Is it time for first line ablation in early paroxysmal AF?

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting just under 1.5 million people in the United Kingdom.¹ AF is associated with increased risks of death², stroke³, heart failure⁴, dementia⁵, decreased quality of life^6,7 and places large financial and societal cost on the NHS⁸. Consequently, a significant amount of research has been conducted investigating the optimal strategy to treat AF.

These treatment strategies are historically divided into rate and rhythm control. The landmark AFFIRM trial comparing these strategies concluded there was no mortality benefit to pursuing rhythm control⁹. Consequently, rhythm control has been reserved for treating symptomatic patients refractory to rate control . However, recent research has shown the condition is more complicated, and certain patient groups benefit more from rhythm control. The EAST-AFNET4 trial recently showed patients experiencing ‘early AF,’ that is a history of less than 1 year, to be one of these groups¹⁰.

Catheter ablation is an effective strategy to maintain sinus rhythm (SR). It can be performed in two ways: radiofrequency or cryo- ablation (effectively hot or cold therapy). In this article, I shall discuss the argument that it is time catheter ablation should be considered a first line treatment for early AF .

AF Is A Progressive Disease

On a pathophysiological level, AF leads to multi-level changes including intracellular calcium dysregulation, and electrical, structural and autonomic nervous system remodelling¹¹. These pathological changes are progressive, making episodes of AF more frequent and longer. This pre-clinical concept of ‘AF begets AF’ was initially demonstrated in seminal experimental work by Wijffels et al. when the authors showed longer durations of rapid atrial pacing (to assimilate and initiate AF) in goats lead to longer AF maintenance once pacing was discontinued¹².

‘AF begets AF’ is a concept seen clinically too. Progression is noted through increasing AF burden in paroxysmal AF (PAF), before eventually changing to persistent AF (PeAF, defined as AF that is continuously sustained beyond 7 days, or perhaps 100% AF burden). This is accompanied by left atrial (LA) structural remodelling, demonstrated in 3D electroanatomical mapping studies where increased low voltage areas (a representation of fibrosis), are seen in patients with PeAF over PAF^13,14. A similar finding has been shown by delayed enhancement MRI¹⁵. On a more macroscopic level, PAF patients with high AF burdens have larger LA dimensions and reduced contractile properties than those with low burdens¹⁶. Collectively, all of this points to a progressive fibrotic atrial cardiomyopathy.

AF Progression Is Associated With Worse Outcomes

These physiological changes translate to poor clinical outcomes. The KP-RHYTHM study¹⁷ retrospectively identified 1965 patients with PAF on 14-day ambulatory ECG monitoring. Patients not receiving anticoagulation were divided into tertiles based upon their AF burden. The highest tertile of AF burden (>11.4%) had a 3.2-fold higher incidence of thromboembolism than the lower two tertiles combined, (0.9 vs 2.9 events per person-year) independent of CHA₂DS₂-VASc score¹⁷. This relationship is also seen across studies using implantable cardiac devices to monitor AF burden¹⁸.

The correlation with increased adverse events has been extended further from PAF to PeAF. Zhang et al noted the association of AF progression and poor outcomes in their meta-analysis of 70,447 patients receiving anticoagulation. Here the risks of stroke, systemic embolism and mortality were all significantly higher in those with PeAF over PAF¹⁹. Indeed, retrospective analysis of direct oral anticoagulant (DOAC) trials, ROCKET AF²⁰, ENGAGE AF²¹ and ARISTOTLE²² consistently show lower rates of stroke in PAF versus PeAF in anticoagulated patients irrespective of baseline risk factors²³. The same finding was shown in non-anticoagulated patients in trials investigating the efficacy of aspirin for AF²⁴.

Other studies have also found significant relationships of increased mortality,²⁵ thromboembolism,²⁵ death from stroke,²⁶ stroke severity,²⁶ decreased brain volume and cognitive ability²⁷ with progression from PAF to PeAF.

Maintaining SR With Antiarrhythmic Drugs (AADs) Is Associated With Reduced Adverse Outcomes

As discussed above, AF is a progressive disease and this progression is related to adverse outcomes. Intervention to stop or slow down this progression can prevent these poor outcomes.

Regarding mortality, the AFFIRM trial showed no mortality benefit between its rhythm and rate control arms. However, post-publication on-treatment analysis discovered that increased time in SR itself was associated with a 47% lower risk of mortalit^y28. Yet, this was offset by a 49% increase with the use of AADs used to try to maintain SR. Consequently, achieving SR with AADs decreased mortality rates, but this was cancelled out by the increased mortality associated with the use of AADs themselves. The mortality improvement with the maintenance of SR was also seen in the DIAMOND study²⁹.

Maintaining SR also reduces risk of stroke. The ATHENA trial showed rhythm control with dronedarone maintained SR greater than placebo in patients with PAF. Specific analysis of stroke in the trial found a relative risk reduction of 34%, (1.2% vs 1.8%, p = 0.027), in the dronedarone arm regardless of anticoagulation³⁰.

