Results from the X-VERT trial have shown that rivaroxaban is a safe and effective alternative to Vitamin K antagonist (VKA) therapy in patients with atrial fibrillation who are undergoing elective cardioversion. Riccardo Cappato, co-principal investigator of the study (University of Milan, Milan, Italy) presented the results at a Hot Line session of the European Society of Cardiology (ESC) congress (30 August – 3 September, Barcelona, Spain). The study was simultaneously published in the European Heart Journal.
Cappato told delegates: “Cardioversion is a common procedure used worldwide to restore normal sinus rhythm in patients with atrial fibrillation. Without adequate anticoagulation, the periprocedural risk of thromboembolic events with cardioversion is estimated to range between 5–7% and 1% for patients receiving a VKA. This is why despite the absence of comparative studies showing superiority of VKA vs novel oral anticoagulant therapy, VKA represents the standard of care before and after cardioversion.”
He continued, “Recent post-hoc analysis from large trials [ROCKET AF, ARISTOTLE and RE-LY] have suggested and supported the use of novel oral anticoagulants as a protective factor in patients undergoing cardioversion.”
The X-VERT (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) phase 3b exploratory trial, he commented, is the first prospective, randomised trial designed to explore the efficacy and safety of once-daily rivaroxaban for the prevention of cardiovascular events in patients with non-valvular atrial fibrillation scheduled for elective cardioversion compared with dose-adjusted VKAs.
Patients were enrolled in X-VERT if they were ≥18 years, had non-valvular atrial fibrillation lasting longer than 48 hours or of unknown duration and where scheduled for cardioversion.
The study included 1,504 patients from 141 centres and 16 countries, who were scheduled to undergo either electrical (97.6%) or pharmacological (2.4%) cardioversion.
Cappato explained that the sample size to establish a non-inferiority of rivaroxaban vs standard of care was calculated to be between 25,000 to 30,000 patients; however, he said, “a trial of this size was not feasible.” So, “It was considered to provide clinically meaningful information in the absence of any information in this field that a descriptive comparison of about 1,500 patients would be sufficient and therefore the study was designed and conducted in the interest of providing informative, relevant information in the context of clinical practice.”
Overall, 1,002 patients were randomised to oral rivaroxaban 20mg once daily and 502 patients to VKA (warfarin or another VKA at the investigator’s discretion, based on local standard of care).
Using established guidelines, patients were assigned to either early (58%) or delayed (42%) cardioversion. The target times between randomisation and cardioversion where between 1–5 days in the early group and between 21 and 56 days in the delayed group. Importantly, Cappato noted, “in patients assigned to rivaroxaban and undergoing early cardioversion a single dose of rivaroxaban could be administered up to four hours prior to cardioversion.” After cardioversion, patients were followed for 42 more days under the assigned drug treatment. After this time, end of study was declared and patients could be transitioned to different oral anticoagulation strategies according to the local standard of care including discontinuation when clinically indicated and were then followed for 30 days.
“The practical advantage of rivaroxaban was demonstrated by the short time to cardioversion compared to patients treated with VKAs,” said Cappato. However, since time to cardioversion was not a prespecificed outcome of the study, this finding should be interpreted with caution, he added.
The primary efficacy outcome was a composite of stroke and transient ischaemic attack, peripheral embolism, myocardial infarction and cardiovascular death. The primary safety outcome was major bleeding.
Cappato said that the study found that 0.51% of patients treated with rivaroxaban were observed to have a primary efficacy outcome of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction or cardiovascular death compared with 1.02% of patients treated with VKA. In addition, 0.61% of patients treated with rivaroxaban were also observed to have a major bleeding event compared with 0.81% for VKA. The differences in both the efficacy and safety primary endpoints were not statistically significant, as this trial was not designed to determine statistical significance.
No clinically important differences in the overall cumulative incidence of adverse events and serious adverse events by treatment assignment or by cardioversion strategy were observed.
In conclusion, Cappato said, “These data are preliminary; however, they offer the first evidence that oral rivaroxaban can be safely used as a possible alternative to VKA therapy for preventing thromboembolic events in patients undergoing elective cardioversion.”
Christoph Bode (University of Freiburg, Freiburg, Germany) discussant of the X-VERT trial at ESC said: “X-VERT is to be considered a landmark trial in the development of novel oral anticoagulants.”
He continued: “Even though 1,500 patients were randomised, the trial was still exploratory in nature because statistically significant results would have required a 25,000 trial. With this limitation, the clinically relevant and cautiously worded conclusion that oral rivaroxaban appears to be an effective and safe alternative to VKAs independent of early or late cardioversion strategy can be supported by my side and should find inclusion into the next guideline update.”
Bode also said that X-VERT raises questions that will trigger further research, including: “When did the endpoints occurred during the time of treatment? How do we deal with detected clots by TEE? The assignment of early vs late strategy was not randomised, the groups were unbalanced and early patients had more TEEs than late cardioversions (65% vs 10%). What about the added value of TEE in late cardioversions? Do the results remain robust for high-risk patients?”
He concluded, “Following X-VERT, our armamentarium for treating patients is richer, our knowledge about anticoagulation in atrial fibrillation is enlarged and we are inspired to further research.”