Highlight
- Early rhythm control therapy significantly reduces cardiovascular events in patients with early atrial fibrillation.
- Diabetes and obesity do not diminish the benefits or safety of early rhythm control therapy in this population.
- Patients with obesity and diabetes presented with higher cardiovascular risk profiles but still benefited similarly from intervention compared to those without these conditions.
Study Background and Disease Burden
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide, associated with increased risks of stroke, heart failure, and mortality. The interplay of metabolic disorders such as obesity and diabetes further exacerbates cardiovascular risk, complicating AF management strategies. Both obesity and diabetes contribute to structural and electrical remodeling of the atria, perpetuating AF and increasing adverse cardiovascular outcomes. With rising global prevalence of obesity and diabetes, understanding how these conditions affect treatment efficacy in AF is crucial. The EAST-AFNET 4 trial previously established that early rhythm control therapy, alongside anticoagulation and risk factor management, improves cardiovascular outcomes compared with usual care in AF patients. However, how body mass index (BMI) categorized obesity and diabetes status modify this benefit remains unclear, representing a critical knowledge gap for tailored clinical care.
Study Design
The EAST-AFNET 4 was an international, investigator-initiated, open-label, parallel-group randomized clinical trial with blinded outcome assessment, conducted across 11 European countries. Eligible participants had early AF, defined as diagnosis within twelve months before enrollment, coupled with cardiovascular conditions. Patients were randomly assigned to receive either early rhythm control therapy—consisting of antiarrhythmic drugs or catheter ablation initiated soon after diagnosis—or usual care focused on symptom management without mandated rhythm control. The primary composite outcome was cardiovascular death, stroke, hospitalization for heart failure, or acute coronary syndrome. This secondary prespecified analysis utilized the final locked dataset (performed in 2024) applying the intention-to-treat principle to evaluate modifications of treatment effect by BMI (obese defined as BMI≥30) and diabetes status.
Key Findings
A total of 2776 patients were included: 1086 with obesity (mean BMI 34.5) and 1690 without obesity (mean BMI 25.9); 46.6% were female, mean age overall 70 years. Patients with obesity were younger (68 vs 72 years) and more often had persistent or nonparoxysmal AF (31% vs 24%). Importantly, mean CHA2DS2-VASc scores were similar between obese and non-obese groups (3.4 vs 3.3), indicating comparable stroke risk profiles.
Regarding treatment effect, early rhythm control significantly reduced the primary composite endpoint in both BMI subgroups with hazard ratios (HR) of 0.69 (95% CI not provided) for obese and 0.84 for non-obese patients, with no significant interaction (P for interaction=0.22) indicating consistent benefit across BMI categories.
For diabetes, 351 patients with diabetes were younger (mean 69 years) but had higher CHA2DS2-VASc scores (4.06 vs 3.11), reflecting heightened baseline stroke risk. Early rhythm control effects were comparable regardless of diabetes status: HR 0.77 (95% CI, 0.57-1.05) for diabetic and 0.78 (95% CI, 0.64-0.96) for non-diabetic patients, with no significant interaction (P=0.93). Safety outcomes, including adverse events, did not differ between diabetic and non-diabetic groups (18.2% vs 16.1%, P=0.99).
These results confirm that early rhythm control therapy maintains its effectiveness and safety in patients with AF irrespective of obesity or diabetes comorbidity.
Expert Commentary
The EAST-AFNET 4 secondary analysis provides clinically relevant insights into managing AF in populations with common metabolic comorbidities. Given that obesity and diabetes often complicate AF pathophysiology through enhanced atrial stretch, inflammation, and fibrosis, concerns existed that these conditions might attenuate rhythm control benefits. However, this robust analysis, encompassing diverse European cohorts and rigorous randomized design, suggests that early rhythm control confers cardiovascular protection equally across these subgroups.
Current AF guidelines emphasize integrated care approaches including anticoagulation and management of concomitant risk factors. This study’s findings reinforce early rhythm control as a cornerstone therapy that can be broadly applied without adjustment for BMI or diabetes presence. Nonetheless, the younger age and higher prevalence of persistent AF among obese patients merit further exploration regarding mechanistic links and optimization of rhythm control strategies.
Limitations include the open-label design which might introduce bias, though blinded outcome adjudication mitigates this risk. Generalizability to non-European populations, or individuals with extreme BMI categories or differing diabetes control states, requires caution. Further research may explore long-term metabolic effects of rhythm control interventions and potential synergistic benefits of weight loss and glycemic optimization.
Conclusion
This secondary analysis from the EAST-AFNET 4 trial demonstrates that early rhythm control therapy effectively reduces major cardiovascular outcomes in patients with newly diagnosed atrial fibrillation, with sustained efficacy and safety irrespective of obesity or diabetes status. These findings support the broad implementation of early rhythm control in managing AF patients, including those with prevalent metabolic comorbidities. Continued focus on comprehensive cardiovascular risk assessment and integrated treatment remains essential to optimize patient outcomes.
References
1. Metzner A, Willems S, Borof K, et al. Diabetes and Obesity and Treatment Effect of Early Rhythm Control vs Usual Care in Patients With Atrial Fibrillation: A Secondary Analysis of the EAST-AFNET 4 Randomized Clinical Trial. JAMA Cardiol. 2025 Sep 1;10(9):932-941. doi: 10.1001/jamacardio.2025.2374.
2. Kirchhof P, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383:1305-1316.
3. January CT, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 Atrial Fibrillation Guideline. Circulation. 2019;140:e125-e151.
4. Lavie CJ, et al. Obesity and Atrial Fibrillation: Mechanistic, Epidemiologic, and Clinical Challenges. Prog Cardiovasc Dis. 2021;64:1-8.
