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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 23  |  Issue : 1  |  Page : 10-15  

Antithrombotic therapy after transcatheter aortic valve replacement


1 Department of Adult Cardiology, Heart Hospital, Hamad Medical Corporation, Doha, Qatar
2 Department of Pharmacy, Heart Hospital, Hamad Medical Corporation, Doha, Qatar

Date of Submission06-Mar-2022
Date of Acceptance06-Apr-2022
Date of Web Publication16-May-2022

Correspondence Address:
Dr. Nazar Mohammed
Department of Adult Cardiology, Heart Hospital, Hamad Medical Corporation, P. O. Box 3050, Doha
Qatar
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartviews.heartviews_36_22

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   Abstract 


Transcatheter aortic valve replacement (TAVR) is a treatment option for patients with asymptomatic severe aortic stenosis who are candidates for a bioprosthesis across the entire spectrum of risk. TAVR carries a risk for thrombotic and bleeding events, focusing on the importance of defining the optimal antithrombotic regimen. Patients undergoing TAVR are mostly elderly and have many comorbidities such as atrial fibrillation (AF) requiring oral anticoagulants (OACs) or coronary artery disease requiring antiplatelet agents. After TAVR among patients without baseline indications for OAC, recent data suggest dual-antiplatelet therapy is associated with an increased risk for bleeding events, particularly early postprocedure compared with single-antiplatelet therapy with aspirin. The risk of leaflet thrombosis in patients undergoing TAVR raised concern about the use of OAC in patients without an initial indication for anticoagulation therapy. Although it showed effectiveness in modulating thrombus formation at the valve level, the bleeding hazard has shown to be unacceptably high, and the net benefit of combining antiplatelet and OAC therapy is unproven. For patients with indications for the use of long-term OAC, such as those with AF, adding antiplatelet therapy increases bleeding events. A favorable effect of new OAC agents over Vitamin K antagonists is debatable. Overall, single-antiplatelet therapy and OAC appear to be reasonable strategies in patients without and with indications for concurrent anticoagulation, respectively. This article aims to review the available published studies and recommendations in the literature regarding the use of antithrombotic therapy post-TAVR.

Keywords: Antiplatelet, antithrombotic, dual-antiplatelet therapy, new oral anticoagulant, oral anticoagulants, transcatheter aortic valve replacement, Vitamin K antagonists


How to cite this article:
Mousa TA, Mahfouz A, Mohammed N. Antithrombotic therapy after transcatheter aortic valve replacement. Heart Views 2022;23:10-5

How to cite this URL:
Mousa TA, Mahfouz A, Mohammed N. Antithrombotic therapy after transcatheter aortic valve replacement. Heart Views [serial online] 2022 [cited 2022 Dec 4];23:10-5. Available from: https://www.heartviews.org/text.asp?2022/23/1/10/345323




   Introduction Top


Transcatheter aortic valve replacement (TAVR) is a treatment option for patients with asymptomatic severe aortic stenosis who are candidates for a bioprosthesis across the entire spectrum of risk.[1],[2] The high likelihood of thromboembolic and bleeding complications in patients undergoing TAVR has raised the importance of antithrombotic optimization peri- and post-TAVR.

The risk of thrombotic events in patients undergoing TAVR raised concern about the use of OAC in patients without an initial indication for anticoagulation therapy.

The 2017 European Society of Cardiology (ESC)/EACTS guidelines recommend either oral anticoagulants (OACs) for patients with other indications for OAC (Ia) or dual-antiplatelet therapy (DAPT, low-dose aspirin with clopidogrel) for 3–6 months post-TAVR, followed by lifelong single-antiplatelet therapy (IIa).[3]

Given recent trials that this review will shed light on, showing excess bleeding risk with the use of additional oral antithrombotic agents without a significant reduction in thrombotic events, ESC/EACTS guidelines were updated in 2021; low-dose aspirin is preferred in the absence of OAC indication. On the other hand, Vitamin K antagonists (VKAs) or new OAC (NOAC) alone is preferred when there is a coexisting indication for OAC.[1]


   Thromboembolic and Bleeding Risk After Transcatheter Aortic Valve Replacement Top


Stroke after TAVR is one of the most feared complications with a significant impact on morbidity and mortality.[4] In landmark trials of TAVR, the major or disabling stroke rate was 0%–5% at 30 days. The rates were generally higher in trials of patients at high surgical risk (e.g., 3.8%–5%) compared with trials of patients at low surgical risk (0%–1.4%).

