Is Exercise the Missing Link in Treating Depression in Heart Failure?

Review

Blumenthal JA, Babyak MA, O’Connor C, et al. Effects of exercise training on depressive symptoms in patients with chronic heart failure. The HF-ACTION randomized trial. JAMA. 2012;308:465-474.

Depression is a common comorbidity experienced by many patients with cardiovascular disease. It has been documented that depression affects as many as 40% of patients with heart failure (HF) specifically, and a few studies have determined that there is an association between increased depressive symptoms and increased morbidity and mortality, as well as decreased quality of life.1 Multiple rationales have been proposed to explain this association, including the potential for depressive symptoms to decrease compliance with evidence-based pharmacologic therapy known to improve these outcomes. Despite this established association, few studies have been able to demonstrate that improvement in depression (with either pharmacologic or nonpharmacologic treatment) results in improved clinical outcomes.

The Sertraline Against Depression and Heart Disease-Heart Failure (SADHART-CHF) trial and Enhancing Recovery in Coronary Heart Disease (ENRICHD—CHF) trial were 2 of the first randomized controlled trials to look at depressive symptoms in patients with coronary disease, and then more specifically, HF.2,3 Both trials aimed to correlate the treatment of depression with clinical outcomes, using a selective serotonin reuptake inhibitor or cognitive behavior therapy, respectively. In both these trials, depressive symptoms improved; however, there was no correlation with improved clinical outcomes. Similarly, the Efficacy and Safety of Exercise Training in Patients with Chronic Heart Failure (HF-ACTION) trial, designed to test the effect of exercise in HF patients, showed nonsignificant reductions in terms of all-cause mortality

and hospitalizations.4,5 After adjustment for highly prognostic predictors of the primary end point, there was a modest significant reduction in all-cause mortality, all-cause hospitalization, and cardiovascular outcomes. These results imply that there may be some benefit of exercise training on clinical outcomes in HF patients.

The present HF-ACTION ancillary study was a predetermined subgroup analysis designed to assess the effects of exercise on depressive symptoms and to

determine whether reduced depressive symptoms were associated with improved patient outcomes.6

Study Design

The HF-ACTION trial was a randomized, controlled trial that enrolled patients ≥18 years of age with symptomatic HF (LVEF ≤35% and NYHA Class II-IV). Patients were excluded if they had a disease, condition, or any other limitation that could interfere with exercise training, any recent or planned major cardiovascular event or procedure, HF secondary to congenital heart disease, performance of exercise training at regular intervals (more than once per week) in the previous 6 weeks, a fixedrate pacemaker or implantable cardioverter defibrillator with heart rate (HR) limits set lower than the target HR, or any exercise testing that would preclude safe exercise training. The primary medical end point was all-cause mortality, hospitalization, or both; the primary psychological end point was depressive symptoms after 3 months of supervised exercise. Secondary outcomes included both medical and psychological end points. Assessment of depression was based on the Beck Depression Inventory II (BDI-II). BDI-II scores of ≥14 are considered to reflect clinically significant depressive symptoms.

A total of 2331 HF patients were enrolled in this study from April 2003 to February 2007. The structured exercise program focused on increasing workout intensity and duration over a period of at least 12 months. Patients received a total of 36 supervised 30-minute training sessions 3 times per week. Once patients achieved 18 supervised train-ing sessions, a treadmill or stationary bicycle was to be used at home and patients were advised to work out for 40 minutes, 5 times per week. Adherence was defined as 90 min/wk or more of supervised exercise training up until 3 months, followed by at least 120 min/ wk of home-based exercise for months

4 to 12. Follow-up was recorded at 3-month intervals for the first year. Patients in the usual care group received information regarding exercise, medications, fluid management, symptom control, and a recommendation of 30 minutes of moderate-intensity training most days of the week. (This recommendation comes from the American College of Cardiology/American Heart Association guidelines; in the study, however, exercise was simply encouraged but without specific recommendations on how to implement.)

