Cardiac rehabilitation (CR) represents the standard of care for patients with coronary heart disease. Despite considerable epidemiological evidence that high levels of stress are associated with worse prognosis, there is limited evidence that reducing stress improves clinical outcomes. Enhancing Standard Cardiac Rehabilitation With Stress Management Training in Patients With Coronary Heart Disease (ENHANCED) was a randomized, clinical trial in which patients referred to CR completed a psychometric stress battery and underwent evaluation of coronary heart disease biomarkers, including measures of endothelial dysfunction, heart rate variability, baroreflex sensitivity, and inflammation, before and after a 12-week treatment program of comprehensive CR alone (n=75) or comprehensive CR enhanced by stress management training (SMT; n=76). SMT consisted of 12 weekly 1.5-hour sessions that provided education, group support, and instruction in methods for coping more effectively with stress (eg, time management, progressive muscle relaxation training, cognitive restructuring, communication skills). A nonrandom sample of CR-eligible patients who declined to engage in CR formed a no-CR comparison group. Results showed that although both CR groups reported less stress, CR enhanced by SMT achieved greater reductions in stress compared with CR alone. Compared with the matched no-CR comparison group, both CR groups had fewer clinical events (all-cause mortality, fatal and nonfatal myocardial infarction, coronary or peripheral artery revascularization, stroke/transient ischemic attack, and unstable angina requiring hospitalization). Moreover, combining stress management training with CR (ie, CR+SMT) resulted in better clinical outcomes compared with CR alone. These findings confirm the value of CR in reducing the risk for adverse clinical events. Furthermore, SMT provided incremental value to standard CR by further reducing stress and improving clinical outcomes. Including SMT as a routine component of standard CR, regardless of patients’ reported levels of stress, should be encouraged.
Enhancing Cardiac Rehabilitation With Stress Management Training: A Randomized, Clinical Efficacy Trial
Abstract
Background—
Cardiac rehabilitation (CR) is the standard of care for patients with coronary heart disease. Despite considerable epidemiological evidence that high stress is associated with worse health outcomes, stress management training (SMT) is not included routinely as a component of CR.
Methods and Results—
One hundred fifty-one outpatients with coronary heart disease who were 36 to 84 years of age were randomized to 12 weeks of comprehensive CR or comprehensive CR combined with SMT (CR+SMT), with assessments of stress and coronary heart disease biomarkers obtained before and after treatment. A matched sample of CR-eligible patients who did not receive CR made up the no-CR comparison group. All participants were followed up for up to 5.3 years (median, 3.2 years) for clinical events. Patients randomized to CR+SMT exhibited greater reductions in composite stress levels compared with those randomized to CR alone (P=0.022), an effect that was driven primarily by improvements in anxiety, distress, and perceived stress. Both CR groups achieved significant, and comparable, improvements in coronary heart disease biomarkers. Participants in the CR+SMT group exhibited lower rates of clinical events compared with those in the CR-alone group (18% versus 33%; hazard ratio=0.49; 95% confidence interval, 0.25–0.95; P=0.035), and both CR groups had lower event rates compared with the no-CR group (47%; hazard ratio=0.44; 95% confidence interval, 0.27–0.71; P<0.001).
Conclusions—
CR enhanced by SMT produced significant reductions in stress and greater improvements in medical outcomes compared with standard CR. Our findings indicate that SMT may provide incremental benefit when combined with comprehensive CR and suggest that SMT should be incorporated routinely into CR.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00981253.
Introduction
Cardiac rehabilitation (CR) is integral to the optimal medical care of patients with coronary heart disease (CHD).1,2 Physical exercise, medical management of elevated blood pressure and lipids, nutritional counseling, and smoking cessation are core components of CR in this country. Although no single study has demonstrated definitively that exercise improves clinical outcomes in CHD patients, a recent meta-analysis concluded that CR reduces cardiovascular mortality and hospitalizations and improves quality of life.3
Clinical Perspective on p 1350
Stress management training (SMT) is not routinely included as a component of CR programs, despite mounting epidemiological evidence that elevated levels of stress are associated with greater risk of death and nonfatal cardiac events.4–6 The fact that SMT is not offered may be the result of inconsistencies in the literature on the relationship between stress and CHD, a lack of consensus about how stress is defined and measured, uncertainty about what approach is most effective, and limited support for the effectiveness of SMT in reducing stress and in improving clinical outcomes in patients with CHD.7 We previously found that CHD patients with mental stress–induced myocardial ischemia receiving either SMT or exercise training had better clinical outcomes compared with control subjects receiving usual care8 and that SMT and exercise each produced comparable improvements in psychological functioning, as well as greater improvements in CHD biomarkers, compared with control subjects receiving usual care.9 Although these findings are encouraging, the added value of combining SMT with exercise training was not assessed. Stand-alone SMT interventions also may have limited real-world relevance because such treatments are often not available in traditional disease-management programs.
