Author + information
- Received October 9, 2016
- Revision received December 15, 2016
- Accepted January 9, 2017
- Published online March 27, 2017.
- Nancy Luo, MDa,b,∗ (, )
- Peter Merrill, PhDb,
- Kishan S. Parikh, MDa,b,
- David J. Whellan, MD, MHSc,
- Ileana L. Piña, MD, MPHd,
- Mona Fiuzat, PharmDa,
- William E. Kraus, MDa,b,
- Dalane W. Kitzman, MDe,
- Steven J. Keteyian, PhDf,
- Christopher M. O’Connor, MDa,g and
- Robert J. Mentz, MDa,b
- aDivision of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
- bDuke Clinical Research Institute, Durham, North Carolina
- cThomas Jefferson University, Philadelphia, Pennsylvania
- dMontefiore-Einstein Medical Center, New York, New York
- eWake Forest School of Medicine, Winston Salem, North Carolina
- fHenry Ford Hospital, Detroit, Michigan
- gInova Heart and Vascular Institute, Falls Church, Virginia
- ↵∗Address for correspondence:
Dr. Nancy Luo, Duke Clinical Research Institute, 2400 Pratt Street, Room 0311 Terrace Level, Durham, North Carolina 27705.
Background The safety and efficacy of aerobic exercise in heart failure (HF) patients with atrial fibrillation (AF) has not been well evaluated.
Objectives This study examined whether outcomes with exercise training in HF vary according to AF status.
Methods HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) randomized 2,331 ambulatory HF patients with ejection fraction ≤35% to exercise training or usual care. We examined clinical characteristics and outcomes (mortality/hospitalization) by baseline AF status (past history of AF or AF on baseline electrocardiogram vs. no AF) using adjusted Cox models and explored an interaction with exercise training. We assessed post-randomization AF events diagnosed via hospitalizations for AF and reports of serious arrhythmia caused by AF.
Results Of 2,292 patients with baseline rhythm data, 382 (17%) had AF, 1,602 (70%) had sinus rhythm, and 308 (13%) had “other” rhythm. Patients with AF were older and had lower peak Vo2. Over a median follow-up of 2.6 years, AF was associated with a 24% per year higher rate of mortality/hospitalization (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.34 to 1.74; p < 0.001) in unadjusted analysis; this did not remain significant after adjustment (HR: 1.15; 95% CI: 0.98 to 1.35; p = 0.09). There was no significant difference in AF event rates by randomized treatment assignment in the overall population or by baseline AF status (all p > 0.10). There was no interaction between AF and exercise training on measures of functional status or clinical outcomes (all p > 0.10).
Conclusions AF in patients with chronic HF was associated with older age, reduced exercise capacity at baseline, and a higher overall rate of clinical events, but not a differential response to exercise training for clinical outcomes or changes in exercise capacity. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)
The disorders of atrial fibrillation (AF) and chronic heart failure (HF) are closely intertwined with aging; both are expected to rise in prevalence, stemming from a continued burgeoning of shared risk factors including hypertension, aging, and obesity (1). More than one-half of patients with HF develop AF, and > one-third with AF develop incident HF (2). In combination, they portend higher mortality risk compared with either in isolation (2).
Physical activity and exercise training improve symptoms and can have antiarrhythmic effects in individuals with paroxysmal AF and may be protective against the development of AF (3–6). In patients with chronic heart failure with reduced ejection fraction (HFrEF), as shown in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study, exercise training is associated with improved exercise capacity, improved quality of life, and reduced all-cause mortality and hospitalization (7,8). In the HF-ACTION primary analysis, AF was highly predictive of the primary endpoint of all-cause mortality or hospitalization, independent of treatment arm, and was used in the adjusted model for the primary analysis (7). However, to date, limited data characterize the implications of exercise training in individuals with both HF and AF and their risk for future AF events.
The HF-ACTION trial is the largest trial to date investigating the effects of aerobic exercise training in stable outpatients with HFrEF (7). Using the HF-ACTION study cohort, we: 1) examine the relationship between baseline AF status and outcomes with exercise training; and 2) describe future AF events, in patients with chronic HF.
The trial design and results of HF-ACTION have been previously reported (7,9). This multicenter, randomized controlled trial compared the long-term safety and efficacy of exercise training plus evidence-based heart failure medical therapy versus medical therapy alone in patients with chronic HF (ejection fraction [EF] <35%) and New York Heart Association (NYHA) functional class II to IV symptoms. There were no inclusion or exclusion criteria regarding the management of AF. Patients were excluded if they had sustained AF with rapid ventricular response on the baseline exercise test performed before enrollment.
