Exercise as an adjuvant therapy against chronic atrial fibrillation

(1)

Alejandro Santos-Lozano, Fabian Sanchis-Gomar, Saray Barrero-Santalla, Helios Pareja-Galeano, Carlos Cristi-Montero, Paz Sanz-Ayan, Nuria Garat-achea, Carmen Fiuza-Luces, Alejandro Lucia

PII: S0167-5273(16)30138-3

DOI: doi:10.1016/j.ijcard.2016.01.140

Reference: IJCA 21895

To appear in: International Journal of Cardiology Received date: 1 January 2016

Accepted date: 5 January 2016

Please cite this article as: Santos-Lozano Alejandro, Sanchis-Gomar Fabian, Barrero-Santalla Saray, Pareja-Galeano Helios, Cristi-Montero Carlos, Sanz-Ayan Paz, Garat-achea Nuria, Fiuza-Luces Carmen, Lucia Alejandro, Exercise as an adjuvant ther-apy against chronic atrial ﬁbrillation, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.01.140

(2)

ACCEPTED MANUSCRIPT

Title:

Exercise as an adjuvant therapy against chronic atrial fibrillation

Running title:

Exercise and atrial fibrillation

Authors:

Alejandro Santos-Lozano*1,2, Fabian Sanchis-Gomar*1, Saray Barrero-Santalla3, Helios Pareja-Galeano1,4, Carlos Cristi-Montero5,6, Paz Sanz-Ayan1, Nuria Garatachea1,7, Carmen

Fiuza-Luces1, Alejandro Lucia1,4 * Denotes equal contribution

Affiliations:

1

Research Institute of Hospital 12 de Octubre ('i+12'), Madrid, Spain.

2

GIDFYS, European University Miguel de Cervantes, Department of Health Sciences, Valladolid, Spain.

3

School of Health Sciences, University of León, León, Spain

4

European University of Madrid, Madrid, Spain

5

Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile

6

Universidad Autónoma de Chile, Temucho, Chile

7

Facultad de Ciencias de la Salud y del Deporte, Universidad de Zaragoza, Huesca, Spain.

Manuscript Type:Letter to the Editor

Word Count: 989

Author for Correspondence: Fabian Sanchis-Gomar, MD, PhD

Research Institute Hospital 12 de Octubre („i+12‟).

Edificio actividades ambulatorias, 6ª planta.

Avda. de Córdoba s/n

28041 Madrid, Spain

Phone: +34 91 779 2784; Fax: +34 91 390 8544

(3)

ACCEPTED MANUSCRIPT

Regular light-moderate exercise (e.g., walking/brisk walking) attenuates risk of

atrial fibrillation (AF) [1]. Yet another question is the potential therapeutic effects of

exercise in patients who already suffer chronic AF, particularly old people. We

performed a systematic review of studies that have investigated the exercise effects in

old people with chronic („permanent‟) AF on: AF reversion, AF burden, or other

relevant medical outcomes, i.e., exercise capacity indicators (mainly peak oxygen

uptake [VO2peak]) and health-related quality of life (QoL).

Searches (with no restriction on publication date) of human-based studies written

in English, Spanish or French were done in Pubmed, Science Direct, and Scopus using

the terms “atrial fibrillation”, “physical activity”, “exercise”, “quality of life”, “exercise

therapy” and “treatment” as well as combinations thereof. Review papers,

meta-analyses and symposium/meeting publications were excluded.

The Cochrane Collaboration risk-of-bias tool was used for assessing the quality of

the revised papers. It includes 6 items (random sequence generation [selection bias],

allocation concealment [selection bias], participants‟ blinding, incomplete outcome

data, selective outcome reporting [reporting bias], and other sources of bias] that were

scored as „1‟ (positive), „0‟ (negative) or „?‟ (unclear). A total quality-score was

calculated for each paper by adding the number of positive items. Studies were ranked

as high/low quality, i.e., a score<4 or≥4 implies „low‟ or „high-quality‟ evidence,

respectively.

From 2,824 published articles on exercise and AF, 883 were potentially eligible.

Of these, 45 were potentially relevant studies and 7 articles were finally identified as

relevant studies [2-8] (Figure 1). Of them, 86% (n=6) were „high-quality‟ papers

[2-4,6-8] (Table 1). Taken together, the 7 studies included 142 patients (80% men) with

(4)

ACCEPTED MANUSCRIPT

diseases (CVD) that are commonly associated with AF (hypertension, coronary artery

or valve disease) although most patients had no severe heart failure or ventricular

dysfunction. Patients received common drug combinations against AF or underlying

CVD (β-blockers, digoxin, diuretics, calcium–antagonists, antigoagulants). No adverse

effects associated with exercise were reported in any of the studies.

