CASTLE-AF: Ablation Reduces Mortality in LV Dysfunction, AF

Susan Jeffrey

August 29, 2017

BARCELONA, SPAIN — Results of a randomized trial show that catheter ablation of atrial fibrillation in patients with left ventricular dysfunction can not only provide symptomatic relief but reduce mortality and hospitalization for worsening heart failure in these patients[1].

Findings of the Catheter Ablation versus Conventional Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial were presented here at the European Society of Cardiology 2017 Congress.

Dr Nassir Marrouche

CASTLE-AF is the only randomized clinical trial to date comparing catheter ablation and pharmacological therapy for patients with coexisting heart failure and AF that measures the hard primary outcomes of mortality and hospitalization for worsening heart failure, said lead author Dr Nassir Marrouche (Comprehensive Arrhythmia Research and Management [CARMA] Center, University of Utah Hospital, Salt Lake City).

"All the studies done on ablation in the past are looking at afib, but this is the first time we're reporting hard primary end points related to ablation," Marrouche told | Medscape Cardiology.

"We have a significant reduction in all-cause mortality and hospitalization for heart failure, we have a significant reduction in mortality alone, we have a significant reduction in cardiovascular mortality, significant reduction in cardiovascular hospitalization—any way you look at it, there's a significant reduction," he said. "And we think this is attributed to cutting the afib burden by almost half, without using antiarrhythmics."


The CASTLE-AF trial was initiated in 2008 to examine the effectiveness of catheter ablation of AF in patients with heart failure in improving mortality and worsening heart-failure progression vs conventional standard treatment.

The primary end point was a composite of all-cause mortality or worsening heart-failure admissions, "whatever comes first," Marrouche said. Secondary end points included all-cause mortality, hospitalization for worsening heart failure, cardiovascular mortality, and cerebrovascular accident, as well as quality of life, exercise tolerance, occurrences of implantable cardioverter defibrillator (ICD) shocks, AF burden, and AF-free intervals.

To be eligible for the study, all patients had to have already been implanted with an ICD or cardiac resynchronization therapy device (CRT-D) with home monitoring capabilities for either a primary- or secondary-prevention indication. Other inclusion criteria included symptomatic paroxysmal or persistent AF, and a left ventricular ejection fraction (LVEF) of less than or equal to 35%; patients had to be in NYHA class 2 or higher and have failed or been intolerant to one or more antiarrhythmic medications or been unwilling to take an antiarrhythmic agent.

Patients were randomized to either conventional treatment according to current guidelines for AF in heart failure (n=184) or to a catheter-ablation protocol using pulmonary-vein isolation (n=179), after a run-in of 5 weeks to optimize heart-failure therapy. They were followed at 3, 6, 12, 24, 36, 48, and 60 months.

Mean age in both groups was about 64 years, the majority of patients were in NYHA class 2, and most patients had persistent or long-standing persistent AF. About 70% of both groups had an ICD, and the remainder a CRT-D.

At 5 years, "catheter ablation led to significant improvement in the primary composite end point of all-cause mortality and worsening heart failure, with a relative risk reduction of 38%," Marrouche said.

Other secondary end points were also significantly improved in the ablation arm.

CASTLE-AF: Primary and Secondary End Points

End point Hazard ratio 95% CI P
All-cause mortality and worsening heart failure 0.62 0.43–0.87 0.007
All-cause mortality 0.53 0.32–0.86 0.011
Worsening heart-failure admissions 0.56 0.37–0.83 0.0004
Cardiovascular mortality 0.49 0.29–0.84 0.008
Cardiovascular hospitalization 0.72 0.52–0.99 0.041

Over the course of the 60 months, data from the implantable devices indicated that AF burden was significantly reduced in patients undergoing catheter ablation of AF vs conventional care.

LVEF change from baseline was also significantly higher vs conventional care at 12-, 36-, and 60-month intervals. "At 5 years, we have an 8% increase in EF vs none in the conventional group, and that's why we're very excited about this," Marrouche said in an interview.

Serious adverse events seen in the trial included pericardial effusion (three in the ablation group vs zero with conventional treatment); severe acute bleeding (three in the ablation group vs zero with conventional treatment); stroke or transient ischemic attack (seven in the ablation group vs 12 with conventional treatment); pulmonary-vein stenosis (one in the ablation group vs zero with conventional treatment); pneumonia (three in the ablation group vs one with conventional treatment); groin infection (one in the ablation group vs zero with conventional treatment); and worsening heart failure (one in the ablation group vs zero with conventional treatment).

The mortality effect of ablation vs conventional care became evident at about 3 years, while reductions in hospitalization for heart failure started happening at 6 months, Marrouche said. "We think there are two reasons this is going on; one, we are lowering the heart-failure remodeling" without the use of antiarrhythmics, he added, "which has been shown to be an issue in these patients."

