CABANA: When Clinical Trials Cause Confusion, Not Clarity

From a scientific standpoint, CABANA was a failure. The largest, most scientifically-designed clinical trial ever carried out to test the merits of catheter ablation for the treatment of atrial fibrillation (AF) against drugs failed to provide an unequivocal answer on whether catheter ablation is superior to drug therapy for patients with AF. But was it a clinical failure?

On an intent-to-treat basis, catheter ablation was level with drugs, which is either a positive or a negative for the device therapy, depending upon your point of view. Does that validate, once and for all, in a large study with sufficiently long-term follow-up, catheter ablation’s place in the treatment of AF? Or is it a surprisingly poor showing for ablation procedures (since, heavily funded by industry, the real question was, is catheter ablation superior?) And, is it fair to analyze CABANA on an as-treated basis, where devices have a better showing on many measures (and since 27% of patients in the drug arm crossed over to the device therapy), or not?  

Those are the controversial questions that have elicited a highly political reaction. Where one stands on the issue depends on which camp one is in—the pharmaceutical or medical side of cardiology, the provider or the payor, or whether you are simply a glass half full or half empty kind of person. Witness, below, the slightly different positioning of the story in various publications when the preliminary results were announced at the Heart Rhythm Society (HRS) meeting in May.

Here, at least, are the facts about the study.    

CABANA, which was funded by the National Institutes of Health and the leading device companies working in AF (Abbott Laboratories Inc. (St. Jude Medical); Johnson &Johnson (Biosense Webster); Medtronic plc and Boston Scientific Corp.) was undertaken to compare state-of-the-art drug therapy to catheter ablation in patients with new onset or undertreated AF of all types—paroxysmal, persistent, and long-standing persistent—in patients eligible for therapy. It was an enormous and costly undertaking—in 10 countries, 2,204 patients were enrolled and followed for five years.

In the ablation arm, clinicians used their preferred ablation catheter and had their choice of therapy—pulmonary vein isolation or wide area circumferential ablation, with or without additional ablations in other areas of the heart. Patients in the drug arm received pharmaceuticals for rate or rhythm control and anti-coagulation. The primary endpoints of the study were all-cause mortality, disabling stroke, serious bleeding, or cardiac arrest. Of the 1,108 patients assigned to ablation on an intent-to-treat basis, only 90.8% of patients got that therapy. Of the 1,096 patients assigned to the drug arm, 1,092 were treated, but 27.5% crossed over to the ablation arm. Initial results presented by the investigators (led by Douglas L. Packer, MD, of the Mayo Clinic) at May’s HRS meeting are shown here. (A more formal publication of the study will be made in the near future.)

In presenting the data, Douglas Packer took the “glass half full” position, noting “We believe CABANA is a landmark trial that provides the evidence we have been looking for in the effectiveness and safety of catheter ablation when compared to drug therapy.” (Douglas Packer notes among his disclosures consulting arrangements with Abbott, Biosense Webster, Boston Scientific, CardioFocus, and St. Jude Medical, among a long list of medical device companies.)

Cardiologist Milton Packer, MD, of Baylor University, has been colorfully vocal in his criticism of the CABANA trial and the reaction to it, noting that trial results must be analyzed on the unbiased intent-to-treat basis. In an editorial in MedPage Today (cited in the graphic above) he writes, "The CABANA investigators presented several ‘alternative’ analyses, which totally undermined the integrity of the trial's randomization process. And surprise, surprise! The ‘alternative facts’ led to the conclusion that catheter ablation worked.” (Milton Packer, no relation to Douglas Packer, is a clinical researcher in cardiovascular medicine himself, as Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, and notes among his disclosures past or present consulting agreements with a long list of mostly pharmaceutical companies, including Novartis, Amgen, and AstraZeneca, among other pharmas).

Admittedly, it’s still early in our understanding of the study, which awaits formal publication of initial results, and perhaps years of sub-group analysis. Said one medical device executive we interviewed for an upcoming feature on atrial fibrillation devices in our publication MedTech Strategist, “This is a landmark study with the heft of the Framingham Study. Insights from this will be coming out, forever.”

