Catheter ablation for atrial fibrillation (AF) produced no significant improvement in clinical outcomes in a large and important new clinical trial. CABANA is the first and long anticipated randomized controlled trial of AF ablation in the more than two decade long history of the procedure.
The results will likely spark an intense controversy in the medical and cardiology community, since AF ablation has become a profitable revenue center in many cardiology practices. The initial response from leaders of the EP community has been to interpret the trial as supporting current clinical practice, but clinical trial experts outside the EP community have reached far harsher conclusions. The response to CABANA is likely to add fuel to the ongoing debate raised by a series of trials, including COURAGE, ORBITA, and ISCHEMIA, over some of the fundamental practices in clinical cardiology.
The Catheter ABlation vs ANtiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial, sponsored by the NIH with additional support from industry, randomized 2,204 patients with AF to catheter ablation or drug therapy. The results were presented by Douglas Packer (Mayo Clinic) at the annual meeting of the Heart Rhythm Society (HRS) in Boston on Thursday.
There was no significant difference between the two arms in the primary endpoint of the trial (the composite of all-cause mortality, disabling stroke, serious bleeding, or cardiac arrest), which occurred in 9.2% of patients in the drug group and 8% of patients in the ablation group (hazard ratio 0.86, CI 0.65-1.15, p =0.303). There were also no significant differences in the individual components of the primary endpoint.
Packer sought solace in positive findings from some secondary analyses of the trial. One secondary outcome, the rate of death or CV hospitalization, was significantly reduced from 58.1% to 51.7% (HR0.83, CI 0.74-0.93, p=0.001). As expected, ablation was also associated with a significant reduction in recurrence of AF (HR 0.53, CI 0.46-0.61, p<0.0001). No safety concerns emerged in the trial.
Despite the neutral finding of the main intention-to-treat (ITT) analysis, the EP community found support in the per protocol analysis. During the course of the trial 9.2% of patients randomized to ablation did not undergo ablation while 27.5% of patients randomized to drug therapy ended up undergoing ablation. The per protocol analysis therefore compared the 1307 patients who underwent ablation with the 897 patients who received drug therapy. In this analysis the composite primary outcome was reduced from 10.9% in the drug group to 7% in the ablation group (HR 0.67, CI 0.50-0.89, p=0.006). All cause mortality was reduced in this per protocol analysis from 7.5% to 4.4%.
Packer concluded that “ablation is an acceptable treatment strategy for treating AF with low adverse event rates even in higher risk patients.” Eric Prystowsky, the trial discussant at HRS, said that the results establish ablation as a first line alternative to drug therapy.
At a news conference Packer defended the per protocol analysis. “You can’t get benefit from a therapy if you don’t get the therapy,” he said.
But a different cardiology trial expert with the last name of Packer, Milton Packer (Baylor Health), warned against efforts to spin the trial using the per protocol analysis. “When investigators are disappointed in the results of a trial, there is an understandable temptation to analyze the data to find something that might look positive. One approach is doing a ‘per-protocol’ analysis, but (even when prespecified) such an approach is inherently biased, because it violates the intention-to-treat principle. Why would you design a randomized trial if you are going to analyze it in a way that is inconsistent with randomization? We do not perform or accept ‘per-protocol’ analyses in trials of drug therapy, and we do not accept them as evidence for efficacy for trials of device therapy. The disappointment in the results of the CABANA trial is particularly striking, since this was an unblinded trial, and thus, was biased toward ablation therapy.”
At an HRS news conference Douglas Packer also said that ablation improved quality of life, but acknowledged in response to a question that this data won’t be presented until the European Society of Cardiology meeting at the end of the summer.
The response of the EP community is demonstrated by the following exchange on Twitter, in which electrophysiologists attempt to use the complexity of the trial to try to ignore or brush aside the failure of the primary endpoint:
Harlan Krumholz (Yale University) said that CABANA will fuel a “long debate, as it has just the type of ambiguous result that can be interpreted through whatever prior belief you had. I take it as a push toward ablation, especially for younger patients – but the results are not definitive. Can’t we find a way in this country to take an important topic like this and run a series of trials and produce a body of evidence – in as close to real-time as possible? For now, it seems that these therapies both remain reasonable – how we communicate this result to patients is the next challenge.”
Sanjay Kaul (Cedars Sinai) said that “the ITT analysis is the only analysis that preserves the advantage of randomization.” Therefore, “the most reliable inference is that CABANA failed to validate the hypothesis that the treatment strategy of percutaneous left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) is superior to current state-of-the-art pharmacologic therapy.” Kaul concluded that it is “time to seriously consider a sham-controlled trial for ablation!”
Milton Packer said that “I am sure that the results of CABANA are profoundly disappointing for the investigators and for the EP community…. The trial failed to yield any reliable evidence that ablation is better than no ablation with respect to important clinical outcomes. The CABANA investigators conclude that catheter ablation is an acceptable treatment for atrial fibrillation, but we already knew that BEFORE the trial. Here is what is new,” Packer said. “The EP community can no longer claim that ablation achieves anything except making the ECG look better.”
Packer agreed with Kaul about the need for a sham-controlled trial. “It is time to do a sham-controlled trial of ablation, along the lines of the ORBITA design for PCI. Until such a trial is done, the EP community carries the burden of proof to demonstrate that ablation is useful and in whom. Let’s see if they step up to the plate and do the right thing. But any belief that CABANA demonstrates the efficacy of ablation therapy is not evidence-based medicine. It simply represents a high level of self-deception.”
Adding additional comments from William Boden and Sanjay Kaul:
I believe it was none other than Eric Prystowsky who once famously quoted that “there is no structural cardiac condition for which a device or procedural intervention does not exist”. While this has certainly been a self-fulfilling prophecy for the past 2+ decades, here we see yet again in the CABANA trial where the ITT analysis of a large, prospective RCT has failed to show a conclusive outcome for the primary endpoint or definitive evidence of benefit for the procedure beyond secondary endpoint analyses.
Yet, if history has taught us anything, it’s that the results of negative/neutral trials that are disliked by the individuals who do these procedures will very likely do little to change practice or dampen the enthusiasm for recommending procedures like AF ablations and a continued “business as usual” approach to management. Perhaps someday we will evolve beyond the current practice of “selective” evidence-based medicine: that is, embrace what you like, and dismiss/discard what you dislike.
Seems like the EP community (not unlike the interventional community) is highly motivated to resolve the ‘cognitive dissonance’ provoked by the null results of the CABANA trial.
Why do the ‘proceduralists’ always always come up with lame excuses in defense of their failed procedures compared with medical therapy?
Remember COURAGE, WATCHMAN, SYMPLICITY-HTN 3!
In the battle between revenue-based medicine vs evidence-based medicine, remuneration always wins…