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Meta Analysis

Optimal Antithrombotic Therapy after Implantation of a Transcatheter Aortic Valve: Warfarin, Aspirin, or Non-Vitamin K Antagonist Oral Anticoagulants? A Systematic Review and Meta-Analysis

Yang, Wenjuan1; Fang, Xiaoyu2; Zhu, Yu1; Tang, Fuqin1; Jian, Zhao1,∗

Editor(s): Xu, Tianyu; Fu, Xiaoxia

Author Information
doi: 10.1097/CD9.0000000000000036
  • Open

Abstract

CLINICAL PERSPECTIVE

WHAT IS NEW?

  • Several commonly used antithrombotic regimens were compared concurrently in all-cause mortality, bleeding events, and embolism events through the meta-analysis.
  • A large study population was included: 738 in direct oral anticoagulants (DOACs) group, 5185 in aspirin group, 1990 in warfarin group, and 14,888 in the dual antiplatelet therapy (DAPT) group.
  • Cumulative evidence showed that aspirin had a favorable benefit-to-risk profile for patients after transcatheter aortic valve implantation/replacement (TAVI/TAVR) with lower rates of all-cause mortality and bleeding events, while DAPT with a higher incidence of bleeding and DOACs without undesirable effects.

WHAT ARE THE CLINICAL IMPLICATIONS?

  • This study had a guiding significance that aspirin monotherapy is superior to DAPT for antiplatelet decision-making for the management of patients after TAVI/TAVR.
  • DOACs had a comparable level of recommendation compared to warfarin when choosing oral anticoagulants, which as a result of no additional risk increase of major clinical outcomes but could greatly simplify post-operative anticoagulant management.

Introduction

Aortic valve disease, including aortic stenosis and aortic insufficiency, is one of the most common types of valvular heart disease; its prevalence is expected to double in the next 2 decades.[1,2] Aortic valve replacement (AVR) is the most common operation for patients with aortic valve disease, with more than 1 million operations performed annually worldwide. The indication for transcatheter aortic valve implantation/replacement (TAVI/TAVR) has rapidly expanded to include patients with severe aortic stenosis in all categories of surgical risk. This expansion was supported by randomized control trials showing superiority or non-inferiority of TAVI/TAVR compared with surgical AVR.[3–6] With the advent of the TAVI/TAVR era, more patients can achieve bioprosthetic valve replacement through this minimally invasive procedure.[7,8]

Long-term oral anticoagulant (OAC) therapy after AVR, which could reduce the incidence of thrombosis associated with mechanical valve replacement, was considered non-essential. However, cases of sub-clinical leaflet thrombosis in the bioprosthetic valve have been frequently reported in recent years.[9–11] As demonstrated by cardiac function determination and imaging evidence, sub-clinical leaflet thrombosis exacerbates valve degeneration and causes irreversible damage, though these effects subside after treatment.[12] This finding suggests that management with antithrombotic therapy after TAVI/TAVR is essential.

Currently, the optimal antithrombotic strategy for patients undergoing TAVI/TAVR remains under debate. The European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines for the Management of Valvular Heart Disease recommends life-long oral anticoagulation therapy for patients with surgically or transcatheterally implanted bio-prostheses who have other indications for anticoagulation (Class I). Dual antiplatelet therapy (DAPT) is considered for the first 3 to 6 months after TAVI/TAVR, followed by life-long single antiplatelet therapy in patients who do not need oral anticoagulation for other reasons (Class IIa).[13] However, all these recommendations are based on empirical evidence; at present, there is a lack of robust clinical evidence.

Based on the current controversial state of therapeutic regimens in this setting, we collected recent original research on antithrombotic strategies in patients after TAVI/TAVR. Subsequently, we compared the safety and efficacy of anticoagulation therapy with warfarin or direct oral anticoagulants (DOACs), antiplatelet with aspirin alone, or aspirin plus clopidogrel. Through this meta-analysis, we sought to assist healthcare professionals in the selection of the most appropriate clinical therapeutic regimen.

