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Roughly a third of patients with heart failure also have atrial fibrillation, a comorbid combination notorious for working synergistically to worsen a patient’s quality of life and life expectancy.
During the past year, radiofrequency catheter ablation of atrial fibrillation in patients with both conditions has gathered steam as a way to intervene in at least selected patients, driven by study results that featured attention-grabbing reductions in death and cardiovascular hospitalizations.
The evidence favoring catheter ablation of atrial fibrillation (AFib) in patients with heart failure, particularly patients with heart failure with reduced ejection fraction (HFrEF), ramped up in 2019, spurred largely by a subgroup analysis from the CABANA trial, the largest randomized comparison by far of AFib ablation with antiarrhythmic drug treatment with 2,204 patients.
The past few months also featured release of two meta-analyses that took the CABANA results into account plus findings from about a dozen earlier randomized studies. Both meta-analyses, as well as the heart failure analysis from CABANA, all point in one direction, as stated in the conclusion of one of the meta-analyses: “In patients with AFib, catheter ablation is associated with all-cause mortality benefit, compared with medical therapy, that is driven by patients with AFib and HFrEF. Catheter ablation is safe and reduces cardiovascular hospitalizations and recurrences of atrial arrhythmias” both in patients with paroxysmal and persistent AFib,” wrote Stavros Stavrakis, MD, and his associates in their systematic review of 18 randomized, controlled trials of catheter ablation of AFib in a total of 4,464 patients with or without heart failure (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: e007414).
Despite these new data and analyses, clinicians seem to have very mixed reactions. Some call for an upgraded recommendation by professional societies that would support more aggressive use of AFib ablation in heart failure patients, and the anecdotal impressions of people who manage these patients are that ablation procedures have recently increased. But others advise caution, and note that in their opinion the efficacy data remain preliminary; the procedure has safety, logistical, and economic concerns; and questions remain about the ability of all active ablation programs to consistently deliver the results seen in published trials.
The meta-analysis led by Dr. Stavrakis showed that catheter ablation of AFib cut all-cause mortality during follow-up by a statistically significant 31%, compared with medical therapy, in all patients regardless of their heart failure status. But in patients with HFrEF, the reduction was 48%, along with a 38% cut in cardiovascular hospitalizations. In contrast, patients without heart failure who underwent AFib ablation showed no significant change in their all-cause mortality, compared with medical management of these patients.
“Based both on our meta-analysis and the CABANA data, patients with AFib most likely to benefit from ablation are patients younger than 65 and those with heart failure,” summed up Dr. Stavrakis, a cardiac electrophysiologist at the Heart Rhythm Institute of the University of Oklahoma in Oklahoma City.
The second meta-analysis, which initially appeared in July, analyzed data from 11 randomized trials of catheter ablations compared with anti-arrhythmic medical therapy for rate or rhythm control with in a total of 3,598 patients who all had heart failure, again including the patients enrolled in the CABANA study. The results showed a significant 49% relative drop in all cause mortality with ablation compared with medical treatment, and a statistically significant 56% cut in hospitalizations, as well as a significant, nearly 7% average, absolute improvement in left ventricular ejection fraction, plus benefits for preventing arrhythmia recurrence and improving quality of life (Eur Heart J. 2019 Jul 11. doi: 10.1093/eurheartj/ehz443).
“The magnitude of the effect seen in the meta-analysis, a 49% reduction in total mortality and a 56% reduction in hospitalizations, is rather staggering, and is larger than typically quoted for other medical interventions or device therapy in heart failure. The treatment effect was uniform among studies, and entirely compatible with the changes in left ventricular function, exercise capacity, and heart failure symptoms. Therefore, although more data are desirable, there are already arguably sufficient data to understand a great deal regarding the impact of a fib ablation,” commented Ross J. Hunter, MRCP, a cardiac electrophysiologist at Barts Heart Centre in London, and his associates in an editorial about this meta-analysis (Eur Heart J. 2019 Oct 22. doi: 10.1093/eurheartj/ehz704).
The heart failure analysis of CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) itself also showed striking findings when first reported at the annual scientific sessions of the Heart Rhythm Society last May. In presentations he made at this meeting, Douglas L. Packer, MD, CABANA’s lead investigator, reported details of a prespecified subgroup analysis of the 778 patients enrolled in CABANA who had heart failure at baseline, slightly more than a third of the total study enrollment. This was more than double the number of patients identified as specifically having heart failure at entry in the initial publication of CABANA’s findings (JAMA. 2019 Mar 15;321[134]:1261-74). Comparison of the 378 patients with heart failure and randomized to undergo ablation with the 400 with heart failure randomized to medical treatment showed a 36% reduction in the study’s primary, composite endpoint relative to the control group in an intention-to-treat analysis, and a 43% relative cut in all-cause mortality during follow-up, Dr. Packer reported at the May meeting. (As of early November 2019, these results had not yet appeared in a published article.) In contrast, in the 1,422 CABANA patients randomized who did not have heart failure, ablation produced results for these endpoints that were similar to and not statistically different from the outcomes in patients treated medically, said Dr. Packer, a cardiac electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn.
The CABANA results added to what had been previously reported from two other landmark studies that documented incremental efficacy of AFib ablation compared with medical treatment in patients with heart failure: The AATAC (Ablation vs Amiodarone for Treatment of AFib in Patients With Congestive HF and an Implanted Device) study, which randomized 203 patients (Circulation. 2016 Apr 26;133[17]:1637-44), and CASTLE-AF (Catheter Ablation vs. Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) trial, which randomized 363 patients (N Engl J Med. 2018 Feb 1;378[5]:417-27). These three studies contributed the most patients and outcomes to the two recent meta-analyses.
“The CASTLE-AF and AATAC trials both showed improved cardiovascular outcomes with ablation in patients with heart failure and AFib. The meta-analysis [by Dr. Stavrakis and his associates] and CABANA subgroup analysis further support use of catheter ablation to improve the outcomes in these patients,” noted Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator.
