Integrated Care to Reduce Atrial Fibrillation Burden

Do Not Underrate the Overweight!

Marcelle D. Smit; Michiel Rienstra; Robert G. Tieleman; Isabelle C. Van Gelder


Europace. 2018;20(12):1875-1876. 

Atrial fibrillation (AF) progression and increased AF burden are associated with cardiovascular morbidity and mortality.[1] Atrial remodelling has been proposed to contribute importantly to AF progression and is caused by various underlying conditions, including obesity.[2] In obesity, atrial remodelling is enhanced through a state of increased inflammation and oxidative stress, amongst other mechanisms. In addition, obesity is related to AF development through increased risk of hypertension, diabetes, and obstructive sleep apnoea along with other risk factors for AF development.[3] Weight reduction therefore presents a highly interesting intervention as part of a risk factor management program to reduce AF and to consequently improve outcome in AF patients.

In this issue of the journal, Middeldorp et al.[4] present the results of the Prevention and Regressive Effect of Weight-Loss and Risk Factor Modification on Atrial Fibrillation (REVERSE-AF) study, in which the influence of weight loss on AF progression was investigated. This study is a post hoc analysis of the Long-term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort (LEGACY) study, a cohort study which had already demonstrated that long-term sustained weight loss in overweight patients was associated with a dose-dependent reduction of AF burden and increased maintenance of sinus rhythm.[5] In the REVERSE-AF study, the focus is now on 'reversal' of the disease process, i.e. on reversal of AF progression, in the same 355 patients as were studied in the previous LEGACY study. These were patients with symptomatic paroxysmal or persistent AF with a body mass index ≥ 27 kg/m2. All were offered to participate in a weight and risk factor management program, with a target of >10% weight loss through meal plans and stimulation to exercise regularly. Furthermore, additional risk factors were targeted and treated, including hypertension, hypercholesterolaemia, glucose intolerance, sleep apnoea, smoking, and excessive alcohol consumption. Patients were divided into three groups according to the weight loss achieved: <3% weight loss or weight gain (Group 1), 3–9% weight loss (Group 2), and ≥10% weight loss (Group 3), consistent with the previous LEGACY study. Primary outcome of AF progression was defined by change in AF category from baseline to the last year of review, categorizing patients into paroxysmal vs. persistent AF, and further categorizing these groups into short (≤48 h) vs. long (>48 h but <1 week) paroxysmal AF, and short (≥1 week but <3 months) vs. long (≥3 months) persistent AF. Atrial fibrillation status for this primary endpoint was determined by patient symptoms, 7-day Holter monitoring, electrocardiogram, or implantable device. Follow-up was approximately 4 years.

The authors found that there was a relationship between weight loss and AF progression, or rather regression. Patients in Group 1 (with the least weight loss or even weight gain) were more likely to progress from paroxysmal to persistent AF (41%) and less likely to regress from persistent to paroxysmal AF (1%); in patients in Group 2 (3–9% weight loss) 32% progressed from paroxysmal to persistent AF, whereas 17% regressed from persistent to paroxysmal AF; and lastly in Group 3 (≥ 10% weight loss) only 3% progressed from paroxysmal to persistent AF, while 36% regressed from persistent to paroxysmal AF. Accordingly, freedom of AF over the final year of follow-up was present in 25% of patients from Group 1, 32% of patients from Group 2, and 52% of patients from Group 3. Beside the regression from persistent to paroxysmal AF, weight loss was also associated with a reduction in AF burden, i.e. short vs. long paroxysmal AF, and short vs. long persistent AF. From these results, the authors concluded that in overweight and obese patients with symptomatic AF, sustained obesity is associated with AF progression, while weight loss is associated with the reversal of the natural progression of AF.