The 2322 patients who completed the BDI-II self-assessment at baseline were included as a part of this subgroup analysis. Baseline demographics were similar between the 2 groups, including median BDI-II scores of 8 in both groups. The median follow-up was 30 months, during which primary medical outcome was reached in 68% of the usual care group versus 66% in the aerobic exercise group (95% CI, 0.81-0.99; P = .03). BDI-II scores at 3 months were also significantly lower in the aerobic

exercise subjects (8.95) compared with the usual care group (9.70) (difference, -0.76; P = .002) and 8.86 and 9.54 (difference, -0.68; P = .01) at 12 months. Similar reductions were seen in patients who had significant depression at baseline (BDI-II score of ≥14), 16.66 for patients in the exercise group versus 17.98 for usual care (difference, -1.31; P = .04). This difference was even more profound at 12 months (exercise versus usual care, 15.85 vs 17.34; P = .02). Patients in the aerobic exercise group exercised for a median of 76 min/wk during the first 3 months, increasing to a median of 95 min/wk during months 4 to 6 and then decreasing to 74 min/wk at

months 10 to 12. During the supervised months, 41% of the sample achieved full adherence; during the home-based phase, 42% of the sample achieved full adherence for months 4 to 6, 41% for months 7 to 9, and 38% for months 10 to 12. In terms of subsequent clinical secondary end points, aerobic exercise was also associated with a lower risk of HF hospitalizations and death (25.7% vs 28.6%; P = .03) and a statistically nonsignificant lower risk of CV hospitalization and death (54.7% vs 57.7%;

P = .09).

References

1. Jiang W, Alexander J, Christopher E, et al. Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Arch Intern Med. 2001;161:1849-1856.

2. O’Connor CM, Jiang W, Kuchibhatla M, et al. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol. 2012;56:692-699.

3. Joynt KE, O’Connor CM. Lessons from SADHART, ENRICHD, and other trials. Psychosom Med. 2005;67(suppl 1):S63-S66.

4. O’Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA.

2009;301:1439-1450.

5. Whellan DJ, O’Connor CM, Lee KL, et al. Heart failure and a controlled trial investigating outcomes of exercise training (HFACTION): design and rationale. Am Heart J. 2007;153:201-211.

6. Blumenthal JA, Babyak MA, O’Connor C, et al. Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-ACTION randomized trial. JAMA. 2012;308:465-474.

7. Uretsky BF, Thygesen K, Armstrong PW, et al. Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial. Circulation. 2000;102:611-616.

Commentary

Improving Clinical Outcome, Especially for the Most Severely Depressed

The HF-ACTION trial and ancillary evaluation provide us with evidence to support structured and supervised exercise as a treatment for depression and as a means of improving clinical outcomes in HF patients. In order to understand the impact of these findings, it is important to understand both the strengths and limitations of the study.

The patient population that was included in this trial is a typical systolic HF population, illustrating the study’s well-thought-out inclusion and exclusion criteria. Baseline demographics of this HF population are similar to previous HF studies in which almost 30% of patients were HF Class III-IV. One piece of demographic data that was not

noted in this patient population was the pharmacologic therapies patients were receiving. The median ß-blocker dose and median dose of loop diuretics were noted and compared; however, other drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and hydralazine and nitrates— which have a proven morbidity and mortality benefit in the HF population—should ideally be noted and compared in any HF study.7 Even though this information was not directly stated, the authors note that patients were medically managed by guideline-based therapy.

The study also did a good job of capturing all the potential confounders in their primary outcome of all-cause mortality and all-cause hospitalizations. HF patients have multiple comorbidities in which exercise may potentially be harmful. Including outcome data that involve not solely cardiovascular outcomes helps practitioners

understand the full implications of exercise and whether this is something that can be introduced to these patients.