“The CABANA trial was very important because it confirmed the safety of catheter ablation, and more importantly suggested that patients with heart failure may benefit the most [from AFib ablation]. The evidence is very strong to advocate ablation as first-line therapy for selected patients with heart failure. Perhaps the optimal patients are those with [New York Heart Association] class I-III or ambulatory class IV heart failure who are on optimized, guideline-directed medical therapy. We have enough data to make this a class I recommendation. The question that remains is whether this is a cost effective strategy. Because it lowers rehospitalization and death, I suspect it is,” said Luigi Di Biase, MD, lead investigator of AATAC, and director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine, both in New York.
Opinions differ on AFib ablation’s role
Despite this expansive assessment of the current status of AFib ablation for patients with heart failure from Dr. Di Biase and shared by others, another camp of cardiologists currently sees ablation as having more limited current utility, as recommended earlier this year by a guideline-update panel representing the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. The guideline update included this new recommendation for how to use AFib ablation in heart failure patients: “AF catheter ablation may be reasonable in selected patients with symptomatic AFib and heart failure with reduced left ventricular ejection fraction to potentially lower mortality rate and reduce hospitalization for heart failure,” a class IIb recommendation. (J Am Coll Cardiol. 2019 Jul 9;74[1]:104-32). The guideline’s text cited the findings from AATAC and CASTLE-AF, but qualified both studies as “relatively small” and with “highly selected patient populations.” The guideline also incorporated the CABANA results into its considerations (although they may not have had the full analysis in heart failure patients available during their deliberations), but cited the study’s main limitation: CABANA failed to show a statistically significant difference in the primary endpoint in its primary, intention-to-treat analysis, which meant that by the strict statistical criteria that trialists apply to study findings, all other endpoints analyzed using CABANA’s are merely “hypothesis generating” and not definitive.
Questions about the extent of patient selection required to see a clear clinical-endpoint benefit from AFib ablation in heart failure patients, as well as the flawed validity of the CABANA results for making unqualified practice recommendation are the main arguments advanced by experts who caution against broader and more routine ablations.
“The findings from the heart failure subgroup of CABANA are hypothesis generating rather than definitive. Even with the recent meta-analysis, uncertainty remains regarding the ability of catheter ablation to improve outcomes beyond reducing AFib-related symptoms,” commented Gregg Fonarow, MD, a heart failure physician and professor of medicine at the University of California, Los Angeles.
“CASTLE-HF had fewer than 100 deaths combined in both arms, which means very unstable results. We don’t know a lot of detail about the heart failure patients in CABANA, and overall we do not have much data from patients with heart failure with preserved ejection fraction [HFpEF],” said Javed Butler, MD, a heart failure physician and professor and chairman of medicine at the University of Mississippi in Jackson. Dr. Butler also voiced his concerns (shared by other heart failure specialists) about the safety of ablation in heart failure patients, noting that “many patients require multiple ablations; many burns result in scarring and can worsen atrial function. In short, ablation of AFib is probably good for selected patients, but to have a class 1 recommendation, we need much larger trials with well-phenotyped heart failure patients,” Dr. Butler said in an interview.
“The totality of data still captures a relatively small number of patients. CASTLE-HF took 8 years to enroll fewer than 400 patients, and the results showed some heterogeneity. Study patients were a decade younger than average HFrEF patients in the community, and thus the effectiveness and safety of catheter ablation in people with more comorbidity and frailty remains in question. Certain HFrEF patients may be less likely to benefit, such as those with amyloid cardiomyopathy. And with the increasing availability of other treatments for HFrEF such as sacubitril/valsartan, dapagliflozin, and MitraClip, it is less clear how catheter ablation would [benefit patients] on top of what is now current best therapy,” said Larry Allen, MD, a heart failure physician and professor of medicine at the University of Colorado in Aurora.
“With these limitations and the fact that catheter ablation is not a simple procedure, a large randomized, controlled trial of ablation, compared with no ablation, in a wide range of HFrEF patients on contemporary therapy would be welcome,” Dr. Allen said. “Given the prevalence of heart failure and AFib and the potential positive and negative implications of catheter ablation running such a trial seems critical for patients and for society.”
“For ablation of AFib in heart failure to become a class I recommendation there will need to be results from larger randomized studies,” summed up Dr. Stavrakis. The meta-analysis that he coauthored noted that “the benefits of catheter ablation for AFib in HFrEF patients have been consistently shown for over a decade now; however, the uptake of this procedure by clinicians in practice has been slow.”
Despite this history of reticence and ongoing caution about ablation, some cardiology experts see the indications for AFib ablation in heart failure steadily creeping forward, buoyed by a safety record that has more benign than ablation’s reputation suggests.
The CABANA results showed that “ablation is remarkably safe in the hands of experienced clinicians, with risks comparable to anti-arrhythmic drugs,” said Peter R. Kowey, MD, a specialist in treating AFib and professor of medicine at Thomas Jefferson University in Philadelphia, who made this assessment during a talk at an AFib meeting in early 2019. Dr. Kowey’s take on what the CABANA safety data showed contrasts with the impression of other cardiologists who are wary of perceived dangers from ablation.
“Ablation comes with a lot of morbidity and mortality. It’s not that the idea of ablation is wrong, but the ability to do it without a lot of adverse effects. ... We’re not quite there yet,” said Douglas L. Mann, MD, a heart failure physician and professor of medicine and chief of the cardiovascular division at Washington University in St. Louis.
“If I had a patient with HFrEF and AFib who was really sick, I’m not so sure I’d send them for ablation, which is not a simple procedure. The patients we tend to send for ablation are selected. Ablation is a big undertaking in patients who are already sick, and it’s expensive. I don’t think the data we have now will change the consensus view, but every heart failure physician is sending some patients for AFib ablation. People are turning to AFib ablation earlier than before. I think the consensus is that ablation is for symptoms or poor rate control, not for better outcomes,” said Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
However, this caution about safety and skepticism over efficacy may be dissipating as experience with ablation accumulates.