One report assessed the effects of acute exercise (modified Bruce protocol) in

patients with AF aged 36–74yr [6]. In 5 of 18 patients scheduled for cardioversion, AF

successfully reversed with the exercise challenge. None of the other 13 patients who

failed to revert AF with the exercise test did so 3h to 7 months later (median=20d). The

study was however an observational one and was not performed ad hoc. There was

heterogeneity in the duration of AF before presentation for cardioversion (8h–7

months), which precludes extrapolating the findings. No study has specifically assessed

the potential effect of chronic exercise for reverting chronic AF.

Two prospective studies showed significant benefits of regular moderate-intensity

exercise (walking/jogging) performed during 4 [5] to 12 months in the exercise capacity

of chronic AF patients but no effects were reported in terms of AF budern itself [2]. Of

the 7 revised studies, only 3 were randomized controlled trials (RCT) assessing ad hoc

the effects of an exercise intervention of 2 [4] to 3-month duration [7,8] performed by

old patients (≥60yr) with permanent AF, on important end-points (although not directly

related to AF itself), i.e., exercise capacity (aerobic or muscle strength tests) or

health-related QoL. Two of these RCTs [7,8] apparently shared the same patient population

and exercise intervention. Essentially all of the abovementioned outcomes improved

with training. The only AF-burden related outcome that has been assessed in an exercise

(5)

ACCEPTED MANUSCRIPT

severity check list (SSCL) in a study reporting attenuation of symptoms after a 2-month

moderate-intensity (70–80% of maximum heart rate) exercise intervention [4].

Finally, a case-control study showed no significant differences between cardiac patients

with chronic AF (mean age 63yr) and their AF-free referents in the magnitude of the

improvements induced by a 3-month exercise ambulatory program (+31% and +25%,

respectively) [3].

The evidence available is based on a low number of studies, usually with small

cohorts, and thus well-powered RCTs are needed. No RCT has specifically targeted

feasibility and safety as main study outcomes, which should be studied in first place

when analyzing the effects of exercise in diseased populations. Keeping these

limitations in mind, current data would overall support the safety of light-moderate

exercise for old people with chronic AF. This is important because these individual

present several problems in terms of exercise prescription and supervision. Ventricular

rate is usually increased in the presence of AF, owing to the absence of atrial kick, with

consequent decreases in ventricular filling and thus in stroke volume. The fact that

VO2peak is low in chronic AF patients (see below), even in the presence of a higher

maximal heart rate (compared to their AF-free peers) and normal resting left ventricular

function, suggests they also have an attenuated stroke volume exercise response [2].

Although exercise interventions do not necessarily impact chronic AF per se or

AF burden (there is very scarce data on these outcomes anyway), they seem to improve

VO2peak and health-related QoL. Especially important is to increase VO2peak in these

patients, because they usually have very low levels at baseline, e.g., averaging 14.8±3.6

[2] or 16.9±5.2mL/kg/min [3]. These VO2peak values are well below the minimum

threshold of fitness, i.e., 8 metabolic equivalents (MET), which is equivalent to 28

(6)

ACCEPTED MANUSCRIPT

Finally, more research, preferably using RCT designs, is needed on the potential of

regular exercise to revert chronic AF.

In summary, while keeping in mind the aforementioned limitations, the current

evidence would indicate that exercise interventions are safe and increase AF patients‟

VO2peak and health-related QoL. Before more data is available allowing to prescribe

individualized exercise for this patient population, clinicians in charge of patients with

chronic AF should encourage them to follow general guidelines launched by the U.S.

Department of Health and Human Services and the World Health Organization [10],

i.e., engaging in≥30min of moderate exercise (like a brisk walk) for≥5d/wk, which

equates to≥150min/wk.

Conflict of interests

None of the authors have any conflict of interest.

References

[1] Sanchis-Gomar F, Santos-Lozano A, Garatachea N, et al. My patient wants to

perform strenuous endurance exercise. What's the right advice? International

journal of cardiology 2015;197:248-253

[2] Mertens DJ, Kavanagh T. Exercise training for patients with chronic atrial

fibrillation. Journal of cardiopulmonary rehabilitation 1996;16:193-196

[3] Vanhees L, Schepers D, Defoor J, et al. Exercise performance and training in

cardiac patients with atrial fibrillation. Journal of cardiopulmonary rehabilitation

(7)

ACCEPTED MANUSCRIPT

[4] Hegbom F, Stavem K, Sire S, et al. Effects of short-term exercise training on

symptoms and quality of life in patients with chronic atrial fibrillation.

