This year marks the 25th anniversary of the discovery that thinning blood using vitamin K antagonists (VKAs) prevents strokes in patients with atrial fibrillation (AFib), the most common sustained cardiac arrhythmia seen in clinical practice. AFib is associated with an increased risk of stroke and cardiovascular disease (CVD).^1,2,4,6  

Cornerstone of AFib management  

According to Prof Kirchhof, anti-coagulation is the cornerstone of AFib management. However, additional measures are required to prevent CV complications.¹  

Warfarin is one of the most widely used anti-coagulants worldwide and reduces the risk of stroke by 62% compared to 22% with aspirin. However, VKAs are associated with an increased risk of haemorrhagic stroke and have a narrow therapeutic index, which require frequent monitoring and dose adjustments. As a result non-adherence to treatment is high.^2,3 

Additional measures required to prevent CV complications include preventative lifestyle changes (eg physical activity, a balanced diet, sufficient sleep, moderate alcohol consumption or abstinence, avoiding or compensating for stress and smoking cessation) as well as a range of CV therapies and interventions (eg anti-hypertensives, anti-arrhythmic drugs, pulmonary vein isolation, AFib ablation or surgery, coronary revascularisation, statins) to reduce the risk of complications.¹  

Despite optimal management with anticoagulants, noted Prof Kirchhof, patients with AFib still suffer strokes, develop acute coronary syndrome (ACS), heart failure (HF) or die because of CVDs (5% of patients per annum).^1,5  

In the Randomized Evaluation of Long-Term Anticoagulant Therapy trial (n=18 133), Marijon et al found that most deaths in patients with AFib treated with anti-coagulants (warfarin or dabigatran) is not caused by stroke, but rather as a result of CVDs.⁶  

Their analysis showed that cardiac deaths (sudden cardiac death and progressive HF) accounted for 37.4% of all deaths, whereas stroke- and haemorrhage-related deaths represented 9.8% of the total mortality. The two strongest independent predictors of cardiac death in this population were HF and prior myocardial infarction.⁶ 

Marijon et al concluded that these results emphasise the need for interventions beyond effective anticoagulation to further reduce mortality in patients with AFib.⁶  

Rhythm control 

Previous studies have failed to show the superiority of rhythm control using anti-arrhythmic drugs over rate control in patients with established AFib, said Prof Kirchhof.^7,8  

Roy et al point out that the potential benefit of rhythm control with respect to mortality may have been neutralised by the harmful effects of then available anti-arrhythmic therapies (2008).⁷ 

According to Prof Kirchhof, the ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter) study was the first to show that being in sinus rhythm translates into clinical benefit. This and older studies by Wijffels et al, showing that ‘AFib begets AFib’ and can lead to damage of the atria, generated the hypothesis for the Early Treatment of AFib for Stroke Prevention Trial (EAST AFNET-4) trial.^1,5,9,10,17 

EAST AFNET-4 (2020) was an international, investigator-initiated, parallel-group, open, blinded-outcome assessment trial and was stopped for efficacy at the third interim analysis after a median follow-up of 5.1 years per patient.^1,5,10 

Participants with early AFib (diagnosed ≤1 year before enrolment) were randomised in a 1:1 ratio to either early rhythm control therapy (group 1), with anti-arrhythmic drugs (n=1395) or (group 2) to usual care (n=1394), consisting primarily of rate control drugs at the start with a move to rhythm control in 15% of patients at the two-year mark.^5,10  

The primary endpoint was a composite of death from CV causes, stroke, or hospitalisation with worsening of HF or acute coronary syndrome. Secondary endpoints were the number of nights spent in the hospital per year, symptoms and left ventricular function. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy.⁵ 

Treatment of CV conditions, anticoagulation, and rate control were required in all patients (as per guideline recommendations). Participating teams could independently select the type of rhythm control therapy – if it was based on current guidelines. In the early rhythm control arm, the initial choice of strategy in almost all patients (95%) included flecainide (36%), amiodarone (20%) or AFib ablation (8%).^5,10 

A first-primary-outcome event occurred in 249 patients assigned to receive early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to receive usual care (5 per 100 person-years). The mean number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively).^5,10   

The percentage of patients with a primary safety outcome event did not differ significantly between the groups. Serious adverse events related to rhythm control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care.  

Most patients (>70%) in both groups were free from AFib symptoms at two years, which indicates that both rate control and rhythm control can control symptoms and maintain cardiac function in patients with early AFib.^5,10   

The authors concluded that early rhythm-control therapy was associated with a lower risk of adverse CV outcomes than usual care among patients with early AFib and CV conditions.^5,10   

In a sub-analysis of the EAST-AFNET 4 trial, Metzner et al assessed whether differences in anti-coagulation, therapy of concomitant diseases, or intensity of care can explain the clinical benefit achieved with early rhythm control.¹¹ 

Oral anticoagulation was used in >90% of patients during follow-up without differences between randomised groups. There were no differences in treatment of concomitant conditions between groups. The type of rhythm control varied by country and centre.¹¹  

Over time, anti-arrhythmic drugs were given to 84% patients in early therapy, and to 14% in usual care. AFib ablation was performed in 24% of patients randomised to early therapy, and in 12% of patients randomised to usual care. Some 97% of rhythm control therapies were in line with class I and class III recommendations of AFib guidelines.¹¹  

One of the questions frequently asked is whether the results of the EAST AFNET-4 trial would have been different if all patients underwent AFib ablation. The honest answer is that we don’t know, said Prof Kirchhof. However, what is clear, is how remarkably successful anti-arrhythmic drug therapy was. Some 80% of patients were in sinus rhythm within two years in the early rhythm control arm.¹  

