitalopram, -5.7; 95% CI, -6.4 to -5.0) compared with those randomized to placebo (-3.5; 95% CI, -4.5 to -2.4; P = .03); participants randomized to escitalopram reported less anxiety compared with those randomized to exercise (-1.67; 95% CI, -2.68 to -0.66; P = .002). Significant postintervention group differences in 24-hour urinary catecholamines were found (exercise z score = 0.05; 95% CI, -0.2 to 0.3; escitalopram z score = -0.24; 95% CI, -0.4 to 0; placebo z score = 0.36; 95% CI, 0 to 0.7), with greater reductions in the exercise group and escitalopram group compared with the placebo group (F1,127 = 4.93; P = .01) and greater reductions in the escitalopram group compared with the exercise group (F1,127 = 4.37; P = .04). All groups achieved comparable but small changes in CHD biomarkers, with no differences between treatment groups.

Conclusions and relevance: Treatment of anxiety with escitalopram was safe and effective for reducing anxiety in patients with CHD. However, the beneficial effects of exercise on anxiety symptoms were less consistent. Exercise and escitalopram did not improve CHD biomarkers of risk, which should prompt further investigation of these interventions on clinical outcomes in patients with anxiety and CHD.

Trial registration: ClinicalTrials.gov Identifier: NCT02516332.

Figure 1.. CONSORT Diagram of Trial Enrollment

CAD indicates coronary artery disease; ECG, electrocardiogram; LM, left main; MDD, major depressive disorder; PTSD, posttraumatic stress disorder.

Figure 2.. Pretreatment and Posttreatment Hospital Anxiety and Depression-Anxiety Subscale (HADS-A) Scores by Treatment Group

Observed mean HADS-A anxiety scores before and after treatment. All changes from pretreatment to posttreatment were statistically significant (−4.57; 95% CI, −5.22 to −3.92; P < .001). Compared with patients in the placebo group, those in the exercise and escitalopram groups showed significantly lower HADS-A scores (F_1,127 = 5.06; P = .03) and the escitalopram group showed lower HADS-A scores compared with the exercise group (F_1,127 = 10.82; P = .002). At posttreatment, there was no difference in HADS-A scores between the exercise group and placebo group (F_1,127 = 0.25; P = .69). Error bars represent SEs.

Figure 3.. 12-Week Time Course of State Anxiety by Treatment Group

Fitted values for the Spielberger State-Trait Anxiety Inventory-State (STAI-S) across 12 weeks of treatment. Covariates included age, sex, self-reported race and ethnicity, baseline Hospital Anxiety and Depression-Anxiety Subscale score, anxiety disorder diagnosis, history of myocardial infarction, and time in weeks. The 2 active treatment groups showed lower anxiety scores compared with the placebo group (F_1,126 = 7.15; P = .01) and the STAI-S scores for the exercise and escitalopram groups were comparable at the end of 12 weeks. The escitalopram group showed more rapid improvements in anxiety symptoms early in the treatment course, while reductions in the exercise group occurred primarily in the latter 6 weeks of the intervention (F_2,1374 = 5.76; P = .003 for treatment group × time interaction). To more fully characterize this interaction, unadjusted follow-up analyses of treatment group differences by treatment phase were examined across early (weeks 1 through 4), middle (weeks 5 through 8), and later treatment phases (weeks 9 through 12). Exploratory follow-up analyses found that although groups did not differ during the first phase of treatment, the escitalopram group began to diverge from the placebo group during the middle phase of treatment (−4.9 STAI-S points compared with placebo; 95% CI, −8.6 to −1.2) and continued to improve during the later phase of treatment (−6.1 STAI points compared with placebo; 95% CI, −10.6 to −1.7). In contrast, participants in the exercise group demonstrated a later trajectory of divergence, with only modest improvements in the middle phase of treatment (−2.6 points compared with placebo; 95% CI, −6.3 to 1.1) with further divergence in the later phase of treatment (−4.7 points compared with placebo; 95% CI, −9.2 to −0.1). Plotted lines represent fitted regression estimates using spline interpolation from exploratory analyses demonstrating that the effects of treatment varied over time.