RESUMO
BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with increased morbidity and mortality. Epicardial injection of botulinum toxin may suppress POAF. OBJECTIVES: This study sought to assess the safety and efficacy of AGN-151607 for the prevention of POAF after cardiac surgery. METHODS: This phase 2, randomized, placebo-controlled trial assessed the safety and efficacy of AGN-151607, 125 U and 250 U vs placebo (1:1:1), for the prevention of POAF after cardiac surgery. Randomization was stratified by age (<65, ≥65 years) and type of surgery (nonvalvular/valve surgery). The primary endpoint was the occurrence of continuous AF ≥30 seconds. RESULTS: Among 312 modified intention-to-treat participants (placebo, n = 102; 125 U, n = 104; and 250 U, n = 106), the mean age was 66.9 ± 6.8 years; 17% were female; and 64% had coronary artery bypass graft (CABG) only, 12% had CABG + valve, and 24% had valve surgery. The primary endpoint occurred in 46.1% of the placebo group, 36.5% of the 125-U group (relative risk [RR] vs placebo: 0.80; 95% CI: 0.58-1.10; P = 0.16), and 47.2% of the 250-U group (RR vs placebo: 1.04; 95% CI: 0.79-1.37; P = 0.78). The primary endpoint was reduced in the 125-U group in those ≥65 years (RR: 0.64; 95% CI: 0.43-0.94; P = 0.02) with a greater reduction in CABG-only participants ≥65 years (RR: 0.49; 95% CI: 0.27-0.87; P = 0.01). Rehospitalization and rates of adverse events were similar across the 3 groups. CONCLUSIONS: There were no significant differences in the rate of POAF with either dose compared with placebo; however, there was a lower rate of POAF in participants ≥65 years undergoing CABG only and receiving 125 U of AGN-151607. These hypothesis-generating findings require investigation in a larger, adequately powered randomized clinical trial. (Botulinum Toxin Type A [AGN-151607] for the Prevention of Post-operative Atrial Fibrillation in Adult Participants Undergoing Open-chest Cardiac Surgery [NOVA]; NCT03779841); A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy and Safety of Botulinum Toxin Type A [AGN 151607] Injections into the Epicardial Fat Pads to Prevent Post-Operative Atrial Fibrillation in Patients Undergoing Open-Chest Cardiac Surgery; 2017-004399-68).
RESUMO
Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes.
