Impact of sustained weight loss on AF draws more attention to benefits of lifestyle change

Atrial fibrillation is a complicated and vexing disorder, placing patients at high risk for a number of events, particularly stroke. In 2015, results of a new study called LEGACY gave physicians and patients with atrial fibrillation some hope. Findings presented at the American College of Cardiology Scientific Sessions demonstrated that sustained weight loss was associated with reduced burden of atrial fibrillation, improved symptom severity and greater odds of arrhythmia-free survival.

The LEGACY study clarified what some have previously suspected: Weight management is an essential part of treatment for AF. The attention that the study has received since the data were presented and subsequently published in the Journal of the American College of Cardiology may prompt physicians who treat AF to change their practice to place greater emphasis on helping their patients lose weight and maintain weight loss.

“The study is already making its way into clinical guidelines and surely will change current clinical practice,” Prashanthan Sanders, MBBS, PhD, FHRS, Knapman–National Heart Foundation chair of cardiology research at the University of Adelaide, clinical director of cardiac electrophysiology at Royal Adelaide Hospital, Australia, and senior author of the LEGACY study, told Cardiology Today.

Before the spotlight was on the LEGACY study, most physicians were aware that weight loss is beneficial for patients with AF, but they “probably weren’t thinking about it very much,” Peter R. Kowey, MD, FACC, FHRS, professor of medicine and clinical pharmacology at Jefferson Medical College, Philadelphia, and chief of cardiology and William Wilkoff Chair in Cardiovascular Research at Lankenau Heart Institute, Wynnewood, Pennsylvania, said in an interview. “We see a lot of patients with AF, and they have a lot of issues, and they might be obese but we don’t get around to discussing it. Now, doctors will be more aware of it. How much more they will be aware of it, and how much they will intervene, is a big question.”

Current evidence base

In recent years, researchers have explored connections between weight management and the effect on AF.

For example, Sanders and colleagues in 2013 published study findings in JAMA concluding that weight reduction with intensive risk factor management in 150 patients with obesity and AF reduced AF symptom burden and severity and contributed to beneficial cardiac remodeling. After a median follow-up of 15 months, patients assigned a weight-loss intervention had a greater reduction in weight (14.3 kg vs. 3.6 kg; P < .001), AF symptom burden score (11.8 vs. 2.6; P < .001) and AF symptom severity score (8.4 vs. 1.7; P < .001). Compared with controls, those in the intervention group at 12 months had a greater decrease in mean number of AF episodes and duration of AF based on Holter monitoring (group x time interaction, P < .001).

Sanders and colleagues also conducted the ARREST-AF study of an aggressive risk factor management program focusing on control of weight, BP, lipids, glucose levels, sleep-disordered breathing, smoking and alcohol counseling compared with standard care. Results published in JACC in 2014 highlighted that aggressive management was associated with greater decreases in AF frequency, duration, symptoms and symptom severity and a higher rate of arrhythmia-free survival after AF ablation without the use of medication (P < .001 for all).

The LEGACY study expanded on that research. Sanders and colleagues investigated whether the effect of weight loss on AF is sustained, whether there is a dose effect and whether weight fluctuation influences the effect.

The study included 355 patients with AF and BMI at least 27 kg/m². All participants were counseled on weight loss and risk factor management, including hypertension, glucose control, sleep apnea, smoking and alcohol use, and offered participation in a physician-led weight management clinic; those who chose not to participate engaged in a self-managed weight-loss program. Patients were stratified by weight loss: 10% or more, 3% to 9% or less than 3%. Patients who lost 10% or more total weight had a greater rate of participation in the physician-led weight management clinic (84% vs. 57% in the 3% to 9% group and 30% in the less than 3% group; P < .001). All three groups averaged approximately 3 years of follow-up, during which weight trends and/or fluctuation were assessed yearly. At least once a year, AF was determined by clinical review, 12-lead ECG and 7-day Holter monitoring.

Patients who lost 10% or more of total weight had a greater decrease in AF burden and symptom severity (P < .001 for all) compared with lower levels of weight loss. This group also had a greater rate of arrhythmia-free survival with and without rhythm control strategies compared with the other weight-loss groups (P < .001 for comparison with both groups). When Sanders and colleagues conducted multivariate analyses, they found that weight loss and weight fluctuation independently predicted AF-related outcomes (P < .001 for both). Additionally, 10% or more weight loss resulted in sixfold greater probability of arrhythmia-free survival compared with 3% to 9% or less than 3% weight loss.

“Weight loss was also associated with beneficial structural remodeling, including significant reductions in left atrial volume and left ventricular hypertrophy,” Sanders told Cardiology Today.

In other results, the researchers found that weight fluctuation of greater than 5% could renew a patient’s risk for AF. Patients whose weight fluctuated by more than 5% during the study period had a twofold increased risk for arrhythmia recurrence.

