Uncertain generalizability limits AFib ablation in HFrEF


Despite several reports of dramatic efficacy and reasonable safety using catheter ablation of atrial fibrillation (AFib) in patients with heart failure, many clinicians, including many heart failure specialists, remain skeptical about whether existing evidence supports using ablation routinely in selected heart failure patients.

Dr. Arnaud Bisson, cardioogist, University of Tours,France Mitchel L. Zoler/MDedge News

Dr. Arnaud Bisson

Though concerns vary, one core stumbling block is inadequate confidence that the ablation outcomes reported from studies represent the benefit that the average American heart failure patient might expect to receive from ablation done outside of a study. A related issue is whether atrial fibrillation ablation in patients with heart failure is cost effective, especially at sites that did not participate in the published studies.

The first part of this article discussed the building evidence that radiofrequency catheter ablation of atrial fibrillation (AFib) can produce striking reductions in all-cause mortality of nearly 50%, and a greater than one-third cut in cardiovascular hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), according to one recent meta-analysis (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]:e007414). A key question about the implications of these findings is their generalizability.

“Experience is an issue, and I agree that not every operator should do it. A common perception is that ablation doesn’t work, but that mindset is changing,” said Luigi Di Biase, MD, director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine in New York. He noted that some apparent ablations failures happen because the treatment is used too late. “Ablation will fail if it is done too late. Think about using ablation earlier,” he advised. “The earlier you ablate, the earlier you reduce the AFib burden and the sooner the patient benefits. Ablation is a cost-effective, first-line strategy for younger patients with paroxysmal AFib. The unanswered question is whether it is cost effective for patients who have both AFib and heart failure. It may be, because in addition to the mortality benefit, there are likely savings from a lower rate of hospitalizations. A clearer picture should emerge from the cost-effectiveness analysis of CASTLE-AF.”

CASTLE-AF (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), which randomized patients with heart failure and AFib to ablation or medical management (N Engl J Med. 2018 Feb 1;378[5]:417-27), is one of the highest-profile studies reported so far showing AFib ablation’s efficacy in patients with heart failure. However, it has drawn skepticism over its generalizability because of its long enrollment period of 8 years despite running at 33 worldwide sites, and by its winnowing of 3,013 patients assessed down to the 398 actually enrolled and 363 randomized and included in the efficacy analysis.

Dr. Mariell Jessup, Chief Science and Medical Officer, American Heart Association, Dallas

Dr. Mariell Jessup

“CASTLE-HF showed a remarkable benefit. The problem was that it took years and years to enroll the patients,” commented Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.

At the annual congress of the European Society of Cardiology in September 2019, French researchers reported data that supported the generalizability of the CASTLE-AF findings. The study used data collected from 252,395 patients in the French national hospital-discharge database during 2010-2018 who had diagnoses of both heart failure and AFib. Among these patients, 1,384 underwent catheter ablation and the remaining 251,011 were managed without ablation.

During a median follow-up of 537 days (about 1.5 years), the incidence of both all-cause death and heart failure hospitalization were both significantly lower in the ablated patients. The ablated patients were also much younger and were more often men, but both groups had several prevalent comorbidities at roughly similar rates. To better match the groups, the French researchers ran both a multivariate analysis, and then an even more intensively adjusting propensity-score analysis that compared the ablated patients with 1,384 closely matched patients from the nonablated group. Both analyses showed substantial incremental benefit from ablation. In the propensity score–matched analysis, ablation was linked with a relative 66% cut in all-cause death, and a relative 71% reduction in heart failure hospitalizations, compared with the patients who did not undergo ablation, reported Arnaud Bisson, MD, a cardiologist at the University of Tours (France).

Another recent assessment of the generalizability of the AFib ablation trial findings used data from nearly 184,000 U.S. patients treated for AFib during 2009-2016 in an administrative database, including more than 12,000 treated with ablation. This analysis did not take into account the coexistence of heart failure. After propensity-score matching of the ablated patients with a similar subgroup of those managed medically, the results showed a 25% relative cut in the combined primary endpoint used in the CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) study (JAMA. 2019 Mar 15;321[134]:1261-74). Among the 74% of ablated patients who met the enrollment criteria for CABANA, the primary endpoint reduction was even greater, a 30% drop relative to matched patients who did not undergo ablation (Eur Heart J. 2019 Apr 21;40[16]:1257-64).