“CASTLE-AF and other data, including evidence for the apparent isolation of beta-blocker benefit to patients in sinus rhythm, have made me much more proactive about considering catheter ablation in my HFrEF patients. I think many other cardiologists have a similar view,” said Dr. Allen in an interview.
“A lot [of heart failure] patients are [being] referred for ablation, depending on the practice, setting, the local availability of electrophysiologists, and patient interest in ablation,” said Dr. Butler.
“We have no absolutely compelling data, but the data we have all point in the same direction. Like most, I am becoming convinced that AFib ablation in heart failure patients is a very valuable method for managing patients, but I can’t point to one study that was conclusive. Results from lots of studies show that it is likely, and when you add them all together it looks indisputable,” commented A. John Camm, MD, an atrial fibrillation specialist and professor of clinical cardiology at St. George’s University in London. “The findings put a responsibility on cardiologists to assess patients with heart failure for AFib. But there are nothing like enough resources to deal with all the patients who have heart failure who also have AFib.”
A rough estimate of just the U.S. volume of patients with heart failure and AFib is likely in the ball park of 2 million people (a third of the estimated 6 million American currently living with heart failure), and with the prevalence of each of these disorders rising precipitously (more than 5 million Americans have AFib) the confluence of the two should also show a steady increase. “It will take a major change in our concept of heart failure management to really address this. Potentially it would mean a large increase in the number of RF ablations of AFib, but the resources for that are not now present,” Dr. Camm said in an interview.
The attractions of catheter ablation also stand in contrast to the limitations of alternative treatments. Ablation is effective in a majority of patients for reducing AFib burden, both the frequency and duration of AFib episodes, and safety issues are mostly limited to the procedural and immediate postprocedural periods. The drugs available for trying to control AFib are beta-blockers, which provide rate control and can help prevent AFib onset, and rhythm-controlling anti-arrhythmic drugs like amiodarone, which have substantial limitations in both their ability to prevent arrhythmia recurrences as well as for safety.
“Most of the conventional antiarrhythmic drugs are contraindicated, frequently ineffective, or not well tolerated in patients with HFrEF. Catheter ablation of AFib provides an increasingly important option for rhythm control in these patients without using antiarrhythmic drugs,” Dr. Di Biase and his associates wrote in a recent review of AFib ablation in heart failure patients (Eur Heart J. 2019 Feb 21;40[8]:663-71).
“The guidelines that are controversial still make amiodarone a class I drug even though it’s been associated with serious side effects and has been shown in several heart failure trials to increase mortality. I can’t believe that ablation is a class IIb recommendation while a drug like amiodarone is a class I recommendation,” Dr. Di Biase said.
And although beta-blockers are a mainstay of heart failure treatment, once AFib becomes established they are less useful for maintaining sinus rhythm. “Beta-blockers provide effective rate control, but they can’t convert patients to sinus rhythm [once AFib begins], and there is no convincing evidence that patients on beta-blockers stay in sinus rhythm longer. You can’t just say: the patient is on a beta-blocker so I’ve done my best,” noted Dr. Jessup.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Stavrakis, Dr, Jessup, and Dr. Di Biase. Dr. Hunter has received research funding, educational grants, and speakers fees from Biosense Webster and Medtronic. Dr. Packer had received honoraria from Biotronik and MediaSphere Medical and research support from several companies. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis, he has received research funding from Abbott, ARCA biopharma, Boston Scientific, Gilead, and Johnson & Johnson, and he had a financial relationship with GlaxoSmithKline. Dr. Fonarow has been a consultant to Abbott, Amgen, Bayer, Janssen, and Novartis. Dr. Butler has been a consultant to several companies. Dr. Allen has been a consultant to Boston Scientific, Janssen, and Novartis. Dr. Kowey has been a consultant to several companies. Dr. Mann has been a consultant to Bristol-Myers Squibb, Corvia, and Novartis, and an adviser to miRagen. Dr. Camm has been a consultant to several companies.
This is part one of a two-part article.
Roughly a third of patients with heart failure also have atrial fibrillation, a comorbid combination notorious for working synergistically to worsen a patient’s quality of life and life expectancy.
During the past year, radiofrequency catheter ablation of atrial fibrillation in patients with both conditions has gathered steam as a way to intervene in at least selected patients, driven by study results that featured attention-grabbing reductions in death and cardiovascular hospitalizations.
The evidence favoring catheter ablation of atrial fibrillation (AFib) in patients with heart failure, particularly patients with heart failure with reduced ejection fraction (HFrEF), ramped up in 2019, spurred largely by a subgroup analysis from the CABANA trial, the largest randomized comparison by far of AFib ablation with antiarrhythmic drug treatment with 2,204 patients.
The past few months also featured release of two meta-analyses that took the CABANA results into account plus findings from about a dozen earlier randomized studies. Both meta-analyses, as well as the heart failure analysis from CABANA, all point in one direction, as stated in the conclusion of one of the meta-analyses: “In patients with AFib, catheter ablation is associated with all-cause mortality benefit, compared with medical therapy, that is driven by patients with AFib and HFrEF. Catheter ablation is safe and reduces cardiovascular hospitalizations and recurrences of atrial arrhythmias” both in patients with paroxysmal and persistent AFib,” wrote Stavros Stavrakis, MD, and his associates in their systematic review of 18 randomized, controlled trials of catheter ablation of AFib in a total of 4,464 patients with or without heart failure (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: e007414).
Despite these new data and analyses, clinicians seem to have very mixed reactions. Some call for an upgraded recommendation by professional societies that would support more aggressive use of AFib ablation in heart failure patients, and the anecdotal impressions of people who manage these patients are that ablation procedures have recently increased. But others advise caution, and note that in their opinion the efficacy data remain preliminary; the procedure has safety, logistical, and economic concerns; and questions remain about the ability of all active ablation programs to consistently deliver the results seen in published trials.
