Introduction

With the increasing number of patients developing atrial fibrillation with aging, along with this arrhythmia occurring in the setting of other heart disease, developing more straightforward approaches to affected patients has never been more critical. With the advent of ablative intervention, many have turned away from drug therapy for a straight entrance into the ablation arena. Recently, the new AF Ablation Consensus Document¹ has suggested that ablation prior to drug therapy could be viewed as a level 2a indication for intervention in previously untreated patients with paroxysmal atrial fibrillation. In those with persistent or longstanding persistent atrial fibrillation, it becomes more difficult in the absence of large scale randomized clinical trials to provide a class of evidence high enough to support direct ablation prior to drug intervention.

AF Drug Therapy

A number of studies in the past twenty years have indicated that many patients can be adequately treated with antiarrhythmic drug therapy. The Canadian Trial chronicled the benefits of Amiodarone with a success rate of higher than 60% at 16 months after initiation of therapy.² Propafenone and Sotalol were effective in 30-40% of patients, which was significantly less effective than seen with Amiodarone. The Athena Trial demonstrated a benefit with Dronedarone when viewed in terms of total mortality or cardiovascular hospitalization.³ This drug also fared well in the subgroup analyses, particularly in patients with acute coronary syndrome, major arrhythmias, and even in terms of stroke outcomes.⁴ On the other hand, some additional confusion was added to the annals of drug treatment when the PALLAS Trial showed excess morbidity and mortality in patients receiving the same Dronedarone in the setting of persistent atrial fibrillation and underlying heart disease.⁵ The AF-CHF study showed no difference between outcomes in patients with heart failure and atrial fibrillation regardless whether they were treated with rate control or rhythm control therapies.⁶ This paralleled the findings of the AFFIRM trial from nearly a decade ago.⁷ It is possible that some of the benefits of drug therapy in the AF-CHF and AFFIRM Trials are countered by side effects, including pro-arrhythmic events and the myriad potential adverse effects of Amiodarone. These issues have raised a concern in some people's minds about a potential futility of antiarrhythmic drug therapy. The side-effect profile in patients with antiarrhythmic drug therapy has been documented over decades. Obviously pro-arrhythmia is of concern, with significant event rates of 0.5–2.5% particularly in patients with underlying heart disease. The side effect profile of Amiodarone has been clearly documented, and other drugs have constitutional side effects. These appear to be largely reversible with discontinuation of the medication, although that may not be the case in lung toxicity with Amiodarone or cardiac arrest related to the institution of other drugs.

AF Ablation

In contrast, ablative intervention has demonstrated high efficacy rates in patients with paroxysmal atrial fibrillation. At least six clinical trials ^8-13 demonstrated 60–75% success rates with ablative intervention verses 7-20% success rates in those treated with drug therapy. Each of these was a randomized clinical trial, although they only ran for one year, and excluded patients with appreciable underlying heart disease and persistent and chronic atrial fibrillation. Still, these point to ablation for more successful outcomes.

Several recent trials, showed less impressive results. MANTR-PAF Trial¹⁴ examined the outcome of drug verses ablative intervention as measured by AF burden. The differences between drug and ablative therapy were limited with some improvement in AF burden, although drug therapy actually performed better than in the previously mentioned clinical trials. RAAFT2¹⁵ also was recently published, demonstrating that first-line ablative intervention for paroxysmal atrial fibrillation was in fact better than that seen with antiarrhythmic drug therapy. Here, however, there was less difference than previously reported in the irrigated-tip and cryoballoon catheter studies.^13,16 This is somewhat expected as these patients were antiarrhythmic therapy naïve, and would be expected to have higher success rates with antiarrhythmic drug therapy. The success rate for ablative intervention was also less than some of the other randomized clinical trials, in part because of higher prevalence of underlying disease and at a longer follow up.

A series of recent longer-term follow-up studies have raised questions about the effectiveness of ablation over time.^17-21 Each of these more recent three- to five-year follow-up studies suggested a lower success rate with ablation in patients with underlying disease. In addition, these studies^17-21 documented a decrease in success rate to 30%–50% at three to five years. This underscores the likelihood of higher recurrence rates over time than those simply described in single-year randomized clinical studies. The presence of hypertension, underlying disease, the actual procedure performed, and left atrial size have all been implicated as contributors to late recurrences ^21,22. As such, it does not appear that a 70–80% success rate is likely to occur with a single ablative intervention with the currently available technology. Nevertheless, several of these studies demonstrate that an additional procedure may increase the success rate of AF ablation to as high as 70–80%.^17-21 Still, this approach can be highly effective, although repeat ablation is required in somewhere between 20 and 50% of patients, depending on the type of atrial fibrillation and underlying disease.