He does, however, think that AFib ablation was a key component of the rhythm control strategy because of the synergistic effect between ablation and anti-arrhythmic drugs.  Two important clinical studies by Darkner et al and  Duytschaever et al demonstrated this synergistic effect, noted Prof Kirchhof.^1,12,13  

Patients with AFib and heart failure 

One of the most challenging group of patients to maintain in sinus rhythm and to treat with rhythm control therapy are those with HF, said Prof Kirchhof.¹  

As mentioned above, even on optimal therapy, many patients with HF and AFib experience CV complications. Additional treatments are needed to reduce these events, especially in patients with HF and preserved LV ejection fraction (LVEF).¹⁴ 

Rillig et al conducted a sub-analysis of the EAST-AFNET 4 trial to assess the effect of systematic, early rhythm control therapy (using anti-arrhythmic drugs or AFib ablation) compared with usual care ( rate control therapy) in patients with HF, defined as New York Heart Association II to III or LV ejection fraction [LVEF] <50%.¹⁴ 

In this sub-analysis around 800 patients with HF were randomised. More than half (n=442) with preserved ejection fraction (HFpEF) mainly received flecainide, whilst those with reduced ejection fraction (HFrEF) mainly amioderone, said Prof Kirchoff.¹ 

He added that outcomes in patients with HF was the same as the main trial. Early rhythm control reduced primary outcome by 24% in patients with HF.  There were also ‘very few safety signals associated with the use of fleciainied in patients with HFpEF’. 

LVEF improved in both groups (LVEF change at two years: early rhythm control 5.3 ± 11.6%, usual care 4.9 ± 11.6%). Early rhythm control also improved the composite outcome of death or hospitalisation for worsening of HF.¹⁴ 

The results of the study by Rillig et al confirms that we should be treating patients with recently diagnosed AFib and HF with rhythm control to prevent their risk of CVD complications, said Prof Kirchhof.^1,14 

What about asymptomatic patients? 

The most recent European Society of Cardiology for the diagnosis and management of AFib recommends rhythm control for symptom and quality of life improvement in symptomatic patients with AFib.¹⁵ 

Most of us have been taught to use rhythm control to treat symptoms. However, if you take the results of the trial into consideration, you should not withhold rhythm control from asymptomatic patients.¹  

To test whether there is an improvement in asymptomatic patients another sub-analysis of the EAST AFNET-4 trial was conducted. Willems et al compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from CV causes, stroke, or hospitalisation with worsening of HF or ACS, analysed in a time-to-event analysis. At baseline, 30.4% patients were asymptomatic (mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 21.1% HF).^1,16  

Asymptomatic patients randomised to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients (eg AF ablation at 24 months: 19.0% in asymptomatic 19.3% symptomatic patients).¹⁶  

Anticoagulation and treatment of concomitant CV conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomised to early rhythm control and in 97/406 patients randomised to usual care, almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomised groups.¹⁶ 

Willems et al concluded that the clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions.¹⁶ 

Take-home messages 

Systematic and early initiation of rhythm control therapy using anti-arrhythmic drugs and AFib ablation reduces CV outcomes by 20% in unselected patients with recently diagnosed AFib when added to oral anticoagulation, rate control and therapy of concomitant CV conditions. 

The safety of early rhythm control therapy was key for this outcome. Consider both anticoagulation and rhythm control in patients with recently diagnosed AFib to achieve optimal clinical outcomes. 

REFERENCES 

1. Kirchhof P. Early rhythm control in patients with atrial fibrillation: What is new? CASSA Symposium 2022. Virtual Series, 5 March. https://www.youtube.com/watch?v=5z69ktp__q4 
2. Ruff CT, Giuliana RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. The Lancet, 2014. 
3. Hart RG, Benvente O, McBride R, and Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med, 1999. 
4. Kirchhof P. The future of atrial fibrillation management: integrated care and stratified therapy. The Lancet, 2017. 
5. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. NEJM, 2020. 
6. Marijon E, Le Heuzey J-Y, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study. Circulation, 2013. 
7. Roy D, Talajic M, Nattel S, et al. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure. NEJM, 2008. 
8. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: The Strategies of Treatment of Atrial Fibrillation (STAF) study. JACC, 2003.  
9. Hohnloser SH, Crijns HJGM, Van Eickels M, et al. Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation. NEJM, 2009. 
10. Kirchhof P, Camm AJ, Goette A et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. NEJM, 2020. 
11. Metzner A, Suling A, Brandes A, et al. Anticoagulation, therapy of concomitant conditions, and early rhythm control therapy: a detailed analysis of treatment patterns in the EAST - AFNET 4 trial. EP Europace, 2022. 
12. Darkner S, Chen X, Hansen J, et al. Recurrence of arrhythmia following short-term oral AMIOdarone after CATheter ablation for atrial fibrillation: a double-blind, randomized, placebo-controlled study (AMIO-CAT trial). Eur Heart J, 2014 
13. Duytschaever M, Demolder A, Phlips T, et al. PulmOnary vein isolation With vs. without continued antiarrhythmic Drug trEatment in subjects with Recurrent Atrial Fibrillation (POWDER AF): results from a multicentre randomized trial. Eur Heart J, 2018. 
14. Rillig A, Magnussen C, Ozga, et al. Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure. Circulation, 2021.  
15. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European Heart Journal, 2021.  
16. Willems S, Borof K, Brandes A, et al. Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial. European Heart Journal, 2022. 
17. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation, 1995.