“The LEGACY study was a wake-up call for electrophysiologists that AF is not just an electrical phenomenon,” John D. Day, MD, FHRS, FACC, director of heart rhythm services at Intermountain Heart Institute, Murray, Utah, and president of the Heart Rhythm Society, said in an interview. “It may be a manifestation of comorbidities. And we need to treat the underlying causes, or they will just develop new AF circuits.”

The correlation between BMI and AF risk is strong across a wide swath of research, according to a meta-analysis conducted by Sanders and colleagues published in May in JACC: Electrophysiology. The researchers analyzed data from 51 studies covering 626,603 individuals. In cohort studies, there was a 29% (OR = 1.29; 95% CI, 1.23-1.36) increased risk for incident AF for every five-unit increase in BMI, and in case-control studies, there was a 19% (OR = 1.19; 95% CI, 1.13-1.26) increased risk. Similarly, for every five-unit increase in BMI, there was a 10% (OR = 1.1; 95% CI, 1.04-1.17) excess risk for postoperative AF and a 13% (OR = 1.13; 95% CI, 1.06-1.22) excess risk for post-ablation AF, according to the results.

Possible mechanisms explored

There are a number of theories about why sustained weight loss has an impact on AF, but the exact mechanism may never be known because so many factors are intertwined, experts told Cardiology Today.

“When somebody loses weight, there are lots of other positive changes that happen at the same time,” Anne B. Curtis, MD, FACC, FHRS, FACP, FAHA, Charles and Mary Bauer professor and chair, UB distinguished professor, department of medicine, University at Buffalo, said in an interview. “So, if you lose weight, your BP becomes more normal, you have less risk for sleep apnea and your lipid/cholesterol profile gets better. All of these things may affect the likelihood of recurrent AF.”

Whether weight loss is an independent effect is unknown because it is uncommon for someone to lose weight and not experience improvement in the other risk factors, Curtis said. “But it is possible that less weight/less mass puts less strain on the heart. When we image the heart on echocardiography, we can see that atrial size will decrease if there is substantial weight loss, and there is less ventricular hypertrophy as well.”

Sanders said the LEGACY results can be explained by a number of factors. “In this study, we observed beneficial effects of weight loss on BP, diabetic control, lipid profile and inflammation, all of which may have contributed to reduction in AF burden,” he said.

Inflammation almost certainly plays a role, according to Kowey, who is the Arrhythmia Disorders Section Editor of Cardiology Today.

“We know that obesity is accompanied by pro-inflammatory changes, and inflammation is important in the pathogenesis of AF. Epicardial adipose tissue is pro-inflammatory, and obese patients obviously have a lot more of that than nonobese patients,” he said.

Another factor may be left atrial pressure.

“With obesity, you get increases in the left atrial pressure as well as the left atrial size,” Day told Cardiology Today. “When the left atrium is under stress, it causes a stretching, and there is irritation of the cardiac myocyte, which may disrupt electrical pathways.”

Implications for clinical practice

Given the latest research and mechanistic understanding, physicians can make a positive impact on their patients with AF if they counsel them about weight loss, even if they do not have resources at their disposal for an intense weight management or risk factor management program, experts said.

“Counseling any patient who is overweight or obese would be prudent. But it has to go hand-in-hand with other risk factor reductions as well: controlling high BP, screening patients for sleep apnea and so on,” Curtis said.

What LEGACY and the related studies have shown is that even patients who lost small amounts of weight have demonstrated improvement in AF symptoms and burden, Day said.

“The big message there is that even if your hospital doesn’t have a nutritionist or cardiac rehab or other resources, simply encouraging the patient to live healthier can have a modest effect,” he said. “From that, one can conclude that just simply mentioning it at the time of their visit can have some benefit.”

Another lesson from the LEGACY study that doctors should remember is that weight loss can have a positive effect on AF, even in those who are moderately overweight, Curtis said.

What is crucial, Kowey said, is making sure patients sustain their weight-loss efforts and do not allow their weight to fluctuate, which involves setting reasonable goals.

“The problem that a lot of my patients have is that they take the weight off and then it comes back,” he said. “The fluctuations appear to mitigate the advantage of the weight loss. So the key issue is getting people onto a regimen that they are comfortable with and can sustain over time. I try to set a reasonable goal for my patients: I might say, ‘Maybe by the next time you come in, you can try to lose 10 lb, and then we’ll talk about it some more.’ I am hesitant to discuss ideal body weight or BMI because, in many of my patients, it sets an unrealistic goal. If you insist on it, they can get terribly frustrated and give up. It can also lead to fluctuation. If they try to lose a lot of weight at once, they go on goofy diets that they can’t sustain. They lose the weight, and then it comes back again. It’s inevitable.”

This requires close supervision by the physician for the long term, Eric N. Prystowsky, MD, and Benzy J. Padanilam, MD, both from the St. Vincent Medical Group, St. Vincent Hospital, Indianapolis, wrote in an editorial that accompanied the publication of the LEGACY findings in JACC.

“Long-term weight loss is feasible through physician-initiated approaches, but the approaches must be rather rigorous and continue over time,” they wrote. “Although it is not clear which of the many benefits of substantial weight loss and its maintenance over time contribute to the reduction of AF burden, there seems little doubt that it is a positive outcome.”