Quality of life improves with SR, even when compared to rate controlled AF when examined by validated questionnaires in double blinded³¹ and open label trials^31,32.

Finally, time in SR is associated with greater improvements in NYHA class, quality of life and mortality for patients with heart failure, as evidenced by the double blinded CHF-STAT trial which compared use of amiodarone vs placebo³³.

Consequently, although rate vs rhythm trials did not show mortality benefit, the specific achievement of SR maintenance is associated with improvements in mortality, stroke, heart failure and quality of life. On average, these benefits are however diminished by the increase mortality associated with the use of AADs themselves.

In summary, AF progression is associated with LA pathophysiological changes and adverse patient outcomes. Maintenance of SR is associated with improved patient outcomes. Therefore, it stands to reason that establishing SR as swiftly as possible should be a priority to maximise this.

Mortality Benefit For Treating Early AF With Rhythm Control

The recent EAST-AFNET4 trial showed a rhythm control strategy for early AF delivered prognostic benefit over usual care, (rate control followed by rhythm control if intolerable symptoms).¹⁰ Here, the rhythm control arm had an incidence of the primary outcome (a composite of cardiovascular death, stroke, or hospitalisation with heart failure or acute coronary syndrome) of 3.9 per 100 person-years compared to 5.0 per 100 person years (p=0.005). There was no significant difference in nights spent in hospital between the groups, nor in all cause mortality

Thus, treating early AF with rhythm control has significant physiological, morbidity and now cardiovascular mortality benefit. This leads one on to discuss what the most effective method of maintaining SR would be.

AADs Have Limited Efficacy

As was shown in the post hoc AFFIRM analysis, the benefit of SR maintenance was offset by the adverse effects of AADs. These adverse effects are a key limiting factor in their use. Furthermore, the efficacy of AADs in achieving SR is limited, the most effective but most toxic being amiodarone, (odds ratio 0.22 for AF recurrence)³⁴. Indeed the authors of AFFIRM say, “Inability to maintain SR and drug intolerance were chief reasons for abandonment of a rhythm control strategy.”

Therefore, having a treatment option that can achieve SR, but could eliminate the use of AADs could provide significantly beneficial outcomes. Pulmonary vein isolation (PVI) via catheter ablation seeks to provide this treatment. AFFIRM was published in 2002, a time when catheter ablation was in its infancy. Indeed only 14 of 2033 patients in the rhythm control arm underwent catheter ablation for atrial arrhythmias in that study⁹.

Catheter Ablation Decreases AF Recurrence and Burden Over Medical Therapy

When compared to medical therapy, catheter ablation is superior at maintaining SR when comparing time to first arrhythmic recurrence when followed up by Holter monitoring or implantable cardiac devices^35,36. However the intermittent nature of Holter monitoring and selection bias of using patients with devices made confirming the superiority of catheter ablation difficult to generalise. However, the recent Canadian trial EARLY-AF³⁷ provided a new gold standard of monitoring patients by using implantable loop recorders (ILR) to eliminate these issues. Using ILRs at the time ofrandomisation to cryoablation or antiarrhythmics, Andrade et al were able to confirm with confidence that atrial arrhythmia recurrence at 1 year was significantly lower in the ablation versus anti-arrhythmic arm (42.9% vs 67.8%). Interestingly, the AF burden was reduced to minimal levels in both arms. Here, catheter ablation was able to decrease AF burden to a median of 0% with an interquartile range (IQR) of 0-0.08%, and AADs 0.13% with IQR of 0.00-1.60%. The ability of ablation to decrease AF burden to this level was also seen in the CIRCA DOSE trial conducted by the same centre (both cryo- and radiofrequency ablation)³⁸ and the CLOSE TO CURE trial (radiofrequency ablation)³⁹. The CIRCA DOSE trial in particular was able to demonstrate a reduction in AF burden pre- and post-procedure by implanting an ILR 30 days prior to ablation, although this was not compared to AADs. Radiofrequency ablation lowered burden from 1.57% to 0.00% (IQR 0.00-0.11%) cryoablation for 4 minutes 3.71% - 0.00% (IQR 0.00-0.24%) and cryoablation for 2 minutes 1.46% to 0.01% (IQR 0.00-0.34%).

Beyond AF burden and recurrence, radiofrequency ablation has also been shown to slow progression of AF from paroxysmal to persistent forms compared to AADs (2.4% vs 17.5% at 3 years)⁴⁰. Consequently, ablation is able to slow disease progression , decrease burden and retard recurrence over medical therapy.

Catheter Ablation has Beneficial Clinical and Physiological Effects over Medical Therapy

Perhaps the most significant catheter ablation trial to date is CABANA which compared catheter ablation to medical therapy (rate or rhythm control)⁴¹. Although CABANA did not show a mortality benefit for catheter ablation in its intention to treat analysis (5.2% vs 6.1%, p = 0.38), it did for the composite of mortality and cardiovascular hospitalisation (51.7% vs 58.1%, p=0.001). CABANA also showed sustained improvements in quality of life in its catheter ablation arm⁴². This effect was repeated in the CAPTAF and EARLY AF trials^37,43.

