Sham-controlled trials and the future of electrophysiology: Reflections on SHAM-PFA

Introduction

Catheter ablation (CA) with pulmonary vein isolation has emerged as an effective strategy to maintain sinus rhythm for patients with atrial fibrillation (AF). Randomized controlled clinical trials demonstrate a reduction in arrhythmia recurrence and symptom burden and improvement in the quality of life (QoL) with CA. This makes CA a preferred option for many symptomatic CA candidates.¹ However, evidence is less definitive when considering hard clinical end points.

The CABANA trial showed no reduction in its primary composite outcome of death, disabling stroke, serious bleeding, or cardiac arrest compared with drug therapy in an intention-to-treat analysis.² However, CA was associated with a marked reduction in AF recurrence and improved QoL,³ but the absence of a sham control left unresolved the degree to which these gains reflected true physiological benefit vs the powerful effects of patient expectation and investigator hopes. This absence of placebo-controlled data is striking, given the scale at which CA has been adopted. For decades, procedural success has been measured primarily by reduction in arrhythmia recurrence and subjective symptom relief. Until recently, no sham-controlled study had addressed any incremental outcome benefit over placebo.

SHAM-PVI, randomizing patients to cryoballoon CA or sham procedure, confirmed that CA conferred a significant reduction in the mean AF burden at 6 months (the primary endpoint). However, the sham procedure was associated with an absolute mean AF burden reduction of 35% from baseline vs 60% from baseline in the CA group. These data underscore the reality that apparent placebo responses are not negligible, can be substantial, and need incorporation into our understanding of the benefits of CA.⁴

The value of sham-controlled data in medicine cannot be overstated. History provides striking examples where sham procedures overturned long-standing practices. ORBITA demonstrated that percutaneous coronary intervention for stable angina did not improve exercise capacity vs sham, despite decades of widespread use.⁵ SYMPLICITY HTN-3 halted the premature enthusiasm for renal denervation for hypertension by showing no benefit over placebo.⁶ FOCUS-CCTRN showed no benefit of transendocardial delivery of bone marrow mononuclear cells in patients with coronary artery disease/left ventricular dysfunction and limiting heart failure/angina vs a sham intervention.⁷ Even the Coronary Drug Project illustrated how adherence to a placebo pill was associated with a profound mortality advantage, highlighting the power of expectation and engagement.⁸ These lessons remind us that, without sham-controlled evidence, procedures may be adopted based on perceived, rather than proven benefit.

The mechanisms of sham effects are complex and multifaceted. What is often termed the “placebo response” may be better understood as a healing or meaning response—the intrinsic capacity of patients to improve, shaped by psychological, social, and contextual elements of the therapeutic encounter.⁹ In AF, where symptoms including palpitations, fatigue, and exercise intolerance are subjective and variable, these effects can be profound. Sham procedures, by replicating the ritual of intervention, can affect symptoms, QoL, and even physiological markers.

Nocebo effects may also play a role.¹⁰ The magnitude of these effects depends upon the intervention, rigor of sham concealment, choice of endpoint, overall study design, and investigators’ expectations.¹¹

PRAGUE-25 demonstrated that lifestyle modification and weight reduction can affect improvements in QoL and functional capacity even without CA.¹² Benefits may occur owing to the engagement in an organized trial, encouraging positive behavioral changes that affect measured end points and may be caused by more than just arrhythmia control alone. Thus, sham interventions that replicate procedural experiences may elicit similar benefits, further highlighting the need for end points that disentangle true physiological benefit from expectation-driven or behavior-mediated improvements. Sham-controlled studies remain a highly reliable means to separate true biological effects of ablation from powerful psychological responses generated by the procedure ritual itself.¹³

The SHAM-PFA trial

Pulsed field ablation (PFA) is emerging as a promising nonthermal modality to treat AF, potentially reducing collateral damage, while maintaining procedural efficacy.¹⁴ The SHAM-PFA study represents an important step, using a sham-controlled design, to evaluate symptomatic and arrhythmia-related benefits of PFA in patients with AF.¹⁵

Designing sham-controlled trials in electrophysiology presents unique challenges. Blinding is paramount but difficult. Although operating physicians cannot be blinded, follow-up physicians, coordinators, and core laboratory staff can and should be—a strategy used effectively in SHAM-PFA. Inadvertent unblinding may still occur. The ubiquity of personal electrocardiographic devices poses a risk given that patients may detect arrhythmias outside study protocols and infer their intervention.¹⁶ Standard blinding approaches may not fully capture these risks, underscoring the need for trial designs that account for patient self-monitoring.

Enrollment and patient selection represent obstacles. Consenting to an invasive sham procedure with a 6-month blinded phase requires a highly motivated, health-literate population, potentially limiting generalizability.¹⁷ Although SHAM-PFA commendably includes patients with comorbidities such as obesity, metabolic syndrome, and sleep apnea, these conditions influence AF burden and symptom perception independently.¹⁸ Without careful stratification or adjustment, treatment effects may be diluted or misclassified. Moreover, placebo responses may vary by sex and race, highlighting the importance of planned subgroup analyses to ensure broad applicability.¹⁹

Crossovers complicate interpretation. In sham-controlled studies, crossover from sham to active therapy may be ethically necessary but crossovers reduce statistical power and diminish between-group differences. Unless explicitly accounted for in power calculations and sensitivity analyses, crossovers may render intention-to-treat analyses difficult to interpret.²⁰

Another key issue lies in postprocedural rhythm management. Allowing antiarrhythmic drugs and cardioversion during the blanking period reflects real-world practice but complicates attribution of success to ablation alone. Patients who exit the blanking period in sinus rhythm may perceive the intervention as successful even if sinus rhythm was pharmacologically or electrically restored, amplifying placebo responses and biasing QoL outcomes.²¹ Analytical strategies that disentangle procedural efficacy from adjunctive measures are essential for valid interpretation.

Conclusion

SHAM-PFA represents a significant and timely advance. PFA is being rapidly adopted on the basis of promising safety and efficacy data, yet, until now, there has been no sham-controlled evaluation. By applying a rigorous, blinded design, continuous monitoring, and validated QoL measures, SHAM-PFA sets a new benchmark of methodological rigor in electrophysiology. Although some design choices such as binary primary endpoints, pragmatic rhythm management allowances, and optimistic power assumptions invite critique, these are not fatal flaws but are opportunities for refinement in future studies.

The importance of SHAM-PFA lies in its example. It demonstrates that even widely adopted electrophysiology procedures deserve the highest evidentiary scrutiny, especially when their main benefits lie in symptom relief rather than survival. We commend the investigators for their courage and vision. Their work should serve as a stepping stone toward larger sham-controlled studies with burden-centric endpoints, robust patient-reported outcomes, and blinding strategies adapted to the modern era of self-monitoring.

The need for sham-controlled trials in electrophysiology is undeniable. Such trials protect patients from unnecessary risks, preserve scientific integrity, and ensure that costly and invasive procedures are truly effective. As the field continues to evolve with innovations such as PFA, sham-controlled trials will be indispensable in defining which therapies genuinely improve patients’ lives and which merely reflect the power of expectation. These are not peripheral issues—they are foundational to advancing electrophysiology with the rigor and integrity it deserves.

Disclosures

The authors have no conflicts of interest to disclose.