The present study was designed to evaluate the potential incremental benefit of SMT when combined with comprehensive CR on a composite measure of psychological stress and CHD biomarkers of risk. In addition, we examined the impact of CR in the CR-alone and CR+SMT groups compared with a nonrandomized, matched-comparison group of CR-eligible patients who elected not to participate in CR (no-CR group) on adverse clinical events over a follow-up period of up to 5.3 years.
Methods
Eligibility and Trial Overview
Enhancing Cardiac Rehabilitation With Stress Management Training in Patients With Heart Disease (ENHANCED) was an efficacy trial examining the effects of SMT when added to comprehensive CR on self-reported stress, CHD biomarkers, and clinical outcomes. Participants underwent baseline measurement of stress, traditional CHD risk factors, and CHD biomarkers and were randomly assigned to either comprehensive CR or comprehensive CR enhanced by SMT (CR+SMT). Participants were reassessed at the completion of the 12-week program and were followed up for clinical events for a median of 3.2 years (range, 0.1–5.3 years). Assessors were blinded to patients’ treatment group assignment at the time of posttreatment assessments, and end points were adjudicated without knowledge of patients’ treatment. The primary end point was a composite psychometric measure of stress. Secondary outcomes included CHD biomarkers and adverse cardiovascular events. A nonrandom sample of CR-eligible CHD patients formed a comparison group for the purpose of determining the event rates for patients with similar demographic and clinical characteristics who elected not to participate in CR.
This study was supported by grant HL093374 from the National Heart, Lung, and Blood Institute; the sponsor had no involvement in the design of the study; the collection, analysis, and interpretation of the data; or in the decision to approve publication of the finished manuscript.
Participants
Outpatients with stable CHD were referred for CR by their personal physicians and underwent medical screening examinations to confirm eligibility. Indications for CR included recent acute coronary syndrome, stable angina with angiographic evidence of coronary disease, and recent coronary revascularization (coronary artery bypass graft surgery or percutaneous coronary intervention). Exclusion criteria included surgery primarily for valve replacement or repair, heart transplantation, left ventricular ejection fraction <30%, and unrevascularized left main stenosis >50%. The protocol was approved by the respective Institutional Review boards at Duke University and the University of North Carolina, and written informed consent was obtained from all participants. The first patient was randomized on April 6, 2010, and the last date for medical event adjudication was July 15, 2015.
Assessment Procedures
Psychological Stress
A global stress measure was the primary outcome, combining the following components with the use of a mean rank constructed separately for each measure at baseline and following treatment10:
Beck Depression Inventory II (BDI-II)11: The 21-item BDI-II is a widely used measure of depression. Scores range from 0 to 63, with higher scores suggesting greater depressive symptoms. Scores ≥14 are suggestive of clinically significant depressive symptoms.
State-Trait Anxiety Inventory (STAI)12: The 20-item STAI was used to assess levels of state anxiety. Scores range from 20 to 80; scores ≥40 suggest clinically significant anxiety in medical patients.13
Patient-Reported Outcomes Measurement Information System (PROMIS) Anger14: The 8-item PROMIS Anger scale assesses several dimensions of anger. Scores range from 8 to 40, with higher scores indicating greater anger.
General Health Questionnaire15: The General Health Questionnaire is a 12-item measure of general distress. Scores range from 0 to 36, with higher scores indicating greater emotional distress.
Perceived Stress Scale16: The 10-item Perceived Stress Scale assesses general distress and perceived ability to adequately cope with current life stressors. Scores range from 0 to 40, with higher scores indicate greater perceived stress.
Exercise Tolerance and Physical Activity
Exercise Treadmill Testing
Patients exercised to exhaustion or other standard end points under continuous electrocardiographic monitoring with a ramped Bruce protocol.17
Accelerometry
Physical activity during daily life was quantified by recording the number of steps on 2 successive days with the Kentz Lifecorder Plus accelerometer NL-2160 (LC; Suzuken Co Ltd, Nagoya Japan).
Leisure-Time Physical Activity
Participants completed the Godin Leisure-Time Exercise Questionnaire18 in which they indicated the number of times they engaged in mild, moderate, and strenuous exercise for >15 minutes.
Blood Lipids
Lipids were measured enzymatically from fasting blood samples (LabCorp Inc, Burlington, NC).
CHD Biomarkers of Inflammation and Autonomic Function
High-sensitivity C-reactive protein was quantified by ELISA. Values >10 mg/L were truncated at 10 to account for acute inflammatory processes that may have skewed the distribution of this blood marker.