Does this imply that we should from now on refer every overweight patient with symptomatic AF to a weight management program as an integral part of a risk factor modification program and would this be sufficient to reduce AF? Though the presented results are quite promising, the REVERSE-AF study in itself is insufficient for such implications. First of all, the study carries important limitations regarding its design. It investigated an intervention, i.e. weight loss reduction through a weight and risk factor management program, but the study was not randomized and no comparison was made with either another intervention or even to no intervention at all. Instead, it was a post hoc analysis of an observational cohort study, and as the authors themselves note, the REVERSE-AF is therefore not able to provide insight into cause-and-effect relationships between individual risk factors such as weight loss, hypertension, improvement of cardiorespiratory fitness, and AF progression.

Likewise, did the weight reduction in itself decrease AF progression? Or did in fact the supplementary modification of additional risk factors, such as hypertension and improvement of cardiorespiratory fitness lead to AF reduction? Though not emphasized by the authors, it is interesting to read that blood pressures turned out to be significantly lower at follow-up as the amount of weight loss increased. Beside blood pressure, no data regarding the possible changes in hypercholesterolaemia, glucose intolerance, sleep apnoea, smoking, and excessive alcohol consumption are provided. Furthermore, there is no insight into the amount and quality of exercise actually accomplished by the patients, which is also an important risk factor target in AF management.[6,7]

Recently, a number of studies have been published demonstrating the importance of integrated care, as also advocated in the guidelines,[8] targeting the AF structural substrate through aggressive treatment of underlying conditions and risk factors, together with 'electrical substrate-based' conventional rhythm control therapy through antiarrhythmic medication, cardioversion, and ablation. Such 'complete packages' lead to improved outcome of rhythm control therapy in AF patients, as shown in the Routine vs. Aggressive Risk Factor Driven Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure (RACE 3) study and the Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation (ARREST-AF) study.[9,10] Targeted therapy of underlying conditions in AF patients was effective to improve blood pressure, lipid profile, weight, body mass index, and heart failure. In addition, on top of that, it was of added value to improve maintenance of sinus rhythm. Therefore, all these studies contribute to the shift to focus on early management of underlying conditions to improve AF outcome, in addition to conventional rhythm control. Conventional rhythm control therapy in the REVERSE-AF study was left to the discretion of the investigators and therefore seems to have had a minor role. Only 25% of patients in Group 1 vs. 52% of patients in Group 3 were free of AF at follow-up. This means that half of patients in whom a total weight loss of at least 10% is accomplished still suffer of episodes of AF, again emphasizing the need to tackle both the structural and electrical substrate when applying a rhythm control strategy.

Finally, we cannot ignore the inevitable question whether significant reduction of AF, e.g. through reversal of AF progression, leads to improved prognosis by reduction of major adverse cardiac and cerebrovascular events. Until recently most rate vs. rhythm control trials failed to show a benefit of sinus rhythm maintenance, perhaps because of insufficient treatment of underlying disease, but also because in the past atrial ablation was not as successful as it is nowadays. The Catheter Ablation vs. Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) study was the first to demonstrate that AF ablation in heart failure patients could improve prognosis, as atrial ablation led to less deaths and less heart failure hospitalizations.[11] Just now, the Catheter Ablation vs. Antiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial was presented.[12] It showed that though patients who underwent ablation had less AF recurrences during follow-up compared with patients treated with medication alone, they did not have a lower rate of the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. Perhaps the other part of the complete package, i.e. substrate-based targeted treatment of underlying conditions, was underrated in the CABANA trial. It would seem logical that aggressive treatment of underlying risk factors, including obesity, will result in better outcome, especially when combining this with more aggressive, and earlier, conventional rhythm control therapy using ablation. This will be investigated in the long-term follow-up study of the RACE 3 trial.

But until then, we are dependent on currently available evidence, though limited by observational data or surrogate endpoints, and the results from the REVERSE-AF are quite encouraging. So regarding the question whether we should refer every symptomatic overweight AF patient to a risk factor management program including weight reduction, we believe that this should be included as a part of the integrated care which the AF patient deserves.