Commentary - Cardioversion in the Modern Era

Educational Objectives

After completing the activity, the clinician will be better able to summarize the data evaluating the non-vitamin K oral antagonists in patients with atrial fibrillation scheduled for cardioversion.

Summary

Take-home Messages:

• Anticoagulation is routinely prescribed to patients with persistent atrial fibrillation (AF) before cardioversion to reduce the risk of thromboembolic events.
• In the last few years, accumulated data have suggested the safety of using non-vitamin K oral antagonists (NOACs) in this setting, whether for the guideline recommended 3 weeks (a delayed strategy) or an early strategy (within hours or a few days) before cardioversion.
• Guidelines now suggest this is a reasonable approach, and data from Europe show a significant shift away from the vitamin K antagonists (VKAs) and toward NOACs in the setting of cardioversion.

Cardioversion was first conceived and used in patients with atrial fibrillation in the late 1950s and early 1960s. The risk of thromboembolism is highest during the first week after cardioversion (5.6%) without adequate anticoagulation. Thus, anticoagulation is routinely prescribed to patients with persistent AF before cardioversion to reduce the risk of thromboembolic events.

Despite the availability of the non-vitamin K oral anticoagulants (NOACs), warfarin continued to be the choice for cardioversion, mostly because of a lack of data on the newer agents. That is not to say the use of warfarin in this setting has a lot of supportive data. The recommendation of therapeutic anticoagulation with warfarin for at least 3 weeks before and 4 weeks after cardioversion was based on small, nonrandomized observational and retrospective studies.

The pivotal RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial compared warfarin with dabigatran 110 mg twice daily (D110) and 150 mg twice daily (D150), and it included a planned post hoc analysis of electrical cardioversions.¹ A total of 1,983 cardioversions were performed in 1,270 patients, most of whom were treated with their assigned medication for at least 3 weeks before cardioversion.

The frequencies of stroke and major bleeding (both within 30 days of cardioversion) were low and comparable for all 3 groups, with or without transesophageal echocardiography guidance (which was encouraged, particularly in patients assigned to dabigatran). For stroke, the 30-day rate was 0.6% for warfarin, 0.3% for D150 mg, and 0.8% for D110 mg. Major bleeding was infrequent in all groups (1.7%, 0.6%, and 0.6% in D110, D150, and warfarin, respectively; D110 vs. warfarin, p = 0.06; D150 vs. warfarin, p = 0.99).

Secondary post hoc analyses of pivotal trials for apixaban and rivaroxaban have similarly shown that NOACs may be an alternative to heparin and warfarin for patients with nonvalvular AF undergoing cardioversion; certainly, event rates were very low. The major limitation of these post hoc analyses was the prolonged period of anticoagulation preceding the cardioversion.

Ezekowitz and colleagues have just reported the results of the EMANATE trial in patients with predominantly new-onset AF.² The primary objective was to compare apixaban to heparin/vitamin K antagonist (VKA) in patients with AF and ≤48 hours of anticoagulation prior to randomization before undergoing cardioversion. Short-duration apixaban was associated with low rates of stroke, systemic embolic events, death, and bleeding in both the apixaban-treated and heparin/VKA-treated patients. Notably, NOAC use did not obviate the need for transesophageal echocardiography (TEE), since imaging revealed approximately 7% of patients with thrombi, of which only one-half had resolved by 1 month.

In evaluating either an early (target period of 1 to 5 days after randomization) or delayed (3 to 8 weeks) cardioversion strategy, Dr. Ezekowitz and others showed in the X-VeRT trial that rivaroxaban appears to be an effective and safe alternative to VKAs, even with prompt cardioversion.³ Much the same was demonstrated in ENSURE-AF (Edoxaban vs. Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation) comparing edoxaban with enoxaparin-warfarin. Moreover, just-published data suggest that patient satisfaction and convenience is better with the NOAC (p < 0.001 for both compared with enoxaparin-warfarin).⁴ Edoxaban also was associated with fewer clinic visits (4.75 visits vs. 7.60 visits; p < 0.001) and fewer hospital days (3.43 days vs. 5.41 days; p < 0.05).

Evolution of Therapy

According to current AF guidelines, anticoagulation is still recommended with warfarin for at least 3 weeks before and 4 weeks after cardioversion.⁵ While not a Class I indication, American College of Cardiology/American Heart Association guidelines note that dabigatran, rivaroxaban, or apixaban is reasonable for the same period before and after cardioversion (Class IIa).

What about short-term anticoagulation just before cardioversion? The data suggest cardioversion might be utilized after 2 hours of an apixaban loading dose, after 6 hours following a loading dose of rivaroxaban, or acutely for patients with negative TEEs who are given edoxaban. The pharmacology of dabigatran suggests it might be appropriate for such acute use. However, while there are data supporting rivaroxaban, apixaban, and edoxaban in an early strategy of anticoagulation before cardioversion, this has not been prospectively tested with dabigatran.

NOAC use is increasing, and there has been a significant decrease in VKA use. Investigators analyzed a European database and found that 77% of the patients were given oral anticoagulants more than 3 weeks prior to the procedure, and 86% were given them more than 4 weeks after the procedure.⁶ NOACs were used in 31.5% of patients, compared to 68.5% who received VKA therapy. During the observation period (September 2014 to October 2015), there was an increase in the use of apixaban (p < 0.001), a slight increase in rivaroxaban (p = 0.028), and no change in dabigatran (p = 0.34) for elective cardioversion. There were differences in use between the countries: Spain used the most VKA (89%), while France used the least (39%, p < 0.001).

In the 2018 European Heart Rhythm Association practical guide to NOAC use in AF, the authors note that a strategy with at least a single NOAC dose ≥4 hours before cardioversion (≥2 hours after an apixaban loading dose) appears safe and effective in patients with AF of ≥48 hours duration, provided that a TEE is performed before cardioversion.⁷ (A similar strategy of starting the NOAC before cardioversion, with use of TEE dependent on institutional policy or elevation of a patient’s stroke risk, is applicable to those with AF of <48 hours duration.)

Readings

1. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011;123:131-6.
2. Ezekowitz MD, Pollack CV Jr, Halperin JL, et al. Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial. Eur Heart J 2018 Apr 6. doi: 10.1093/eurheartj/ehy148. [Epub ahead of print]
3. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014;35:3346-55.
4. Goette A, Kwong WJ, Ezekowitz MD, et al. Edoxaban therapy increases treatment satisfaction and reduces utilization of healthcare resources: an analysis from the EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of atrial fibrillation (ENSURE-AF) study. Europace 2018 Jun 27. doi: 10.1093/europace/euy141. [Epub ahead of print]
5. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014 Dec 2;64(21):e1-76. www.onlinejacc.org/content/64/21/e1
6. Papp J, Zima E, Bover R, et al. Changes in oral anticoagulation for elective cardioversion: results from a European cardioversion registry. Eur Heart J Cardiovasc Pharmacother 2017;3:147-50.
7. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330-1393.

Disclosures

Michael D. Ezekowitz, MB, ChB, FACC
Armetheon Inc (C); Merck & Co Inc (C); Bristol-Myers Squibb Co (C); Johnson and Johnson Services Inc (C); Pfizer (C); Boehringer Ingelheim GmbH (C); Janssen Global Services LLC (C); Bayer AG (C); DAIICHI SANKYO CO Ltd (C)

Acknowledgements

CME/CE INFO

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