Materials and methods

Search strategy and selection criteria

Data were retrieved until September 2020. Research literature published in English was identified through several online databases, namely PubMed, EMBASE, and the Cochrane Library. Search terms included anticoagulation or anticoagulant therapy or antiplatelet therapy or antithrombosis; and biological valve, bioprosthetic valve, transcatheter aortic valve replacement, transcatheter aortic valve implantation, TAVI, and TAVR. The inclusion criteria were as follows: (1) all study patients underwent TAVI/TAVR and received antithrombotic therapy, such as OAC, DOAC, single antiplatelet therapy, DAPT, etc; (2) the interventions compared in this study were antithrombotic strategies to prevent the occurrence of thrombotic events in patients; (3) randomized controlled trials or prospective observational studies; (4) investigation of at least 1 outcome, such as all-cause mortality, clinical adverse events (eg, stroke, systemic thrombosis, and myocardial infarction), and bleeding events (eg, life-threatening, disabling, or major bleeding defined by Valve Academic Research Consortium-2[14] or Bleeding Academic Research Consortium Definition for Bleeding[15]), with a follow-up period of ≥3 months.

The exclusion criteria were (1) research content was identical or irrelevant to the purpose of the present study; (2) lack of the required outcome index or availability of fragmentary original information; and (3) the full text is not available.

Two researchers independently searched the databases, selected the relevant literature according to the requirements, and extracted data from the articles. All screening steps were based on the inclusion and exclusion criteria. In case of divergence between the views of the 2 initial researchers, a third researcher was consulted and a consensus was reached through discussion.

Study outcomes

The primary outcomes were all-cause mortality, serious adverse events, and bleeding, which occurred >30 days after TAVI/TAVR. Serious adverse events included stroke, systemic thrombosis, and myocardial infarction. In particular, ischemic stroke was defined as a focal neurologic deficit lasting for ≥24 hours with no sign of hemorrhage on cerebral imaging, which was verified radiologically through cerebral computed tomography at the onset of symptoms and after 48 hours. Systemic embolism was defined as an acute vascular insufficiency associated with clinical or radiographic evidence of arterial occlusion and not associated with another likely cause. Bleeding was defined according to the statements of the Valve Academic Research Consortium-2 and the Bleeding Academic Research Consortium.

Data synthesis and analysis

The included studies were evaluated using the Cochrane Collaboration's tool for assessing the risk of bias in randomized controlled trials, which has 3 levels: A (low bias), B (moderate bias), and C (high bias); the Newcastle-Ottawa Scale was used for observational studies. A Newcastle-Ottawa Scale score ≥5 indicated that the quality of the study was sufficient for inclusion in the statistical analysis.

Meta-analysis was performed using STATA 15.0. Higgins I2 was used to evaluate statistical heterogeneity, which represents the percentage of variation between the sample estimates caused by heterogeneity. The Higgins I2 can take values ranging from 0% to 100%, with 100% denoting the maximum level of heterogeneity. Typically, I2 values <25%, 25% to 50%, >50% to 75%, and >75% denote low, moderate, moderate-high, and high heterogeneity, respectively.[16] For I2 ≤ 50%, the fixed-effects model was selected to perform the analysis. Otherwise, the random-effects model was chosen, with pertinent 95% confidence interval (CI) and z scores for two-tailed hypothesis testing. The P values <0.05 denoted statistically significant differences.

Results

Eligible studies

A total of 13 studies were finally included,[17–29] 4 compared DOAC with warfarin,[17–20] 1 compared aspirin with warfarin,[21] 6 compared aspirin plus clopidogrel (DAPT) with aspirin monotherapy,[22–27] and 2 compared DAPT and aspirin monotherapy with warfarin concurrently.[28,29] The flowchart for the process of study selection is displayed in Figure 1.

F1
Figure 1:
Flow chart of the literature search process.

Of the 23,497 patients included in this analysis, 738 (3.1%), 1990 (8.5%), 14,888 (63.4%), and 5881 (25.0%) received DOAC, warfarin, DAPT, and aspirin monotherapy, respectively. The majority of patients in the DOAC versus warfarin study had indications for OAC, which was different from the other groups (aspirin vs. warfarin and DAPT vs. aspirin). The characteristics of included studies are listed in Table 1,[17–29] while Table 2 displays the main clinical features of the study populations.