Heart rate variability and baroreflex sensitivity were obtained from beat-to-beat heart rate and blood pressure recorded from patients in the supine position with a Nexfin noninvasive blood pressure monitor (Nexfin model 1, BMEYE BV, Amsterdam, the Netherlands).19 Heart rate variability was assessed from R-R interval changes elicited during a 100-second controlled breathing task and during 5 minutes of normal relaxed breathing by estimating power spectra with the Welch algorithm.20 Baroreflex sensitivity also was estimated during this 5-minute resting condition with the use of cross-spectral analysis to estimate the magnitude of the transfer function relating R-R interval oscillations to systolic blood pressure oscillations across the 0.07- to 0.1299-Hz, or low-frequency, band.
Medical End Points
Patients documented all medical encounters annually up to 5 years after enrollment. Medical records were reviewed, and events, categorized on the basis of American College of Cardiology/American Heart Association criteria,21 were adjudicated by a physician assistant and a study cardiologist blinded to treatment condition. The following medical events were included: all-cause mortality, fatal and nonfatal myocardial infarction (MI), coronary or peripheral artery revascularization, stroke/transient ischemic attack, and unstable angina requiring hospitalization.
Interventions
Patients were randomized to either comprehensive CR alone or CR+SMT. All patients were followed up medically by their local cardiologists or primary care physicians, who were blinded to treatment condition and who managed any episodes of escalating symptoms or evidence of disease progression.
Comprehensive Cardiac Rehabilitation
Patients participated in CR at Duke University’s Center for Living (n=113) and the University of North Carolina’s Wellness Center in Chapel Hill (n=38). Comprehensive CR programs are similar throughout the state of North Carolina; patients engage in aerobic exercise 3 times a week for 35 minutes at a level of 70% to 85% of their heart rate reserve as determined at the time of their initial exercise treadmill test. Patients also received education about CHD, nutritional counseling based on American Heart Association guidelines, and 2 classes devoted to the role of stress in CHD.
SMT-Enhanced CR
Patients in the CR+SMT group received the identical comprehensive CR intervention plus SMT. SMT was adapted from our previous work,8,9 which combined education, group support, and cognitive-behavior therapy. The intervention was delivered in 12 weekly 1.5-hour sessions in groups of 4 to 8 participants. The SMT intervention is based on a cognitive-behavioral model in which stress is conceptualized as an imbalance between high demands (often environmental but also can be self-imposed) and more limited coping resources. Therefore, the intervention is directed at reducing demands and increasing coping abilities. The initial sessions are designed to establish rapport, to promote group cohesion and social support, and to provide a scientific basis for the importance of stress as a risk factor for adverse cardiovascular events. Strategies for reducing demands, including prioritizing, time management, establishing personal values, and avoiding stress-producing situations, are presented. Subsequent sessions focus on modifying responses to situations that cannot be readily changed. Several sessions are devoted to training in progressive muscle relaxation techniques and the use of visual imagery to reduce stress. Emphasis is placed on the importance of cognitive appraisals in affecting stress responses, with recognition of irrational beliefs and cognitive distortions such as overgeneralization, catastrophizing, and all-or-nothing thinking. Later sessions focus on the importance of effective communication, including topics of assertiveness and anger management. Instruction in problem-solving strategies is also provided in which participants are encouraged to apply the skills that they have learned to address everyday problems. Methods included brief lectures, group discussion, role playing, instruction in specific behavioral skills, and weekly homework assignments.
Nonrandomized, No-CR Comparison Group
To estimate the impact of CR, with and without SMT, on clinical outcomes, we collected medical event data for comparison with individuals who were referred to CR during the same time period as the CR-alone and CR+SMT participants but who elected not to participate. Eligible patients were stratified on the basis of age, sex, history of MI, and date of referral. A total of 886 patients whose geographical location would have enabled them to participate in CR at Duke or University of North Carolina through CR referral records were identified, from whom 75 were randomly selected, within strata by research personnel blinded to patients’ medical outcome data. Patients found to have enrolled in CR elsewhere also were excluded, although participation in self-initiated physical activity or stress reduction (eg, psychotherapy) was permitted.
Statistical Analysis
Treatment effects were evaluated with general linear models adjusted for baseline through SAS 9.2 (PROC GLM, SAS Institute, Cary, NC). For our primary analysis of change in stress, a preplanned rank-based global measure of stress was created with the use of the BDI-II, General Health Questionnaire, STAI, PROMIS Anger, and Perceived Stress Scale scores. In this approach, the global measure was created by ranking each participant on each individual stress measure at baseline and after treatment.10 A mean rank score was created by averaging across all stress measures at pretreatment and after treatment. Treatment effects were analyzed following the intention-to-treat principle, with posttreatment missing data (<5%) managed with multiple imputation methods available in SAS (PROC MI). We first examined changes in our global stress outcome and, if significant, explored changes in individual components of the stress composite in a secondary explanatory step.22 Our primary interest was not so much to identify which component is important but rather to assess the effectiveness of treatment on a single, global measure of stress based on the elements making up the stress construct. We did not correct for multiple components because, as noted by Tandon,23 the Bonferroni correction fails to make efficient use of the collective data, especially when one expects several measures (eg, stress, anger, depression, anxiety) to behave similarly and there is no a priori reason to believe that one of these measures would be more significant than another. Analyses of treatment changes in CHD biomarkers, lipids, and aerobic fitness/physical activity were conducted with the posttreatment value used as the outcome variable, controlling for the respective pretreatment level, with group assignment as the predictor of interest. In these analyses, a Bonferroni correction was applied to adjust for multiple comparisons separately within each outcome domain (ie, CHD biomarkers, lipids, and aerobic fitness/physical activity).