Although embolic protection devices reduce peri-TAVR silent brain infarct, they have not improved clinical outcomes. Later-occurring stroke can also occur usually due to thromboembolic phenomena potentially originating from TAVR prosthesis or secondary to atrial fibrillation (AF). Moreover, the incidence of peri-TAVR myocardial infarction (MI) is very low (1%–3%) in patients with existing coronary artery disease.[5],[6],[7]

Major life-threatening and disabling bleeding frequently occurs in 3%–11% within the 1st year of the procedure.[5],[6],[7] Of these, 50% are procedure-related despite improvements in access-site assessment by computed tomography (CT), ultrasound-guided puncture, smaller-bore catheters, and low-profile suture-closure devices.[7] The older age of TAVR patients, their comorbidities, the frequent presence of acquired von Willebrand factor defect, and moderate thrombocytopenia post-TAVR, all increase bleeding risk and should be considered when choosing optimal antithrombotic therapy. Hence, bleeding risk assessment pre- and periodically post-TAVR is mandatory [Figure 1].[1]
Figure 1: Risk factors for bleeding and thrombotic/ischemic in patients undergoing TAVR for antithrombotic therapy. TAVR: Transcatheter aortic valve replacement

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   Antithrombotic Therapy Peri-Transcatheter Aortic Valve Replacement Top


Low-dose aspirin is the recommended treatment in TAVR patients without OAC indication. Aspirin usually is initiated before the TAVR procedure.

In contrast to the clinical benefits associated with the loading dose of clopidogrel and maintenance doses post-PCI, there was no reduction in thromboembolic events peri-TAVR associated with the loading dose of clopidogrel and maintenance doses.[8]

Although the thromboembolic effect on peri-TAVR is not known in patients receiving OAC, the use of VKA or NOAC during TAVR is considered safe. This is supported by an observational study where there was no increase in bleeding, transfusion, or vascular complications as compared with NOAC discontinuation.[9] When NOAC is continued during TAVR, periprocedural aspirin is usually not needed.

During TAVR, unfractionated heparin (UFH) is routinely used (reference activated clotting time: 250–300 seconds to reduce catheter thrombosis and thromboembolism). To prevent vascular access-site complications and bleedings, protamine sulfate may be used before closure to reverse the anticoagulation of UFH. Bivalirudin would be used alternatively in patients with contraindications to UFH.


   Antithrombotic Treatment Post Transcatheter Aortic Valve Replacement in Patients Without OAC Indication Top


In PCI, DAPT is the cornerstone of thrombotic and ischemic protection after stenting.[10] The same recommendation is extrapolated in TAVR despite the significant differences between PCI and TAVR. Recent observational studies and a small randomized controlled trial (RCT) reported no difference in thromboembolic events between aspirin with clopidogrel and aspirin alone, but DAPT increased major bleeding [Figure 2].[11]
Figure 2: Summary of clinical studies for the use of antithrombotic therapy in patients undergoing TAVR without OAC indication. TAVR: Transcatheter aortic valve replacement, OAC: Oral anticoagulant

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The aspirin versus aspirin clopidogrel following transcatheter aortic valve implantation (ARTE) (aspirin versus aspirin + clopidogrel following transcatheter aortic valve implantation) trial, in particular, was prematurely stopped after the inclusion of 74% of the planned study population (total of 222 patients), demonstrating that single-antiplatelet therapy with aspirin reduces the risk for major or life-threatening bleeding events while not being associated with an increased risk for MI or stroke.[9] Notably, in ARTE, the main divergence of the event curves occurred immediately after TAVR, and preprocedural loading with clopidogrel was common practice.