Although the results seem promising, there are a few potential limitations to implementation of exercise training in this patient population. Patients who were randomized to exercise had to be willing and able, which may mean these selected patients are motivated and healthier than the typical HF patient. Second, in a study involving a treatment arm that includes follow-up visits, the amount and type of attention given to both arms of the trial must be compared because increased patient interaction with clinicians and physicians may pose a potential bias to the treatment arm. Structured physical exercise includes follow-up visits with physicians and clinicians, posing the potential bias that patients are also encouraged to adhere to lifestyle management and medication compliance; it may also serve as a type of cognitive therapy. The study did address this potential bias, trying to reduce it by calling all patients every 2 weeks for the first 9 months, monthly until 24 months, and quarterly thereafter to provide an equal amount of contact time between study arms. The authors state that through biweekly phone calls to the usual care group, patients were asked if they were engaging in some sort of exercise, and an average of 40% to 50% stated that they were, causing a potential crossover that may decrease the impact of the results.

In terms of clinical implications of the trial, the statistically significant results of decreased BDI-II scores may not correlate well with clinical significance. Some reports have suggested that a 50% reduction in depressive symptoms is clinically meaningful in trials of patients with major depression, but this has never been correlated

between BDI-II scores. At study entry, the mean BDI-II score for these patients was 8, which may represent a less depressed population; other studies involving depressive symptoms have included patients with BDI-II scores of greater than 10. Further, in patients with BDI-II scores >14 at baseline, although they were decreased more significantly in the exercise group, the median still remained above 14 in both groups. Additionally, and possibly complicating evaluation of this end point, at baseline about 20% of patients were already taking an antidepressant medication. Antidepressant medication use was recorded at baseline and 12 months; however, this was not controlled. Participants with more severe depressive symptoms at baseline were more likely to be taking an antidepressant medication and also were more likely to have more severe HF. Despite this difference in results, the clinical significance of this was not determined.

Adherence to a treatment group, or exercise protocol in this case, is often a potential limitation to the outcomes of a study. Although the results do not show that adherence affected significance, adherence could have decreased the potential to find an even greater difference between groups. Although adherence was low, a promising result is that adherence seemed consistent for those patients who continued to adhere to the exercise program for the entire 12 months, possibly showing that this may be used as a specific therapy for certain patients who are willing to try an exercise program. This type of structured program comes with significant cost, which may not be available to all communities and patients. This may prevent practitioners from using this type of program for all patients, especially with there being the greatest benefit in patients with greater depressive symptoms. This could imply that only patients with severe clinical depression should receive this type of structured therapy. Another significant point that should be noted is that future studies that assess exercise therapy must be directed on how to increase adherence, reduce cost, and encourage patients to continue exercise management; this may mean assessing other types of exercise methods different from walking and cycling.

These limitations must be considered when assessing the results and considering initiation of similar exercise programs for HF patients. The results of the present study do seem promising, and can help justify increased counseling and, potentially, administration of structured exercise programs for patients suffering from symptomatic HF. Given the more drastic improvement in outcomes and depressive symptoms for exercise in the clinically severely depressed subset, this might represent a good initial target population for clinicians.

About the Authors

Carolyn Hempel, PharmD, is a PGY-2 Cardiology Pharmacy Specialty Resident and is Chief Pharmacy Resident at University of Kentucky HealthCare, Lexington, KY. Her residency research project at the University of Kentucky Chandler Medical Center is on evaluating a pharmacist’s impact on 30-day readmission rates in heart failure patients through implementation of a medication reconciliation process. Dr Hempel was assisted in the writing of this article by Tracy E. Macaulay, PharmD, BCPS-AQ Cardiology, Clinical Pharmacy Specialist-Cardiology, PGY2 Residency Program Director-Pharmacology, and Adjunct Assistant Professor at University of Kentucky Health- Care, Department of Pharmacy Services and Division of Cardiovascular Medicine, Lexington, KY.