International journal of cardiology 2007;116:86-92

[5] Plisiene J, Blumberg A, Haager G, et al. Moderate physical exercise: a

simplified approach for ventricular rate control in older patients with atrial

fibrillation. Clinical research in cardiology : official journal of the German

Cardiac Society 2008;97:820-826

[6] Gates P, Al-Daher S, Ridley D, Black A. Could exercise be a new strategy to

revert some patients with atrial fibrillation? Internal medicine journal

2010;40:57-60

[7] Osbak PS, Mourier M, Kjaer A, et al. A randomized study of the effects of

exercise training on patients with atrial fibrillation. American heart journal

2011;162:1080-1087

[8] Osbak PS, Mourier M, Henriksen JH, Kofoed KF, Jensen GB. Effect of physical

exercise training on muscle strength and body composition, and their association

with functional capacity and quality of life in patients with atrial fibrillation: a

randomized controlled trial. Journal of rehabilitation medicine 2012;44:975-979

[9] Franklin BA, McCullough PA. Cardiorespiratory fitness: an independent and

additive marker of risk stratification and health outcomes. Mayo Clinic

proceedings 2009;84:776-779

(8)

ACCEPTED MANUSCRIPT

Table 1. Main characteristics of the studies included in the systematic review on exercise in patients with atrial fibrillation (AF)

Author

(Year)

Type of patients,

underlying diseases Medical treatment Study design Group/s Exercise Sample size Mean±SD (or range) age

Main exercise effects Safety

Cochrane Collaboration

risk- of-bias

(over 6)

Gates et al.,

2010 [6]

A small cohort of patients with AF [of a duration of 8 hours to 7 months before presentation (median=18 hours)] who were scheduled to undergo electrical cardioversion Not specified Anecdotal observation Only one

Acute bout of exercise: exercise stress test (modified Bruce protocol) before scheduled

cardioversion Acute bout:

n=18 (89% men)

56 (36, 74) years

5 patients (28%) of total had successful reversion of AF with exercise while the other 13 patients remained in AF. No patient who failed to revert AF with the exercise test did so 3 hours to 7 months later (median 20 days)

Exercise was terminated prematurely in 4 of the 13 subjects in whom AF was not reverted with exercise ( 2 developed suspected ischemic chest pain)

- Sequence generation (+) - Allocation concealment (-)

- Blinding of participants, personnel and outcome assessors (-)

- Incomplete outcome data (+)

- Selective outcome reporting (+)

(9)

ACCEPTED MANUSCRIPT

Hegbom et

al., 2007 [4]

Chronic AF patients, all NYHA class I/ II, with HF (15%), organic heart disease (23%), hypertension (31%) or CAD (15%)

Digoxin (31%) β-blockers (31%) Ca2+ antagonists (46%)

ACE-I/ARB (31%)

RCT Training

3 sessions/week during 2 months 45 min/session at 70% to 90% of max HR

n=13 (100%

men)

62±7 years

↑ Exercise capacity with training

↑QoL domains using SF-36 scale (vitality, emotional role, corporal pain, and physical functioning) and improvements in ADL

↓ AF symptoms (frequency and severity)

No adverse reports were found during the training period.

- Sequence generation (+) - Allocation concealment (+)

(10)

ACCEPTED MANUSCRIPT

Chronic AF patients: all NYHA class I/II, with HF (20%), organic heart disease (20%), hypertension (27%) or CAD (13%)

Digoxin (13%) β-blockers (38%) Ca2+ antagonists (38%) ACE-I/ARB (20%) Control No exercise training during this period n=15 (87% men) 65±7 years

using SSCL - Other sources of bias (+)

Mertens et

al., 1996 [2]

Patients referred for exercise

rehabilitation with chronic AF of mixed etiology (valve disease, CAD, idiopathic) Digoxin (87%) Anticoagulants (60%), β-blockers (42%) Acetylsalicylic acid (10%) Prospective cohort No groups Walking 5 times/week at 60% to 80% of VO2max and/or at

the VT, together with a RPE of 12 to 14 on the original Borg scale of perceived n=20 (65% men) 61 years

After 1 year, a significant training effect was shown for VO2max (+15%, p<0.02;

VO2 at VT (+14%,

p<0.01), and peak power output (+21%,

p<0.05)

No serious ventricular arrhythmias were seen

- Sequence generation (+) - Allocation concealment (-)

(11)

ACCEPTED MANUSCRIPT

exertion. Measurements taken at beginning of exercise program, and repeated after 1 year.

