Use of Direct Oral Anticoagulants Among Patients Undergoing Cardioversion: The Importance of Timing Before Cardioversion.

Cardioversion, whether pharmacological or electrical, is associated with a risk of thromboembolic events on the order of 5% to 7% within 30 days in nonanticoagulated patients.1, 2 The risk of thromboembolism is at its highest within the first 7 days after cardioversion (>80% of events), with the greatest risk within the first 2 days (≈70% of events).3 Thus, the incidence of thromboembolic events within the first week is analogous to the yearly incidence in moderate‐risk nonvalvular atrial fibrillation (NVAF) patients who have not undergone cardioversion. This risk can be mitigated to <1% within 30 days with the use of therapeutic anticoagulation before, during, and after cardioversion.3 Thromboembolic risk is not negated by a low CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack), or CHA2DS2‐VASc (adding vascular disease, age 65–74 years, and female sex) score or by a negative transthoracic esophageal echocardiogram (TEE) because of thrombus formation after cardioversion because of left atrial stunning.3, 4 The single biggest risk factor for thrombus formation is inadequate anticoagulation.4 The conventional approach is to anticoagulate, most commonly with an oral vitamin K antagonist (VKA), for a minimum of 3 weeks before, during, and for a minimum of 4 weeks postcardioversion. The recommendation to anticoagulate for 3 weeks before cardioversion is based on pathophysiologic and observational data, but has not been confirmed by randomized controlled trials.5, 6 In addition, the retrospective analysis by Gallagher et al demonstrated that thromboembolic events were significantly more common at international normalized ratio (INR) 1.5 to 2.4 versus ≥2.5 (0.93% versus 0%, P=0.012), reinforcing the importance of establishing therapeutic anticoagulation before cardioversion.7 Prior studies evaluating parenteral anticoagulation as a means to expedite time to cardioversion over conventional oral VKA therapy have all ensured “therapeutic anticoagulation” at the time of cardioversion. These studies have shown noninferiority between parenteral anticoagulation and conventional therapy, with cardioversion time ranging from 1 to 3 days versus 21 to 30 days, respectively.8, 9 Though the benefits of oral VKAs have long been established in NVAF with respect to stroke reduction, VKAs have the disadvantages of required monitoring and follow‐up, complex drug and food interactions, a narrow therapeutic range, and slow onset of action.10, 11, 12, 13, 14 Since 2010, the US Food and Drug Administration (FDA) has approved the oral direct thrombin inhibitor (DTI) dabigatran (Pradaxa) and 3 oral factor Xa (FXa) inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) for prevention of stroke and systemic embolism (SSE) in patients with NVAF.15 These agents have all shown either superiority or noninferiority to warfarin in reducing the risk of SSE in this patient population with similar or reduced major bleeding.16, 17, 18, 19 In these clinical trials, all of these agents have shown a reduction in the risk of intracranial hemorrhage as compared with warfarin. Oral DTI and oral FXa inhibitors have the potential advantages of a rapid onset, fixed dosing, no required routine monitoring, and fewer drug/food interactions as compared with VKAs. Of particular interest is the rapid onset of action and the potential to avoid parenteral anticoagulation and the delay in action of VKAs, culminating in faster time to cardioversion, improved maintenance of sinus rhythm, and potentially reduced hospitalization days and health‐system costs.20, 21, 22, 23 As such, these agents offer a potential alternative to conventional anticoagulation strategies for cardioversion. However, there is discordance between the major guidelines pertaining to how best to utilize these agents pericardioversion.5, 20, 24, 25, 26 Given the lack of data, inconsistencies among the guidelines, and the expanding role of oral DTI and oral FXa inhibitor anticoagulants, we reviewed the literature evaluating dabigatran, rivaroxaban, apixaban, and edoxaban in patients requiring cardioversion for atrial fibrillation (AF). Furthermore, we evaluated the pharmacokinetic and pharmacodynamic data for each agent to determine the optimal timing of administration to achieve therapeutic anticoagulation and thus be safely eligible for early cardioversion.