Catheter ablation has become an integral part of the management of atrial fibrillation (AF). Based on the phenomenological observation of ectopic beats arising from the pulmonary veins (PV) as the initiation mechanism of AF and subsequent evidence of efficacy from randomized clinical trials, PV isolation (PVI) has been the undisputed procedural technique for more than 2 decades for paroxysmal AF ablation. Although not uniformly effective, its shortcomings have been attributed to the technical limitations of catheter techniques and technologies in achieving complete and durable PVI-technical failures, rather than mechanistic paradigm failures.
The validity of PVI as a mechanistic paradigm is debatable for persistent AF because the more logical therapeutic target would be the substrate that sustains AF beyond its initiation, rather than AF's initiating triggers. The inferior results of PVI in persistent AF compared with paroxysmal AF are consistent with this contention. Thus, multiple strategies have been attempted to improve ablation results in persistent AF using approaches that add additional interventions to standard PVI (beyond-PVI). Under the (unsubstantiated) assumption that fractionation and complexity of local electrical signals conveys mechanistic relevance, ablation of complex potentials has been proposed. Additionally, with the goal of eliminating macroreentrant circuits around the left atrial roof and mitral annulus, linear lesions in the roof and mitral isthmus were proposed. When studied in randomized clinical trials, both strategies failed to improve on the results of PVI, as did expansion of the lesion set to include the posterior left atrial wall.
Despite these negative trial results, questions remain: Did these approaches that move beyond PVI fail because they just don't work or because they were not properly implemented? Several lines of arguments support the rationale for a potential value of beyond-PVI strategies.
First, it is unlikely that a single mechanistic paradigm applies to all patients all the time. AF is highly variable, and the categorization as persistent AF is only a chronological one with very loose mechanistic implications. Thus, analysis of AF characteristics may select individuals who respond to specific strategies: the presence of rapid posterior wall activations or low-voltage scar areas supports targeting specific regions. And yet, the beneficial effect in some patients may be diluted when studied in clinical trials that include broader patient populations.
Second, any ablation strategy is subject to implementation inadequacy undermining its value in a clinical trial. Ablation success and durability is suboptimal for all strategies and can be as low as 51% for radiofrequency ablation of the mitral isthmus. Additionally, incomplete lesion sets may be proarrhythmic, not only diluting a potential benefit but fully negating it. In this context, techniques and technologies that lead to more reliable ablation have potential to make a meaningful impact. Pulsed field ablation, alone or in combination with radiofrequency ablation can improve the results of PVI in persistent AF, illustrating that improving PVI's implementation has therapeutic impact.
In this context, ethanol infusion in the vein of Marshall (EIVOM) can allow for significant improvements in the success and durability of mitral isthmus ablation. The value of EIVOM in persistent AF was tested in the Vein of Marshall Ethanol for Unablated Persistent AF (VENUS) trial, which showed improved outcomes when EIVOM was added to an aggressive ablation strategy that included PVI, posterior wall isolation, and others. Additionally, subgroup analysis showed that achieving successful perimitral block further increased the benefit of EIVOM. VENUS validated the value of EIVOM, but given the unrestricted ablation strategies in both EIVOM and control groups, VENUS could not assess the value of beyond-PVI strategies.
In this issue of JAMA, Sang et al present the results of the Prospective Randomized Comparison Between Upgraded 2C3L Versus PVI Approach for Catheter Ablation of Persistent Atrial Fibrillation (PROMPT-AF) trial, in which 498 patients with persistent AF were randomized to either a limited ablation consisting of PVI or to a comprehensive ablation strategy including PVI plus linear lesions including mitral isthmus ablation with EIVOM, left atrial roof, and cavotricuspid isthmus. Using the conventional primary end point of freedom from any atrial arrhythmia lasting 30 seconds or more, an absolute reduction in the risk of recurrence of 9.2% was found, with a hazard ratio of 0.73 (95% CI, 0.54-0.99). A number of secondary end points were assessed and favored the linear lesion group, but differences did not reach statistical significance for any of them.
The PROMPT-AF trial demonstrates the value of EIVOM for improving outcomes of persistent AF ablation. Although EIVOM-specific mechanisms -- such as parasympathetic denervation -- may apply, conceptually, the results provide further proof that improving the reliability of a lesion set -- as EIVOM does for the mitral isthmus -- can improve outcomes. The lesion set had been tested in the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II (STAR-AF II) with negative results, but adding EIVOM as well as improved catheter technologies (such as contact force sensing), improved its implementation. Thus, strategies beyond PVI do have value for persistent AF.
PROMPT-AF has several limitations. The effects of the linear lesion set are clinically relevant but were still modest and far from curative. Rhythm was monitored on follow-up using a wearable single-lead monitor for 24 hours once every week, along with periodic Holter monitoring, with less than universal adherence. The authors chose an unconventional definition of persistent AF (AF of 3-month duration), and more patients in the lines group had long-standing persistent AF. Using the standard AF clinical trial end point of freedom from atrial arrhythmias lasting 30 seconds or more led to differences in outcomes. This end point only partially reflects the clinically relevant effects of the procedure. Conceptually, AF burden may appear a more useful end point, but it is also statistically challenging to analyze, and differences were not apparent between randomization groups.
It is unclear whether further improvements in ablation technologies would lead to continued outcome improvements in persistent AF. Pulsed field ablation, which uses nonthermal irreversible electroporation and may increase ablative efficacy, has disrupted the AF ablation landscape by facilitating PVI and (theoretically) reducing its risks, but whether such disruption will translate into better outcomes is yet to be determined. EIVOM requires specialized technical expertise and is not uniformly available. It is possible that pulsed field ablation may lead to effective mitral isthmus ablation without the technical demands of EIVOM, and may achieve equivalent physiological effects and clinical results, potentially replacing EIVOM, but substantial additional research is required. Ultimately, it is the lesion set -- and not the technology used to create it -- that determines therapeutic success. It is unlikely that any fixed lesion set (PVI or beyond) would ever reach universal AF cure, unless mechanistically guided, individualized approaches are developed. Even with improved lesion reliability, we are still facing the humbling fact that the mechanistic foundation of ablative strategies for persistent AF is speculative, simplistic, and incomplete. Unless a more complete, individualized, mechanistic understanding of persistent AF guides our therapies, we will continue to be limited by the success ceiling of PVI and its add-ons.
Corresponding Author: Miguel Valderrábano, MD, PhD, Division of Cardiac Electrophysiology, Department of Cardiology, Houston Methodist Hospital, 6550 Fannin St, Ste 1801, Houston, TX 77030 ([email protected]).