"There is also evidence that heart-failure decompensation leads to worsening prognosis in heart-failure patients," coauthor Dr Johannes Brachmann (Klinikum Coburg, Germany) added in an interview. "So if we prevent hospitalization for worsening heart failure, then the outcome of these patients will also be better.

"Heart-failure outcome is not a linear development, but every time a patient is going into decompensation, the restitution is getting worse and worse," Brachmann added, "and so I think that's also another factor to explain why the reduction in heart-failure hospitalization was first, and then mortality was following."

Novel Findings

Invited discussant for the trial results was Dr Carina Blomstrom-Lundqvist (Uppsala University, Sweden), who said that the results of CASTLE-AF are highly relevant to clinical practice, as well as novel and "unexpected."

"We've seen from several prior trials that heart failure associated with atrial fibrillation does have an increased mortality, so the study is highly relevant," she said. Five previous trials comparing AF ablation with rate control using medication or AV node ablation, or with rhythm control with amiodarone, all used AF freedom as their primary end point. The majority of those trials showed improvements in quality of life, LV function, and exercise capacity, she noted.

The largest trial to date, Ablation vs Amiodarone for Treatment of Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted ICD/CRTD (AATAC), published in 2016[2], also used freedom from AF as the primary end point, but hospitalizations and mortality were also reduced in the AF-ablation arm compared with the amiodarone arm, Blomstrom-Lundqvist noted.

Other published meta-analyses have also shown data in the same direction—improvement of LVEF by AF ablation, she added.

"The CASTLE-AF trial is novel, because it's the first time we use as a primary end point mortality and hospitalization, which both combined and separately showed reduction of these events in the AF-ablation arm compared with conventional treatment, and the follow up was long term," she said. "One unexpected finding I think was that the maintenance of sinus rhythm was very high in the ablation arm even after 5 years, which is usually not the pattern you see."

The study raises other questions, though; for example, whether the results would apply to asymptomatic as well as the symptomatic patients included in the trial. The study population was relatively young, in their 60s, and the majority were in NYHA class 2 with long-standing AF, "so maybe there is a bias toward recruiting healthier patients who could tolerate the procedure of AF ablation," she speculated.

Further, it's unclear whether the results can be applied equally to ischemic and nonischemic heart-failure patients, or whether less experienced centers will be able to achieve the same results with the same low complication rates.

"The take-home message is it's time to offer AF-ablation procedures at an early stage in CHF patients with AF," Blomstrom-Lundqvist concluded. "But we'll be careful to select the patients, and that selection should reflect the populations included in the trial."

Impressive Results, Interpreted With Caution

Prof Dan Atar (Oslo University Hospital Ulleval, Oslo, Norway), a spokesperson for the ESC and coauthor on the most recent ESC AF guidelines, also pointed to the need for careful patient selection.

"This is of course extremely interesting in the context that in the past years for afib treatment, we have emphasized more and more and strengthened the recommendation for rhythm control rather than frequency or rate control," Atar told | Medscape Cardiology.

In AF patients, enforcing rhythm control means trying to reestablish sinus rhythm, and one of the means of establishing sinus rhythm apart from antiarrhythmic drugs is catheter ablation, he said.

"Ablation has kind of exploded in the world as a procedure, but it had not yet had very solid data that showed, apart from a symptom benefit, another benefit such as recurrence of afib, morbidity, mortality, quality of life, all these aspects," he noted. CASTLE-AF took patients that were documented in paroxysmal or persistent atrial fibrillation and stratified them to ablation or not, "and that is the innovative approach."

"When we interpret the stunning beneficial result, we must exercise care about one aspect, namely the baseline population," Atar cautioned. Patients with AF, a very low EF, and a previously implanted ICD are a highly selected population and one that at least in Europe is not very prevalent, he said, "so that result, which is very impressive in terms of reduction of mortality and hospitalizations, we must see it in the context that these are very selected patients, sick patients."

That said, he added, "for some of these very sick patients, ablation appears to be a very good alternative. For a long time we have shied away and had a feeling that the more remodeled and altered the atria and ventricles are, the less the success rate of ablation in itself. And in this sense, this trial successfully circumvents this notion and tells us that yes, we can go ahead and try ablation in patients with really sick atria and ventricles."

Looking at what has happened with the ESC recommendation on ablation between the 2012 and 2016 guidelines, he concluded, "we have increased the grade of recommendation also for ablation in those who have quite severe heart failure, so it fits very nicely into the picture—again, to be interpreted with some caution."

The trial was supported by Biotronik. Marrouche reports he is a consultant for, receivers royalties from, or is an owner/stockholder of Abbott, Biotronik, Wavelet Health, Cardiac Design, Medtronic, Preventice, Vytronus, Biosense Webster, Marrek, Boston Scientific) and has research contracts with Abbott, Boston Scientific, GE Healthcare, Siemens, Biotronik, Vytronus, and Biosense Webster. Blomstrom-Lundqvist reports no relevant financial relationships.

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