BARCELONA, Spain — Uninterrupted apixaban appears to be as safe as warfarin and other vitamin K antagonists (VKAs) in patients at risk for stroke undergoing atrial fibrillation (AF) ablation, results of the AXAFA-AFNET 5 trial suggest.
The primary composite endpoint of all-cause death, stroke, or major bleeding (Bleeding Academic Research Consortium score of 2 to 5) occurred in 6.9% of patients randomly assigned to apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and 7.3% to VKAs (P =.0002 for noninferiority; 90% CI, –4.0% to 3.3%).
There were one death in each group; 2 strokes, both in the apixaban group; 4 TIMI major bleeding events (one in a patient receiving apixaban); and 24 major bleeds according to the International Society on Thrombosis and Haemostasis criteria (10 in the apixaban group), Professor Paulus Kirchhof, from the University of Birmingham, United Kingdom, reported at the European Heart Rhythm Association (EHRA) 2018 congress. The findings were simultaneously published online in the European Heart Journal.
He noted that the trial was powered only for a wide noninferiority margin of the primary outcome but that it is the first controlled AF ablation trial of novel oral anticoagulants (NOACs) done exclusively in patients at high stroke risk.
Other recent AF trials to show similar safety with uninterrupted anticoagulation with a NOAC vs warfarin include the smaller AEIOU trial with apixaban, VENTURE-AF with rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals), and RE-CIRCUIT with dabigatran (Praxada, Boehringer Ingelheim).
The 633 patients who received treatment in AXAFA-AFNET 5 were 4 years older than in most prior trials; 30% had mild cognitive impairment at baseline, and their mean CHA2DS2-VASc score was 2.4, Kirchhof observed.
Procedural details were also close to clinical practice, with no limitations on use of radiofrequency ablation or cryoablation with or without transesophageal or intracardiac echocardiography.
The quality of anticoagulation was “amazing,” he said, with a median VKA time in target therapeutic range of 84% and 307 of 318 patients taking all apixaban doses or all but one apixaban dose per week.
Results of an MRI substudy in 323 patients with analyzable scans showed no significant differences in the percentage of patients receiving apixaban or VKAs who had one brain lesion (16.7% vs 11.8%; P = .211), two lesions (4.3% vs 8.7%; P = .111), or more than two lesions (6.2% vs 4.3%; P = .463).
“We do not have any adequately powered trial to look at small differences in overt stroke,” but “our brain MRI study is the first to demonstrate that if you count all these small silent brain lesions you don’t see a difference in apixaban and vitamin K antagonists, again underpinning the safety of apixaban or vitamin K antagonists on continuation anticoagulation in patients undergoing atrial fibrillation ablation,” Kirchhof told theheart.org | Medscape Cardiology.
About 25% of patients undergoing AF ablation have small acute brain lesions on MRI imaging, and cognitive decline has been reported 90 days after AF ablation but not after other ablation procedures or in patients with AF without ablation, he told attendees. “So that is a worry when you talk about quality of life.”
Quality of life improved equally in both groups, and for the first time, cognitive function also improved, albeit as assessed on a single test without differentiating of functional domains, Kirchhof said. At the end of the study, 7.2% fewer patients than at baseline had mild cognitive impairment on the Montreal Cognitive Assessment (P = .005).
“The take-home message in this trial is that continuous apixaban seems to be as safe as warfarin for AF ablation procedures, even with a morning dose,” discussant Carina Blomström-Lundqvist, MD, PhD, from Uppsala University, Sweden, said.
She joined Kirchhof in calling for more research into the high rate of brain lesions by MRI but expressed surprise at the lack of a significant reduction in major bleeding with apixaban, as shown in a recent updated meta-analysis of uninterrupted NOACs vs VKAs.
Nonetheless, event rates were low in all four recent NOAC trials, and “Differences in populations and procedures may well explain the different outcomes in bleeding rates and silent strokes with novel oral anticoagulants and vitamin K antagonists,” Blomström-Lundqvist said.
Commenting for theheart.org | Medscape Cardiology, RE-CIRCUIT study chair Hugh Calkins, MD, from Johns Hopkins Hospital, Baltimore, Maryland, said the results of the two trials are quite different, noting that uninterrupted dabigatran reduced the relative risk for major bleeding by 77%.
“I found it disappointing that the Eliquis arm was not superior to the warfarin arm, which is what I would have expected based on the RE-CIRCUIT results, but maybe this means that all NOACs aren’t created equally and based on mechanism of actions, they have different effects,” he said.
Differences in patient populations and study design, such as use of a “subtherapeutic” international normalized ratio goal of 1.8 and not requiring transesophageal echocardiography in all patients, may also have played a role, he added.
During a discussion of the results, Calkins asked how bleeding events were handled and whether Kirchhof is nervous that updated guidelines for NOACs in AF, released at this meeting and recommending holding one dose before ablation, will result in a higher stroke risk than was seen in the trial.
“With RE-CIRCUIT and AXAFA, I am completely at ease to give patients a morning dose in their twice-daily treatment and to continue anticoagulation, as we do with vitamin K antagonists,” Kirchhof replied.
Tamponades were all managed with pericardiocentesis, no reversal agents were used, and anticoagulation was stopped in only two or three patients, he said.
Another audience member questioned heparin dosing in the trial, suggesting that patients taking NOACs receive far more heparin to achieve the same activated clotting time (ACT) and that this may explain why apixaban recipients were better off. Kirchhof replied that they will look into this but that the protocol stipulated an identical ACT.
“There are differences in the achieved ACT, and actually the variability in ACT was higher in the apixaban arm at first glance than in the vitamin K antagonist arm,” he said. “I suspect that a lot of the bleeding risk may actually be due to that variability, and it may well be that we can get NOAC therapy even better by adjusting our habits of giving heparin to NOACs.”
The study was sponsored by AFNET and partially funded by BMS/Pfizer, the German Centre for Cardiovascular Research, and the German Ministry of Education and Research. Kirchhoff reported relationships with the British Heart Foundation and European Union and being the inventor of two patents held by the University of Birmingham. Blomström-Lundqvist reported no relevant financial disclosures. Calkins reported receiving lecture fees/honoraria from Boehringer Ingelheim and Medtronic and consulting for Medtronic, Abbott Medical, and AtriCure.
European Heart Rhythm Association (EHRA) 2018. Presentation 951. Presented March 20, 2018.
Eur Heart J. Published online March 20, 2018. Full text
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