For analysis of clinical events, we evaluated the effects of treatment using Cox proportional hazards model (PROC PHREG) with dummy coding constructed to compare the CR, CR+SMT, and nonrandomized no-CR comparison groups. To account for potential treatment differences in important medical predictors of clinical events, we controlled for age, heart failure, and treatment site in our models. Within our analyses of clinical event models, the first event after randomization was coded as the event, and those participants with no events or who dropped out were censored at the time of last contact. We also examined the impact of treatment on clinical events among CR+SMT and CR-alone participants compared with the no-CR group. We evaluated the extent to which models met assumptions, including additivity, linearity, proportional hazards, and distribution of residuals. A priori power estimates suggested that we would have 80% power to detect a 0.47-SD difference in the stress composite between the CR+SMT and CR-alone groups.
Results
Participant Flow
Figure 1 displays the flow of participants during the trial. Of the 577 individuals who were considered for CR, 164 met initial inclusion criteria and 151 were randomized: 75 to comprehensive CR and 76 to CR+SMT.
Medical outcome data also were obtained for 75 individuals who were referred to CR but, for a variety of reasons (eg, inconvenient, too busy, preferred to exercise on their own, not interested), elected not to participate in CR (no-CR).
Participant Characteristics
Demographic, background, and medical characteristics of the CR groups and no-CR patients are shown in Table 1. The treatment groups were similar on background clinical and demographic characteristics and were similar to the no-CR comparison group.
| Variable | CR+SMT(n=76) | CR Alone (n=75) | No CR (n=75) |
|---|---|---|---|
| Background and demographics | |||
| Age, mean (SD), y | 61.8 (10.8) | 60.4 (10.6) | 60.9 (9.1) |
| Female, n (%) | 31 (41) | 24 (32) | 28 (37) |
| White, n (%) | 58 (76) | 51 (68) | 50 (67) |
| Married or cohabitating, n (%) | 50 (66) | 49 (65) | 41 (55) |
| Employed full-time, n (%) | 29 (38) | 28 (37) | 34 (45) |
| Current or former smoker, n (%) | 38 (50) | 41 (55) | 49 (65) |
| Body mass index, mean (SD), kg/m2 | 30.2 (5.9) | 30.8 (5.2) | 30.3 (5.8) |
| Medical history | |||
| Hypertension, n (%) | 58 (76) | 60 (80) | 58 (77) |
| Hyperlipidemia, n (%) | 61 (80) | 57 (76) | 64 (85) |
| Diabetes mellitus, n (%) | 25 (33) | 31 (41) | 28 (37) |
| MI history, n (%)* | 38 (50) | 43 (57) | 41 (55) |
| CABG history, n (%)* | 21 (28) | 17 (23) | 22 (29) |
| Heart failure, n (%) | 5 (7) | 3 (4) | 5 (7) |
| Chronic kidney disease, n (%) | 2 (3) | 3 (4) | 3 (4) |
| Charlson Comorbidity Index, mean (SD) | 1.2 (1.1) | 1.3 (1.0) | 1.3 (1.1) |
| LVEF, mean (SD), % | 55.1 (9.6) | 54.3 (7.4) | 54.3 (7.0) |
| Indication for CR, n (%) | |||
| CABG | 19 (25) | 10 (13) | 19 (25) |
| PCI† | 29 (38) | 23 (31) | 11 (15) |
| MI | 3 (4) | 8 (11) | 11 (15) |
| MI+CABG | 2 (3) | 2 (3) | 4 (5) |
| MI+PCI | 20 (37) | 26 (35) | 20 (27) |
| Angina | 3 (4) | 6 (8) | 10 (13) |
| ACE inhibitor or angiotensin receptor blocker, n (%) | 47 (62) | 55 (73) | 46 (61) |
| β-Blocker, n (%) | 66 (87) | 67 (89) | 66 (88) |
| Calcium channel blocker, n (%) | 10 (13) | 17 (23) | 13 (17) |
| Diuretic, n (%) | 22 (29) | 23 (31) | 24 (32) |
| Other blood pressure medication, n (%) | 2 (3) | 5 (7) | 2 (3) |