Supervised training involved aerobic exercise (walking, treadmill, or cycle ergometer) 3 times weekly for 36 sessions, followed by transition to a home-based exercise program for an additional 2 years. The exercise goal was 90 min per week for the first 3 months, followed by 120 min per week thereafter. Follow-up occurred over a median of 2.6 years. The protocol was approved by the institutional review board or ethics committee at each institution and the coordinating center. All patients provided written informed consent.
AF status and outcomes
Patient characteristics, medical history, health status, and physiological parameters at rest and during exercise testing were collected on standardized forms at baseline and repeated at 3 months, 12 months, and 24 months. Health status was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Beck Depression Inventory II (10,11). All patients underwent graded cardiopulmonary exercise testing to evaluate safety and exercise capacity at baseline, including a 12-lead electrocardiogram (ECG) for assessment of baseline rhythm, and this testing was repeated at 3 months, 12 months, and 24 months. Performed using a modified Naughton treadmill protocol or a leg ergometer, exercise continued until sign- or symptom-limited maximal exertion was reached. Peak oxygen uptake (Vo2) was defined as the Vo2 at peak exercise, either within the last 90 s of exercise or the first 30 s of recovery, whichever was higher. Exercise volume was calculated for the subpopulation randomized to exercise therapy. Using metabolic equivalent hours of exercise per week to represent the product of exercise intensity (where 1 metabolic equivalent is ∼3.5 ml O2 · kg−1 · min−1), exercise volume was derived during months 1 to 3 for patients who did not experience a clinical event or were not censored in that time period (12).
For the present study, AF status was determined by presence on ECG at baseline cardiopulmonary stress test or an investigator-reported past medical history of AF. Patients with and without AF were compared. In the AF study groups, the composite primary endpoint of all-cause mortality and all-cause hospitalization, and secondary endpoints of all-cause mortality alone and cardiovascular mortality or HF hospitalization were assessed with and without adjustment for variables found to be significantly associated with outcomes in prior HF-ACTION analyses (13,14). The occurrence of new or recurrent AF events after randomization was diagnosed through investigator reports of AF hospitalizations or serious adverse arrhythmia caused by AF.
Baseline characteristics were reported by AF status. Categorical variables were reported as frequencies and percentages and compared using Pearson chi-square or Fisher exact tests. Continuous variables were reported as median (25th and 75th percentile) and compared using the Wilcoxon rank sum test.
We used unadjusted and adjusted Cox proportional hazards models to assess the association between exercise training and each clinical outcome stratified by baseline AF status. Adjusted general linear models were also used to assess the association between exercise training and exercise capacity and health status outcomes stratified by baseline AF status. Unadjusted and adjusted logistic regression models were used to assess the association between exercise training and future AF events in the full trial population as well as by baseline AF status. We explored the interaction between AF and treatment assignment for the primary and secondary outcomes using adjusted Cox models. In the AF patients, we performed exploratory analysis investigating the association of resting heart rate control and anticoagulation use on clinical and quality of life outcomes using Cox proportional hazards modeling for mortality/hospitalization and general linear modeling for exercise capacity and health status outcomes. All analyses were then repeated separating the AF group into those with past history of AF and those with AF on baseline ECG to evaluate bias between the 2 populations. Two-tailed p values <0.05 were considered statistically significant. SAS version 9.4 (SAS Institute, Cary, North Carolina) was used for all analyses.
Of the 2,331 patients enrolled in the HF-ACTION study, 39 patients (2%) were missing baseline ECG or documentation of AF status. Excluding another 308 (13%) patients with “other” rhythm on ECG, this analysis included 1,984 patients: 382 (17%) with AF by past medical history only (n = 244) or rhythm on cardiopulmonary exercise (n = 138) and 1,602 (70%) with sinus rhythm. Baseline characteristics are shown in Table 1. Overall, patients with AF were more likely to be older, male, and white compared with those without baseline AF. At baseline, patients with AF were more likely to have NYHA functional class III to IV symptom limitations and lower left ventricular EF (LVEF). They had a higher burden of comorbidities including more diabetes, history of myocardial infarction, and worse renal function. All patients reported >90% use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at baseline, but patients with AF had lower doses of beta-blockers and higher doses of loop diuretics. Furthermore, compared with patients in sinus rhythm, patients with AF had significantly higher utilization of anti-arrhythmic medications and lower baseline exercise capacity as measured by peak Vo2 and 6-min walk test distance. Even after adjusting for baseline covariates known to predict outcome, peak Vo2 and 6-min walk test remained statistically different between AF and sinus rhythm patients (p < 0.001 and p = 0.002, respectively). However, patients randomized to exercise training in both groups exhibited similar exercise volume between month 1 and month 3. AF patients reported similar baseline quality of life and depression as measured by the KCCQ and Beck Depression Inventory II score.
