Finding the Optimal Approach to Ablation of Persistent AF

It's frustrating. You have completed the point-to-point ablation lesion set, and the pulmonary veins are isolated. That's the good news. The bad news is the patient remains in atrial fibrillation. I hate that. Now what?

Here is where the practice of medicine gets tricky. There are different paths. Some key opinion leaders suggest making more lines (LA roof or mitral isthmus) or ablating funny-looking signals, which we call complex-fractionated electrograms (CFAEs). Other leaders say stop, resist the urge. Doing more ablation, the minimalists contend, only increases the risk for complications, including procedural mishaps and/or postablation flutters.

Why is there such varied opinion? Look at this quote from the 2012 Heart Rhythm Society (HRS)/European Heart Rhythm Association (EHRA)/European Cardiac Arrhythmia Society (ECAS) consensus statement on AF ablation^[1]:

There have been no prospective multicenter randomized clinical trials of ablation vs antiarrhythmic drug therapy that have precisely defined the outcomes of AF ablation in [the persistent-AF] patient population.

A few sentences later, in the same document:

Whereas many electrophysiologists prefer to perform circumferential PV isolation as the initial procedure in all AF patients, there are other EPs who feel strongly about creating linear ablation lesions and also targeted ablation of areas of the atrium demonstrating a high degree of CFAEs. And a final group of EPs advocate for a stepwise approach to AF ablation whereby the procedure is continued until AF terminates.

This is an old-age problem in medicine. When there is little evidence, one gets eminence.

And this is what makes the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Part 2 (STAR AF 2) trial, presented yesterday at the European Society of Cardiology 2014 Congress , so compelling. Dr Atul Verma (University of Toronto, ON) did the honors of presenting the important study in a hot-line session. The discussant of the trial, Dr Paulus Kirchhoff (University of Birmingham, UK), told the audience he recently surveyed ablationists across Europe as to how they approach persistent AF in the EP lab. His findings: one-third did PVI alone, one-third did PVI plus lines and one-third did PVI plus CFAE. He began his discussion of STAR AF 2 trial by saying: "This trial made me think."

Here is a summary of the methods, results, and conclusions of STAR AF 2.

The study was conducted in 48 experienced centers in 12 countries, including China.
589 patients with persistent AF were randomized in a 1:4:4 format to PVI alone (n=67), PVI+lines (n=259), or PVI+CFAE ablation (n=263). The reasoning behind uneven randomization was that the guidelines recommended more ablation in persistent AF.
Patients were blinded to the strategy. Repeat ablation was allowed in the first three to six months, but the strategy of ablation remained the same—an important fact.
The strategy of each ablation approach was typical. A circular catheter was used to demonstrate exit and entrance block for PV isolation. LA roof and mitral isthmus lines were confirmed with pacing techniques, and CFAE sites were identified with a St Jude Medical 3D-mapping system.
Patients were followed closely for 18 months. They were given a transtelephonic card to transmit weekly or for symptoms.
The primary outcome was freedom from a documented AF episode (>30 s) after one procedure, with or without rhythm drugs.
Baseline characteristics of the patients were well matched. Of note, 80% of patients had been in AF continuously for six months, and more than half the cohort had CHADS scores of >1.
Ablation characteristics suggested skillful ablation. PVI was successful in 97% of all groups; CFAE were eliminated in 80%; roof lines were successful in 93% and mitral isthmus lines in 75%.
Procedure and fluoroscopy times were increased in the two PVI-plus groups. On average, patients in the additional ablation groups had 60 more minutes of procedure time and 10 to 12 minutes extra X-ray exposure.
The primary outcome was reached in 59% of patients in the PVI-alone group, 48% in the PVI+CFAE group, and in 44% of the PVI+lines group. The numerical superiority of PVI alone did not reach statistical significance (p=0.15).
After two ablation procedures, the results were similar. Again, there were no differences in success: 72% for PVI alone; 60% for PVI+CFAE, and 58% for PVI+lines (p=0.18).
Complications did not differ in statistical significance, but sedation-related issues, access-site problems, and fluid overload were numerically higher in the extra-ablation groups. Three patients suffered transient ischemic attacks (TIA) or strokes and one patient died; all four were in the groups with more extensive ablation.
The authors made two conclusions: First, additional ablation beyond PVI increased procedure time but did not improve freedom from AF. Second, PVI alone achieved freedom from AF in little more than half the patients, which is comparable to published success rates for ablation in patients with paroxysmal AF.

Thoughts

This is an important trial. It should, and likely will, change the ablative approach to persistent AF. And, if we do as Dr Kirchhoff suggests—that is, think—STAR-AF 2 will help us better understand the systemic disease of AF. I also hope these findings force a history lesson onto the electrophysiology community—namely, what is it that makes us hold on so strongly to ideas not based in evidence?

I'm trying to contain my enthusiasm. The affect heuristic looms large. When findings appeal to your bias (mine is surely less is more), it's easy to take shortcuts. That said, I do not find much not to like in STAR AF 2. The study was international, involved typical persistent-AF patients, stuck to strict ablation protocols, and had rigorous (albeit sans implantable loop recorder [ILR]) follow-up.

The results were clear and definitive. Though critics might point to the 1:4:4 assignments of patients and subsequent small numbers in the PVI-alone group, I'd posit this saved the extra-ablation cohort. PVI alone may have been superior had patients been equally distributed.

The data on complications are notable as well. AF treatment turns on balancing the risk of the disease against the risk of treatment. More ablation means more risk. It's no surprise to me that the only death (atrial-esophageal fistula) and thromboembolic events occurred in the extra-ablation groups.

One immediate if-then take-away from STAR AF 2 is that if PVI-alone techniques are equivalent then cryoballoon ablation has to be considered for treating patients with persistent AF. Here, I would point you to the remarkable work from Cardioangiologisches Centrum Bethanien in Frankfurt, Germany, a team that has published extensively on the use of cryoballoon ablation. They have multiple posters here at ESC. This one shows a significant reduction in pericardial tamponade using balloon techniques^[2], while this one shows excellent long-term results with cryoballoon ablation in patients with persistent AF^[3]. And the message goes further than just cryoballoon ablation. Any technique, such as endoscopic laser ablation , that safely and durably isolates the pulmonary veins may work.

But the lessons of STAR AF 2 aren't as cursory as a less-is-more approach to ablation is preferred. (In the practice of medicine, less is almost always more.) Just looking at ablation approaches is too simple. Let's look at the fact that some of the best centers in the world got to only 60% success—and with PVI alone. Why would this be, and, why would less ablation be as effective?

These observations should nudge us to consider why patients get AF in the first place. It's clear that in most (not all) cases, AF is a manifestation of systemic disease affecting the atria. It may be increased atrial stretch from hypertension or sleep apnea; it may be fibrosis from obesity; inflammation from many different sources; autonomic imbalance, genetics, or even epigenetics. The point is it's not the same, and it's surely not a surgical disease. Extensive ablation doesn't work in persistent AF for the same reason pills and stents don't work in atherosclerosis.

I look forward to the conversations this study will generate for the years to come.

JMM

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