Toronto, ON - First introduced into clinical practice 10 years ago by the groundbreaking laboratory of Dr Michel Haissaguerre (Hôpital Cardiologique du Haut-Lévêque, Bordeaux, France), radiofrequency (RF) catheter ablation is increasingly being hailed as a permanent "cure" for atrial fibrillation (AF). Despite such optimism, many clinicians question the long-term efficacy of the procedure and warn that the associated risks have not been fully evaluated. While many single-center series exist, there are no randomized, controlled clinical trials testing the efficacy of AF ablation against existing therapies, such as antiarrhythmic drug therapy and anticoagulation, in a clinical trial setting.

Dr Michel Haissaguerre

"I think this is a concern," Dr Bernard Gersh (Mayo Clinic, Rochester, MN) told heartwire. "There have been a lot of studies, and it is a promising technique, one that does have its complications. The procedure is certainly not harmless." One of the issues, he says, is that researchers currently only have short-term efficacy data, about two years in certain subsets of patients. "There is a lot of enthusiasm for the procedure," Gersh said, "but I absolutely think it is about time the technique was subjected to the time-honored scrutiny of a randomized trial."

The Food and Drug Administration (FDA) would also like to see AF ablation tested in a clinical trial setting. In 2004, the agency issued a guidance document for industry detailing its recommendations for clinical trial design associated with catheter-ablation devices used in the treatment of AF. According to the FDA, randomized, controlled trials still reflect the best way to collect clinical data to support the safety and effectiveness of catheter devices intended to treat arrhythmia.

Dr Bernard Gersh (Copyright Mayo Clinic)

"Most of the data that are out there discuss symptomatic improvement, and these are largely observational experiences, with no blinding and no randomization involved," FDA medical officer Dr Randall Brockman told heartwire. "When you talk about improvements in quality of life or reductions in symptomatic episodes of atrial fibrillation, it's a little hard to be sure that you're seeing a treatment effect and not the effects of placebo. Placebo can be very powerful. We learned that from other therapeutic lines, and so we're very sensitive to it. Catheter ablation may be very helpful and the jury is coming in, but it's not in yet."

Dr Carlo Pappone (Source: San Raffaele University Hospital)

AF affects between two and three million people in the US alone. The most common of the cardiac arrhythmias, it was initially thought to be little more than a nuisance but is now known to significantly increase the risk of stroke as well as cardiovascular death and overall mortality. It also adversely affects quality of life, with many patients feeling like they've been "kicked in the stomach" during a symptomatic arrhythmic episode. Typically, treatment with antiarrhythmic drugs and anticoagulation is considered front-line therapy in patients with symptomatic AF, despite the fact that these therapies can be suboptimal, with potentially serious adverse effects.

The promise of one day curing AF using RF ablation is alluring. One recent nonrandomized study, conducted by Dr Carlo Pappone (San Raffaele University Hospital, Milan, Italy), showed that patients with symptomatic AF treated with an ablation technique targeting the pulmonary vein had significantly improved mortality, morbidity, and quality of life over those treated with antiarrhythmic drugs [1]. Results showed that after a median follow-up of 2.5 years, fewer patients in the ablation group had died or had AF recurrence or episodes of heart failure or stroke compared with the medically treated group.

We're missing a lot of things at this point. Everything is based on, 'This is how I think my patients are doing.'

Despite these results, the reality is that catheter ablation of AF is not an easy procedure to perform, with the procedure considered technically demanding and time consuming. It also carries risks. A recent worldwide survey of more than 8000 AF-ablation procedures reported an overall complication rate of 6%, a not-trivial figure that investigators say should influence proper patient selection [2]. In this survey, conducted by Dr Richard Cappato (Arrhythmia and Electrophysiology Center, Milan, Italy) and colleagues, significant pulmonary vein stenosis was reported in 1.3% of all cases.

Dr Richard Cappato (Source: European Cardiology Society)

"We're missing a lot of things at this point," Dr Hugh Calkins (Johns Hopkins University Medical Center, Baltimore, MD) told heartwire. "Everything is based on, 'This is how I think my patients are doing.' If history holds true, the results are always worse when the procedure is held up to a multicenter, rigorous study, where you prospectively define the complications and evaluate. We need better data on the true efficacy and safety of the procedure in patients selected as part of a multicenter study in a rigorous, prospective fashion."