The meta-analysis led by Dr. Stavrakis showed that catheter ablation of AFib cut all-cause mortality during follow-up by a statistically significant 31%, compared with medical therapy, in all patients regardless of their heart failure status. But in patients with HFrEF, the reduction was 48%, along with a 38% cut in cardiovascular hospitalizations. In contrast, patients without heart failure who underwent AFib ablation showed no significant change in their all-cause mortality, compared with medical management of these patients.
“Based both on our meta-analysis and the CABANA data, patients with AFib most likely to benefit from ablation are patients younger than 65 and those with heart failure,” summed up Dr. Stavrakis, a cardiac electrophysiologist at the Heart Rhythm Institute of the University of Oklahoma in Oklahoma City.
The second meta-analysis, which initially appeared in July, analyzed data from 11 randomized trials of catheter ablations compared with anti-arrhythmic medical therapy for rate or rhythm control with in a total of 3,598 patients who all had heart failure, again including the patients enrolled in the CABANA study. The results showed a significant 49% relative drop in all cause mortality with ablation compared with medical treatment, and a statistically significant 56% cut in hospitalizations, as well as a significant, nearly 7% average, absolute improvement in left ventricular ejection fraction, plus benefits for preventing arrhythmia recurrence and improving quality of life (Eur Heart J. 2019 Jul 11. doi: 10.1093/eurheartj/ehz443).
“The magnitude of the effect seen in the meta-analysis, a 49% reduction in total mortality and a 56% reduction in hospitalizations, is rather staggering, and is larger than typically quoted for other medical interventions or device therapy in heart failure. The treatment effect was uniform among studies, and entirely compatible with the changes in left ventricular function, exercise capacity, and heart failure symptoms. Therefore, although more data are desirable, there are already arguably sufficient data to understand a great deal regarding the impact of a fib ablation,” commented Ross J. Hunter, MRCP, a cardiac electrophysiologist at Barts Heart Centre in London, and his associates in an editorial about this meta-analysis (Eur Heart J. 2019 Oct 22. doi: 10.1093/eurheartj/ehz704).
The heart failure analysis of CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) itself also showed striking findings when first reported at the annual scientific sessions of the Heart Rhythm Society last May. In presentations he made at this meeting, Douglas L. Packer, MD, CABANA’s lead investigator, reported details of a prespecified subgroup analysis of the 778 patients enrolled in CABANA who had heart failure at baseline, slightly more than a third of the total study enrollment. This was more than double the number of patients identified as specifically having heart failure at entry in the initial publication of CABANA’s findings (JAMA. 2019 Mar 15;321[134]:1261-74). Comparison of the 378 patients with heart failure and randomized to undergo ablation with the 400 with heart failure randomized to medical treatment showed a 36% reduction in the study’s primary, composite endpoint relative to the control group in an intention-to-treat analysis, and a 43% relative cut in all-cause mortality during follow-up, Dr. Packer reported at the May meeting. (As of early November 2019, these results had not yet appeared in a published article.) In contrast, in the 1,422 CABANA patients randomized who did not have heart failure, ablation produced results for these endpoints that were similar to and not statistically different from the outcomes in patients treated medically, said Dr. Packer, a cardiac electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn.
The CABANA results added to what had been previously reported from two other landmark studies that documented incremental efficacy of AFib ablation compared with medical treatment in patients with heart failure: The AATAC (Ablation vs Amiodarone for Treatment of AFib in Patients With Congestive HF and an Implanted Device) study, which randomized 203 patients (Circulation. 2016 Apr 26;133[17]:1637-44), and CASTLE-AF (Catheter Ablation vs. Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) trial, which randomized 363 patients (N Engl J Med. 2018 Feb 1;378[5]:417-27). These three studies contributed the most patients and outcomes to the two recent meta-analyses.
“The CASTLE-AF and AATAC trials both showed improved cardiovascular outcomes with ablation in patients with heart failure and AFib. The meta-analysis [by Dr. Stavrakis and his associates] and CABANA subgroup analysis further support use of catheter ablation to improve the outcomes in these patients,” noted Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator.
“The CABANA trial was very important because it confirmed the safety of catheter ablation, and more importantly suggested that patients with heart failure may benefit the most [from AFib ablation]. The evidence is very strong to advocate ablation as first-line therapy for selected patients with heart failure. Perhaps the optimal patients are those with [New York Heart Association] class I-III or ambulatory class IV heart failure who are on optimized, guideline-directed medical therapy. We have enough data to make this a class I recommendation. The question that remains is whether this is a cost effective strategy. Because it lowers rehospitalization and death, I suspect it is,” said Luigi Di Biase, MD, lead investigator of AATAC, and director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine, both in New York.
Opinions differ on AFib ablation’s role
Despite this expansive assessment of the current status of AFib ablation for patients with heart failure from Dr. Di Biase and shared by others, another camp of cardiologists currently sees ablation as having more limited current utility, as recommended earlier this year by a guideline-update panel representing the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. The guideline update included this new recommendation for how to use AFib ablation in heart failure patients: “AF catheter ablation may be reasonable in selected patients with symptomatic AFib and heart failure with reduced left ventricular ejection fraction to potentially lower mortality rate and reduce hospitalization for heart failure,” a class IIb recommendation. (J Am Coll Cardiol. 2019 Jul 9;74[1]:104-32). The guideline’s text cited the findings from AATAC and CASTLE-AF, but qualified both studies as “relatively small” and with “highly selected patient populations.” The guideline also incorporated the CABANA results into its considerations (although they may not have had the full analysis in heart failure patients available during their deliberations), but cited the study’s main limitation: CABANA failed to show a statistically significant difference in the primary endpoint in its primary, intention-to-treat analysis, which meant that by the strict statistical criteria that trialists apply to study findings, all other endpoints analyzed using CABANA’s are merely “hypothesis generating” and not definitive.
Questions about the extent of patient selection required to see a clear clinical-endpoint benefit from AFib ablation in heart failure patients, as well as the flawed validity of the CABANA results for making unqualified practice recommendation are the main arguments advanced by experts who caution against broader and more routine ablations.
