Author + information
- Dipak Kotecha, MD, PhD∗ (, )@ICVS_UoB,
- Charles V. Pollack Jr., MA, MD,
- Raffaele De Caterina, MD, PhD,
- Giulia Renda, MD, PhD and
- Paulus Kirchhof, MD
- ↵∗University of Birmingham Institute of Cardiovascular Sciences, Medical School, Vincent Drive, Birmingham B15 2TT, United Kingdom
Cardioversion of symptomatic atrial fibrillation (AF) is commonly used to restore sinus rhythm, both acutely and as part of a long-term rhythm control strategy (1). This approach is associated with a risk of stroke; however, the efficacy of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) for the prevention of thromboembolism is unclear. We performed a meta-analysis of trials that have randomized patients with AF undergoing cardioversion to DOAC or VKA. An online search was performed of PubMed and the Cochrane library, in addition to manual screening. We used an intention-to-treat approach with a fixed effects model. Our aim was to provide clinicians with a clear understanding of which anticoagulation strategy provides the safest outcome for patients with AF undergoing cardioversion.
The search identified 124 studies, of which 3 prospective trials met inclusion criteria (2–4). In total, 5,203 patients were included in this analysis (2,850 randomized to receive DOACs and 2,353 randomized to receive VKAs). Their mean age was 65 ± 11 years; 32% were female; and the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category [female]) score was ≥2 in >70% of patients. All 3 trials required treatment with the allocated anticoagulant before cardioversion, and in VKA-treated patients, parenteral heparin was used to bridge warfarin therapy until an international normalized ratio ≥2.0 was achieved. Approximately one-half of patients had early cardioversion guided by imaging (mainly transesophageal echocardiography). Study treatment after cardioversion was continued for 28 to 42 days, with a 30-day safety follow-up. The risk of bias in these trials was low, apart from potential performance bias due to the open-label designs.
The primary outcome was the composite of stroke, systemic embolism, myocardial infarction, and cardiovascular death. This outcome occurred in 12 (0.42%) of 2,850 patients randomized to receive a DOAC versus 23 (0.98%) of 2,353 patients randomized to receive a VKA (Figure 1). DOAC therapy considerably reduced primary outcome events compared with VKA, with a pooled risk ratio of 0.42 (95% confidence interval [CI]: 0.21 to 0.86; p = 0.017) and no heterogeneity between trials (I2 = 0%; p = 0.84).
Secondary outcomes: 1) stroke and systemic embolism occurred in 5 (0.18%) of 2,850 DOAC-treated patients versus 13 (0.55%) of 2,353 VKA-treated patients. The pooled risk ratio was 0.33 (95% CI: 0.12 to 0.91; p = 0.032), and there was no heterogeneity between trials (I2 = 7.5%; p = 0.34). There were no significant differences between DOACs and VKAs in: 2) all-cause mortality (risk ratio: 0.58; 95% CI: 0.22 to 1.52; p = 0.27), or 3) major bleeding (risk ratio: 0.61; 95% CI: 0.28 to 1.34; p = 0.22); however, both point estimates were consistent with the benefit seen for other outcomes (Figure 1).
Our analysis suggests that DOAC therapy should be considered the default approach for cardioversion of AF, with one-half the rate of thromboembolic events compared with anticoagulation with warfarin. Warfarin and other VKAs should be restricted to those patients who are not eligible for DOAC therapy; for example, those with mechanical heart valves, moderate to severe mitral stenosis, or severe chronic kidney disease. We show the safety of DOAC therapy in patients with newly initiated oral anticoagulation, including those requiring rapid cardioversion with imaging guidance, and those undergoing cardioversion after 3 weeks of anticoagulation. Due to the short onset of action and the predictable dosing of DOACs, clinicians can commence a DOAC immediately without the need for parenteral heparin (1).
This meta-analysis is limited by the nature of the trials included, which only studied the short-term effects of anticoagulation. None of the trials were individually powered for clinical outcomes, although the power for our pooled analysis was >0.99 for the stroke-related composite outcomes. More than 90% of patients underwent electrical cardioversion, and although there is no a priori reason to suspect a difference with pharmacological cardioversion, data in this context are scarce. Further studies are needed to address the remaining gaps in evidence, including the identification of those at risk of adverse events despite oral anticoagulation, and the optimal timing of both anticoagulant agents and cardioversion to minimize stroke risk. In combination with integrated approaches to AF care and stratification of therapy (5), the routine use of DOACs for cardioversion can improve safety for patients undergoing cardioversion.
Please note: No specific funding was used. Dr. Kotecha is funded by a National Institute for Health Research Career Development Fellowship (CDF-2015-08-074). The opinions expressed are those of the authors and do not represent the National Institute for Health Research or the UK Department of Health. Dr. Pollack has received personal fees from Bristol-Myers Squibb/Pfizer has received grants and personal fees from Boehringer Ingelheim, Janssen Pharma, Portola; has received grants from Daiichi-Sankyo; has received grants from CSL Behring, during the conduct of the study; and has received grants and personal fees from AstraZeneca, outside the submitted work. Dr. De Caterina has received grants, personal fees, and nonfinancial support from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Merck, Novartis, and Roche; and personal fees from Lilly, during the conduct of the study. Dr. Renda has received personal fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo, outside the submitted work. Dr. Kirchhof has received research support from the European Union, the British Heart Foundation, the Leducq Foundation, the Medical Research Council (U.K.), the German Centre for Cardiovascular Research, 3M Medica, MEDA Pharma, AstraZeneca, Bayer HealthCare, Biosense Webster, Boehringer Ingelheim, Daiichi-Sankyo, German Cardiac Society, Medtronic, Merck Sharp & Dohme, Otsuka Pharma, Pfizer/Bristol-Myers Squibb, Sanofi, Servier, Siemens, and Takeda; has received honoraria from several such companies; and is listed as an inventor on 2 pending patents held by the University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783).
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