Pulmonary Vein Isolation vs Sham Intervention in Symptomatic Atrial Fibrillation: The SHAM-PVI Randomized Clinical Trial

Abstract

Importance: There are concerns that pulmonary vein isolation for atrial fibrillation may have a profound placebo effect, but no double-blind randomized clinical trials have been conducted.

Objective: To determine whether pulmonary vein isolation is more effective than a sham procedure for improving outcomes in atrial fibrillation.

Design, setting, and participants: Double-blind randomized clinical trial conducted at 2 tertiary centers in the UK between January 2020 and March 2024 among patients with symptomatic paroxysmal or persistent atrial fibrillation. Major exclusion criteria included long-standing persistent atrial fibrillation, prior left atrium ablation, other arrhythmias requiring ablative therapy, a left atrium of 5.5 cm or larger, and ejection fraction of less than 35%.

Intervention: Participants were randomly assigned to receive pulmonary vein isolation with cryoablation (n = 64) or a sham procedure with phrenic nerve pacing (n = 62).

Main outcomes and measures: The primary end point was atrial fibrillation burden at 6 months, excluding a 3-month blanking period. Secondary outcomes included quality-of-life measures, time to events, and safety. Atrial fibrillation burden was measured by an implantable loop recorder.

Results: A total of 126 participants were randomized (mean age, 66.8 years; 89 men [70.63%]; 20.63% with paroxysmal atrial fibrillation). The absolute mean atrial fibrillation burden change from baseline to 6 months was 60.31% in the ablation group and 35.0% in the sham group (geometric mean difference, 0.25; 95% CI, 0.15-0.42; P < .001). The estimated difference in the overall Atrial Fibrillation Effect on Quality of Life score at 6 months, favoring catheter ablation, was 18.39 points (95% CI, 11.48-25.30 points). The Short Form 36 general health score also improved substantially more with ablation, with an estimated difference of 9.27 points at 6 months (95% CI, 3.78-14.76 points).

Conclusions and relevance: Pulmonary vein isolation resulted in a statistically significant and clinically important decrease in atrial fibrillation burden at 6 months, with substantial improvements in symptoms and quality of life, compared with a sham procedure.

Trial registration: ClinicalTrials.gov Identifier: NCT04272762.

Figure 1.. Participant Flow Through the SHAM-PVI Trial

^aEach excluded patient was recorded as having a single reason on screening logs (eg, “met exclusion criteria”). ^bRandomization was stratified according to type of atrial fibrillation (paroxysmal or persistent).

Figure 2.. Primary Outcome: Mean and Geometric Mean AF Burden in All Patients, Patients With Persistent AF, and Patients With Paroxysmal AF

AF indicates atrial fibrillation. ^aMixed models with repeated measures. The geometric mean is on a ratio scale and describes the relative reduction in mean AF at the end point for participants in the ablation group compared with participants in the sham group, accounting for their baseline values. P < .001 for geometric mean difference at 6 months.

Figure 3.. Estimated Differences in Secondary Outcomes: AFEQT Scores at 6 Months, MAFSI Scores at 3 and 6 Months, and SF-36 Scores at 6 Months

AFEQT indicates Atrial Fibrillation Effect on Quality of Life questionnaire; MAFSI, Mayo AF-Specific Symptom Inventory; SF-36, 36-Item Short Form Health Survey. Additional AFEQT and MAFST estimates at 3 months are available in eTables 3-6 and eFigures 4 and 5 in Supplement 2. AFEQT overall and subscale scores range from 0 to 100. A score of 0 corresponds to complete disability (responding “extremely” limited, difficult, or bothersome to all questions answered), while a score of 100 corresponds to no disability (responding “not at all” limited, difficult, or bothersome to all questions answered). A change of 5 points or greater is considered to be a clinically important difference. MAFSI frequency scores were measured via 5-item Likert scale ranging from 0 (never) to 4 (always) and summed to generate a summary score with a theoretical range from 0 (no atrial fibrillation [AF] symptoms) to 40 (all symptoms constant). MAFSI severity scores were measured via 4-item Likert scale ranging from 0 (never) to 3 (severe) and summed to generate a summary score with a theoretical range from 0 (no AF symptoms) to 30 (all 10 symptoms at the most severe level). Scores for each SF-36 domain range from 0 to 100, with higher scores defining a more favorable health state. ^aMixed models with repeated measures.