How Was a Sham-Controlled Trial for Atrial Fibrillation Ablation in Humans Ever Justified?

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EP LAB DIGEST. 2024;24(10):6.

Bradley P Knight, MD, FACC, FHRS

Dear Readers,

Since the recognition in 1998 by Haïssaguerre and colleagues that the pulmonary veins (PVs) are the site of triggers and maintenance of atrial fibrillation (AF) in many patients with paroxysmal AF, various strategies have been deployed to durably ablate the cardiac tissue surrounding the PVs to create an electrical barrier between the PVs and left atrium to prevent AF. The result has been a reduction in the global burden of AF and an improvement in the quality of life for a vast number of patients suffering from AF around the world. However, despite the logic inherent in the procedure and decades of data from randomized controlled trials comparing ablation therapy to medical therapy, skeptics and self-described “medical conservatives” have continued to call for a sham-controlled randomized trial. 

Those skeptics should now be satisfied. In September 2024, the first sham-controlled AF ablation trial was published by Dulai et al¹ simultaneous with presentation of the study findings at the European Society of Cardiology (ESC) Congress 2024. The SHAM-PVI study was a double-blind randomized clinical trial in the United Kingdom of 126 patients with symptomatic paroxysmal (21%) or, in most cases, persistent (79%) AF. Participants randomized to ablation had PV isolation performed using a standard cryoballoon catheter, and patients randomized to a sham procedure underwent transfemoral phrenic nerve pacing. Both the ablation and sham procedures involved placement of 2 femoral venous sheaths while on uninterrupted oral anticoagulation under moderate sedation. The primary endpoint was AF burden at 6 months, excluding a 3-month blanking period, as measured using an implantable loop recorder. The absolute mean AF burden dropped by 60% in the ablation group compared to 35% in the sham group (P<.001). Quality of life also improved in the ablation group. 

Before jumping to the conclusion that this study demonstrated that catheter ablation for AF has a placebo effect comparable to a 35% reduction in AF burden, it is important to note that in each group all patients who were in AF at the time of their procedure (79% of patients in each group) underwent electrical cardioversion at the same time. Furthermore, 48% of patients in the sham group underwent repeat cardioversion during the blanking period. So, this study might be better described as a trial comparing catheter ablation to cardioversion for AF.

There are at least 2 reasons why this sham-controlled study was never necessary and should never have been performed. First, anyone who performs catheter ablation procedures for AF and has witnessed acute termination of AF at the moment of PV isolation, at times with persistence of PV fibrillation, appreciates that at least in some patients, PV isolation results in an immediate cure. One can argue how durable the lesions are and which patients with more advanced AF benefit from PV isolation alone, but there is no doubt that PV isolation immediately restores and maintains sinus rhythm in some patients. Second, many clinical trials have randomized patients to catheter ablation vs medical therapy and have demonstrated objective, documented reductions in the time to first recurrence of AF and AF burden. 

Why was the SHAM-PVI study performed? To satisfy “medical conservatives”? How was this sham-controlled study justified by the investigators and institutions? Where was the equipoise? There is biological plausibility that PV isolation prevents recurrent AF. What is the biological plausibility that a sham procedure of transfemoral phrenic nerve pacing prevents AF? Thankfully, no patient in the trial who underwent a sham intervention suffered a serious complication. However, it is certainly possible that one could have occurred, especially if more patients had been enrolled. And for what purpose?

1.     Dulai R, Sulke N, Freemantle N, et al. Pulmonary vein isolation vs sham intervention in symptomatic atrial fibrillation: the SHAM-PVI randomized clinical trial. JAMA. Published online September 02, 2024. doi:10.1001/jama.2024.17921