New drug candidate for AFib fails in first-in-human trial—in fact, it made matters worse
Researchers had hoped a new drug targeting inflammation may be an effective treatment for atrial fibrillation (AFib). However, they found that the drug was actually associated with an increased AFib risk as opposed to a reduced risk. The group shared its findings in Circulation: Arrhythmia and Electrophysiology.[1]
“The pathogenesis of AFib, the most common arrhythmia affecting adults, remains incompletely understood,” wrote first author Zachary T. Yoneda, MD, MSCI, an electrophysiologist with Vanderbilt University Medical Center, and colleagues. “Numerous clinical risk factors, such as obesity, the metabolic syndrome, hypertension and aging, are well-recognized risk factors for the development of AFib, but it remains unknown whether these risk factors act independently or whether they convey risk through a final common pathway. As these comorbidities are associated with inflammation, it has been proposed that inflammation is a major common mechanism that may be a potentiator in the development of AFib.”
The group noted that inflammation and oxidative stress are closely related to one another, and oxidative stress is “increasingly recognized” for its role in AFib development. Does this mean pharmaceutical treatments targeting inflammation could potentially help reduce a patient’s risk of developing AFib?
To learn more, Yoneda et al. performed a first-in-human study of 2-HOBA, a compound known to interfere with isolevuglandins in the body in a way that could potentially slow AFib development. The group hypothesized that treating a patient with 2-HOBA could reduce their risk of AFib recurrence following catheter ablation.
The team’s analysis focused on nearly 100 AFib ablation patients treated at a single facility. The median age was 63 years old, and 64.6% of patients were male. All patients in the study were white, a detail the authors highlighted as a “major limitation” of their work.
While 43 patients were treated with 2-HOBA, another 39 received a placebo. Unexpectedly, treatment with the drug was linked to substantially worse patient outcomes. In fact, 60.5% of patients in the treatment arm and 35.9% of patients in the placebo arm showed signs of AFib occurrence after 28 days. A full year later, long after the treatment arm had stopped taking 2-HOBA, the odds of event-free survival were comparable for patients who had been given the drug and those who had not.
“Though inflammation and oxidative stress have been recognized as increasingly important AFib mechanisms, 2-HOBA proved ineffective in reducing AFib,” the authors wrote. “Paradoxically, 2-HOBA increased the risk of AFib recurrence in the first 28 days following catheter ablation. The results are robust and remain of the same level of magnitude despite prespecified adjustment for age, sex, BMI, method of ablation, de novo versus repeat ablation, hours of monitoring and AFib status.”
The research team added that these results were consistent enough that they do not appear to be any statistical anomal. The trial was simply not successful, with the results turning out to be “in the opposite direction of the hypothesis.”
Another miss as research teams keep seeking answers
Reviewing these findings, Yoneda and colleagues noted that attempts to target AFib through antioxidant and anti-inflammatory mechanisms have been “disappointing to date.”
“Vitamin C, colchicine and corticosteroids have all been attempted for treatment and prevention of recurrence in AFib, with at best modest results,” they wrote. “Omega-3 fatty acids have more recently garnered attention given the increasing signal for improvement in cardiovascular outcomes with omega-3 supplementation. With regards to AFib, results have been mixed, with some evidence for harm and some evidence for benefit.”
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Michael has more than 19 years of experience as a professional writer and editor. He has written at length about cardiology, radiology, artificial intelligence and other key healthcare topics.