The relationship between all-cause death/hospitalization and AF groups is shown in Figure 1, and the clinical outcomes are shown in Table 2. Over a median follow-up of 2.6 years, in unadjusted analysis and regardless of randomized group, the primary outcome occurred in a significantly higher percentage of patients with AF (64.6%/year) than in patients in sinus rhythm (40.8%/year) (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.34 to 1.74; p < 0.001). However, after adjustment for dosage of beta-blocker, KCCQ symptom stability, LVEF, country, sex, ventricular conduction, Weber class, blood urea nitrogen, and mitral regurgitation, AF status was not significantly associated with increased risk for mortality/hospitalization (HR: 1.15; 95% CI: 0.98 to 1.35; p = 0.09). Each of the other cardiovascular endpoints was also associated with worse outcomes in patients with AF in the univariate model, but differences were attenuated when adjusted for other clinical variables. Additionally, there was no evidence of a differential effect of exercise training based on AF status (all interaction p > 0.10).
We tested the interaction between AF status and randomization group for short-term functional and quality of life outcomes (Table 3). There were no significant interactions between baseline AF status and randomization group for change in quality of life and functional capacity from baseline to 3 months. Compared with patients in sinus rhythm at 3 months of follow-up, patients with AF in the exercise training group had similar improvements in distance in 6-min walk test (median 22 vs. 20 m) and in peak Vo2 (0.6 vs. 0.7 ml/min/kg). In patients with sinus rhythm, exercise training (as compared with usual care) was associated with a modest improvement in KCCQ overall summary score (5.6 vs. 2.6), consistent with the primary trial results in the overall population (8). Patient with AF reported small improvements in health status in both exercise and usual care groups (3.1 vs. 3.1). Indeed, a lower proportion of AF patients in exercise training experienced a clinically noticeable improvement of 5 or more points on KCCQ compared with patients in sinus rhythm assigned to exercise training (45.6% vs. 51.9%) (11).
Over median follow-up of 2.6 years, 5.5% (54 of 990) of patients randomized to exercise training, compared with 5.7% (57 of 994) of patients in usual care, experienced a post-randomization AF event defined as a hospitalization due to AF or serious adverse event reported for symptomatic AF (p = 0.80). Among those patients with AF, 10.9% (21 of 193) of those randomized to exercise training experienced subsequent AF events compared to 9% (17 of 189) in usual care (p = 0.50) (Online Table 1).
In sensitivity analyses separating the AF cohort into 2 groups (history of AF and documented AF on baseline ECG), we did not find significant differences in outcomes between the 2 (Online Tables 1 to 4). Despite the older age of subjects in the group with AF on ECG compared with patients in the AF history group (median 66 vs. 62 years), they exhibited similar cardiopulmonary reserve and performance parameters on their baseline cardiopulmonary exercise testing, with mean peak Vo2 at 13.4 ml/kg/min for both groups. Both AF groups showed similarly high rates of all-cause mortality or hospitalization (64.2%/year and 65.4%/year for AF on ECG and AF by history) and no differential response to exercise training (Online Table 4). Because rate of future AF event was generally low in the trial population, there was also no significant difference in future AF rates by randomization group between the 2 AF subgroups (Online Table 1).
In an exploratory analysis among patients with AF, we investigated the association of resting heart rate control on clinical outcomes. There was a trend toward a significant association between strict resting heart rate control of <80 beats/min and all-cause death or hospitalization (p = 0.05); however, this association was attenuated after multivariable adjustment (Table 4). There was also no significant association between strict heart rate control with improvement in functional status and quality of life outcomes (p > 0.10; data not shown).
This analysis examined the relationship between AF and outcomes and exercise training and AF in patients with HFrEF. We had several important findings (Central Illustration). First, HF patients with AF were, in general, older and exhibited more comorbidities and lower exercise capacity at baseline. HF patients with AF had significantly worse outcomes across all clinical endpoints compared with those without AF; however, these relationships did not remain significant after adjustment for other important clinical variables. Second, there was no significant interaction between randomization group assignment and AF status on clinical or functional status outcomes. Despite having more severe HF, stable outpatients with HF and AF were able to receive similar benefits with exercise training when using a structured and monitored intervention. Importantly, exercise training did not lead to an increase in AF events in HF patients with AF.