But where does this leave us today? One executive interviewed for our MedTech Strategist AF article notes that clinicians he speaks with still believe catheter ablation is appropriate for the right patients, and that there is nothing new here. Indeed, a similar phenomena happened in the field of percutaneous coronary intervention (PCI), in the aftermath of the 2,000+ patient COURAGE study, which failed to show a long-term survival benefit of PCI. Interventionalists continue to argue for the improvement in symptoms and quality of life that the procedures offer, and the same argument could be made in AF catheter ablation.

One executive we interviewed sees a positive signal for ablation in the study. “If you follow the patients who got ablation and the patients who received drugs, the patients who were ablated did much better. They had lower morbidity, lower rates of stroke, and fewer hospitalizations. So if you are practical about the fact that more than 2,000 patients were studied, there was a definite trend in support of ablation, although the study was not scientifically positive.”

Others cite technological or technical limitations in the study; the fact that in the early years, ablation catheters were not as advanced as they are now, or, for reasons of safety or lack of visualization, clinicians don’t always make the complete ablations they think they’re making, and these, of course, are arguments for improved devices visualization and ablation devices under development by device companies working in atrial fibrillation. Said one executive from a start-up developing a new imaging technology for the electrophysiology lab, “If we are saying that drugs and ablation today are on par with each other, and we have a means to add a bunch of effectiveness to that, then that speaks well.”

Indeed, as designed, CABANA failed to unequivocally answer at least one of the basic clinical unknowns in the field in not providing the evidence-based authority for the superiority/non-inferiority of one device or technique over another in clinical practice. The benefit of this kind of evidence-based medicine is to provide clarity to clinicians faced with decisions to make in daily practice, but CABANA, so far, has generated confusion, not confidence.

It will be tragic if the outcomes of CABANA have a chilling effect on the willingness of industry to fund scientifically-powered and designed clinical trials, since there are many unanswered questions in the field of AF. There is no consensus on the etiology of the disease, whether any ablation strategy other than pulmonary vein isolation works, how to treat patients with persistent AF, and what exactly, is limiting the efficacy of catheter ablation, since single-procedure success rates at one year are about 69% for paroxysmal AF and 51% for persistent and long-standing persistent AF. The murkiness of CABANA calls into question whether, going forward, the conventional large, randomized controlled clinical trial is the best vehicle for answering fundamental scientific questions about disease processes and therapies.

But we live in a time where data analytics have become extremely sophisticated, and Big Data is King. As Wendy Diller suggested in last week’s Community Blog, the availability of lots of “real world data” might provide platforms for answering these kinds of questions (see this post, The Power of Ubiquitous Digital Health Data). Longitudinal data amassed from large numbers of patients thanks to ubiquitous devices and computing platforms might be able to cost-effectively (and in a more high-powered way) answer complex clinical unknowns. Organizations like Google’s Verily are capturing longitudinal data on large numbers of patients for research purposes, says Diller, pointing to Verily’s 15-month old Baseline Project, the goal of which is to create a baseline of human health and a computational platform that can, at a low cost, collect continuous information for research purposes.

CABANA failed to unequivocally answer at least one of the basic clinical unknowns in the field in not providing the evidence-based authority for the superiority/non-inferiority of one device or technique over another in clinical practice.

Within the medical device industry, ResMed Inc. hopes to be able to use patient-gathered data to answer clinical questions to inform its own growth strategy. Since it serves sleep apnea patients that wear devices every night of their lives, ResMed has built a digital health strategy around the data that can be gathered from these devices. In an interview with Jim Hollingshead, president of ResMed’s Sleep Business, published in MedTech Strategist in June, he noted how difficult it would be to conduct the clinical trials to demonstrate that treating sleep apnea results in reductions of its co-morbidities. He says “If we had enough data, we think we could show that patients who stay adherent have lower incidences of the other diseases,” but, he adds, “You couldn’t do this with a randomized controlled trial, it wouldn’t be economical.” ResMed hopes that through its platform and by building partnerships with IDNs and other payors, it can gather enough data to prove its cases over time.

Perhaps there are suitable Big Data or digital health strategies for the field of atrial fibrillation (around arrhythmia monitoring devices, for example?) Atrial fibrillation, which, as noted, is a major cause of stroke, has a worldwide prevalence of 33 million, which is why, despite the many unknowns in the field, it continues to attract so much innovation. For more on some of the newer device approaches to AF, look for “Catheter Ablation after CABANA: What Are We Missing?” in the August issue of MedTech Strategist.

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