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Non‐vitamin K oral anticoagulants versus vitamin K antagonists in post transcatheter aortic valve replacement patients with clinical indication for oral anticoagulation: A meta‐analysis

Abstract Background Current guidelines recommend oral anticoagulation (OAC) following transcatheter aortic valve replacement (TAVR) in patients with clinical indication, but the optimal antithrombotic regimen remains uncertain. We aimed to compare the efficacy and safety of non‐vitamin K oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in patients undergoing TAVR with concomitant indication of OAC. Hypothesis Comparing with VKAs therapy, NOACs are similar in reducing the all‐cause mortality and major bleeding in post‐TAVR patients requiring OAC medication. Methods We searched the databases of PubMed, Embase, and Cochrane library databases to identify studies that investigated NOACs versus VKAs after TAVR in patients with another indication of OAC, which were published before 28th September 28, 2021. The effectiveness of outcomes was all‐cause mortality and stroke or systemic embolism, while the main safety outcome was major and/or life‐threatening bleeding. The hazard ratio (HR) with 95% confidence interval (CI) was used as a measure of treatment effect. Results Our search identified eight studies. We included 4947 post‐TAVR patients with another indication of OAC allocated to the NOAC (n = 2146) or VKA groups (n = 2801). There were no significant differences in the all‐cause mortality (HR: 0.91, 95% CI: 0.77–1.08, p = .29, I 2 = 47%), stroke or systemic embolism (HR: 0.96, 95% CI: 0.68–1.37, p = .84, I 2 = 0%), and major and/or life‐threatening bleeding (HR: 1.09, 95% CI: 0.89–1.32, p = .40, I 2 = 30%) in both groups. Conclusion Among post‐TAVR patients who required OAC therapy, NOACs therapy compared to VKAs is similar in reducing the all‐cause mortality, stroke or systemic embolism, and major and/or life‐threatening bleeding events.


| INTRODUCTION
With recent improvements in technology, transcatheter aortic valve replacement/implantation (TAVR/TAVI) has developed into an available treatment for not only high surgical risk patients with severe symptomatic aortic stenosis (AS) but also intermediate and low surgical risk patients with AS. [1][2][3][4] During clinical practice, more than 30% of patients who underwent TAVR are needed to maintain long-term oral anticoagulation (OAC) treatment, mostly due to atrial fibrillation (AF), and around 9% of patients with early post-TAVR will develop an additional AF, which leads to the increasing number of patients after TAVR with OAC. [5][6][7] Many national society and expert groups recommend oral anticoagulants for patients post-TAVR with an indication for permanent OAC, [8][9][10][11]  The rates of life-threatening or major bleeding were comparable between the two groups. 12 However, a multicenter, open-label, randomized controlled trial (RCT) indicated that edoxaban in AF patients who underwent TAVR was noninferior to VKAs for a composite outcome of adverse clinical events (HR: 1.05, 95% CI: 0.85-1.31, p = .01 for noninferiority), and the incidence of major bleeding was higher with the edoxaban than with the VKAs (HR: 1.40, 95% CI: 1.03-1.91, p = .93 for noninferiority). 13

| Summary measures
The primary outcomes were all-cause mortality and stroke or systemic embolism. The safety of outcome was major and/or lifethreatening bleeding. Stroke or systemic embolism was defined as transient ischemic attack (TIA), ischemic stroke, systemic embolism, arterial thromboembolism, and cerebrovascular events. We accepted the definition of major and/or life-threatening bleeding from each study. The hazard ratios of each outcome were extracted for the meta-analysis.

| Statistical analysis
This meta-analysis reported effect sizes as pooled HR and 95% CI.
The I 2 statistic was used to analyze the heterogeneity. The fixedeffect model was used when the heterogeneity was low (I 2 ≤ 25%). Otherwise, the random-effect model was applied. 16 The Egger's linear regression test was employed to assess for the presence or absence of publication bias. 17 The RevMan software (version 5.4.5) and STATA version 12.0 were used for all the analysis.

| Study selection and study characteristics
A total of 542 articles were found, 270 articles were excluded after duplicates removed, 259 articles were excluded after reading the titles and abstracts, three articles [18][19][20] were excluded because the full texts were not published, and other two articles 21,22 were excluded because of the lack of HRs or short follow-up duration ( Figure 1). The two RCTs 13,23 and six observational studies 12,24-28 were initially included, and a total of 4947 patients were allocated to the NOAC (n = 2146) or VKA (n = 2801) groups.
Studies profiles and patient characteristics of eight studies were summarized in Table 1  Duration of follow-up ranged from 1 to 3 years.
Only one study 12 did not combine anticoagulants with antiplatelet drugs. The proportion of antiplatelet combination was not available in one study. 23 In six other studies, the situation of concomitant antiplatelet therapy was described. In the NOAC group, apixaban was used in seven studies 12,23-28 ; rivaroxaban and dabigatran were used in five studies 12,[24][25][26][27] ; and edoxaban was used in four studies. 12,13,26,27 The specific use of NOAC dose was found in the two RCTs 13,23 and one observational study, 28 Figure S1 and Table S2.   A majority of the population included in the study had AF as an indication of OAC therapy. It is well known that the AF increases the incidence of thrombosis, stroke, heart failure, and mortality, which could be reduced by appropriate antithrombotic therapy. The prevalence of pre-existing and new-onset AF in previous TAVR studies ranged from 15%-49% to 3%-23%, respectively. 30 Comparing patients with pre-existing AF and no AF, patients with new-onset AF were related to a significantly higher risk of bleeding, stroke, and admissions from heart failure. 31

CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.

DATA AVAILABILITY STATEMENT
All data, models, and code generated or used during the study appear in the submitted article.