Prior studies have demonstrated worse prognosis when patients have AF and HF in combination. Two adjusted analyses of the Framingham Study population demonstrated up to 2-fold increased risk of death in patients with conjoint HFrEF and AF (2,15). In the SOLVD (Studies of Left Ventricular Dysfunction) trials, AF in patients with reduced ventricular function was again independently associated with an increased risk of progressive heart failure and death (16). Similarly, AF was a strong predictor of mortality and hospitalization in the primary analysis of HF-ACTION (7). In our analysis, the increased mortality risk seen in HFrEF patients with AF was attenuated after adjustment for additional clinical variables, highlighting the convergence of common comorbidities. Nonetheless, a consistent trend in the adjusted effect estimates across the primary and secondary outcomes suggests persistent higher risk in patients with AF. Our study may have been underpowered to detect the independent risk of AF in HF due to a smaller cohort of AF patients.
Results from HF-ACTION showed that exercise training conferred modest improvements in exercise parameters (mean 4% increase in peak oxygen consumption) (7). In our analysis, patients with AF had significantly lower functional class and exercise capacity at baseline, as measured by peak Vo2 (11% reduction compared with sinus rhythm) and 6-min walk distance (6% reduction). These findings corroborate findings from historical studies that AF independently predict lower baseline exercise capacity (17). Despite having lower exercise capacity at baseline, patients with AF had similar modest improvements in peak Vo2 (median 4% increase) and 6-min walk distance (median 6% increase). Even modest improvements in peak Vo2 may be important: as a measure of cardiorespiratory fitness, peak Vo2 more strongly predicts future cardiovascular disease than measures of simple physical activity (18,19). Prior studies evaluating exercise training in AF patients have demonstrated larger improvements in exercise capacity (20,21). However, these studies were small in size and included few patients with heart failure.
In recent prospective observational cohort and trial populations, exercise training has been associated with positive benefits in patients with AF (3,4,22,23). In a recent 20,000 adult observational cohort study, investigators observed lower all-cause mortality in AF patients who self-reported regular physical activity (22). None of these studies evaluated patients with concomitant HF and AF. The HF-ACTION study showed that exercise training reduced all-cause mortality and hospitalizations, and improved peak Vo2 at 3 and 12 months in patients with chronic HF (7). This trial population afforded the unique opportunity to examine exercise training among patients with AF and HF within a clinical trial setting. In our analysis, exercise training had no differential effect based on AF status. Although exercise training led to similar increases in functional capacity at 3 months in patients with AF as with those in sinus rhythm, we did not detect benefits in the primary or secondary clinical outcomes.
American College of Cardiology/American Heart Association HF Guidelines recommend exercise training in patients with chronic HF and reduced EF (24). Despite recognized benefits, however, theoretical concerns persist that exercise increases adrenergic tone and can provoke both ventricular and supraventricular arrhythmias (25). A prior analysis from our group found no evidence for increased implantable cardioverter-defibrillator shocks in HF patients who underwent exercise training (26). Recently, 2 groups independently showed that, regardless of rate or rhythm control strategy, exercise training in nonpermanent AF patients was associated with reduced—not increased—short-term arrhythmia burden (3,4). In our analysis, exercise training was not associated with reduced future AF events. However, despite protocol designed attempts to simulate the number of medical contacts between study arms, it is likely that the exercise training arm experienced increased opportunity for AF identification given the additional supervised training sessions. Despite this setting of increased observation, those with underlying history of AF randomized to exercise were no more likely to experience a future AF event compared to usual care. Although we had limited power to detect anything other than a large treatment effect, our study parallels prior research in evaluating the occurrence of ventricular arrhythmias in HF patients during exercise and reaffirms the overall safety of exercise training for this population (26).
Results from the HF-ACTION study also showed that exercise training conferred a modest, but significant, improvement in health status as measured by the KCCQ (8). In our analysis, patients with AF had significantly lower functional class and exercise capacity, but reported similar disease-specific health status compared with patients in sinus rhythm at baseline. And although patients with AF achieved similar short-term gains in cardiopulmonary reserve and functional status with exercise training, they reported minimal improvement in self-reported health status with exercise. Exercise has been previously shown to modestly improve quality of life and symptoms in patients with permanent AF, but with use of a different health status measure (Short Form-36) (21,27). The use of different instrument scales to assess health status and different types of exercise intervention makes it difficult, however, to compare these results to our study.