The concern echoed by experts in the field is that while the single-center data continue to slowly accumulate, more and more electrophysiologists are already performing the procedure. The study by Cappato et al, which surveyed 181 electrophysiology labs around the world, showed that the number of patients undergoing catheter ablation of AF increased from 18 in 1995 to 5500 in 2002.

As the number of labs open for ablation business continues to grow, the patient pool also continues to expand. In many early series only patients with paroxysmal AF and no structural heart disease were eligible for catheter ablation. However, the inclusion criteria have been relaxed, with later series including patients with persistent, even chronic, AF, and more recently, those with heart disease [3].

"The typical candidate is a patient with symptomatic, difficult-to-manage atrial fibrillation," Dr Peter Gallagher (Central Baptist Hospital Heart Institute, Lexington, KY) told heartwire. "The key word is symptomatic. In general, these patients range from 25 to 75 years of age. Patients over 75 years probably have a higher complication rate, and therefore the risk/benefit ratio is not as favorable.  Previously, patients had primarily paroxysmal atrial fibrillation, but now we tend to tackle more persistent cases of AF.  Some unique situations for catheter ablation may be to try to reduce disease burden in a patient who cannot take Coumadin due to bleeding or for people who have a job that requires they stay in normal rhythm, such as those in the military, professional athletes, or pilots."

Dr Andrea Natale (Source: Cleveland Clinic)

At Central Baptist, Gallagher said the electrophysiologists ablate between 80 and 120 AF cases per year. Six years ago, their center was the one of the first in the US performing a high volume of the procedures. The bigger centers are even busier. Dr Andrea Natale, medical director for the Center for Atrial Fibrillation at the Cleveland Clinic, told heartwire that the center performs five to six AF ablations every day and that the waiting list extends from anywhere between four and nine months. Smaller centers perform fewer procedures, and their success and complication rates vary, he noted.

"Atrial fibrillation ablation is technically very challenging," he said. "This is the deterrent for less skilled hands in embracing the procedure."

The procedure Dr Hugh Calkins (Source: Johns Hopkins University Medical Center) The objective of initial catheter ablation was to replicate the Cox-Maze procedure by segmenting the atria to reduce the amount of available tissue to sustain reentry. Since the 1990s, however, when Haissaguerre and colleagues revealed the existence of a number of local triggers located predominantly within the pulmonary veins responsible for the initiation of AF, most procedures now focus on electrically isolating the pulmonary veins from the atrium. According to Calkins, who was an author on the paper surveying the methods, efficacy, and safety of AF worldwide, the most commonly used technique is circumferential pulmonary-vein ablation with isolation. The procedure involves creating encircling lesions around the pulmonary veins, disconnecting them at their junction with the left atrium. This technique produces a circular scar that blocks impulses from firing within the pulmonary vein and disconnects the pathway of abnormal rhythm. The continuous series of white circles encircling the pulmonary veins represent radiofrequency ablation sites. Additional linear lesion sets are sometimes created, such as one connecting the two circular lesions that surround the pulmonary veins and one connecting the mitral valve annulus to the circular lesion that surrounds the left pulmonary vein. [Click on the image for a larger view.] The procedure remains challenging because the lesions must be placed as far onto the left atrial tissue as possible and outside the pulmonary veins. Because of the variability in each patient's anatomy in terms of the size and number of pulmonary veins, magnetic resonance (MR) imaging scans before the ablation procedure helps provide an anatomical roadmap of left atrial pulmonary veins, making the procedure less "blind." The integration of three-dimensional electrical activation maps of the heart with high-resolution computed tomography (CT) and MR imaging are also making the procedure easier. In Italy, Pappone and colleagues have also recently developed a variation of the technique known as anatomically based circumferential pulmonary-vein ablation. This purely anatomic approach combines aspects of both the Maze and pulmonary-vein-isolation approaches, as the ablation targets both triggers and substrate modification. Other labs advocate using linear lesions in combination with pulmonary-vein ablation, such as an additional lesion sets connecting the two circular lesions surrounding the pulmonary veins and another connecting the mitral valve annulus to the circular lesion set around left pulmonary veins. Because of difficulties in performing the lesions, several technologies have also been designed to assist in the procedure, although many are still some years away from clinical use. Different balloon ablation devices, including laser, focused ultrasound, and cryotechnology-based balloon catheters, are all currently being tested. The hope with these new balloon-ablation systems is that users will be able to quickly and safely isolate the pulmonary veins with fewer lesions and without the risk of pulmonary-vein stenosis. The balloon-ablation devices have undergone preclinical testing in animals, and human studies have also begun. Robotic and magnetic navigation devices are also being tested as a means to move and position the catheters for successful ablation. "The technology continues to improve and we have lots of things coming on," said Calkins. "It's getting better all the time, but this is far from a mature field."

