A first randomized comparison of catheter ablation vs rate-control or rhythm-control drug therapy for atrial fibrillation (AF) wasn"t the invasive procedure"s moment of truth some in the field had anticipated.
No significant difference in a composite clinical primary endpoint, or in mortality, was seen for the two approaches to treating AF in the open-label Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial, in a follow-up of about 4 years.
In that intention-to-treat (ITT) analysis, the secondary endpoint of time to first AF recurrence was significantly reduced by 47% in the ablation group (P < .0001) compared with the drug therapy group.
For some observers here at the Heart Rhythm Society (HRS) 2018 Scientific Sessions, CABANA didn"t add much to what"s already appreciated about ablation for AF, one of the most common cardiac procedures.
For others, its subgroup analysis and other supplemental analyses provided new insights about which patients with AF might most benefit clinically from the invasive electrophysiologic procedure.
For example, patients younger than 65 years seemed to show a pronounced benefit from ablation, while patients older than 75 showed little. Patients with heart failure seemed to especially benefit.
Moreover, there was a significant 33% reduction in the primary endpoint (P = .006), consisting of death, disabling stroke, serious bleeding, or cardiac arrest among patients who actually under went AF ablation, after patient dropouts were excluded.
In that "treatment-received" analysis of the trial, there was also a 40% drop in mortality (P = .005) for patients who underwent ablation compared with those managed with drug therapy. A per-protocol analysis that omitted patients who crossed over to the treatment group to which they were not assigned came to similar results.
One potential message from CABANA is that "if you don"t get the ablation, you"re not going to get the benefit of ablation," said Douglas L. Packer, MD, Mayo Clinic, Rochester, Minnesota, one of the trial"s principal investigators, who presented the study.
"Could you say that everybody who has atrial fibrillation should be ablated? That"s simply not the case." The trial, he said, "identified a group of patients who are most likely to benefit, and a group of patients who are most likely to improve from the standpoint of quality of life and comfort."
Useful for Shared Decision Making
The electrophysiology community has been waiting a long time for the results to this trial, observed Fred M. Kusumoto, MD, Mayo Clinic, Jacksonville, Florida, told theheart.org | Medscape Cardiology. And it has to digest the information before acting on the results.
But it should "give more momentum" to ablation therapy, with quality-of-life outcomes still driving decisions about whether to use ablation or drug therapy, said Kusumoto, who co-chaired the session that featured CABANA.
Another co-moderator, Christine M. Albert, MD, MPH, from Brigham and Women"s Hospital, Boston, Massachusetts, also commented that she wants to wait for CABANA"s formal publication, and more information from the subgroup analyses, before she"d offer ablation sooner to younger patients, for example.
But the availability of clinical trial results does make a difference to her now, she added. "I think it makes me a little more confident when I have that discussion about offering ablation. Right now, we"ve got hard data to talk to a patient about. And I think that"s really useful for shared decision making."
One of the trial"s informative findings, Albert noted, is that there was no important indication of harm from AF ablation. "I think that"s really important. We didn"t really know that for sure. We knew there was a pretty high complication rate, and we were really doing this for the most part for symptoms. But now we can look at these data and see that there wasn"t really harm."
Concerns About Ablation for Older Patients
The apparent lack of benefit in older patients caught the eye of many observers here at the HRS sessions. Many such patients undergo AF ablation, said Eric N. Prystowsky, MD, St VincentHospital and HealthCenter, Indianapolis, Indiana, assigned discussant following Packer"s presentation.
With the CABANA data, he said, he now has concerns that the older group may be exposed to ablation"s risks without gaining clinically.
Also, he urged electrophysiologists who perform AF ablation to avoid indication creep and to read the CABANA formal publication. "When it comes out, look carefully at who was in the trial." The findings, he said, "do not apply to every patient who has atrial fibrillation."
Still, Prystowsky said about AF ablation, "Without a doubt, I think the bulk of data now presented suggests at the very least it"s equivalent and I think in many cases probably superior to drug therapy. And I think our patients should be allowed to have this first-line treatment, by people who know what they"re doing."
Subgroup analyses are typically underpowered for conclusions and so should be interpreted with caution, Sana Al-Khatib, MD, from Duke University Medical Center, Durham, North Carolina, told theheart.org | Medscape Cardiology.
Still, "You can certainly pick up on some signals." Given CABANA, she said, operators may well perform AF ablation less in older patients, "but also more often in younger patients in whom maybe the referring physician had been reluctant, or the patients had been reluctant, about undergoing an invasive procedure."
In the ITT analysis, the hazard ratio (HR) for the primary end point among patients younger than 65 years was 0.52 (95% CI, 0.27 - 1.00). It was 0.41 (95% CI, 0.20 - 0.85) in the per-protocol analysis.
Concern About Lack of Blinding
Others did not put a lot of weight on the trial"s per-protocol and treatment-received analyses. "This is an open-label trial, so the only valid way of analyzing is intention-to-treat," said Milton Packer, MD, Baylor Heart and Vascular Institute, BaylorUniversity, Dallas, Texas.
