11th June 2025, A/Prof Chee L Khoo
Atrial fibrillation (AF) is associated with 1.5 – 2-X risk of death (1,2), 2.4-X risk of stroke (2), 5-X risk of heart failure (HF) (2), 1.5-X risk of myocardial infarction (MI) (3), 2-X risk of sudden cardiac death (4), 1.6-X risk of chronic kidney disease (CKD) (2), 1.5-X risk of cognitive impairment or dementia (5) and 1.3-X risk of peripheral artery disease (PAD) (2). Apart from anti-coagulation to prevent thrombo-embolic strokes, management of AF has historically been divided into rate and rhythm control strategies. The current gold standard favour rate control over rhythm control. This came after the AFFIRM and RACE trials 20 years ago. A number of recent studies has swung the pendulum back towards rhythm control as we relooked at the origin data from the two trials. This has significant implications in primary care.
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial reported in 2004 (6). Prior to the AFFIRM trial, initial therapies were usually attempts to restore and maintain normal sinus rhythm (NSR) hoping to decrease morbidity. All they had available then for rhythm control were anti-arrhythmics like amiodarone, sotolol, propafenone, procainamide, quinidine, flecainide, disopyramide, and/or moricizine which were not that efficaceous and often “toxic” (potentially contributing to adverse outcomes). After an average of 3.5 years, 63% of the rhythm group and 35% of the rate group were in NSR. However, there was no difference in the combined endpoint of death and CVA nor any benefit in quality of life or improved cognitive function. The rhythm group had slightly higher deaths, CVA and hospitalisations although they were not statistically significant.
The Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial Fibrillation (RACE) trial also compared rhythm vs rate control in 35 hospitals in Netherlands. (7) They had similar findings – rhythm control had more adverse events (cardiovascular deaths, heart failure hospitalisations etc) than the rate control group.
The AFFIRM trial had 4060 patients while the RACE trial only 522 patients but both were instrumental in swinging the pendulum towards rate control over rhythm control which is what we have here today. Interestingly, in both studies, the rhythm group had more thromboembolism than the rate control group. It was thought that the patients in the rhythm group either were not anticoagulated or had sub therapeutic INRs.
Over the last 20 years, we have learned a lot about AF other than just thromboembolic strokes. It is very insightful to look at the 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation’s Goals of Therapy with Rhythm Control (8):
- In patients with reduced LV function and persistent (or high burden) AF, a trial of rhythm control should be recommended to evaluate whether AF is contributing to the reduced LV function.
- In patients with symptomatic AF, rhythm control can be useful to improve symptoms.
- In patients with a recent diagnosis of AF (<1 year), rhythm control can be useful to reduce hospitalizations, stroke, and mortality.
- In patients with AF and HF, rhythm control can be useful for improving symptoms and improving outcomes, such as mortality and hospitalizations for HF and ischemia.
- In patients with AF, rhythm-control strategies can be useful to reduce the likelihood of AF progression.
- In patients with AF, rhythm-control strategies may be useful to reduce the likelihood of development of dementia or worsening cardiac structural abnormalities.
Up until now, we have been ablating primarily when there are symptoms. The Goals of Therapy above brings up a number of concepts which are very relevant to our patients in primary care:
AF and heart failure
AF and HF commonly occur together. Catheter ablation for AF in patients with HF has been shown in a number of clinical trials to significantly lower composite primary endpoint of cardiovascular death, stroke, or hospitalization due to HF or acute ischemic syndrome (EAST-AFNET 4, CASTLE-AF, CASTLE-HTX) (9 – 11).
Progression of AF/Burden of AF
Patients with AF may not be in AF all the time. AF commonly, but not always, progresses over time to a higher burden and becomes more sustained. In 2 registry studies, progression to a more sustained form of AF burden was observed in 26% to 28% of patients undergoing a rate-control strategy compared with 6% to 11% of patients treated with a rhythm-control strategy.