One of the major reasons for the exponential growth of catheter ablation worldwide is that drug therapy is simply ineffective in a large number of patients. The Cleveland Clinic's Natale said that while there are data supporting the use of both rate and rhythm control for the management of AF, managing patients with symptomatic AF remains difficult. The problem with these approaches is that even in the best-case scenario, over four or five years perhaps 30% or 40% of patients have their AF under control, he said.

"There are a number of large series showing that in patients who failed drug therapy, the ablation of atrial fibrillation is an effective therapy," said Natale. "I think that from a scientific point of view and from a clinical point of view, they are sufficient. Catheter ablation of atrial fibrillation has evolved in the past five or six years and really is one of the few options that we have to cure it. With either one or two ablation procedures, we have been able to eliminate their atrial fibrillation completely."

Calkins told heartwire that current success rates typically depend on the patient and the length of follow-up. For an ideal candidate—a young patient with paroxysmal AF—success rates are best, with approximately 70% to 80% of patients free from AF after one procedure and as many as 85% free from AF after a second touch-up ablation. For difficult-to-treat patients, those with chronic AF, success rates are lower. In the recent AF-ablation survey of 8745 patients, 52% were free from AF in the absence of antiarrhythmic drugs at one year, and an additional 24% became asymptomatic with the continued use of formerly ineffective drug therapy. Still, to speak of a cure, most EPs know that they will have to demonstrate not only an absence of AF symptoms but also reductions in stroke and possibly mortality.

Given the large numbers of people in the US and worldwide with AF, some experts say it is unrealistic to think drug therapy might soon be obsolete. DrEric Prystowsky (The Care Group, Indianapolis, IN), a member of the ACC/AHA/ESC committee that wrote the 2001 guidelines for the management of AF, told heartwire that he is a believer in ablation but, based on the number of people worldwide with the arrhythmia, it will be impossible to accommodate everybody with the procedure.

Dr Eric Prystowsky

Prystowsky also points to the recent spate of trials comparing rate control vs rhythm control, among them the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) studies, showing that not every patient needs to be in normal sinus rhythm. For those patients requiring conversion to and maintenance of sinus rhythm, there are different options available to clinicians, he said.

"The concept of antiarrhythmic drug therapy to maintain sinus rhythm has a basic premise to maintain safety first," said Prystowsky. "That means that while there might be five or six drugs that might work for an individual, you try to select a drug for that patient that is least likely to cause harm. Most studies would suggest that amiodarone is the most effective across the board. But in those patients with lone atrial fibrillation and those who are younger, there are drugs that, in my experience, have been equally effective as amiodarone. Flecainide and propafenone, for example, have been as effective, and both are far less toxic long term."

In patients with good left ventricular function and without coronary disease and heart failure, Prystowsky said flecainide, propafenone, and sotalol are good first-line treatments, whereas dofetilide and amiodarone are clearly relegated to second-line status. If there is significant left ventricular hypertrophy, where thick ventricles tend to be more proarrhythmic, amiodarone is considered the drug of choice, he said. Amiodarone is also believed to have the best safety profile in heart failure, although dofetilide has been used in some heart-failure trials. In coronary disease, sotalol, amiodarone, and dofetilide are recommended, Prystowsky noted.

For the argument that too many patients fail drug therapy and that it is ineffective long-term, Prystowsky said that he has longitudinal follow-up on patients in his practice for an average of six years, with some patients managed on drug therapy for more than 10 years. Overall, more than two thirds of his patients have remained in sinus rhythm, he said, noting that this follow-up is three or four years longer than any existing ablation follow-up.

When I say remain in sinus rhythm you have to remember that nobody is under the illusion that a patient has zero recurrence.