“The findings from the heart failure subgroup of CABANA are hypothesis generating rather than definitive. Even with the recent meta-analysis, uncertainty remains regarding the ability of catheter ablation to improve outcomes beyond reducing AFib-related symptoms,” commented Gregg Fonarow, MD, a heart failure physician and professor of medicine at the University of California, Los Angeles.
“CASTLE-HF had fewer than 100 deaths combined in both arms, which means very unstable results. We don’t know a lot of detail about the heart failure patients in CABANA, and overall we do not have much data from patients with heart failure with preserved ejection fraction [HFpEF],” said Javed Butler, MD, a heart failure physician and professor and chairman of medicine at the University of Mississippi in Jackson. Dr. Butler also voiced his concerns (shared by other heart failure specialists) about the safety of ablation in heart failure patients, noting that “many patients require multiple ablations; many burns result in scarring and can worsen atrial function. In short, ablation of AFib is probably good for selected patients, but to have a class 1 recommendation, we need much larger trials with well-phenotyped heart failure patients,” Dr. Butler said in an interview.
“The totality of data still captures a relatively small number of patients. CASTLE-HF took 8 years to enroll fewer than 400 patients, and the results showed some heterogeneity. Study patients were a decade younger than average HFrEF patients in the community, and thus the effectiveness and safety of catheter ablation in people with more comorbidity and frailty remains in question. Certain HFrEF patients may be less likely to benefit, such as those with amyloid cardiomyopathy. And with the increasing availability of other treatments for HFrEF such as sacubitril/valsartan, dapagliflozin, and MitraClip, it is less clear how catheter ablation would [benefit patients] on top of what is now current best therapy,” said Larry Allen, MD, a heart failure physician and professor of medicine at the University of Colorado in Aurora.
“With these limitations and the fact that catheter ablation is not a simple procedure, a large randomized, controlled trial of ablation, compared with no ablation, in a wide range of HFrEF patients on contemporary therapy would be welcome,” Dr. Allen said. “Given the prevalence of heart failure and AFib and the potential positive and negative implications of catheter ablation running such a trial seems critical for patients and for society.”
“For ablation of AFib in heart failure to become a class I recommendation there will need to be results from larger randomized studies,” summed up Dr. Stavrakis. The meta-analysis that he coauthored noted that “the benefits of catheter ablation for AFib in HFrEF patients have been consistently shown for over a decade now; however, the uptake of this procedure by clinicians in practice has been slow.”
Despite this history of reticence and ongoing caution about ablation, some cardiology experts see the indications for AFib ablation in heart failure steadily creeping forward, buoyed by a safety record that has more benign than ablation’s reputation suggests.
The CABANA results showed that “ablation is remarkably safe in the hands of experienced clinicians, with risks comparable to anti-arrhythmic drugs,” said Peter R. Kowey, MD, a specialist in treating AFib and professor of medicine at Thomas Jefferson University in Philadelphia, who made this assessment during a talk at an AFib meeting in early 2019. Dr. Kowey’s take on what the CABANA safety data showed contrasts with the impression of other cardiologists who are wary of perceived dangers from ablation.
“Ablation comes with a lot of morbidity and mortality. It’s not that the idea of ablation is wrong, but the ability to do it without a lot of adverse effects. ... We’re not quite there yet,” said Douglas L. Mann, MD, a heart failure physician and professor of medicine and chief of the cardiovascular division at Washington University in St. Louis.
“If I had a patient with HFrEF and AFib who was really sick, I’m not so sure I’d send them for ablation, which is not a simple procedure. The patients we tend to send for ablation are selected. Ablation is a big undertaking in patients who are already sick, and it’s expensive. I don’t think the data we have now will change the consensus view, but every heart failure physician is sending some patients for AFib ablation. People are turning to AFib ablation earlier than before. I think the consensus is that ablation is for symptoms or poor rate control, not for better outcomes,” said Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
However, this caution about safety and skepticism over efficacy may be dissipating as experience with ablation accumulates.
“CASTLE-AF and other data, including evidence for the apparent isolation of beta-blocker benefit to patients in sinus rhythm, have made me much more proactive about considering catheter ablation in my HFrEF patients. I think many other cardiologists have a similar view,” said Dr. Allen in an interview.
“A lot [of heart failure] patients are [being] referred for ablation, depending on the practice, setting, the local availability of electrophysiologists, and patient interest in ablation,” said Dr. Butler.
“We have no absolutely compelling data, but the data we have all point in the same direction. Like most, I am becoming convinced that AFib ablation in heart failure patients is a very valuable method for managing patients, but I can’t point to one study that was conclusive. Results from lots of studies show that it is likely, and when you add them all together it looks indisputable,” commented A. John Camm, MD, an atrial fibrillation specialist and professor of clinical cardiology at St. George’s University in London. “The findings put a responsibility on cardiologists to assess patients with heart failure for AFib. But there are nothing like enough resources to deal with all the patients who have heart failure who also have AFib.”
A rough estimate of just the U.S. volume of patients with heart failure and AFib is likely in the ball park of 2 million people (a third of the estimated 6 million American currently living with heart failure), and with the prevalence of each of these disorders rising precipitously (more than 5 million Americans have AFib) the confluence of the two should also show a steady increase. “It will take a major change in our concept of heart failure management to really address this. Potentially it would mean a large increase in the number of RF ablations of AFib, but the resources for that are not now present,” Dr. Camm said in an interview.
The attractions of catheter ablation also stand in contrast to the limitations of alternative treatments. Ablation is effective in a majority of patients for reducing AFib burden, both the frequency and duration of AFib episodes, and safety issues are mostly limited to the procedural and immediate postprocedural periods. The drugs available for trying to control AFib are beta-blockers, which provide rate control and can help prevent AFib onset, and rhythm-controlling anti-arrhythmic drugs like amiodarone, which have substantial limitations in both their ability to prevent arrhythmia recurrences as well as for safety.
