Safety of Novel Asundexian Compared to Apixaban in Patients with Atrial Fibrillation (PACIFIC-AF Trial)

Safety of Novel Asundexian Compared to Apixaban in Patients with Atrial Fibrillation (PACIFIC-AF Trial)
Rachel Wedemeyer, PharmD, M Health Fairview

Background: Oral anticoagulant therapy, preferably with direct-acting oral anticoagulants (DOACs), is recommended for patients with atrial fibrillation to reduce risk of stroke due to atrial thrombi. However, these DOAC medications increase the risk of bleeding which poses a serious safety risk to patients. Asundexian, a novel oral small molecule activated coagulation factor XIa (FXIa) inhibitor, may reduce cardioembolic stroke risk while causing only minimal increased risk of bleeding.

Purpose: This trial aimed to determine the optimal dose of asundexian and assess if lower incidence of bleeding was demonstrated in patients with atrial fibrillation taking asundexian compared to those taking apixaban.

Study Design: This study was an international, multicenter, randomized, double-blind, double-dummy phase 2 trial comparing asundexian and apixaban. Included participants had atrial fibrillation documented by electrocardiography within the previous 12 months, a CHA2DS2-VASc score of two or higher (males) or three or higher (females), an indication for treatment with an oral anticoagulant but not currently treated with any oral anticoagulant or treated with a DOAC, with at least one bleeding risk feature (history of previous bleeding requiring medical attention within 12 months, estimated glomerular filtration rate (eGFR) of 30-50 mL/min, or current indication[1] [2]  for aspirin). Exclusion criteria included stroke within the last 30 days of screening, uncontrolled hypertension (>160/100 mmHg), known bleeding disorders, eGFR < 30 mL/min, and known significant liver disease. Participants were randomly assigned in a 1:1:1 ratio to 20 mg asundexian daily, 50 mg asundexian daily, or standard dosing of apixaban (5 mg twice daily with dose reduction to 2.5 mg twice daily when clinically indicated) treatment groups. Participants were supplied with active medication based on randomized group assignment and the matching placebo of the medication (asundexian or apixaban) for the medication the participant was not selected to take. Participants took active medication for 12 weeks and completed a safety follow-up visit 14-21 days after the end of the treatment period. Use of non-steroidal anti-inflammatory drugs (NSAIDs) was strongly discouraged during the treatment period, however aspirin under 100 mg daily was permitted. The primary outcome was the composite of major bleeding or clinically relevant non-major bleeding per International Society on Thrombosis and Haemostasis (ISTH) criteria. Secondary safety outcomes were all bleeding, ISTH major bleeding, ISTH clinically relevant non-major bleeding, and ISTH minor bleeding. Ischemic stroke, systemic embolism, myocardial infarction, and cardiovascular death were analyzed in an exploratory manner.

Results: A total of 251 participants were assigned to receive asundexian 20 mg, 254 participants were assigned to receive asundexian 50 mg, and 250 participants were assigned to receive apixaban. The average age of participants was 73.7 years, with 46% being older than 75 years. Participants frequently had other comorbidities including heart failure (44%), hypertension (89%), and diabetes (32%). Asundexian 20 mg resulted in an 81% reduction in baseline FXIa at trough concentrations and 90% reduction at peak. Asundexian 50 mg resulted in a 92% reduction in FXIa at trough concentrations and 94% reduction at peak. ISTH major or clinically relevant non-major bleeding occurred three times in the asundexian 20 mg group, one time in the asundexian 50 mg group, and six times in the apixaban group. The ratio of incidence proportions for all bleeding events in asundexian (pooled 20 mg and 50 mg daily data) versus apixaban was 0.42 [95% CI 0.26 - 0.67].

Conclusions: Asundexian at both 20 mg and 50 mg daily had lower observed rates of bleeding compared to apixaban. Both doses of asundexian also led to similar suppression of FXIa with once-daily dosing. This study provides additional evidence that asundexian can be an effective DOAC while minimizing bleeding risk.

Key Point: This study shows the potential benefits of a novel anticoagulant and warrants a phase 3 trial to continue assessing efficacy and safety of this medication.

Reference:

  1. Piccini JP, Caso V, Connolly SJ, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022;399(10333):1383-1390. doi:10.1016/S0140-6736(22)00456-1.