Table 1 - Characteristics of included studies
Author Year Type Experimental group Control group Follow-up period Inclusion Exclusion Quality score
Kalogeras et al[17] 2020 Multicenter, retrospective DOAC Warfarin 2 years Consecutive patients who underwent TAVI in 4 centers Patients with a prosthetic metallic valve 9
Jochheim et al[19] 2019 Multicenter, retrospective DOAC VKAs 1 years Patients requiring OAC who underwent TAVR procedure and survived during hospital stay 9
Butt et al[20] 2019 Multicenter, retrospective DOAC VKAs 3 years Patients who underwent first-time TAVI and were alive at the time of discharge 1. Expired during admission2. No history of atrial fibrillation3. Not receiving treatment with OAC4. Had an outcome in the blanking period 9
Geis et al[18] 2018 Single-center, retrospective DOAC VKAs 1 years Patients with concomitant indications for OAC treatment after TAVI 1. Transapical aortic valve implantation2. Mechanical heart valve prosthesis 8
Colli et al[21] 2013 Multicenter, prospective Aspirin Warfarin 6 months Patients who were in sinus rhythm prior to undergoing bioprosthetic isolated AVR or concomitant AVR and CABG 1. Recipients of coronary stents2. Underwent emergency operation3. History of chronic anticoagulation4. History of cerebral ischemia5. Double valve implantation and recipient of coronary stent6. Not in sinus rhythm before AVR7. History of coagulopathy and bleeding disorder 8
D’Ascenzo et al[29] 2017 Multicenter, retrospective AspirinDAPT Warfarin 1 years Patients who underwent balloon-expandable TAVI 8
Poliacikova et al[28] 2013 Single-center, retrospective AspirinDAPT Warfarin 6 months Patients with symptomatic severe aortic stenosis who underwent TAVR 5
Sherwood et al[27] 2018 Multicenter, retrospective DAPT Aspirin 1 years Patients who underwent TAVR 1. No indication for antiplatelet or anticoagulant therapy2. Developed atrial fibrillation/flutter3. Missing data 8
Rodés-Cabau et al[22] 2017 Multicenter, RCT DAPT Aspirin 1 years Patients who underwent TAVR 1. Chronic anticoagulant treatment2. Major bleeding within 3 months before the TAVR procedure3. Prior intracranial bleeding4. Implantation of drug-eluting stent within 1 year prior to TAVR procedure5. Allergy to clopidogrel and/or aspirin A
Ichibori et al[24] 2017 Single-center, retrospective DAPT Aspirin 1 years Consecutive patients who underwent TAVI using balloon-expandable aortic valves Patients with indications for OAC therapy prior to TAVI 8
Durand et al[25] 2014 Multicenter, prospective DAPT Aspirin >30 days Consecutive patients with serve aortic stenosis for TAVR 5
Ussia et al[26] 2011 Single-center, RCT DAPT Aspirin 6 months Patients who underwent TAVR A
Brouwer et al[23] 2020 Multicenter, RCT DAPT Aspirin 1 years Patients who were scheduled to undergo TAVI and did not have an indication for long-term oral anticoagulation therapy 1. Implantation of a drug-eluting coronary artery stent within 3 months2. Implantation of a bare-metal stent within 1 month prior to TAVI A
“—“ Data is not available from the original text.
Score was calculated by Newcastle-Ottawa Scale.
Score was calculated by Cochrane Newcastle-Ottawa Scale.AVR: Aortic valve replacement; CABG: Coronary artery bypass grafting; DAPT: Dual antiplatelet therapy; DOAC: Direct oral anticoagulants; OAC: Oral anticoagulant; RCT: Randomized controlled trial; TAVI: Transcatheter aortic valve implantation; TAVR: Transcatheter aortic valve replacement; VKA: Vitamin K antagonist.