| Diabetes medication, n (%) | 22 (29) | 25 (33) | 32 (43) |
| Nitrates, n (%) | 42 (55) | 43 (57) | 43 (57) |
| Aspirin, n (%) | 72 (95) | 72 (96) | 73 (97) |
| Other antiplatelet medication, n (%) | 56 (74) | 53 (71) | 45 (60) |
| Psychotropic medication, n (%) | 26 (34) | 26 (35) | 24 (32) |
| Statin, n (%) | 66 (87) | 66 (88) | 65 (87) |
| Lipids and blood pressure, mean (SD) | |||
| Total cholesterol, mg/dL | 175.4 (46.4) | 161.7 (42.0) | … |
| LDL cholesterol mg/dL† | 109.6 (42.5) | 94.1 (40.6) | … |
| HDL cholesterol, mg/dL | 40.5 (11.9) | 41.6 (11.9) | … |
| Serum triglycerides, mg/dL | 132.8 (74.4) | 150.1 (88.4) | … |
| Systolic blood pressure, mm Hg | 113.5 (15.0) | 116.6 (16.7) | … |
| Diastolic blood pressure, mm Hg | 61.9 (7.6) | 62.9 (9.0) | … |
| Aerobic fitness and physical activity, mean (SD) | |||
| Exercise treadmill test duration, min | 7.7 (2.5) | 7.3 (2.4) | … |
| Metabolic equivalents | 8.6 (2.4) | 8.2 (2.6) | … |
| Accelerometry steps, n | 10 774 (5783) | 10 840 (6312) | … |
| Accelerometry light activity, min | 29.9 (14.1) | 31.5 (16.8) | … |
| Accelerometry moderate activity, min | 91.6 (53.2) | 91.5 (59.1) | … |
| Accelerometry total activity, min | 121.7 (63.1) | 123.4 (70.1) | … |
| Leisure-time physical activity, min | 22.4 (19.7) | 18.5 (22.5) | … |
| CHD biomarkers, mean (SD) | |||
| HRV-DB, ms | 149 (118) | 171 (123) | … |
| Low-frequency HRV, ln ms2 | 4.0 (1.1) | 4.2 (1.4) | … |
| High-frequency HRV, ln ms2 | 4.9 (0.9) | 5.2 (1.2) | … |
| Baroreflex sensitivity, ms/mm Hg | 6.1 (3.7) | 7.0 (5.1) | … |
| hsCRP, mg/L | 2.6 (3.1) | 2.7 (2.8) | … |
| Composite stress measures, mean (SD) | |||
| BDI-II | 8.1 (7.7) | 9.0 (9.0) | … |
| STAI-S | 35.1 (11.8) | 36.3 (11.8) | … |
| PROMIS Anger | 16.1 (5.5) | 16.2 (6.1) | … |
| General Health Questionnaire | 12.6 (5.9) | 12.3 (6.0) | … |
| Perceived Stress | 15.3 (8.2) | 15.4 (7.9) | … |
ACE indicates angiotensin-converting enzyme; BDI-II, Beck Depression Inventory-II; CABG, coronary artery bypass grafting; CHD, coronary heart disease; CR, cardiac rehabilitation; ENHANCED, Enhancing Standard Cardiac Rehabilitation With Stress Management Training in Patients With Coronary Heart Disease; HDL, high-density lipoprotein; HRV, heart rate variability; HRV-DB, heart rate variability during deep breathing; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; PROMIS, Patient-Reported Outcomes Measurement Information System; SMT, stress management training; and STAI-S, Spielberger Anxiety Inventory-State.
*
Includes medical history for event and current indication for referral to CR (ie, recent event).
†
P<0.05 for treatment group differences.
Treatment Adherence
Exercise attendance was similar for both CR groups. Participants in CR alone and CR+SMT each completed a mean of 33 of a possible 36 exercise sessions (92% attendance). Attendance at SMT classes was excellent, with participants attending a median of 11 of 12 sessions. Six participants (4%) did not complete the treatment protocol: 3 from CR and 3 from CR+SMT.
We used a modified version of the Morisky Adherence Scale24 to assess medication adherence before and after the 12-week CR program, with scores ranging from 0 to 7. Participants in CR-alone and CR+SMT were very adherent on study entry: 95% indicated that they never or rarely missed taking their heart medications. Adherence was maintained over the 12 weeks, and there was no difference in adherence between the 2 groups after treatment (CR+SMT=0.30, CR-alone=0.36; P=0.52).