First, the HF-ACTION study enrolled HF patients with power to detect a primary effect in mortality and hospitalization. As such, this secondary analysis evaluating a subpopulation may be underpowered to detect an interaction effect. Second, incident AF that did not result in a hospitalization or reporting of severe adverse event was not captured in this analysis. At the same time, in the setting of a trial, ascertainment bias may be present that increased reporting of AF during more frequent medical surveillance. Even so, there was likely underdetection and reporting of less symptomatic AF events, which may increase risk of type 2 error. Third, because the HF-ACTION study only enrolled patients with reduced EF, we can make no conclusions regarding exercise training in patients with AF and HF with preserved EF. Prior studies have described the association of AF with poor outcomes in HF with preserved EF, and further study will be needed to evaluate how exercise training affects this population (2,28). Fourth, adherence to HF-ACTION training protocol by enrolled subjects was below the targeted level and fell to 74 min out of a targeted 120 min. The results of this analysis need to be interpreted in the context of this modest adherence. Last, we did not adjust for multiplicity of statistical testing, and these results should be viewed as exploratory.
After adjustment for clinical variables, prevalent AF in ambulatory HF patients with reduced ejection fraction was associated with significantly reduced exercise tolerance and functional capacity, but not with mortality or hospitalization. This study supports current guideline recommendations that exercise can lead to short-term improvements in functional status in patients with both HF and AF. However, the long-term effects and best mode of exercise training in this medically complex population deserves further study.
COMPETENCY IN PATIENT CARE: Although patients with HF who also have AF are typically older and have more comorbidities and limited exercise capacity compared to those without AF, they may still exhibit a positive functional response to exercise training.
TRANSLATIONAL OUTLOOK: Randomized trials are needed to compare the safety and efficacy of various exercise training protocols in patients with both HF and AF and develop criteria that identify patients most likely to improve.
For supplemental tables, please see the online version of this paper.
The HF-ACTION trial was funded by the National Heart, Lung, and Blood Institute. Dr. Mentz receives research support from the National Institutes of Health (U10HL110312 and R01AG045551-01A1), Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Luitpold, Medtronic, Merck, Novartis, Otsuka, and ResMed; honoraria from HeartWare, Janssen, Luitpold Pharmaceuticals, Novartis, ResMed, and Thoratec/St. Jude; and has served on an advisory board for Luitpold and Boehringer Ingelheim. Dr. Keteyian is a technical consultant for NimbleHeart, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Nanette K. Wenger, MD, MACC, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- atrial fibrillation
- confidence interval
- ejection fraction
- heart failure
- heart failure with reduced ejection fraction
- hazard ratio
- Kansas City Cardiomyopathy Questionnaire
- left ventricular ejection fraction
- New York Heart Association
- oxygen uptake
- Received October 9, 2016.
- Revision received December 15, 2016.
- Accepted January 9, 2017.
- 2017 American College of Cardiology Foundation
- Mozaffarian D.,
- Benjamin E.J.,
- Go A.S.,
- et al.
- Santhanakrishnan R.,
- Wang N.,
- Larson M.G.,
- et al.
- Pathak R.K.,
- Elliott A.,
- Middeldorp M.E.,
- et al.
- Malmo V.,
- Nes B.M.,
- Amundsen B.H.,
- et al.
- Faselis C.,
- Kokkinos P.,
- Tsimploulis A.,
- et al.
- Kapa S.,
- Asirvatham S.J.
- Green C.P.,
- Porter C.B.,
- Bresnahan D.R.,
- Spertus J.A.
- Keteyian S.J.,
- Leifer E.S.,
- Houston-Miller N.,
- et al.
- O'Connor C.M.,
- Whellan D.J.,
- Wojdyla D.,
- et al.
- Wang T.J.,
- Larson M.G.,
- Levy D.,
- et al.
- Dries D.L.,
- Exner D.V.,
- Gersh B.J.,
- Domanski M.J.,
- Waclawiw M.A.,
- Stevenson L.W.
- Pardaens K.,
- Van Cleemput J.,
- Vanhaecke J.,
- Fagard R.H.
- Proietti M.,
- Boriani G.,
- Laroche C.,
- et al.
- Morseth B.,
- Graff-Iversen S.,
- Jacobsen B.K.,
- et al.
- Yancy C.W.,
- Jessup M.,
- Bozkurt B.,
- et al.
- Thompson P.D.,
- Franklin B.A.,
- Balady G.J.,
- et al.
- Piccini J.P.,
- Hellkamp A.S.,
- Whellan D.J.,
- et al.
- McManus D.D.,
- Hsu G.,
- Sung S.H.,
- et al.