Po-01-167 efficacy of botulinum toxin type a (agn-151607) for the prevention of postoperative atrial fibrillation in cardiac surgery patients: atrial fibrillation and anticoagulation results from the phase 2 nova study

Oral anticoagulation reduces the risk of stroke but also increases the risk of bleeding. Prevention of post-operative atrial fibrillation (POAF) could result in a lower burden of oral anticoagulation and bleeding events. AGN-151607 has been proposed to prevent POAF and its safety/efficacy was tested in a multicenter randomized trial. (1) Assess proportion of NOVA study patients free from AF and anticoagulation and (2) assess time to anticoagulation post cardiac surgery. NeurOtoxin for the preVention of post-operative Atrial fibrillation (NOVA; NCT03779841) was a randomized, multicenter, placebo-controlled, double-blind trial that assessed safety and efficacy of 5 epicardial injections of AGN-151607 125U and 250U vs placebo for prevention of POAF after CABG and/or valve surgery. Patients underwent continuous ECG monitoring for 30 days after surgery. Primary endpoint was proportion of patients with continuous AF ≥30 seconds by mITT (received treatment and ECG patch). Prespecified anticoagulation endpoints included proportion of patients free from AF ≥30 seconds and anticoagulant medication at any point up to 12-month follow-up (or early discontinuation) and time to anticoagulation. The mITT population included 312 patients (placebo n=102, 125U n=104, and 250U n=106). Primary endpoint occurred in 46.1% of placebo, 36.5% of 125U (relative risk [RR] 0.80 [95% CI 0.58, 1.10]; P=0.16), and 47.2% of 250U groups (RR 1.04 [95% CI 0.79, 1.37]; P=0.78). In CABG patients ≥65 years, 125U demonstrated a reduction in the primary endpoint (RR 0.49 [95% CI 0.27, 0.87; P=0.0096). Of 213 completed patients at the time of primary analysis (placebo n=71, 125U n=70, 250U n=72), the AF-free and anticoagulation-free endpoint was met in 45.1% of placebo, 62.9% of 125U (RR 1.38 [95% CI 1.02, 1.88]; P=0.0336), and 47.2% of 250U groups (RR 1.06 [95% CI 0.77, 1.47]; P=0.7115) (Table). The KM plot demonstrates that numerically fewer patients in the 125U group received anticoagulation due to AF and had a longer time to anticoagulation compared to placebo (HR=0.676 [95% CI 0.328, 1.393]; P=0.3025) (Figure). In completed patients, a higher proportion receiving 125U AGN-151607 were free from AF and anticoagulation vs placebo (nominal P=0.03). Additionally, there was a trend of less anticoagulation with 125U vs placebo and, among those anticoagulated, it was administered later in recovery compared to placebo (P=0.30).Tabled 1Proportion of Participants free from AF through 12 months Post-Surgery and not taking any Anticoagulant Drugs, Modified Intent-to-treat PopulationStatisticsPlacebo (N=102)AGN-151607 125 U (N=104)AGN–151607 250 U (N=106)N1 [1]717072No AF and No Anticoagulants, n (%)32 (45.1)44 (62.9)34 (47.2)95% CI [2](33.2, 57.3)(50.5, 74.1)(35.3, 59.3)vs. PlaceboRisk Difference, %17.82.295% CI [3](0.8, 34.0)(–14.4, 18.8)Relative Risk [4]1.381.0695% CI(1.02, 1.88)(0.77, 1.47)Odds Ratio [4]2.111.1495% CI(1.06, 4.23)(0.56, 2.34)P-value [4]0.03360.7115AF is defined here as any continuous episode of Atrial fibrillation or Atrial flutter ≥ 30 seconds over the 12-month study period post-surgery. [1] Number of participants with a completion status recorded (excludes ongoing participants; includes participants that completed or prematurely discontinued the study for any reason). [2] Exact (Clopper-Pearson) 95% CI is constructed using the binomial distribution. [3] Exact unconditional 95% CI using the score statistic. [4] P-values, Relative risks and Odds ratios (and their corresponding 95% CI) for each pairwise comparison of AGN-151607 versus Placebo are obtained from Cochran-Mantel-Haenszel test controlling for type of surgery (presence or absence of valve surgery) and age group (< 65 or ≥ 65 years). Open table in a new tab