Effects of Treatment on Stress
Time and treatment changes for the stress measures are presented in Table 2, adjusted for the pretreatment level of each outcome. Both CR groups showed reductions on each stress component after treatment (P≤0.001). A treatment group main effect was observed for the global stress score in which the CR+SMT group showed greater reductions compared with the CR-alone group (P=0.022). In secondary explanatory analyses, we found that the CR+SMT group showed greater improvements in anxiety (STAI; P=0.025) and distress (General Health Questionnaire; P=0.049) and tended to show greater reductions in perceived stress (Perceived Stress Scale; P=0.063) compared with the CR-alone group. The univariate analyses of the stress components were not corrected and serve as a guide to interpretation of the global test results. Of note, 34 individuals exhibited clinically elevated levels of depression before treatment (ie, BDI-II ≥14) and 48 individuals reported clinically significant levels of anxiety (STAI ≥40). In supplementary analyses among this depressed subgroup, individuals in the CR+SMT group exhibited 14.0-point reduction (95% confidence interval [CI], 9.2–18.8) on the BDI-II, compared with reductions of 7.8 (95% CI, 2.7–12.9) points in the CR group (P=0.07). Individuals with high anxiety in the CR+SMT group reported a 14.2-point reduction (95% CI, 9.6–18.8) compared with a 9.8-point (95% CI, 5.4–14.2) reduction in the CR-alone group (P=0.18).
| Variable | CR+SMT (n=76) | CR (n=75) | Cohen d | Time Effect | P, CR+SMT Versus CR |
|---|---|---|---|---|---|
| Beck Depression Inventory-II | −3.5 (−5.0 to −2.1) | −2.6 (−4.1 to −1.2) | 0.15 | <0.001 | 0.37 |
| Spielberger Anxiety Inventory-State | −5.6 (−7.4 to −3.7) | −2.6 (−4.5 to −0.7) | 0.37 | <0.001 | 0.025 |
| General Health Questionnaire | −4.8 (−5.8 to −3.7) | −3.3 (−4.4 to −2.2) | 0.33 | <0.001 | 0.049 |
| PROMIS Anger questionnaire | −2.0 (−3.0 to −1.0) | −1.0 (−2.1 to 0.0) | 0.22 | 0.001 | 0.16 |
| Perceived Stress Scale | −4.2 (−5.4 to −3.0) | −2.6 (−3.9 to −1.3) | 0.30 | <0.001 | 0.063 |
Values are represent change scores (T2−T1) and are presented as mean change (95% confidence interval). Effect sizes are presented with the Cohen d. P values are not adjusted for multiple testing. CR indicates cardiac rehabilitation; PROMIS, Patient-Reported Outcomes Measurement Information System; and SMT, stress management training.
CHD Biomarkers, Lipids, and Exercise Capacity/Physical Activity
CR, alone and combined with SMT, was associated with significant improvements in CHD biomarkers, lipids, and exercise capacity/physical activity during daily life. However, there were no treatment group differences on any of the measures (Table 3).
| Variable | CR+SMT (n=76) | CR (n=75) | Time Effect | P, CR+SMT Versus CR |
|---|---|---|---|---|
| Lipids, mg/dL | ||||
| Total cholesterol | −22.9 (−31.9 to −14.0) | −20.0 (−29.7 to −10.2) | <0.01 | 0.99 |
| LDL cholesterol | −24.2 (−31.7 to −16.8) | −22.4 (−30.5 to −14.3) | <0.01 | 0.99 |
| HDL cholesterol | 3.0 (1.2 to 4.7) | 2.7 (0.7 to 4.6) | <0.01 | 0.99 |
| Triglycerides | −7.4 (−21.2 to 6.4) | −11.2 (−26.6 to 4.2) | 0.22 | 0.99 |
| CHD biomarkers | ||||
| hsCRP, mg/L | −0.9 (−1.4 to −0.5) | −0.4 (−0.9 to 0.0) | <0.01 | 0.95 |
| HRV-DB, ms | 13.1 (−8.0 to 34.3) | 26.0 (5.5 to 46.5) | 0.055 | 0.99 |
| Low-frequency HRV, log transformed | 0.17 (−0.08 to 0.41) | 0.28 (0.04 to 0.51) | 0.075 | 0.99 |
| High-frequency HRV, log transformed | 0.08 (−0.11 to 0.27) | 0.22 (0.03 to 0.41) | 0.17 | 0.99 |
| Baroreflex sensitivity, ms/mm Hg | 0.47 (−0.39 to 1.33) | 0.93 (0.09 to 1.77) | 0.21 | 0.99 |
| Aerobic fitness and physical activity | ||||
| Leisure-time physical activity, min | 20.6 (15.6 to 25.5) | 15.9 (10.8 to 21.0) | <0.01 | 0.67 |
| Exercise treadmill duration, min | 1.2 (0.8 to 1.7) | 1.5 (1.1 to 1.9) | <0.01 | 0.99 |
| Exercise treadmill metabolic equivalents | 1.5 (1.1 to 1.8) | 1.5 (1.2 to 1.9) | <0.01 | 0.99 |
| Accelerometry total steps, n | 1412 (213 to 2610) | 687 (−520 to 1893) | 0.092 | 0.99 |
Values are presented as mean change scores from baseline (95% confidence intervals). P values are adjusted for multiplicity within each domain with a Bonferroni correction. CHD indicates coronary heart disease; HDL, high-density lipoprotein; HRV, heart rate variability; HRV-DB, heart rate variability during deep breathing; hsCRP, high-sensitivity C-reactive protein; and LDL, low-density lipoprotein.