For patients with heart failure, CABANA suggested a benefit for catheter ablation with a relative risk reduction of 39% for mortality, stroke, major bleeding or cardiac arrest. Although this did not quite pass the point of statistical significance CASTLE-AF was able to statistically demonstrate this beneficial effect in a highly selected heart failure population⁴⁴.

A recent nationwide cohort study of 27,097 patients in Korea also confirmed catheter ablation was associated with a decreased risk of dementia independent of stroke and other co-morbidities⁴⁵.

Despite clinical improvements elsewhere, reduction in stroke rates following catheter ablation have been more difficult to establish, perhaps due to the increased emphasis on compliance with anticoagulation⁴⁶. This has driven stroke rates to levels <1% and equivalent to patients without AF⁴⁷. Regardless of this, EAST-AFNET4, whilst not exclusively a catheter ablation trial, did note a significant reduction in stroke rates in its rhythm control arm (0.6 vs 0.9%)¹⁰.

Catheter ablation is also associated with improved physiological markers, including NT-proBNP and left ventricular ejection fraction⁴⁸.

In terms of safety, the most common complications from catheter ablation seen in the CABANA trial were vascular access issues such as haematoma, pseudoaneurysm, and arteriovenous fistulae, (3.9%). Pericardial effusion requiring drainage had an incidence of < 1%. No atrio-oesophageal fistulae or procedure related deaths occurred⁴¹.

So although catheter ablation is not associated with decreased mortality for all patients , It is associated with improved quality of life, decreased hospitalisation, decreased risk of dementia, improved physiological markers and for select groups decreased adverse cardiovascular outcomes, all compared to the use of medical therapy and maintaining an acceptable safety profile.

Catheter Ablation as a First Line Therapy

The 2020 ESC guidelines on the management of AF state catheter ablation should be considered before a trial of AADs in patients with paroxysmal AF episodes⁴⁹ (Class IIa). These recommendations are based upon 3 prospective trials, RAAFT⁵⁰, RAAFT II⁵¹ and MANTRA-PAF⁵² which examined outcomes between AADs and radiofrequency ablation as a first line therapy. Both RAAFT and RAAFT II showed superiority of radiofrequency ablation for AF recurrence at 12 and 24 months follow up respectively. The larger MANTRA-PAF trial, although not showing a statistically significant difference in AF burden up to 18 months, did at 24 months. A follow up study showed this effect persisted to 5 years⁵³. Furthermore, more patients were arrhythmia free at this time and had improved physical quality of life.

So, there was the suggestion from these trials that early radiofrequency ablation could decrease AF recurrence and burden in the long term . Interestingly, since the publication of these guidelines in August 2020, two further trials investigating the effect  on AF recurrence of first line cryoablation vs AADs for treating PAF have been published, STOP-AF⁵⁴ and EARLY-AF³⁷. EARLY-AF  as discussed above used ILRs to confirm AF recurrence following intervention. The ablation arm showed a significantly lower recurrence rate and burden with an improvement in quality of life. STOPAF used 24-hour ambulatory ECGs and produced a similar result with a recurrence rate 74.6% vs 45.0%. Although STOP-AF and EARLY-AF provide strong evidence for the efficacy of ablation on suppression of atrial arrhythmias, the effect on quality of life is more difficult to definitively conclude bearing in mind that no sham trial on AF ablation has been conducted.

Alongside first line ablation providing arrhythmic freedom greater than AADs, delaying ablation from time of diagnosis decreases ablation success rates and risks adverse outcomes^55. By investigating the time from diagnosis to ablation in 4535 patients, Bunch et al noted increased AF recurrence, mortality and heart failure hospitalisation in patients with delayed ablation greater than 180 days when followed up at one year. This suggests time is of the essence in PAF, and delays may push patients beyond physiological points of no return.

The combination of RAAFT I, RAAFT II, MANTRA-PAF, EARLY AF and STOP AF provide increasing evidence that ablation is a more effective, long lasting first line therapy for suppressing atrial arrhythmias in symptomatic PAF than AADs. Furthermore, it provides improved quality of life, and has a more sustained response. It is the most effective rhythm control strategy available. Lastly when considering the results of the EAST-AFNET4 trial, there is now evidence for mortality improvements in early AF. Although there is not a prospective trial that examines mortality after catheter ablation specifically in early PAF, with catheter ablation as the most effective rhythm control therapy, it is not a stretch to hypothesise mortality benefit will be seen in years to come .

Conclusions

Evidence for the use of catheter ablation first line is accumulating.

Early AF is a subgroup of patients likely to benefit from swift initiation of rhythm control.Early AF is purely based on patient history. A more granular approach such as AF burden may benefit future studies to assess benefits of intervention.

Catheter ablation provides the most effective method for maintaining SR without disproportionate increases in adverse effects.

The rate vs rhythm control debate is alive and well, and it will continue to be discussed for years to come.

Disclosures

None

References

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