Bristol-Myers Squibb Company and Pfizer Inc. presented findings from EMANATE (Eliquis evaluated in acute cardioversion coMpared to usuAl treatmeNts for AnTicoagulation in subjEcts with NVAF), a Phase 4 clinical trial, during a late-breaking hot line presentation at the ESC Congress 2017, organized by the European Society of Cardiology, in Barcelona, Spain. This descriptive, randomized, open-label trial explored the safety and efficacy of apixaban 5 mg twice daily (2.5 mg lower dose when two of the following were present: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133μmol/L)) vs. standard of care (parenteral heparin and/or vitamin K antagonist). The outcomes measured in this study were the occurrence of acute stroke, systemic embolism, major bleeding, clinically relevant non-major bleeding and all-cause death in non-valvular atrial fibrillation patients undergoing cardioversion. This is an investigational use for Eliquis. Eliquis is not FDA-approved for the reduction of stroke in NVAF patients undergoing cardioversion (please see indications and important safety information for Eliquis later in the press release).
Cardioversion, which could be achieved pharmacologically, through electrical shock, or through both means, could quickly restore a heart’s normal rhythm.1 A concern related to cardioversion is the potential for a blood clot in the heart to travel to the brain (stroke) or other areas (systemic embolism). Guidelines recommend that patients being considered for cardioversion require at least three weeks of oral anticoagulation to minimize the potential of cardioversion-related stroke.2,3 However, delaying patient intervention could make it increasingly difficult to achieve and maintain normal heart rhythm.iii Patients with NVAF may undergo early cardioversion at the discretion of a cardiologist or emergency room physician to enable the heart to pump more effectively.
“The EMANATE trial exemplifies the Bristol-Myers Squibb-Pfizer Alliance’s commitment to expanding understanding of the utility of Eliquis across broad NVAF patient populations and clinical settings,” said Rory O’Connor, M.D., Chief Medical Officer, Pfizer Innovative Health. “These exploratory findings add to the growing body of knowledge for Eliquis in different NVAF patients, including those at higher-risk.”
This EMANATE study randomized patients with recently diagnosed NVAF who were anticoagulation-naïve (defined as having received less than 48 hours of anticoagulation) to either apixaban or standard of care (warfarin with or without heparin). The study protocol encouraged the use of image guidance according to the guidelines to determine the absence of a clot in the heart, allowing earlier cardioversion, or anticoagulation for a minimum of three weeks before cardioversion. Anticoagulation was administered from randomization until 30 days after cardioversion. If cardioversion was not performed, anticoagulation was to be administered for a maximum of 90 days. The apixaban dose was 5 mg twice daily (or dose reduced per standard criteria). If the imaging study showed no clot in the heart, five doses of apixaban were administered to achieve steady-state blood levels before cardioversion. Alternatively, if no clot was detected, an immediate cardioversion could be undertaken following a single 10 mg loading dose of apixaban (or dose reduced per standard criteria) administered at least two hours before cardioversion, followed by a maintenance regimen. The loading dose enabled patients to quickly attain steady state-like concentrations of anticoagulation, allowing for earlier cardioversion.
Results showed that, in the intent-to-treat (ITT) population (n=1500; Eliquis n=753, heparin/VKA n=747), there were no strokes or systemic emboli in the Eliquis group compared to six strokes (one hemorrhagic and five ischemic) and no systemic emboli in the standard of care group. In the safety analysis population (n=1436; Eliquis n=735, heparin/VKA n=721), which included all patients receiving one dose of study drug, there were numerically fewer major bleeding events in the apixaban treatment group (n=3) than those randomly assigned to standard of care (n=6), and numerically fewer clinically relevant non-major bleeding events in the apixaban treatment group (n=11) than those randomly assigned to standard of care (n=13). It is important to note that Eliquis increases the risk of bleeding and can cause serious, potentially fatal, bleeding. There were two deaths in the Eliquis group (one due to acute alcoholic hepatitis prior to dosing, and one due to complications related to perforation of the colon) and one in the standard of care group.
“The current standard of care for reducing the risk of stroke in the setting of cardioversion is heparin and warfarin, which require monitoring and potential dose adjustment. This can delay performing cardioversion,” said Michael D. Ezekowitz, M.B., Ch.B., D.Phil., Professor of Medicine in the Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia and Lankenau Medical Center and Bryn Mawr Hospital. “The EMANATE study points to apixaban as a potential alternative approach. Further research is merited to confirm these findings.”
“Clinicians often prefer cardioversion earlier after a patient is diagnosed with non-valvular atrial fibrillation because the sooner the intervention, the more likely the patient is able to revert back to a regular heart rhythm,” said Christoph Koenen, M.D., MBA, VP, Development Lead, Eliquis, Bristol-Myers Squibb. “These exploratory data offer preliminary insights into the potential effects of Eliquis in this high-risk clinical setting. Further investigation is needed to better understand anticoagulation for early cardioversion.”
