2-Hydroxybenzylamine for Treatment of Atrial Fibrillation: A First-in-Human Clinical Pilot Trial.

Background: Inflammation is a common mechanism for atrial fibrillation (AF). 2-Hydroxybenzylamine (2-HOBA) is a novel therapeutic that scavenges isolevuglandins-a downstream mediator of inflammation and oxidative stress. 2-HOBA is safe and reduces AF in mice, prompting a first-in-human pilot clinical trial.

Methods: Participants were enrolled and randomized 1:1 to placebo or 2-HOBA (750 mg p.o. TID) 3 days before a planned AF ablation. Participants were monitored for 28 days after their ablation for recurrence of AF as detected by smartwatch single-lead ECG recordings. Blood was collected at the time of ablation for measurement of isolevuglandin levels. The study drug was stopped at 28 days. A 12-month extended follow-up period was used to monitor for any residual effect of the study drug on AF recurrence.

Results: 2-HOBA increased the risk of AF recurrence in the postablation population (odds ratio, 3.65 [95% CI, 1.31-10.16]; P=0.013) after prespecified adjustment for potential confounders. This increased risk of recurrence remained despite post hoc adjustment for other clinical risk factors. There was no difference in isolevuglandin levels between the 2-HOBA and placebo groups. After the study drug was stopped, there was no difference in AF recurrence between the 2-HOBA and placebo groups during the 12-month extended follow-up.

Conclusions: 2-HOBA was associated with a higher risk of AF recurrence when tested early after AF ablation. This result was unexpected based on preclinical data, but paradoxical associations with AF have been previously reported for other drugs that target inflammation and oxidative stress pathways, such as omega-3 fatty acids. The mechanisms for AF immediately following ablation may be different from AF that occurs under other conditions, and the generalizability of these results to all forms of AF remains unknown.