- Other sources of bias (+)

Osbak et al.,

2011 [7]

Patients with chronic AF (mean duration 5±6 years) but without: severe HF (NYHA classes I/II), severe refractory hypertension, or previous heart valve surgery. Hypertension: 82% β-blockers (67%), digoxin (38%), ACE-I/ARB (54%), diuretics (29%), statins (21%), warfarin (87%)

RCT Active

3 sessions/week of aerobic exercise during 12 weeks. Session duration of 30 to 60 min at 70% of maximum exercise capacity. n=24 (75% men) 70±7 years

↑ Maximum aerobic exercise capacity in active group whereas control group lost capacity.

↑ 6MWT and QoL domains using SF-36 scale (physical functioning, general No adverse effects or safety issues were found

(12)

ACCEPTED MANUSCRIPT

health perceptions, and vitality physical) with training

↓ Resting HR and fat % in active group.

↔ No changes in natriuretic peptides Patients with

chronic AF (mean duration 7±10 years) but without: severe HF (NYHA classes I-II), severe refractory hypertension, or previous heart valve surgery. Hypertension: 65%

β-blockers (57%) Digoxin (39%) ACE-I/ARB (44%) Diuretics (17%) Statins (17%) Warfarin (78%)

Control

No exercise intervention

n=23 (74% men)

(13)

ACCEPTED MANUSCRIPT

Osbak et al.,

2012 [8]

Same as above study

RCT (same as

above study)

Training

Same as above study Same as above study Same as above study

↑ Muscular strength with training

Same as above study

Same as above study Control

Same as above study Same as above study Same as above study Plisiene et

al., 2008 [5]

Chronic AF patients, 10% with CAD and 50% with arterial hypertension. None had relevant coronary ischemia, left ventricular β-blockers (90%) Digoxin/digitoxin (30%) ACE-I/ARB (40%) Warfarine (70%) Aspirine (30%) Prospective pilot study No groups

45 min of walking/jogging twice a week for 4 months with assessment before and after the training period n=10 (70% men) 59±10 years

Trend toward a decrease of mean VR in 24-hour Holter-ECGs by 12% while there was no significant decrease in the minimal VR.

↓ VR (range 5-10%) was observed at ~all

Not actually reported. In 2 patients the beta-blocker and in 1 patient the digoxin was ceased as VR

- Sequence generation (?) - Allocation concealment (?)

(14)

ACCEPTED MANUSCRIPT

dysfunction or valve disease.

exercise levels during exercise treadmill testing

↑ Exercise capacity

↑ Subjective health perception control on Holter-ECGs had improved. There was no relevant bradycardia leading to a withdrawal of negative dromotropic medication.

Vanhees et

al., 2000 [3]

Cardiac patients referred for ambulatory exercise

rehabilitation with chronic AF (of

whom 74%

Digoxin (90%). No other specification.

Case/control Case (AF)

Ambulatory exercise program (3 times/week, 90 min/session), during 3 months

n=19 (89% men)

63±6 years

Before training, VO2peak

was significantly lower in patients with AF compared with those with no AF (p<0.05)

↑ VO2peak with training

in both groups (+31%, No complication s occurred during the training period Authors

(15)

ACCEPTED MANUSCRIPT

completed the exercise training program) Underlying diseases: CAD (56%), valve disease (47%), arterial

hypertension 32%)

in AF and +25% in non-AF patients)

The gain in VO2peak did

not significantly differ between both groups

↓ Resting HR in both groups after training.

concluded that exercise training can be carried out safely in AF patients

Similar dropout from the programs in patients with (26%) or without AF (25%)

(+)

Control group of cardiac patients in normal sinus rhythm

(CAD, 52%, valve disease, 48%; arterial

hypertension, 20%)

Digoxin (90%). No other specification.

Control (no AF)

Same as above

n=44 (93% men)

(16)

ACCEPTED MANUSCRIPT

Abbreviations: 6MWT, 6-minute walk test; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin II type I receptor blocker; CAD, coronary heart disease; HF, heart

failure: HR, heart rate; NYHA, New York Heart Association; PA, physical activity; SF-36, 36-item short form health survey; QoL, quality of life; RCT, randomized controlled

trial; RPE, rate of perceived exertion; SSCL, arrhythmia-related symptom severity check list; VO2max, maximum oxygen uptake; VO2peak, peak oxygen uptake; VR, ventricular rate;

(17)