“Most of the conventional antiarrhythmic drugs are contraindicated, frequently ineffective, or not well tolerated in patients with HFrEF. Catheter ablation of AFib provides an increasingly important option for rhythm control in these patients without using antiarrhythmic drugs,” Dr. Di Biase and his associates wrote in a recent review of AFib ablation in heart failure patients (Eur Heart J. 2019 Feb 21;40[8]:663-71).
“The guidelines that are controversial still make amiodarone a class I drug even though it’s been associated with serious side effects and has been shown in several heart failure trials to increase mortality. I can’t believe that ablation is a class IIb recommendation while a drug like amiodarone is a class I recommendation,” Dr. Di Biase said.
And although beta-blockers are a mainstay of heart failure treatment, once AFib becomes established they are less useful for maintaining sinus rhythm. “Beta-blockers provide effective rate control, but they can’t convert patients to sinus rhythm [once AFib begins], and there is no convincing evidence that patients on beta-blockers stay in sinus rhythm longer. You can’t just say: the patient is on a beta-blocker so I’ve done my best,” noted Dr. Jessup.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Stavrakis, Dr, Jessup, and Dr. Di Biase. Dr. Hunter has received research funding, educational grants, and speakers fees from Biosense Webster and Medtronic. Dr. Packer had received honoraria from Biotronik and MediaSphere Medical and research support from several companies. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis, he has received research funding from Abbott, ARCA biopharma, Boston Scientific, Gilead, and Johnson & Johnson, and he had a financial relationship with GlaxoSmithKline. Dr. Fonarow has been a consultant to Abbott, Amgen, Bayer, Janssen, and Novartis. Dr. Butler has been a consultant to several companies. Dr. Allen has been a consultant to Boston Scientific, Janssen, and Novartis. Dr. Kowey has been a consultant to several companies. Dr. Mann has been a consultant to Bristol-Myers Squibb, Corvia, and Novartis, and an adviser to miRagen. Dr. Camm has been a consultant to several companies.
This is part one of a two-part article.
Roughly a third of patients with heart failure also have atrial fibrillation, a comorbid combination notorious for working synergistically to worsen a patient’s quality of life and life expectancy.
During the past year, radiofrequency catheter ablation of atrial fibrillation in patients with both conditions has gathered steam as a way to intervene in at least selected patients, driven by study results that featured attention-grabbing reductions in death and cardiovascular hospitalizations.
The evidence favoring catheter ablation of atrial fibrillation (AFib) in patients with heart failure, particularly patients with heart failure with reduced ejection fraction (HFrEF), ramped up in 2019, spurred largely by a subgroup analysis from the CABANA trial, the largest randomized comparison by far of AFib ablation with antiarrhythmic drug treatment with 2,204 patients.
The past few months also featured release of two meta-analyses that took the CABANA results into account plus findings from about a dozen earlier randomized studies. Both meta-analyses, as well as the heart failure analysis from CABANA, all point in one direction, as stated in the conclusion of one of the meta-analyses: “In patients with AFib, catheter ablation is associated with all-cause mortality benefit, compared with medical therapy, that is driven by patients with AFib and HFrEF. Catheter ablation is safe and reduces cardiovascular hospitalizations and recurrences of atrial arrhythmias” both in patients with paroxysmal and persistent AFib,” wrote Stavros Stavrakis, MD, and his associates in their systematic review of 18 randomized, controlled trials of catheter ablation of AFib in a total of 4,464 patients with or without heart failure (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]: e007414).
Despite these new data and analyses, clinicians seem to have very mixed reactions. Some call for an upgraded recommendation by professional societies that would support more aggressive use of AFib ablation in heart failure patients, and the anecdotal impressions of people who manage these patients are that ablation procedures have recently increased. But others advise caution, and note that in their opinion the efficacy data remain preliminary; the procedure has safety, logistical, and economic concerns; and questions remain about the ability of all active ablation programs to consistently deliver the results seen in published trials.
The meta-analysis led by Dr. Stavrakis showed that catheter ablation of AFib cut all-cause mortality during follow-up by a statistically significant 31%, compared with medical therapy, in all patients regardless of their heart failure status. But in patients with HFrEF, the reduction was 48%, along with a 38% cut in cardiovascular hospitalizations. In contrast, patients without heart failure who underwent AFib ablation showed no significant change in their all-cause mortality, compared with medical management of these patients.
“Based both on our meta-analysis and the CABANA data, patients with AFib most likely to benefit from ablation are patients younger than 65 and those with heart failure,” summed up Dr. Stavrakis, a cardiac electrophysiologist at the Heart Rhythm Institute of the University of Oklahoma in Oklahoma City.
The second meta-analysis, which initially appeared in July, analyzed data from 11 randomized trials of catheter ablations compared with anti-arrhythmic medical therapy for rate or rhythm control with in a total of 3,598 patients who all had heart failure, again including the patients enrolled in the CABANA study. The results showed a significant 49% relative drop in all cause mortality with ablation compared with medical treatment, and a statistically significant 56% cut in hospitalizations, as well as a significant, nearly 7% average, absolute improvement in left ventricular ejection fraction, plus benefits for preventing arrhythmia recurrence and improving quality of life (Eur Heart J. 2019 Jul 11. doi: 10.1093/eurheartj/ehz443).
“The magnitude of the effect seen in the meta-analysis, a 49% reduction in total mortality and a 56% reduction in hospitalizations, is rather staggering, and is larger than typically quoted for other medical interventions or device therapy in heart failure. The treatment effect was uniform among studies, and entirely compatible with the changes in left ventricular function, exercise capacity, and heart failure symptoms. Therefore, although more data are desirable, there are already arguably sufficient data to understand a great deal regarding the impact of a fib ablation,” commented Ross J. Hunter, MRCP, a cardiac electrophysiologist at Barts Heart Centre in London, and his associates in an editorial about this meta-analysis (Eur Heart J. 2019 Oct 22. doi: 10.1093/eurheartj/ehz704).