Comparison of Clinical Events in the CR-Alone and CR+SMT Groups
Thirty-nine participants (26%) experienced a clinical event over a follow-up period of up to 5.3 years (median, 3.2 years; interquartile range, 2.2, 4.3 years; Table 4). Time-to-event models demonstrated that participants randomized to CR+SMT experienced a lower event rate (18%) compared with individuals randomized to CR (33%; hazard ratio [HR]=0.47; 95% CI, 0.24–0.91; P=0.03). The estimated optimism for model fit was modest (17%), suggesting minimal bias from overfitting.
| Group | Total Events, n (%) | Death, n | MI, n | Stent/CABG, n | Stroke/TIA, n | Peripheral Revascularization, n | AnginaRequiring Hospitalization, n |
|---|---|---|---|---|---|---|---|
| CR+SMT (n=76) | 14 (18) | 0 | 1 | 9 | 1 | 1 | 2 |
| CR alone (n=75) | 25 (33) | 2 | 6 | 11 | 1 | 3 | 2 |
| No CR (n=75) | 35 (47) | 4 | 9 | 12 | 3 | 0 | 7 |
CABG indicates coronary artery bypass grafting; CR-alone, cardiac rehabilitation alone; CR+SMT, cardiac rehabilitation enhanced with stress management training; MI, myocardial infarction; No CR, nonrandomized comparison group who did not participate in cardiac rehabilitation; and TIA, transient ischemic attack.
Comparison of Clinical Events in the CR Groups and Matched No-CR Control Subjects
To assess the impact of CR on medical outcomes, we compared patients randomized to the CR-alone and CR+SMT groups with the no-CR comparison group, which was matched on age, indication for referral to CR, and time of referral. The follow-up interval was identical for the CR patients and no-CR control subjects. We observed 35 clinical events in the no-CR group (47%) compared with 39 in the CR groups (26%; HR=0.35; 95% CI, 0.22–0.56; P<0.001; Figure 2).
Mediators of CR and Medical Events
We also examined whether reductions in stress levels mediated the relationship of CR with clinical events. Greater reductions in stress were associated with a lower rate of clinical events (HR=0.58; 95% CI, 0.34–0.99; P=0.048). Controlling for reductions in stress attenuated the relationship between treatment group and clinical events (HR=0.59; 95% CI, 0.31–1.14; P=0.11), whereas the relationship between stress and clinical events became marginally significant (HR=0.60; 95% CI, 0.35–1.02; P=0.059), suggesting that reduced stress partially mediated the effects of treatment group on clinical outcomes.
Discussion
Although there is substantial epidemiological evidence that high levels of stress are associated with worse medical outcomes,4–6 there is considerably less evidence that interventions designed to reduce stress improve those outcomes.25 In the present trial, stress management added to comprehensive CR resulted in greater reductions in patient-reported stress compared with CR alone. Furthermore, reductions in stress were associated with reduced risk of adverse clinical events, with an almost 50% reduction in clinical events compared with CR without SMT.
Participants in both CR and CR+SMT achieved improvements in blood lipids, heart rate variability, inflammation, exercise tolerance, and self-reported leisure-time physical activity. In a secondary analysis, we also noted that CR was associated with better clinical outcomes relative to a no-CR comparison group. The overall event rates were higher for patients who elected not to engage in CR compared with those receiving CR alone or CR+SMT. These findings contrast with results from the recent Rehabilitation After Myocardial Infarction Trial (RAMIT) study,26 which found that comprehensive CR had no effect on mortality or cardiac or psychological morbidity and concluded that the evidence for the value of CR was weak. Important differences in how CR is practiced in England and the United States may explain the discrepant results. In the British study, CR was performed weekly for only 6 to 10 weeks, whereas in the United States, CR is more intensive. In the ENHANCED trial, patients engaged in exercise 3 times per week for 12 weeks and participated in nutrition and stress classes; patients randomized to the CR+SMT group received an additional 1.5 h/wk of group SMT. Although patients in the CR+SMT group reported reduced symptoms of anxiety, depression, and stress, the stress reduction program for the RAMIT trial did not reduce patients’ stress levels, which could account for the differences in clinical outcomes.
Several other large, randomized, controlled trials reported no benefit of SMT compared with usual care in reducing stress and improving clinical outcomes. Jones and West27 randomized 2328 post-MI patients to 7 weekly sessions of SMT or usual care and followed them up for 12 months. After 6 months, the prevalence rates of clinical anxiety and depression remained high, and there were no group differences in levels of anxiety or depression after treatment. Moreover, there was no difference between the groups in the incidence of MI, cerebrovascular accident, heart failure, or revascularizations. Frasure-Smith and colleagues28 randomized 1376 post-MI patients to a stress management intervention delivered over the telephone or to usual care. After treatment, there were no group differences in anxiety or depression, nor was there a difference in clinical outcomes. The Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial29 examined the benefits of a cognitive-behavioral intervention in 2400 post-MI patients who were depressed or who reported low social support. Results showed a modest 2-point difference in BDI scores in the intervention group compared with usual care, and there were no differences in the combined end point of all-cause mortality and nonfatal reinfarction. These studies also provided SMT as a sole intervention, without exercise or other elements of comprehensive CR. Thus, not all interventions designed to reduce stress are successful, and the failure to reduce stress may provide one explanation for the failure to observe improved medical outcomes.