AF Ablation in CHF

Ablative intervention in patients with underlying heart failure has also been shown to be favorable in terms of symptoms, structural remodeling, and ejection fraction.^23-25 The same parallel finding of recurrences over the course of three to five years in patients with heart failure, as seen with other trials in normal hearts has been suggested by Cha, et al.²²

AF Ablation Complications

There is a potential for significant complications with ablative intervention.^26,27 Myocardial perforation with tamponade occurrence occurs in 0.5–3% of patients. The chance of a significant stroke is somewhere between 0.5 and 1.5%. The possibility of myocardial infarction is certainly uncommon, but possible. On the other hand, a number of recent studies have demonstrated that the asymptomatic cerebral emboli (ACE) rates are as high as 5–30%, although in carefully undertaken ablation, ACE rates of 5–10%, seem more realistic.

Other complications have been well chronicled in the 2nd International Ablation Registry and other meta-analyses.^26,27 Phrenic nerve injury can occur with a higher likelihood in patients undergoing cryoballoon ablation. Even this risk is less common with additional experience. The STOP AF study suggested an 11.3% risk of phrenic nerve injury (with resolution in the majority), while the accompanying CAP "Continuing Access Protocol" and other international observational reports have suggested that this risk is in the 3–4% range.⁹ There are a variety of other complications including atrio-esophageal fistula formation that may be seen in 1 in 750 to 1000 with AF ablation. The likelihood of a complication decreases in experienced hands. Still, ablation complications may occur in very well experienced centers.

Given the lower than initially anticipated success rate of AF ablation, late recurrences requiring repeat ablation, and the risk of complications provides a strong incentive for 1) improving outcomes with better tools, and 2) the need for longer-term follow up to establish the actual efficacy of ablative intervention.

It remains unclear whether drug or ablative therapy is best from a standpoint of long-term mortality or major consequences such as myocardial perforation, esophageal injury, pulmonary vein stenosis, and phrenic nerve injury. Additional evaluation of long-term outcomes is also required, as is a careful look at the economics of drug or ablative therapy, and long-term quality-of-life outcomes.

Fortunately, there are a several studies that have taken a look at mortality of stroke benefits of ablation. An observational study²⁸ demonstrated a significant improvement in mortality and stroke risk in patients undergoing an ablation than those matched patients with atrial fibrillation undergoing no treatment. In this study, successful ablation improved patient outcomes to a point equal to that seen in patients without any atrial fibrillation. Similarly, a recent study from Hunter, et al.²⁹ shows similar findings, when comparing mortality and stroke outcomes of patients successfully undergoing AF ablation, and those having no atrial arrhythmias, versus those reported in the European AF registry. Obviously, both of these are more or less observational studies, albeit case-matched studies.

The CABANA trial is also working to understand long-term efficacy outcomes, complication rates, the impact on healthcare economics, and quality of life achieved in both ablation and drug treated patients. This NIH funded study, also undertaken in conjunction with industry partners, has already enrolled 1155 patients. The general design is as seen in Figure 1. The enrollment rate is increasing, and it remains fully anticipated that the trial will give us substantially increased guidance in treating patients with atrial fibrillation. While the results of the trial will not be available for several years, review of the demographics of these patient populations indicates that 42% have paroxysmal atrial fibrillation and about 58% have persistent or longstanding arrhythmia. Fifteen percent of patients have heart failure, while 6% have an ejection fraction less than 35% ³⁰. Prior hospitalization for atrial fibrillation has been seen in 40% of patients, with DCCV required in 38% with pharmacologic CV in 15%. Likewise, ablation for atrial flutter was required previously in 13% of patients, while 6% had a prior stroke. As such, there is a much higher presence of comorbidities in the CABANA population, similar to that seen in AFFIRM, but to a lesser degree than seen in AF CHF. Given the potential of this trial for informing drug and ablative treatment, we are convinced that every effort should be made to enroll patients in this study through screening patients referred by internists, cardiologists, and even family practitioners outside of ablation sites. Information regarding the location of individual sites is available on the CABANA website, "www.cabanatrial.org". This site also contains helpful information regarding atrial fibrillation occurrence, prevalence, approaches, and a map of nearest enrolling centers. Patients are also currently being enrolled in Canada, UK, Germany, Italy, Czech Republic, Russia, Australia, Korea, and China. We believe that CABANA will guide therapy and will inform the allocation of health care economics for years to come. Until then, we are left with good, albeit incomplete information with knowledge gaps that CABANA will undoubtedly fill.

References

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24. Gentlesk P, WH S, Gerstenfeld EP, et al. Reversal of Left Ventricular Dysfunction Following Ablation of Atrial Fibrillation. J Cardiovasc Electrophysiol 2007;18:9-14.
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29. Hunter R, McCready J, Diab I, et al. Maintenance of Sinus Rhythm with an Ablation Strategy in Patients with Atrial Fibrillation Associated with a Lower Risk of Stroke and Death. Heart 2012;98:48-52.
30. Packer D. HRS CABANA Investigators Meeting. 2013.

Keywords: Acute Coronary Syndrome, Anti-Arrhythmia Agents, Atrial Fibrillation, Atrial Flutter, Heart Failure, Myocardial Infarction, Phrenic Nerve, Pulmonary Veins

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