Did AF Ablation 'Debulking' Explain Clinical Gains in CASTLE-AF?

May 13, 2018

BOSTON — There's a new twist to the recent CASTLE-AF trial's finding that catheter ablation of atrial fibrillation (AF) in patients with heart failure (HF) was superior to rhythm- or rate-control drugs at lowering the risk for death or HF hospitalizations.

A post hoc analysis of the study suggests the clinical event risk dropped off significantly after ablation, probably because the treatment pared down the total burden of AF more thoroughly than was seen with drug therapy.

Moreover, AF ablation was the superior treatment for warding off AF recurrences, but the endpoint "time to first recurrence" in the analysis didn't predict clinical outcomes, observed study co-chair Johannes Brach­mann, MD, PhD, from II Medical Klinik Klinikum Coburg, Germany, when presenting the findings here at the Heart Rhythm Society (HRS) 2018 Scientific Sessions.

They point to reduction of AF burden by ablation as a likely effective strategy for improving outcomes in HF with AF, Brachmann and others at the sessions observed.

Consideration of AF "debulking" as a treatment goal would represent something of a shift away from the traditional take in clinical trials and practice that treatment success means prevention of AF recurrence, observed Andrew D. Krahn, MD, from the Sauder Family and Heart & Stroke Foundation of British Columbia, Vancouver, Canada.

At a media briefing on the study, Krahn said the CASTLE-AF post hoc analysis "is very informative to help us understand and counsel patients that undergoing the ablation will not eliminate all your atrial fibrillation, much of the time. But it will substantially reduce it, and that's associated with a better outcome."

In the clinical trials, observed Andrea M. Russo, MD, from Cooper University Hospital, Camden, New Jersey, "maybe we've been looking at the wrong thing."

The current analysis, she said at the briefing, suggests "that it isn't necessary to eliminate AF entirely with ablation to get this outcomes benefit from reduced AF burden."

Russo and Krahn, who are not involved in CASTLE-AF but co-moderated the session that featured the post hoc analysis, cautioned that its findings apply only to patients like those in the trial, who had HF with reduced ejection fraction, and aren't relevant to the broad population of people with AF.

Time to Change the Guidelines?

For CASTLE-AF-like patients, the treatment landscape does seem to be evolving, observed Mark S. Link, MD, University of Texas Southwestern Medical Center, Dallas, as the assigned discussant following Brach­mann's formal presentation of the trial.

"I would argue that there's becoming plenty of evidence that antiarrhythmic drugs are of little benefit in heart failure with reduced ejection fraction," Link said. Current guidelines that encourage attempts to control AF with drugs before resorting to ablation in such patients should probably be revised, he proposed.

"There's some debate, I think, in the literature whether rate-control alone would be good enough. But I would certainly argue that 'they have to fail an antiarrhythmic drug to go to ablation' is a real stretch with the data that we've seen today."

As previously reported by theheart.org | Medscape Cardiology, CASTLE-AF had randomly assigned 363 patients with symptomatic paroxysmal or persistent AF, NYHA class II to IV HF, a left ventricular ejection fraction less than 35%, and an implantable defibrillator to undergo AF ablation or receive guidelines-based rate- or rhythm-control drug therapy.

Entry to the trial required that patients hadn't responded to or poorly tolerated or declined a prior trial of antiarrhythmic drug therapy.

For those who received ablation compared with medical management, the adjusted hazard ratio (HR) for the primary endpoint of death from any cause or hospitalization for worsening HF was 0.62 (95% CI, 0.43 - 0.87; P = .007) over a median of 37.8 months.

A high AF burden, assessed using their dual-chamber or biventricular-pacing devices, was associated with increased risk for the primary endpoint at 1 year, Brachmann pointed out at the HRS sessions.

Across both arms of the study, he said, the odds ratio (OR) was 3.34 (95% CI, 1.50 - 7.46; P = .003) for an AF burden of greater than 5% to 80% or less relative to a burden of 5% or less. The OR was 2.51 (95% CI, 1.12 - 5.66; P = 0.026) for an AF burden greater than 80%.

"As Treated" in CASTLE-AF

Importantly, the post hoc analysis compared the patient groups on an as-treated basis, that is by the treatment they actually received after accounting for crossovers and other changes to the randomization. That made the comparison between 150 patients who underwent ablation within 12 weeks of baseline and 210 who did not.

AF burden went from being similar at baseline in both groups, to significantly and sharply lower (P < .001) throughout the follow-up in the ablation group vs those not getting ablation; no important absolute reduction in AF burden was seen in the latter patients.

In both groups, recurrence of AF per se appeared to be unrelated to risk for the primary endpoint. Time to first AF recurrence was significantly delayed in the ablation group compared with the other patients (P < .0001). But taking AF recurrence as a time-dependent variable, Brach­mann said, its HR for predicting death or HF hospitalization was 1.40 (P = .46) after ablation and 0.96 (P = .91) without ablation.

However, reduced AF burden after ablation significantly predicted the primary endpoint as well as mortality.

For example, a 30% reduction at 180 days corresponded to an HR of 3.13 (95% CI, 1.21 - 8.13; P = .019) for freedom from the primary endpoint. The HR was 4.55 (95% CI, 1.09 - 19.1; P = .038) for survival.

Indeed, the key message from the analysis for physicians and patients is that "lowering the burden with an ablation procedure improves mortality and hospitalization," said the other study co-chair, Nassir F. Marrouche, MD, from the University of Utah Health Sciences Center, Salt Lake City, at the media briefing. And that, he added, can't be said about rhythm control with drugs or by cardioversion.

CASTLE-AF was supported by BIOTRONIK. Brachmann discloses receiving honoraria and serving on an advisory board or speaker´s bureau for Biotronik, Medtronic, St Jude Medical, Boston Scientific, Sorin, Boehringer Ingelheim, Bayer, Pfizer/Bristol-Myers Squibb, Daiichi Sankyo, and Siemens. Krahn discloses receiving compensation for services for Medtronic and receiving research grants from Boston Scientific and Medtronic. Russo discloses compensation for services from Boston Scientific, Biotronik, St. Jude Medical, Medtronic, and Zoll Medical; receiving research grants from Boston Scientific, Boehringer Ingelheim, and Medtronic; and receiving fellowship support from Medtronic. Link had no disclosures. Marrouche discloses receiving honoraria from or consulting or holding stock options for Biosense Webster, Sanofi-Aventis, MRI Interventions, Bristol-Myers Squibb, Boehringer-Ingelheim, Biotronik, Ecardio, St. Jude Medical, Medtronic, Arapeen, MARREK, Daiichi Sankyo, Cardiac Designs, and VytronUs and receiving research grants from MRI Interventions, Sanofi, Biosense Webster, Boehringer-Ingelheim, Biotronik, MARREK, Medtronic, Boston Scientific, Catheter Robotics, and VytronUs.

Heart Rhythm Society (HRS) 2018 Scientific Sessions. Abstract B-LBCT02. Presented May 11, 2018.

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