Table 2 - Baseline characteristics of the study populations.
Study characteristics Experimental group Control group



Author Primary endpoint Bleeding definition Patient number Age (years) Female, % Hypertension, % Pre-TAVI AF, % Patient number Age (years) Female, % Hypertension, % Pre-TAVI AF, %
Kalogeras et al[17] Major bleeding, minor bleeding BARC 39 83.5 ± 5.8 41 71.8 39 83.0 ± 4.7 43.6 51.3
Jochheiml et a[19] All-cause mortality, stroke, myocardial infarction, life-threatening/disabling bleeding, minor bleeding BARC 326 81.6 ± 6.7 52.1 89.9 99.9 636 81.1 ± 6.1 52.7 89.5 99.9
Butt et al[20] All-cause mortality, systemic embolism, major bleeding, life-threatening/disabling bleeding 219 83 (78–85) 46.1 87.2 516 82 (77–85) 46.3 88.6
Geis et al[18] All-cause mortality, stroke, systemic embolism, major bleeding, life-threatening/disabling bleeding, minor bleeding VARC 154 83.1 ± 5.3 51 95 94 172 83.0 ± 4.9 55 92 94
Colli et al[21] All-cause mortality, systemic embolism, myocardial infarction, major bleeding 618 74.8 ± 7.0 43 62.9 500 74.6 ± 7.0 43 66
D’Ascenzo et al[29] All-cause mortality, stroke, major bleeding VARC 605 81 ± 4 63 82 10 105 81 ± 5 58 82 60
605 81 ± 5 62 77 12
Poliacikova et al[28] All-cause mortality, stroke, major bleeding, life-threatening/disabling bleeding, minor bleeding VARC 91 82.0 ± 6.9 53.8 11 22 80.3 ± 4.5 45.5 9.09
58 81.6 ± 6.3 55.2 27.6
Sherwood et al[27] All-cause mortality, stroke, myocardial infarction, major bleeding 13,546 84 (78–88) 48.2 3148 84 (78–88) 49.6
Rodés-Cabau et al[22] All-cause mortality, stroke, myocardial infarction, major bleeding, life-threatening/disabling bleeding VARC 111 79 ± 9 36.9 77.5 111 79 ± 9 46.8 79.8
Ichibori et al[24] All-cause mortality, stroke, myocardial infarction, life-threatening/disabling bleeding VARC 66 83 ± 6 63.6 78 84 ± 6 64.1
Durand et al[25] All-cause mortality, stroke, myocardial infarction, vascular complications, major bleeding, life-threatening/disabling bleeding, minor bleeding VARC 128 84.6 ± 5.8 60.9 70.3 35.2 164 82.7 ± 6.3 45.1 70.7 23
Ussia et al[26] All-cause mortality, stroke, myocardial infarction, major bleeding, life-threatening/disabling bleeding, minor bleeding VARC 40 80 ± 6 50 88 10 39 81 ± 4 59 80 15
Brouwer et al[23] All-cause mortality, stroke, myocardial infarction, major bleeding, life-threatening/disabling bleeding, minor bleeding VARC, BARC 334 79.5 ± 6.4 47.9 76.3 331 80.4 ± 6.2 49.5 73.4
“—“ Data is not available from the original text.
Three antithrombotic strategies were compared concurrently, that experimental group included aspirin monotherapy and DAPT, and the control group was warfarin.
According to the original study, there are 2 forms of age: mean ± SD and median (Q1–Q3).AF: Atrial fibrillation; BARC: Bleeding Academic Research Consortium; TAVI: Transcatheter aortic valve implantation; VARC: Valve Academic Research Consortium.

The bioprosthetic aortic valve implantation was performed through TAVR. The follow-up period ranged from 3 months to 3 years (3 and 9 studies recorded data at 3–6 months and ≥1 year, respectively), except in 1 study (30-day data were collected).

Clinical outcome

DOAC versus warfarin groups

Four studies were included in this group, involving a total of 2101 patients. Three studies had available data on all-cause mortality. The death occurred in 209 patients (9.9%). All-cause mortality was not significantly different between the DOAC and warfarin groups (risk ratio (RR): 1.03; 95% CI: 0.65–1.64; P = 0.909; Phet = 0.105) [Figure 2A]. Clinical adverse events and bleeding were recorded in all 4 studies, occurring in 67 (3.2%) and 390 (18.6%) patients, separately. There was no statistically significant difference in the rate of clinical adverse events between the DOAC and warfarin groups (RR: 1.59; 95% CI: 0.99–2.58; P = 0.057; Phet = 0.738) [Figure 2B]; of note, the analysis system excluded 1 study volitionally. Similarly, there was no statistically significant difference in the rate of bleeding events (RR: 0.93; 95% CI: 0.78–1.11; P = 0.437; Phet = 0.338) [Figure 2C]. The all-cause mortality analysis demonstrated an I2 > 50%; hence, the random-effects model was used for analysis, and subgroup analysis was performed to investigate the source of heterogeneity. The results of the subgroup analysis showed that the sample size and percentage of patients with diabetes or chronic kidney disease had medium to high intra-group heterogeneity, which might be the cause of death-outcomes heterogeneity. Publication bias was also tested using Egger plot and the P > 0.05 suggested the absence of publication bias [Figure 2D and 2E].