The POPULAR TAVI RCT (cohort A) showed aspirin alone decreased bleeding in comparison with aspirin with clopidogrel. Bleeding occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin with clopidogrel (risk ratio [RR]: 0.57; 95% confidence interval [CI]: 0.42–0.77; P = 0.001), while the composite of cardiovascular death, stroke, or MI for aspirin alone was noninferior to aspirin with clopidogrel (9.7% and 9.9%, P = 0.004 for noninferiority).[7]

Based on this RCT, low-dose aspirin is preferred over aspirin with clopidogrel post-TAVR in patients without OAC indication.

The recent GALILEO trial randomized patients without OAC indication to low-dose rivaroxaban (10 mg) plus low-dose aspirin for 3 months, followed by rivaroxaban alone versus low-dose aspirin with clopidogrel for 3 months than aspirin alone.

GALILEO trial was terminated due to the significant increase in all-cause mortality (hazard ratio [HR]: 1.69; 95% CI: 1.13–2.53), the increase in Valve Academic Research Consortium (VARC) major, VARC life-threatening or disabling bleeding (HR: 1.5; 95% CI: 0.95–2.37), and the increase in the composite of death and thromboembolic events (HR: 1.35; 95% CI: 1.01–1.81).[7] Therefore, the use of rivaroxaban plus aspirin is not recommended in patients without OAC indication after TAVR.

The ATLANTIS (Anti-Thrombotic Strategy after Trans-Aortic Valve Implantation for Aortic Stenosis) randomized trial (n = 1510) compared the superiority of an apixaban-based strategy with the standard of care strategy to reduce the risk of thromboembolic and bleeding complications for post-TAVR.[11]

The primary endpoint consisted of stroke, deep-vein thrombosis, pulmonary embolism, MI, systemic emboli, intracardiac or valve thrombosis, death, and major bleeding. There was no difference in the primary composite endpoint between the two groups (HR: 0.92; 95% CI: 0.73–1.16), considering two-third of the participants without a baseline OAC indication. In the analyses of secondary outcomes, apixaban was found to reduce the risk for bioprosthetic valve thrombosis (mostly subclinical; HR: 0.23; 95% CI: 0.11–0.50) and the risk for deep-vein thrombosis or pulmonary embolism. Among patients without indications for OAC, the HR for apixaban versus antiplatelet therapy (single or dual) was 0.88 (95% CI: 0.66–1.17).

In additional exploratory analyses, apixaban showed an increased risk for a composite of stroke, transient ischemic attack, systemic embolism, and death (a difference driven only by noncardiovascular death) and a lower risk for valve thrombosis (HR: 0.19; 95% CI: 0.08–0.47).

These strategies are applicable in TAVR patients if there is no relevant coronary artery disease with or without recent coronary stents.[1] If a patient undergoes TAVR in the context of a recent or concomitant PCI, a mandatory period of DAPT is required based on the clinical presentation 6 months post-elective PCI and 12 months post-PCI for the acute coronary syndrome (the duration will be reduced to half in case of high bleeding risk). A recent consensus document from the European Association of Percutaneous Cardiovascular Interventions advises that in TAVR patients with PCI within 3 months, DAPT should be as short as possible (i.e., 1–6 months) because of the high bleeding risk.[12]


   Antithrombotic Treatment Posttranscatheter Aortic Valve Replacement in Patients With OAC Indication Top


Almost all patients with AF undergoing TAVR (prevalence 40%) have an indication for OAC based on the CHA2DS2-Vasc score. NOACs are recommended over VKA in AF patients (Class Ia) according to the most updated AF guidelines.[13] In post-TAVR patients, the Danish registry found the same risk of thromboembolism, bleeding, or all-cause mortality among NOAC and VKA.[14]

A German registry demonstrated higher all-cause mortality, MI, and cerebrovascular events at 1 year with NOAC versus VKA.[15] In an observational study in AF patients, VKA alone reduced major or life-threatening bleeding in comparison to VKA and aspirin with comparable ischemic events.[16]

Current data showed the inconsistent outcome of the thromboembolic risk associated with NOAC. Therefore, supporting evidence is lacking for the favorable oral anticoagulation (i. e. NOAC over VKA) in AF patients post-TAVR.