More research to be done

Recent research has convincingly demonstrated that losing weight and keeping it off is beneficial for patients with AF, but there remains more work to be done.

It would be helpful if the findings from Sanders and colleagues are replicated in other populations, and if longer-term follow-up is conducted, Day said.

“Sanders and his group are ahead of the curve, and I’d like to see more research coming from other centers. I think that we will see that over time,” he said. “My question is, do [patients] stay in remission, or is [AF] going to eventually come back in 5 to 10 years? That is a fascinating question.”

Kowey said he would like to see whether the same effect is produced if patients use weight-loss drugs.

“I would like to see some systematic studies with weight-loss drugs in patients with AF because you can’t assume that dietary intervention to lose weight will have the same impact as drug-induced reductions in weight,” he said. “If [manufacturers] could do a good, well-controlled, randomized, double blind AF study and show that you could reduce the AF burden with [drug-induced] weight loss, that would be terrific. I would use those drugs in my practice because they would at least help patients get started on the way. These drugs are not the panacea, but the thought is that the positive reinforcement of seeing yourself lose 5% to 10% of your body weight gets you headed in the right direction.”

Mechanistic studies would also be helpful, Kowey said, but would be difficult to conduct “because there are so many confounders and it is difficult to control for them all.” He discussed the possibility of careful measurement of inflammatory markers or studying diabetics vs. nondiabetics or hypertensives vs. nonhypertensives. “There are ways to control the experiments, but they are very difficult designs.”

In their editorial, Prystowsky and Padanilam suggested that future studies use more aggressive monitoring, such as implantable loop recorders, for more precise assessment of AF burden reduction.

In addition, they wrote, “a more fundamental question that will require additional research is whether we can achieve primary prevention of AF by early attention to factors such as obesity, diabetes, hypertension and [obstructive sleep apnea]. Also, there are no data on stroke reduction with these approaches; therefore, it is advisable to maintain anticoagulation as per current recommendation until these data are known.”

Profound impact

The LEGACY study and related research are likely to have a profound impact on the care of patients with AF, as they indicate that treatment for AF must include treatment for comorbidities.

“This certainly gets us thinking that we can’t treat AF in isolation,” Day said. “That is the real take-home message. We have to address the diabetes, the hypertension, the metabolic syndrome.”

This can be an encouraging message for physicians and patients. Long-term studies of ablation therapies indicate that the effects of ablation on AF wane over time, but perhaps addressing obesity and other comorbidities in a sustained manner can offer a permanent solution.

“The general feeling was, once you get AF, you’re cursed for life,” Day said. “That was the teaching, and most cardiologists probably believe that today. But the fascinating thing with LEGACY is that 46% of the patients went into remission without drugs or procedures. There is a message of hope there.” – by Erik Swain

References:

Abed HS, et al. JAMA. 2013;doi:10.1001/jama.2013.280521.

Pathak RK, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.09.028.

Pathak RK, et al. J Am Coll Cardiol. 2015;doi:10.1016/j.jacc.2015.03.002.

Prystowsky EN, Padanilam BJ. J Am Coll Cardiol. 2015;doi:10.1016/j.jacc.2015.03.568.

Wong CX, et al. J Am Coll Cardiol EP. 2015;doi:10.1016/j.jacep.2015.04.004.

For more information:

Anne B. Curtis, MD, FACC, FHRS, FACP, FAHA, can be reached at 100 High St., D2-76, Buffalo, NY 14203; email: abcurtis@buffalo.edu.

John D. Day, MD, FHRS, FACC, can be reached at 5169 Cottonwood St., Murray, UT 84107; email: john@drjohnday.com.

Peter R. Kowey, MD, FACC, FHRS, can be reached at Lankenau Medical Office Building East, Suite 558, 100 E. Lancaster Ave., Wynnewood, PA 19096; email: koweyp@mlhs.org.

Prashanthan Sanders, MBBS, PhD, FHRS, can be reached at Centre for Heart Rhythm Disorders, Department of Cardiology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia; email: prash.sanders@adelaide.edu.au.

Disclosures: Curtis reports consulting for Daiichi Sankyo, Janssen Pharmaceuticals and Sanofi Aventis. Prystowsky reports receiving consultant fees from CardioNet, Medtronic and Topera Medical, honoraria from Medtronic and serving on the board of directors/holding equity in Stereotaxis. Padanilam reports receiving speaker honoraria from Medtronic. Sanders reports serving on advisory boards for Biosense Webster, Medtronic, Merck Sharpe & Dohme, Sanofi and St. Jude Medical, receiving lecture and/or consultant fees from Biosense Webster, Biotronik, Boston Scientific, Medtronic, Merck Sharpe & Dohme, Sanofi and St. Jude Medical, and research funding from Biotronik, Boston Scientific, Medtronic, Sorin and St. Jude Medical. Day and Kowey report no relevant financial disclosures.