F2
Figure 2:
Statistical analysis results of the DOAC versus warfarin groups. (A) Forest plot of all-cause mortality; (B) Forest plot of clinical adverse events; (C) Forest plot of bleeding events; (D) Egger publication bias plot; (E) Subgroup analysis results. CI: Confidence interval; CKD: Chronic kidney disease; Coef: Coefficient; d.f.: Degree of freedom; DOAC: Direct oral anticoagulant; MSE: Mean-square error; M-H: Mantel-Haenszel test; No.: Number; RR: Risk ratio; SND: Standard normal deviate; Std_Eff: Standard efficiency; Std. Err.: Standard error.

Aspirin versus warfarin groups

Three studies were included in this analysis, involving a total of 1941 patients. All-cause death occurred in 228 patients (11.7%). Aspirin was associated with a significantly lower rate of all-cause mortality compared with warfarin (RR: 0.71; 95% CI: 0.54–0.93; P = 0.012; Phet = 0.845) [Figure 3A]. Clinical adverse events occurred in 15 patients (0.8%); there was no significant difference observed between the 2 groups (RR: 0.38; 95% CI: 0.14–1.07; P = 0.068; Phet = 0.593) [Figure 3B]. Bleeding occurred in 43 patients (2.2%); the incidence of bleeding was lower in the aspirin group compared with the warfarin group (RR: 0.43; 95% CI: 0.22–0.83; P = 0.012; Phet = 0.569) [Figure 3C]. There was no significant heterogeneity among the studies. Egger publication bias plot suggested the absence of reporting bias [Figure 3D].

F3
Figure 3:
Statistical analysis results of the aspirin versus warfarin groups. (A) Forest plot of all-cause mortality; (B) Forest plot of clinical adverse events; (C) Forest plot of bleeding events; (D) Egger publication bias plot. CI: Confidence interval; Coef: Coefficient; d.f.: Degree of freedom; MSE: Mean-square error; M-H: Mantel-Haenszel test; No.: Number; RR: Risk ratio; SND: Standard normal deviate; Std_Eff: Standard efficiency; Std. Err.: Standard error.

Aspirin plus clopidogrel versus aspirin groups

Eight studies were included in this analysis, involving a total of 19,455 patients. All-cause mortality occurred in 2258 patients (11.6%), with a significantly lower rate observed in patients receiving DAPT (RR: 0.89; 95% CI: 0.82–0.98; P = 0.013; Phet = 0.299). Clinical adverse events occurred in 1012 patients (5.2%); there was no significant difference in the incidence of clinical adverse events between the DAPT and warfarin groups (RR: 1.09; 95% CI: 0.94–1.26; P = 0.268; Phet = 0.554). Bleeding occurred in 701 patients (3.6%) in 8 studies, with a significantly higher rate observed in the DAPT group compared with the aspirin monotherapy group (RR: 2.06; 95% CI: 1.39–3.07; P < 0.001; Phet = 0.001) [Figure 4]. Egger publication bias test did not show significant publication bias. Nevertheless, Higgins I2 test revealed obvious heterogeneity in the analysis of bleeding events. For this reason, subgroup analysis was performed to determine the origin of this heterogeneity. Figure 4E illustrates that study type, follow-up time, and sample size exhibited moderate heterogeneity, which may induce heterogeneity to the whole analysis.

