COMMENTARY

We Still Need a Sham-Controlled Trial for AF Ablation

John M. Mandrola, MD

Disclosures

May 10, 2019

The following is an edited version of a talk I gave at HRS. I last wrote about the possibility that atrial fibrillation  (AF) ablation exerted a strong placebo effect in 2016. Three years on, the debate continues.

The best way to answer the question is to conduct a sham-controlled trial, although I prefer the term "placebo-controlled" trial because as I learned from Professor Darrel Francis, "sham" implies something is a farce or bogus.

Why Ablate?

We electrophysiologists have all had these cases: Before his ablation he was in and out of the hospital. He had multiple cardioversions and could not tolerate AF even for a few days. After the ablation he felt terrific. Only, at his 3-month check, he was in AF.

This is no fluke. Nine years ago, the Mayo Clinic group published a prospective case series of more than 500 symptomatic patients who underwent AF ablation.[1] They reported on AF recurrence, quality of life (QOL), and AF symptoms.

Most patients improved. But get this: QOL improvement was not closely linked to ablative efficacy. While there was a trend toward better QOL in patients with AF elimination, improvement was also seen in patients with AF control on rhythm drugs, and in those with recurrent AF.
The researchers wrote that "the clinical relevance of these findings is substantial." Yes, indeed. Since then, we have results from CABANA, which found that catheter ablation did not significantly reduce the primary composite of hard outcomes compared with medical management.[2] In 2019, we do AF ablation to improve quality of life. QOL is a reasonable endpoint, but it is more susceptible to the placebo effect.

In the Canadian-led DISCERN AF study,[3] 50 patients who had AF ablation also had implantable loop recordings from before and after the procedure. Crucially, the patients were blinded to the results. Ablation reduced AF burden but markedly increased the proportion of asymptomatic AF episodes. In fact, being postablation was the strongest predictor of having asymptomatic AF.

The Ethical Case for a Proper Trial

The argument to do a placebo-controlled trial is best made by making the ethical case for it. In 2000, Ezekiel Emanuel and coauthors outlined multiple characteristics that make clinical research ethical.[4]  

Value: The first ethical requirement is that the clinical research must be valuable. To date, of the hundreds of studies on AF ablation, none have tested it against a placebo.

To explain why a placebo test is valuable, I highlight the work of Harvard researcher Ted Kaptchuk, who has published extensively on the placebo effect.

Kaptchuk's main point is that the placebo effect relies on complex neurobiologic mechanisms that may even have genetic signatures.[5] Placebos are not simply inert fake-outs; rather, they include a confluence of caring signals and expectations—from both clinician and patient. Kaptchuk and others have shown a dose-response curve: Larger capsules exert more effect than smaller ones, and interventions such as surgery give larger effects than pills. What's more, caregiver interactions with the patient greatly enhance placebo effects.[6]

Think about the size of the placebo effect of AF ablation. We have close relationships with our patients. We've seen them multiple times, discussed their fears, explained AF, and tried medicines. Then, when the day comes for ablation, the electrophysiology lab presents an elaborate theater: Patients get general anesthesia (in some places, jet ventilation); they have postop discomfort; and, for full effect, we discharge our patients with healthy doses of optimism.

Value always means thinking about costs. The AF ablation market is worth billions of dollars. What if we are wrong; think of the wasted dollars. Yet, the ultimate value of a placebo-controlled trial is about protecting our patients. While AF ablation has become safer in recent years, you cannot do this procedure without the risk of harming or even killing a person. No procedure is totally safe, but putting people in harm's way should come with a high bar of benefit. 

Scientific Validity: To be ethically sound, a trial must have a fair and honest null hypothesis; there must be equipoise. Those who think there is not equipoise cite the greater reduction of AF burden after AF ablation vs rhythm drugs.

 We've all seen images from pacing devices showing that ablation has vanquished AF episodes. But as I've already noted, AF episodes are a poor surrogate marker for symptoms or stroke.  

Now let me tell you another story: I have a patient who underwent standard pulmonary vein isolation (PVI). His CHADSVASC score was 2. He had resolution of AF but remained on direct-acting oral anticoagulation. One year after the "successful" PVI, he had a large embolic stroke. He was in sinus rhythm at the time of his stroke, and for weeks after. The workup revealed no other source of thrombus other than the left atrium.

AF ablation improved this man's quality of life; eliminated his surrogate marker, AF episodes; but did not prevent his stroke.

Another finding from the CABANA trial that supports the validity of placebo-controlled trial: At 3 years, 50% of patients in the ablation arm had AF vs 69% of the drug arm. Yes, this difference met statistical significance, but do we really think such an imperfect procedure is valid enough to forgo a proper placebo-controlled test? We don't talk about placebo trials for Wolff-Parkinson-White ablation because the ablation permanently eliminates the causal pathway. This is hardly the case for AF ablation.

Favorable Risk-Benefit Ratio: Emanuel and colleagues write that research can be justified only if (a) the potential risk to an individual is minimized, (b) the potential benefits to an individual are enhanced, and (c) the potential benefits to individuals and society are proportionate to or outweigh the risks.

To reduce risk and enhance benefit, a placebo-controlled trial of AF ablation would have to have adequate power and be conducted in a manner that would protect blinding and minimize risks in the control arm. This could be accomplished by having only skilled operators do the procedures and perhaps forgo the transseptal. (Though I think the risks of left atrial access is no more than putting a flow wire across a left atrial descending artery lesion, as was done in the ORBITA "sham" percutaneous coronary intervention study.)

We should also not overplay the risks of being in the control arm. I had AF for a year or so. The scariest part of having AF was thinking about having my left atrium froze or burned. Yes, the downside of being randomized to the control arm of an ablation trial would be—if the trial was positive—less benefit than in the active arm, but the upside is zero chance of dying from esophageal injury.

Conclusions

In summary, you have imperfect correlation of AF episodes and quality of life, and possibly even stroke risk; you have an expensive and risky procedure that surely puts out a massive caring signal; you have no obvious causal mechanism and no compelling data on hard outcomes.

 A placebo-controlled trial of AF ablation meets all ethical requirements of clinical research, and, if medicine is to be guided by evidence, we need the courage to do this trial.

It is time.

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