"When I say remain in sinus rhythm you have to remember that nobody is under the illusion that a patient has zero recurrence," said Prystowsky. "When I say remain on drugs, I mean that the patient is having minimal recurrences to the point where they feel they are still in good control of their atrial fibrillation and therefore stay on the drugs. We really aren't talking about perfect control, but I think the idea that everybody winds up in permanent atrial fibrillation is simply not true."

In addition, Prystowsky said that there are some exciting new drugs in the development stages, such as new atrial-specific agents. The discovery of an atrial-specific repolarizing current (the ultrarapid potassium current, IKur) in humans has opened up possibilities for developing class 3 drugs effective in AF without the risks of ventricular proarrhythmia.

In addition to the need for long-term data, what complicates the issue of curing AF is anticoagulation. According to Gersh, clinicians should be "very careful" about advocating catheter ablation of AF with the intention of getting a patient off anticoagulation therapy.

"If clinicians push for catheter ablation, and the necessary studies, for the reason of taking a patient off warfarin, they are going to be very disappointed," said Gersh. "Many episodes of recurrent atrial fibrillation are asymptomatic, and many of the follow-up results that we have so far are asymptomatic recurrences. Just because they are free from recurrences at 18 months doesn't mean they are going to be so at five years. Right now, if a patient is on anticoagulation, I am very nervous about discontinuing anticoagulants. Any long-term ablation study is going to have to show that the procedure eliminates recurrences, and we just don't have the data that far out."

The FDA echoes those concerns, with Brockman telling heartwire that he is not aware of any evidence suggesting it is safe to take patients off anticoagulation after ablation.

"Stroke remains one of the largest and most devastating complications of atrial fibrillation, and there are good data on anticoagulation with atrial fibrillation to show that it works," Brockman said. "One of the concerns we have is that with all the ablating going on is that patients will be taken off Coumadin. In terms of long-term data, it would be valuable to know this is safe."

Because of the difficulties with drug therapy, some experts believe catheter ablation of AF will evolve to a front-line therapy. In one of the first studies comparing catheter-based ablation of AF as a first-line treatment with standard antiarrhythmic drug therapy, investigators showed that pulmonary-vein isolation was associated with less AF recurrence, improved quality of life, and a lower hospitalization rate at one year [4].

"The question as to whether or not this is something that you can justify as a first-line therapy is starting to come up," noted Calkins. "I personally don't think we can, the evidence just isn't there. Maybe in certain patients, like a pilot or a professional athlete, then maybe you can justify it. But with the risks—one in 100 risk of tamponade and one in 200 risk of stroke—it is very hard to justify in patients that have not yet failed drug therapy."

Some doctors are pretty enthusiastic about ablation as a primary therapy, but they're only enthusiastic until a patient has a stroke. . . . Then the enthusiasm tends to go down a little bit.

Calkins predicts that there is probably a two- to five-year horizon before ablation of AF is a primary therapy. "Some doctors are pretty enthusiastic about ablation as a primary therapy, but they're only enthusiastic until a patient has a stroke or some type of devastating consequence. Then the enthusiasm tends to go down a little bit," he notes.

The experts heartwire spoke with all cautioned that catheter ablation of AF is still a technically demanding procedure and needs to be performed only by experienced operators. But many of the electrophysiology fellows being trained are quite good at the technique, and evolving technology will only help as well, they noted. The ability to integrate three-dimensional electrical activation maps of the heart with CT and MR imaging and the availability of new catheters can only make the procedure easier. For many, though, while the procedure offers promise to one day possibly cure AF as well as a possible substitute for long-term drug therapy, clinical trials are still needed.

"The only thing that's missing is the data," said Calkins. "I think it will come but it might take some time. I'm a believer in the procedure. I do lots of these myself and have seen pretty good results, but there has never been a procedure in the field of electrophysiology with such a high complication rate. There have been more than a handful of deaths from this procedure, and as more and more people start doing it and are on that learning curve, it could be a bit of a mess."

"Randomized, controlled trials are not the only type of evidence, but they tend to be the best," added Brockman. "Most clinicians want to practice evidence-based medicine, and we can't always have it, but it's doable in this case. It would be nice to know that the thousands of people that are having this procedure done every year are having it done for a good reason."