F4
Figure 4:
Statistical analysis results of the DOAC versus warfarin groups. (A) Forest plot of all-cause mortality; (B) Forest plot of clinical adverse events; (C) Forest plot of bleeding events; (D) Egger publication bias plot; (E) Subgroup analysis results. CI: Confidence interval; DAPT: Dual antiplatelet therapy; Coef: Coefficient; d.f.: Degree of freedom; MSE: Mean-square error; M-H: Mantel-Haenszel test; No.: Number; RR: Risk ratio; SND: Standard normal deviate; Std_Eff: Standard efficiency; Std. Err.: Standard error.

Discussion

The present meta-analysis compared the effects of 4 antithrombotic strategies (3 most frequently used and 1 novel) in patients after TAVI/TAVR. The major finding was that aspirin showed a favorable risk-benefit profile compared with warfarin, with lower rates of all-cause mortality and bleeding. DAPT was linked to a low risk of all-cause mortality and a higher incidence of bleeding events compared with aspirin monotherapy. The advantages of DOAC in non-valvular atrial fibrillation were not observed in TAVI/TAVR.

AVR is widely performed in China. According to the White Book of Chinese Cardiovascular Surgery and Extracorporeal Circulation published in 2019, valvular heart disease accounted for 29% of cases of cardiovascular diseases. In addition, the number of heart valve operations performed in 2019 was 73,561, increased by 6.79% compared with 2018.[30] There are approximately 130,617 valve replacement cases reported in 2019 in the United States and the TAVR volume (72,991) exceeded all forms of SAVR (57,626).[31] Notably, the use of biologic valve prostheses for aortic valves in the United States was dramatically increased from 11.5% to 51.6%.[32] Similarly, the utilization rate of bioprosthetic valves in China has been increasing annually at a constant rate of 15% to 20% in the past 5 years.[33]

Nevertheless, both ischemic and hemorrhagic complications are still not irrelevant, particularly in frail patients and those with comorbidities, such as those undergoing TAVI/TAVR.[34] This evidence indicates the pivotal role of antithrombotic therapy in this setting. Recently, it was shown that early post-operative sub-clinical leaflet thrombosis may be related to the degradation of the bioprosthetic valve and eventually lead to adverse clinical outcomes.[12] However, at present, there is uncertainty regarding the most appropriate antithrombotic strategy after valve implantation. In the past, oral anticoagulation was considered non-essential after bioprosthetic valve replacement. DAPT has emerged as the preferred approach in accordance with the indications for surgical aortic valve replacement, mimicking the strategy applied to percutaneous coronary stent implantation without TAVI/TAVR.

The 2020 American Heart Association and American College of Cardiology Guidelines currently recommend antithrombosis with aspirin monotherapy for patients undergoing TAVI/TAVR in whom anticoagulation is not indicated (Class IIa). DAPT consisting of clopidogrel and aspirin for 6 months or a vitamin K antagonist is recommended to achieve an international normalized ratio of 2.5 for ≥3 months after TAVI/TAVR in low bleeding risk patients (Class IIb). Of note, low-dose rivaroxaban plus aspirin is contraindicated for patients in whom anticoagulation is not indicated (Class III: Harm).[35] The 2017 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines for the Management of Valvular Heart Disease provided similar recommendations. Only 1 randomized trial comparing DOAC with warfarin has been conducted thus far. The results did not show a difference in clinical outcomes between the 2 strategies.[36] A retrospective study found that the 30-day all-mortality in the DOAC and warfarin groups after matching was comparable. Furthermore, the rates of major and life-threatening bleeding defined by Bleeding Academic Research Consortium did not differ either.[25] Another study found a positive net clinical benefit of DOAC over warfarin, which was primarily attributed to the lower rates of both major bleeding and thromboembolic events.

Warfarin is recognized as a standard anticoagulant agent for patients with mechanical valve replacement.[13] A study compared the effectiveness of warfarin and antiplatelet therapy following surgical AVR with a biological prosthesis. The results suggested that warfarin alone was associated with a higher incidence of major bleeding,[37] which was consistent with the outcome of this meta-analysis.