Without blinded randomization, he explained to theheart.org | Medscape Cardiology, knowledge of treatment assignment can influence adjudication of events.
"No one does a per-protocol analysis for a drug trial anymore," as they were long ago discredited, he said, and the same standard should apply to device trials.
Before CABANA, "the electrophysiology community claimed, or believed, that there was a benefit of doing ablation above and beyond making the electrocardiogram look better. This trial now provides evidence that the claim is not true."
He also took issue with assertions of possible benefit in younger patients and other subgroups. In no subgroup analysis, ITT or otherwise, he pointed out, was there an interaction P value that was significant. "I"m sorry, that"s not a subgroup analysis that indicates benefit," Packer said.
"When a trial disappoints, there are a variety of things investigators do to rationalize why they spent 7 or 8 years and didn"t get a positive result. The things that they do include doing per-protocol analyses or doing subgroup analyses to find some good news," he said. "That doesn"t make it valid."
During the discussion period after his presentation, at which Milton Packer was not present, Douglas Packer also touted the importance of ITT analyses but saw major value in the alternative analyses.
"You have to show the intention-to-treat. That"s the bedrock of clinical trials," he said. "But when you have this number of crossovers, when you have people who are not getting the therapy, then on-treatment analyses are required."
CABANA enrolled 2204 patients in 10 countries in North America, Western and Eastern Europe, Asia, and Australia; they were considered candidates for either treatment strategy and had never before undergone arrhythmia ablations.
They were randomly assigned to undergo AF ablation by pulmonary vein isolation (using any of several lesion configurations and choice of devices from different companies) or pharmacologic rhythm control or rate control (at physicians" discretion and according to guidelines).
There was no placebo group; treatment assignment was open-label.
The ITT analysis showed no differences in the primary endpoint or mortality, but the HR for the first occurrence of AF (after a blanking period) was 0.53 (95% CI, 0.46 - 0.61; P < .0001) for ablation vs rate-control or rhythm-control drug therapy.
Of patients assigned to the ablation group, 90.8% actually underwent ablation. Of those assigned to the drug group, 99.6% received the protocol therapy but 27.5% crossed over to the ablation group.
In the per-protocol analysis, the primary endpoint was significantly reduced with ablation vs drugs (HR, 0.73; 95% CI, 0.54 - 0.99; P = .046).
Improvements after AF ablation were more strongly significant in the treatment-received analysis, which included 1307 patients who had ablation and 897 patients treated with drugs. After AF ablation compared to drug therapy, the following were seen:
Primary endpoint: HR, 0.67 (95% CI, 0.50 - 0.89; P = .006);
All-cause mortality: HR, 0.60 (95% CI, 0.42 - 0.86; P = .005); and
Death or cardiovascular hospitalization: HR, 0.83 (95% CI, 0.74 - 0.94); P = .002).
Milton Packer also had reservations about another quirk of the study, that its primary endpoint was changed midstream, further complicating its interpretation.
After slow enrollment and with fewer deaths than expected, CABANA leaders gave up on total mortality as the primary endpoint and shifted to a composite of death from any cause, disabling stroke, serious bleeding, or cardiac arrest. Accordingly, the target enrollment went from 3000 to 2200.
Douglas Packer told theheart.org | Medscape Cardiology that "probably more than half" of the final trial population had been enrolled by the time the primary endpoint shifted.
"Turns out it didn"t matter, because the outcomes were the same whether you had total mortality or not as your primary endpoint," he said.
CABANA was supported by the National Heart, Lung, and Blood Institute, St. Jude Medical, Biosense Webster, Medtronic, and Boston Scientific. Douglas Packer discloses receiving compensation from Abbott, Abiomed, Aperture Diagnostics, Biosense Webster, Boston Scientific, CardioFocus, CardioInsight Technologies, Johnson & Johnson, Mediasphere Medical, Medtronic, SIEMENS, Spectrum Dynamics, and St. Jude Medical; receiving royalties from Wiley-Blackwell, Blackwell Publishing, and St. Jude Medical; receiving grants from the American Heart Association, Boston Scientific, Endosense, CardioInsight Technologies, SIEMENS, Medtronic, CardioFocus, Hansen Medical, Thermedical, Biosense Webster, St. Jude Medical, and the Robertson Foundation; and having other relationships with SIEMENS, WebMDGlobal, Biosense Webster, and Medtronic. Prystowsky discloses receiving compensation from CardioNet and Medtronic and having stock or stock options or other equity interest in Stereotaxis, Medtronic, and St. Jude Medical. Neither Al-Khatib nor Kusumoto had disclosures. Albert discloses receiving compensation from Myokardia and research grants from Roche Diagnostics and St. Jude Medical. Milton Packer discloses that he is not related to Douglas Packer and doesn"t believe they"ve ever met, adding, "The second part is reversible, the part that we"re not related is not."