The heart failure analysis of CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) itself also showed striking findings when first reported at the annual scientific sessions of the Heart Rhythm Society last May. In presentations he made at this meeting, Douglas L. Packer, MD, CABANA’s lead investigator, reported details of a prespecified subgroup analysis of the 778 patients enrolled in CABANA who had heart failure at baseline, slightly more than a third of the total study enrollment. This was more than double the number of patients identified as specifically having heart failure at entry in the initial publication of CABANA’s findings (JAMA. 2019 Mar 15;321[134]:1261-74). Comparison of the 378 patients with heart failure and randomized to undergo ablation with the 400 with heart failure randomized to medical treatment showed a 36% reduction in the study’s primary, composite endpoint relative to the control group in an intention-to-treat analysis, and a 43% relative cut in all-cause mortality during follow-up, Dr. Packer reported at the May meeting. (As of early November 2019, these results had not yet appeared in a published article.) In contrast, in the 1,422 CABANA patients randomized who did not have heart failure, ablation produced results for these endpoints that were similar to and not statistically different from the outcomes in patients treated medically, said Dr. Packer, a cardiac electrophysiologist and professor of medicine at the Mayo Clinic in Rochester, Minn.
The CABANA results added to what had been previously reported from two other landmark studies that documented incremental efficacy of AFib ablation compared with medical treatment in patients with heart failure: The AATAC (Ablation vs Amiodarone for Treatment of AFib in Patients With Congestive HF and an Implanted Device) study, which randomized 203 patients (Circulation. 2016 Apr 26;133[17]:1637-44), and CASTLE-AF (Catheter Ablation vs. Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) trial, which randomized 363 patients (N Engl J Med. 2018 Feb 1;378[5]:417-27). These three studies contributed the most patients and outcomes to the two recent meta-analyses.
“The CASTLE-AF and AATAC trials both showed improved cardiovascular outcomes with ablation in patients with heart failure and AFib. The meta-analysis [by Dr. Stavrakis and his associates] and CABANA subgroup analysis further support use of catheter ablation to improve the outcomes in these patients,” noted Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator.
“The CABANA trial was very important because it confirmed the safety of catheter ablation, and more importantly suggested that patients with heart failure may benefit the most [from AFib ablation]. The evidence is very strong to advocate ablation as first-line therapy for selected patients with heart failure. Perhaps the optimal patients are those with [New York Heart Association] class I-III or ambulatory class IV heart failure who are on optimized, guideline-directed medical therapy. We have enough data to make this a class I recommendation. The question that remains is whether this is a cost effective strategy. Because it lowers rehospitalization and death, I suspect it is,” said Luigi Di Biase, MD, lead investigator of AATAC, and director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine, both in New York.
Opinions differ on AFib ablation’s role
Despite this expansive assessment of the current status of AFib ablation for patients with heart failure from Dr. Di Biase and shared by others, another camp of cardiologists currently sees ablation as having more limited current utility, as recommended earlier this year by a guideline-update panel representing the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. The guideline update included this new recommendation for how to use AFib ablation in heart failure patients: “AF catheter ablation may be reasonable in selected patients with symptomatic AFib and heart failure with reduced left ventricular ejection fraction to potentially lower mortality rate and reduce hospitalization for heart failure,” a class IIb recommendation. (J Am Coll Cardiol. 2019 Jul 9;74[1]:104-32). The guideline’s text cited the findings from AATAC and CASTLE-AF, but qualified both studies as “relatively small” and with “highly selected patient populations.” The guideline also incorporated the CABANA results into its considerations (although they may not have had the full analysis in heart failure patients available during their deliberations), but cited the study’s main limitation: CABANA failed to show a statistically significant difference in the primary endpoint in its primary, intention-to-treat analysis, which meant that by the strict statistical criteria that trialists apply to study findings, all other endpoints analyzed using CABANA’s are merely “hypothesis generating” and not definitive.
Questions about the extent of patient selection required to see a clear clinical-endpoint benefit from AFib ablation in heart failure patients, as well as the flawed validity of the CABANA results for making unqualified practice recommendation are the main arguments advanced by experts who caution against broader and more routine ablations.
“The findings from the heart failure subgroup of CABANA are hypothesis generating rather than definitive. Even with the recent meta-analysis, uncertainty remains regarding the ability of catheter ablation to improve outcomes beyond reducing AFib-related symptoms,” commented Gregg Fonarow, MD, a heart failure physician and professor of medicine at the University of California, Los Angeles.
“CASTLE-HF had fewer than 100 deaths combined in both arms, which means very unstable results. We don’t know a lot of detail about the heart failure patients in CABANA, and overall we do not have much data from patients with heart failure with preserved ejection fraction [HFpEF],” said Javed Butler, MD, a heart failure physician and professor and chairman of medicine at the University of Mississippi in Jackson. Dr. Butler also voiced his concerns (shared by other heart failure specialists) about the safety of ablation in heart failure patients, noting that “many patients require multiple ablations; many burns result in scarring and can worsen atrial function. In short, ablation of AFib is probably good for selected patients, but to have a class 1 recommendation, we need much larger trials with well-phenotyped heart failure patients,” Dr. Butler said in an interview.
“The totality of data still captures a relatively small number of patients. CASTLE-HF took 8 years to enroll fewer than 400 patients, and the results showed some heterogeneity. Study patients were a decade younger than average HFrEF patients in the community, and thus the effectiveness and safety of catheter ablation in people with more comorbidity and frailty remains in question. Certain HFrEF patients may be less likely to benefit, such as those with amyloid cardiomyopathy. And with the increasing availability of other treatments for HFrEF such as sacubitril/valsartan, dapagliflozin, and MitraClip, it is less clear how catheter ablation would [benefit patients] on top of what is now current best therapy,” said Larry Allen, MD, a heart failure physician and professor of medicine at the University of Colorado in Aurora.
“With these limitations and the fact that catheter ablation is not a simple procedure, a large randomized, controlled trial of ablation, compared with no ablation, in a wide range of HFrEF patients on contemporary therapy would be welcome,” Dr. Allen said. “Given the prevalence of heart failure and AFib and the potential positive and negative implications of catheter ablation running such a trial seems critical for patients and for society.”
