A 68-year-old female with a past medical history of hypertension, remote ischemic cerebrovascular accident , type II diabetes mellitus, heart failure with preserved ejection fraction, and chronic kidney disease (CKD 3 with creatinine clearance [CrCl] of 40 mL/min) presents with progressive shortness of breath and palpitations for the past five days. A 12-lead electrocardiogram reveals atrial fibrillation (AF) with rapid ventricular response to 135 beats per minute and no acute ischemic changes; blood pressure is 134/70 mm Hg. She is admitted, started on metoprolol, and anticoagulated with unfractionated heparin given her CHA2DS2-VASc score of 7. On the third day of her hospital stay she continues to have symptomatic AF with a rapid ventricular response to 127, despite uptitration of metoprolol and a trial of diltiazem. Blood pressure remains stable. The cardiology team decides to attempt synchronized cardioversion, but the morning activated partial thromboplastin time (aPTT) is 40 seconds. Transesophageal echocardiogram (TEE) is performed, which excludes a left atrial thrombus.
The correct answer is: B. Start rivaroxaban 15 mg daily now, discontinue heparin infusion, and cardiovert in three hours, continuing rivaroxaban 15 mg daily for at least four weeks, but likely indefinitely.
The patient is presenting with likely new-onset AF of duration > 48 hours, given symptoms began five days prior to admission. CHA2DS2-VASc score of 7 portends a 9.6% annualized risk for stroke, therefore it is reasonable to initiate anticoagulation on admission, especially if cardioversion is anticipated. This could be done utilizing unfractionated heparin infusion, low molecular weight heparin, fondaparinux, or a non-vitamin K antagonist (NOAC). NOACs are available for use both pre-cardioversion and post-cardioversion; guidelines for the use of rivaroxaban, apixaban, and dabigatran in cardioversion are based on results from one randomized trial with rivaroxaban: eXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in patients with non-valvular aTrial fibrillation scheduled for cardioversion (X-VeRT), and several post-hoc analyses and meta-analyses from the phase III randomized clinical trials: Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE), Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) With Dabigatran Etexilate, and Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF).
X-VeRT was a multinational, open-label, randomized clinical trial comparing rivaroxaban to vitamin K antagonist (VKA) therapy pre-cardioversion in a 2:1 ratio. Subjects could have early cardioversion (one to five days of rivaroxaban or usual VKA therapy before the procedure) versus delayed cardioversion (three to eight weeks of therapy prior to procedure). Patients were randomized to rivaroxaban 20 mg once daily (or 15 mg once daily in subjects with CrCl < 50 mL/min), or a VKA with target INR of 2.0-3.0. Parenteral anticoagulation in addition to VKA therapy prior to cardioversion was utilized, as deemed necessary by the clinician. TEE was performed according to standard guidelines. Subjects were followed for a primary efficacy composite outcome of stroke, transient ischemic attack, systemic embolism, myocardial infarction, or cardiovascular death. The primary safety outcome was major bleeding.1
There were only 10 total primary endpoints achieved in the overall treatment group, with 0.51% versus 1.02% event rates in the rivaroxaban and warfarin arms, respectively (relative risk [RR] 0.50; 95% confidence interval [CI] 0.15-1.73). There was no difference in treatment effect according to early versus delayed cardioversion. Regarding the primary safety outcome, major bleeding occurred in 0.6% and 0.8% in the rivaroxaban and warfarin arms, respectively (RR 0.76; 95% CI 0.21-2.67). In addition to appearing relatively safe and effective compared to warfarin, rivaroxaban was also associated with a shorter time to cardioversion compared with VKAs (P<0.001).1
A recent meta-analysis included 3,512 subjects with AF who underwent cardioversion treated with NOACs, which also included data from X-VeRT. There was no difference in primary endpoint of ischemic stroke or systemic embolism with NOACs compared to VKA (RR 0.60; 95% CI 0.2-1.8), or in major bleeding (RR 1.27; 95% CI 0.58-2.81).2 Limitations with the analysis of each study individually existed in that the trials were not adequately powered to assess outcomes specific to cardioversion. In addition, there was large heterogeneity with regards to use of TEE pre-cardioversion. The X-VeRT population had the highest number of pre-cardioversion TEEs, reflective of its study design. Regardless, the use of a NOAC as a safe and effective alternative to standard of care in cardioversion for the prevention of stroke or systemic embolism is currently supported by class I level evidence.3
In assessing the patient in question, the best answer is B. Heparin infusion can be discontinued, and rivaroxaban, which has a short onset of action and reaches maximum concentration in two to four hours, can be started immediately at a reduced dose (15 mg) when CrCl ≤ 50 mL/min. Cardioversion can be performed the same day, with continued anticoagulation for at least four weeks, or even indefinitely, given the likelihood of AF recurrence and high stroke risk.
Answer A is incorrect. Given the quick onset of action of rivaroxaban, no bridging therapy with heparin is required prior to cardioversion. The higher dose of rivaroxaban (20 mg) is not indicated in this patient with CKD, as it portends an increased risk of bleeding.
Answer C is incorrect. In addition to the incorrect rivaroxaban dose, the patient requires cardioversion during this hospitalization. It is, however, reasonable in patients with rate-controlled, asymptomatic AF to be cardioverted as an outpatient after three weeks of anticoagulation with rivaroxaban.
Answer D is incorrect. A heparin infusion bridging strategy with warfarin is an appropriate method of anticoagulation prior to cardioversion. However, the aPTT is low, and heparin would need to be increased. Warfarin will not reach a therapeutic INR for several days.
Answer E is incorrect. Cardioversion while aPTT is subtherapeutic may be safe given left atrial thrombus was excluded on TEE. However, full anticoagulation at time of cardioversion is optimal in this setting, and delaying the initiation of rivaroxaban until outpatient follow-up would be inappropriate, placing the patient at increased risk for stroke.
References
- Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonist for cardioversion in atrial fibrillation. Eur Heart J 2015;35:3346-55.
- Caldeira D, Costa J, Ferreira JJ, Lip GY, Pinto FJ. Non-vitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and meta-analysis. Clin Res Cardiol 2015;104:582-90.
- January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071-104.
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