In this study, aspirin monotherapy was linked to a higher rate of all-cause mortality and a lower rate of bleeding events versus DAPT; however, there was no difference in the incidence of clinical adverse events between the 2 therapies. A network meta-analysis revealed that there was no significant difference in mortality between aspirin monotherapy and DAPT; however, the former therapy was associated with significantly lower rates of bleeding versus the latter strategy.[38] The randomized trial reported a similar lower hemorrhagic risk with these regimens.[26]

The reported incidence of stroke among patients with atrial fibrillation in the first year after TAVI/TAVR ranged 3% to 12%; approximately a quarter and half of those events occurred within the first 24 hours and 30 days after TAVI/TAVR, respectively.[29,39,40] Periprocedural stroke is caused by embolization of a calcified native valve or aortic tissue. Stroke at later stages is more often related to valve thrombosis (ie, native or prosthetic valve thrombosis or atherothrombotic disease); therefore, it is more amenable to antithrombotic therapy.[41]

At present, the optimal antithrombotic strategy for patients after bioprosthetic valve replacement, in whom anticoagulation therapy is not indicated, remains unclear. In addition to the 4 anticoagulant strategies examined in our analysis, the safety and effectiveness of other regimens for patients undergoing TAVI/TAVR (ie, warfarin plus aspirin,[42] warfarin plus clopidogrel,[43] aspirin plus apixaban,[44] warfarin plus DAPT,[37] etc) have also been compared. The anticoagulation regimen after bioprosthetic valve replacement should be individualized, and the duration of therapy also warrants further investigation.

More large-scale, randomized trials should be conducted to comprehensively compare various anticoagulation regimens and indications for the optimal duration of therapy. The objective of the Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement (ADAPT-TAVR) trial (NCT03284827) is to evaluate the curative effect of non-vitamin K antagonist oral anticoagulant (NOAC) and DAPT. The aim of the Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients with Atrial Fibrillation (ENVISAGE-TAVI AF) trial (NCT02943785) is to compare the anticoagulation effects of NOAC (edoxaban) and vitamin K antagonist after TAVI in patients with atrial fibrillation. The choice of antiplatelet or anticoagulant regimens remains a challenge. Thus, the Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions (1:1) (AVATAR) trial (NCT02735902) aims to investigate the effects of vitamin K antagonist and DOAC treatment with aspirin. The Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis (ATLANTIS) trial (NCT02664649) compared the difference between new OACs and standard of care, which included anticoagulant and antithrombotic regimens. These ongoing, multicenter, randomized clinical trials may assist us in resolving more doubts about the best antithrombotic strategy after TAVI/TAVR.

Certain limitations of the present study should be acknowledged. The combination of data from different trials (ie, randomized trials and non-randomized studies) produced heterogeneity. Nevertheless, the inclusion of multiple studies design may significantly improve the quality of the systematic review and contribute to better understanding, easier interpretation of findings, and clarification of contradictory results.[16]

In addition, the analysis included only patients undergoing TAVR to yield more targeted results. However, this reduced the number of studies included in this analysis, potentially leading to selection bias.

The duration of DAPT or the follow-up period also differed between studies. There are few reported studies with short-term follow-up periods. In this analysis, studies with long-term survival data were prioritized for inclusion, since these may better reflect the effects of drug treatment.

Conclusion

The current meta-analysis integrated the latest data on antithrombotic strategies in patients after TAVI/TAVR. Aspirin exhibited a favorable risk-benefit profile, with a lower incidence of all-cause mortality and bleeding versus warfarin. Although DAPT was also associated with a significantly lower rate of all-cause mortality, it was linked to a higher incidence of bleeding events. DOACs did not provide significant benefits compared with warfarin.

Acknowledgments

We thank Prof. Xiangyu Ma from the Department of Epidemiology, College of Preventive Medicine, Army Medical University for his assistance in data analysis.

Funding

This study was supported by the Foundation for Talent in Clinical Research of The Army Medical University (No. 2018XLC3021).

Author contributions

Participated in research design: Zhao Jian.

Participated in the writing of the paper: Wenjuan Yang, Yu Zhu, Zhao Jian.

Participated in the performance of the research: Wenjuan Yang, Yu Zhu.

Participated in data acquisition: Fuqin Tang.

Participated in data analysis: Wenjuan Yang, Xiaoyu Fang.

Conflicts of interests

None.

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Keywords:

Antithrombotic therapy; Transcatheter aortic valve implantation; Transcatheter aortic valve replacement; Meta-analysis

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