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Direct Oral Anticoagulants or Vitamin K Antagonists after TAVR: Insights from the ENVISAGE-TAVI AF and ATLANTIS TrialsFunding The present article received no external funding.
Patients undergoing transcatheter aortic valve replacement (TAVR) have a concomitant indication for oral anticoagulation (OAC) in about 20 to 50% of the cases, mostly atrial fibrillation (AF). However, it is still unclear whether direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) should be favored in this setting.
Therefore, we aimed to compare randomized controlled trials (RCTs) comparing DOACs or VKA strategies in patients who underwent TAVR requiring OAC. The ATLANTIS stratum 1 (apixaban or VKA) and the ENVISAGE-TAVI AF (edoxaban or VKA) trials were therefore included for qualitative and quantitative analyses. The Review Manager software (RevMan-5.4) was utilized for the meta-analysis. The hazard ratio (HR) or risk ratio (RR) and the 95% confidence intervals (CIs) for endpoints were pooled using a random-effects model. A two-sided p-value <0.05 was considered statistically significant. The Higgins I 2 was used to assess studies' heterogeneity results. We classified heterogeneity in mild (I 2 < 25%), moderate (25 ≤ I 2 < 50%), severe (50 ≤ I 2 < 75%), and very severe (I 2 ≥ 75%).
Altogether, the ENVISAGE-TAVI AF and ATLANTIS stratum 1 trials enrolled 1,877 patients requiring OAC (936 vs. 941 receiving DOACs or VKA, respectively) [Table 1]. The pooled estimate of the overall mortality ([Fig. 1A]) was similar between DOACs and VKA (HR: 0.89; 95% CI: 0.69–1.16, p-value = 0.39; I 2 = 0%). Moreover, there was no statistically significant difference in cardiovascular deaths ([Fig. 1B]) between the two treatment strategies (RR: 1.15; 95% CI: 0.83–1.61, p-value = 0.40; I 2 = 0%). On the other hand, major/life-threatening bleeding events ([Fig. 1C]) were also comparable (HR: 1.26; 95% CI: 0.74–2.13, p-value = 0.40; I 2 = 62%); however, heterogeneity resulted severe (I 2 = 62%).
Abbreviations: DOAC, direct oral anticoagulant; TAVR, transcatheter aortic valve replacement; VKA, vitamin K antagonist.
It is known that major late bleeding complications after TAVR are a strong independent long-term predictor of mortality in this population. Notably, although in the ENVISAGE-TAVI AF trial major bleeding events were higher in the edoxaban arm as compared to VKA (mainly driven by gastrointestinal [GI] events), intracranial, life-threatening, and fatal bleeding events were similar. Unfortunately, the ATLANTIS trial did not report specific major bleeding subtypes. Thus, a subgroup analysis in terms of GI bleedings could not be performed. Notably, absolute rates of major bleeding in VKA arms differ between the two studies (7.0 vs. 11.4% in the ENVISAGE and ATLANTIS, respectively). Indeed, possible subtherapeutic international normalized ratio or VKA overdose might also have influenced the different incidences observed in the studies and, consequently, heterogeneity of our results. Also, the larger sample size (and higher power) in ENVISAGE-TAVI AF may have disclosed increased bleeding for edoxaban. It should also be taken into consideration that discrepancies in concomitant antiplatelet therapy (APT) might additionally partially influence the observed heterogeneity. Furthermore, in the ATLANTIS trial a dose reduction strategy (i.e., apixaban 2.5 mg bid) was also recommended in patients with concomitant APT for acute coronary syndrome or recent coronary stenting. On the other hand, percutaneous coronary intervention within 7 days or STEMI (ST-elevation myocardial infarction) within 30 days from TAVR was excluded from the ENVISAGE-TAVI AF trial. Interestingly, among patients who also received APT in the latter study, major bleeding complications were higher in the edoxaban arm than in the VKA one, which might further explain the observed differences in major bleeding between the two studies.
Our study presents some limitations. A pooled stratification of our results by specific concomitant APT therapy could not be performed. Furthermore, the ENVISAGE-TAVI AF trial enrolled patients with AF, while the OAC stratum in the ATLANTIS trial was multiple (with AF as an indication for OAC in 86.1%). Again, different follow-ups might have affected our results.
In conclusion, the two pivotal available RCTs suggest that edoxaban or apixaban is a valuable alternative to VKA in terms of efficacy in patients who underwent TAVR with concomitant indication for OAC. However, further data are needed to better clarify their safety in major bleeding events, especially GI ones.
Received: 10 August 2022
Accepted: 27 October 2022
Article published online:
30 December 2022
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