The ENHANCED trial provided SMT to all patients randomized to the CR+SMT intervention, regardless of their baseline levels of stress, and did not specifically target patients in acute distress or with significant psychopathology. Few randomized, controlled trials include only patients meeting a clinical threshold for psychological symptoms or psychiatric pathology, and in studies with and without patients with diagnosed psychopathology, the results are often not reported separately.30 Some meta-analyses suggest that patients with greater psychopathology at baseline show smaller reductions in depression with treatment compared with patients with less psychopathology.30 We found that patients with greater stress tended to exhibit larger improvements. For example, depressive symptoms were reduced in both the CR and CR+SMT groups, which is not surprising given that depressive symptoms are reduced by CR31 and that exercise has been shown to reduce depressive symptoms in patients with major depression,32 stable CHD,33 and heart failure.34 Although failing to achieve statistical significance, it is noteworthy that in our subset of patients with elevated depressive symptoms on study entry, the addition of SMT to CR appeared to be especially beneficial. The CR+SMT group exhibited a 14-point reduction in BDI-II scores compared with an 8-point reduction in the CR-alone group. A 6-point difference is considered clinically meaningful and is greater than the 2- to 3-point differences observed in placebo-controlled trials of antidepressant medications35–37 and in trials of psychotherapy in CHD patients.29
Limitations
Our sample was small, and we observed few hard end points (eg, death and nonfatal MI). A larger sample would provide greater power to detect treatment group differences in specific stress components. Although the effect sizes were relatively modest, because comprehensive CR alone has been shown to produce significant improvements in quality of life,3 the incremental benefit of SMT to standard CR should not be underestimated. In addition, analysis of clinical events offered promising evidence for the value of CR+SMT in improving clinical outcomes, which will need to be confirmed in larger trials. CR participants had better clinical outcomes compared with patients who elected not to engage in CR. Patients in the no-CR comparison group were matched on age, sex, and history of MI; did not differ on any measured clinical or demographic characteristic; and continued to exhibit significantly higher rates of clinical events in sensitivity analyses adjusted for age, sex, ejection fraction, and medical comorbidities. However, it is possible that patients in the nonrandom comparison group may have differed from the CR participants in ways that we did not measure, which may have contributed to their higher rates of clinical events. We used a global measure of stress, combining scores from multiple instruments. Because there is no universally accepted single measure of stress, we selected well-validated instruments on the basis of epidemiological evidence that distress,15,38 depression,39–43 anxiety,44–46 and anger,47,48 generally subsumed under the term stress, are associated with increased risk for adverse outcomes in CHD patients. Composite measures of stress have been used in other studies,6 but there is still no gold standard for measuring stress, and our global measure combines scores from well-validated instruments, each with excellent psychometric properties. Adherence to the program was excellent, with few dropouts. Research volunteers may have been especially motivated to participate in the program, which may limit the generalizability of our findings.
Conclusions
Patients randomized to CR enhanced by SMT had greater reductions in stress and had better clinical outcomes compared with patients randomized to CR alone. In the same way that exercise training does not target only those patients with low levels of physical fitness, the present findings indicate that SMT could be beneficial for all cardiac patients and suggest that SMT should be incorporated into comprehensive CR. A multisite effectiveness trial is needed to confirm the applicability of these findings to the larger CR population.
Acknowledgments
We express our thanks and gratitude to the members of our Data and Safety Monitoring Board—Nanette Wenger, MD (chair), Mark Appelbaum, PhD, and Nancy Houston Miller, RN—for their guidance and support of this study. Thanks also are extended to Michael Babyak, PhD, for his statistical advice and to our research staff, including Jenny Wang, PhD, Rachel Funk, BA, Sarah Newman, MA, Maureen Hayes, BA, Payton Kendsersky, BA, Michael Ellis, Catherine Wu, MS, Heidi Scronce, BS, Lauren Williamson, BS, and Monika Grochulski, BS. We also want to thank the staff at the respective exercise sites—Karen Craig (Duke), Elizabeth Mattheson (University of North Carolina), and Alycia Hassett, MD (Duke Regional Hospital)—for their support.
CLINICAL PERSPECTIVE
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© 2016 American Heart Association, Inc.
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Received: 10 August 2015
Accepted: 12 February 2016
Published online: 21 March 2016
Published in print: 5 April 2016
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This work was supported by grant HL093374 from the National Heart, Lung, and Blood Institute.
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