“For ablation of AFib in heart failure to become a class I recommendation there will need to be results from larger randomized studies,” summed up Dr. Stavrakis. The meta-analysis that he coauthored noted that “the benefits of catheter ablation for AFib in HFrEF patients have been consistently shown for over a decade now; however, the uptake of this procedure by clinicians in practice has been slow.”
Despite this history of reticence and ongoing caution about ablation, some cardiology experts see the indications for AFib ablation in heart failure steadily creeping forward, buoyed by a safety record that has more benign than ablation’s reputation suggests.
The CABANA results showed that “ablation is remarkably safe in the hands of experienced clinicians, with risks comparable to anti-arrhythmic drugs,” said Peter R. Kowey, MD, a specialist in treating AFib and professor of medicine at Thomas Jefferson University in Philadelphia, who made this assessment during a talk at an AFib meeting in early 2019. Dr. Kowey’s take on what the CABANA safety data showed contrasts with the impression of other cardiologists who are wary of perceived dangers from ablation.
“Ablation comes with a lot of morbidity and mortality. It’s not that the idea of ablation is wrong, but the ability to do it without a lot of adverse effects. ... We’re not quite there yet,” said Douglas L. Mann, MD, a heart failure physician and professor of medicine and chief of the cardiovascular division at Washington University in St. Louis.
“If I had a patient with HFrEF and AFib who was really sick, I’m not so sure I’d send them for ablation, which is not a simple procedure. The patients we tend to send for ablation are selected. Ablation is a big undertaking in patients who are already sick, and it’s expensive. I don’t think the data we have now will change the consensus view, but every heart failure physician is sending some patients for AFib ablation. People are turning to AFib ablation earlier than before. I think the consensus is that ablation is for symptoms or poor rate control, not for better outcomes,” said Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.
However, this caution about safety and skepticism over efficacy may be dissipating as experience with ablation accumulates.
“CASTLE-AF and other data, including evidence for the apparent isolation of beta-blocker benefit to patients in sinus rhythm, have made me much more proactive about considering catheter ablation in my HFrEF patients. I think many other cardiologists have a similar view,” said Dr. Allen in an interview.
“A lot [of heart failure] patients are [being] referred for ablation, depending on the practice, setting, the local availability of electrophysiologists, and patient interest in ablation,” said Dr. Butler.
“We have no absolutely compelling data, but the data we have all point in the same direction. Like most, I am becoming convinced that AFib ablation in heart failure patients is a very valuable method for managing patients, but I can’t point to one study that was conclusive. Results from lots of studies show that it is likely, and when you add them all together it looks indisputable,” commented A. John Camm, MD, an atrial fibrillation specialist and professor of clinical cardiology at St. George’s University in London. “The findings put a responsibility on cardiologists to assess patients with heart failure for AFib. But there are nothing like enough resources to deal with all the patients who have heart failure who also have AFib.”
A rough estimate of just the U.S. volume of patients with heart failure and AFib is likely in the ball park of 2 million people (a third of the estimated 6 million American currently living with heart failure), and with the prevalence of each of these disorders rising precipitously (more than 5 million Americans have AFib) the confluence of the two should also show a steady increase. “It will take a major change in our concept of heart failure management to really address this. Potentially it would mean a large increase in the number of RF ablations of AFib, but the resources for that are not now present,” Dr. Camm said in an interview.
The attractions of catheter ablation also stand in contrast to the limitations of alternative treatments. Ablation is effective in a majority of patients for reducing AFib burden, both the frequency and duration of AFib episodes, and safety issues are mostly limited to the procedural and immediate postprocedural periods. The drugs available for trying to control AFib are beta-blockers, which provide rate control and can help prevent AFib onset, and rhythm-controlling anti-arrhythmic drugs like amiodarone, which have substantial limitations in both their ability to prevent arrhythmia recurrences as well as for safety.
“Most of the conventional antiarrhythmic drugs are contraindicated, frequently ineffective, or not well tolerated in patients with HFrEF. Catheter ablation of AFib provides an increasingly important option for rhythm control in these patients without using antiarrhythmic drugs,” Dr. Di Biase and his associates wrote in a recent review of AFib ablation in heart failure patients (Eur Heart J. 2019 Feb 21;40[8]:663-71).
“The guidelines that are controversial still make amiodarone a class I drug even though it’s been associated with serious side effects and has been shown in several heart failure trials to increase mortality. I can’t believe that ablation is a class IIb recommendation while a drug like amiodarone is a class I recommendation,” Dr. Di Biase said.
And although beta-blockers are a mainstay of heart failure treatment, once AFib becomes established they are less useful for maintaining sinus rhythm. “Beta-blockers provide effective rate control, but they can’t convert patients to sinus rhythm [once AFib begins], and there is no convincing evidence that patients on beta-blockers stay in sinus rhythm longer. You can’t just say: the patient is on a beta-blocker so I’ve done my best,” noted Dr. Jessup.
CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. Dr. Stavrakis, Dr, Jessup, and Dr. Di Biase. Dr. Hunter has received research funding, educational grants, and speakers fees from Biosense Webster and Medtronic. Dr. Packer had received honoraria from Biotronik and MediaSphere Medical and research support from several companies. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis, he has received research funding from Abbott, ARCA biopharma, Boston Scientific, Gilead, and Johnson & Johnson, and he had a financial relationship with GlaxoSmithKline. Dr. Fonarow has been a consultant to Abbott, Amgen, Bayer, Janssen, and Novartis. Dr. Butler has been a consultant to several companies. Dr. Allen has been a consultant to Boston Scientific, Janssen, and Novartis. Dr. Kowey has been a consultant to several companies. Dr. Mann has been a consultant to Bristol-Myers Squibb, Corvia, and Novartis, and an adviser to miRagen. Dr. Camm has been a consultant to several companies.
This is part one of a two-part article.