Dr. Jonathan P. Piccini, cardiac electrophysiologist, Duke University, Durham, N.C. Mitchel L. Zoler/MDedge News

Dr. Jonathan P. Piccini

“Professional societies are working to clarify best practices for procedural volume, outcomes, etc.,” said Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator. “There are some data on ablation cost effectiveness, and they generally favor” positive cost efficacy, with more analyses now in progress,” he noted in an interview.

Many unanswered questions remain about AFib in heart failure patients and how aggressively to use ablation to treat it. Most of the data so far have come from patients with HFrEF, and so most experts consider AFib ablation in patients with heart failure with preserved ejection fraction (HFpEF) a big unknown, although nearly 80% of the heart failure patients enrolled in CABANA (the largest randomized trial of AFib ablation with more than 2,200 patients) had left ventricular ejection fraction of 50% or greater, which translates into HFpEF. Another gray area is how to think about asymptomatic (also called subclinical) AFib and whether that warrants ablation in heart failure patients. The presence or absence of symptoms is a major consideration because the traditional indication for ablation has been to reduce or eliminate symptoms like palpitations, a step that can substantially improve patients’ quality of life as well as their left ventricular function. The indication to ablate asymptomatic AFib for the purpose of improving survival and reducing hospitalizations is the new and controversial concept. Yet it has been embraced by some heart failure physicians.

“Whether or not AFib is symptomatic doesn’t matter” in a heart failure patient, said Maria Rosa Costanzo, MD, a heart failure physician at Edward Heart Hospital in Naperville, Ill. “A patient with AFib doesn’t get the atrial contribution to cardiac output. When we look deeper, a patient with ‘asymptomatic’ AFib often has symptoms, such as new fatigue or obstructive sleep apnea, so when you see a patient with asymptomatic AFib look for sleep apnea, a trigger for AFib,” Dr. Costanzo advised. “Sleep apnea, AFib, and heart failure form a triad” that often clusters in patients, and the three conditions interact in a vicious circle of reinforcing comorbidities, she said in an interview.

The cardiac electrophysiology and arrhythmia community clearly realizes that catheter ablation of AFib, in patients with or without heart failure, has many unaddressed questions about who should administer it and who should undergo it. In March 2019, the National Heart, Lung, and Blood Institute held a workshop on AFib ablation. “Numerous knowledge gaps remain” about the best way to use ablation, said a summary of the workshop (Circulation. 2019 Nov 20;doi: 10.1161/CIRCULATIONAHA.119.042706). Among the research needs highlighted by the workshop was “more definitive studies ... to delineate the impact of AFib ablation on outcomes in patients with heart failure with preserved ejection fraction.” The workshop recommended establishing a national U.S. registry for AFib ablations with a reliable source of funding, as well as “establishing the cause-effect relationship between ventricular dysfunction and AFib, and the potential moderating role of atrial structure and function.” The workshop also raised the possibility of sham-controlled assessments of AFib ablation, while conceding that enrollment into such trials would probably be very challenging.

The upshot is that, even while ablation advocates agree on the need for more study, clinicians are using AFib ablation on a growing number of heart failure patients (as well as on growing numbers of patients with AFib but without heart failure), with a focus on treating those who “have refractory symptoms or evidence of tachycardia-induced cardiomyopathy,” said Dr. Piccini. Extending that to a first-line, class I indication for heart failure patients seems to need more data, and also needs clinicians to collectively raise their comfort level with the ablation concept. If results from additional studies now underway support the dramatic efficacy and reasonable safety that’s already been seen with ablation, then increased comfort should follow.

CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. CASTLE-AF was funded by Biotronik. Dr. Di Biase, Dr. Jessup, and Dr. Bisson had no disclosures. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis; he has received research funding from Abbott, ARCA, Boston Scientific, Gilead, and Johnson & Johnson; and he had a financial relationship with GlaxoSmithKline. Dr. Costanzo has been a consultant to Abbott.

This is part 2 of a 2-part story. See part 1 here.

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