Should we be ordering more 24-hour Holter monitoring to ascertain the burden of AF in patients with “stable” AF. Perhaps, a referral back to the cardiologist might be warranted. It seems that our cardiologists are currently only offering ablation in symptomatic patients. In the EAST-AFNET 4 trial, the composite outcome of death, stroke, or cardiac hospitalization was reduced in all patients regardless of whether symptoms were present or not.
Development of dementia
AF is associated with increased cognitive impairment, progressive increase in AF burden, and structural changes in the heart (12, 13). In a very recent case-control and prospective before–and–after study, Guo et al enrolled patients with AF and compared their glymphatic activity using brain MRI with healthy controls (14). Brain glymphatic function was impaired in patients with AF, mediates the association between AF and cognitive decline, and was improved after ablation therapy.
Implications in general practice
Managing AF is not just about managing the thromboembolic risk with anticoagulants. Heart failure is a very common comorbidity. Managing heart failure should include consideration of catheter ablation. Improvement in adverse cardiac outcomes is observed with ablation irrespective of whether the patient is symptomatic or not.
AF is usually progressive where the AF burden increases over time. AF is also associated with cognitive impairment. Like other complications of AF, increasing cognitive impairment is associated with progressive increase in AF burden. Ablation may reduce the progression and the burden of AF leading to reduction in adverse outcomes.
We should be monitoring the burden of AF and not just monitoring symptoms of heart failure or dyspnoea. While ablation is not suitable for all patients with AF, the option should be explored in all patients with AF. The pendulum appears to have swung back towards rhythm control as the evidence mounts.
References:
1. Emdin CA, Wong CX, Hsiao AJ, et al. Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies. BMJ. 2016;532:h7013.
2. Odutayo A, Wong CX, Hsiao AJ, et al. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and metaanalysis. BMJ. 2016;354:i4482.
3. Ruddox V, Sandven I, Munkhaugen J, et al. Atrial fibrillation and the risk for myocardial infarction, all-cause mortality and heart failure: a systematic review and meta-analysis. Eur J Prev Cardiol. 2017;24:1555–1566.
4. Rattanawong P, Upala S, Riangwiwat T, et al. Atrial fibrillation is associated with sudden cardiac death: a systematic review and meta-analysis. J Interv Card Electrophysiol. 2018;51:91–104.
5. Papanastasiou CA, Theochari CA, Zareifopoulos N, et al. Atrial fibrillation is associated with cognitive impairment, all-cause dementia, vascular dementia, and Alzheimer’s disease: a systematic review and meta-analysis. J Gen Intern Med. 2021;36:3122–3135.
6. Olshansky B, Rosenfeld LE, Warner AL, et al. AFFIRM Investigators. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol. 2004 Apr 7;43(7):1201-8
7. Van Gelder IC, Hagens VE, Bosker HA, et al, for the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group: A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–1840
8. Joglar JA, Chung MK, Armbruster AL, et al; Peer Review Committee Members. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024 Jan 2;149(1):e1-e156.
9. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med. 2020;383:1305–1316.
10. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med. 2020;383:1305–1316.
11. Sohns C, Marrouche NF, Costard-Jäckle A, et al. Catheter ablation for atrial fibrillation in patients with end-stage heart failure and eligibility for heart transplantation. ESC Heart Fail. 2021 Apr;8(2):1666-1674.
12. Senoo K, Suzuki S, Otsuka T, et al. Progression to the persistent form in asymptomatic paroxysmal atrial fibrillation. Circ J. 2014;78:1121–1126.
13. Disertori M, Lombardi F, Barlera S, et al. Clinical characteristics of patients with asymptomatic recurrences of atrial fibrillation in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial. Am Heart J. 2011;162:382–389. 14. Manolis TA, Manolis AA, Apostolopoulos EJ, Melita H, Manolis AS. Atrial Fibrillation and Cognitive Impairment: An Associated Burden or Burden by Association? Angiology. 2020;71(6):498-519.