The POPULAR TAVI (cohort B) randomized AF patients undergoing TAVR to NOAC alone or NOAC plus clopidogrel for 3 months. Bleeding was significantly lower with NOAC alone versus NOAC plus clopidogrel (21.7% versus 34.6%; RR 0.63, 95% CI 0.43–0.90, P = 0.01), while the composite of cardiovascular death, stroke, or MI was noninferior (13.4% and 17.3%, respectively; 95% CI for noninferiority, −11.9 to 4.0).[6]

In the ATLANTIS trial, patients on OAC were randomized to apixaban or VKA. In the stratum of patients with indications for OAC (n = 451), the HR for the primary outcome was 1.01 (95% CI: 0.68–1.51), and no differences between groups were noted in exploratory analyses of either ischemic or bleeding secondary endpoints [Figure 3].[11]
Figure 3: Summary of clinical studies for the use of antithrombotic therapy in patients undergoing TAVR with OAC indication. TAVR: Transcatheter aortic valve replacement, OAC: Oral anticoagulant

Click here to view


A dedicated randomized trial on the use of NOACs or VKA in patients with AF, ENVISAGE-TAVI AF (Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients with AF) was conducted to compare edoxaban versus VKA. The primary efficacy outcome, all-cause mortality, myocardial infarction, ischemic stroke, systemic thromboembolic event, valve thrombosis, or major bleeding, for edoxaban versus VKA, was 17.3/100 person-years (PY) versus 16.5/100 PY (HR: 1.05, 95% confidence interval [CI]: 0.85–1.31, P = 0.01 for noninferiority). The primary safety endpoint, major bleeding found to be 9.7/100 PY versus 7/100 PY (HR 1.40, 95% CI 1.03–1.91, P = 0.93 for noninferiority).

ENVISAGE-TAVI AF trial found noninferiority of edoxaban to VKA regarding efficacy in AF patients undergoing TAVR. Bleeding (mainly gastrointestinal bleeding) was higher in patients who received edoxaban compared to VKA.[17]


   Transcatheter Aortic Valve Replacement Valve Thrombosis Top


TAVR valve thrombosis rarely leads to heart failure due to increased transvalvular gradients (1%–3%).[5],[6] In recent studies, subclinical leaflet thrombosis was identified in up to a quarter of patients on antiplatelet therapy, and there is evidence that NOAC effectively prevents and reverses leaflet thrombosis.[5],[18] Nevertheless, spontaneous regression of subclinical leaflet thrombosis may occur without antithrombotic therapy modification.

Although a high rate of thromboembolic events is associated with subclinical leaflet thrombosis, this was not reported in other studies such as the GALILEO trial. The PARTNER-3-CT substudy only showed a slightly higher valvular gradient when subclinical leaflet thrombosis was present, at 1 and 12 months. These clinical trials are, however, too small to conclude a detrimental impact of leaflet thrombosis on valve function or clinical outcome, and there is no evidence to support routine CT for the detection of subclinical leaflet thrombosis post-TAVR.


   Conclusions Top


TAVR poses specific challenges for antithrombotic therapy, including a population of mostly elderly patients who are exposed to the risk for thrombotic, ischemic, and bleeding complications. TAVR poses specific challenges for antithrombotic therapy, including a population of mostly elderly patients who are exposed to the risk for thrombotic, ischemic, and bleeding complications. In the same time, those population have unknown pathophysiology and outcomes of platelet- or thrombin-mediated processes that sustain thrombus formation at the level of the leaflets or frame of the implanted bioprosthesis. The use of aspirin alone is well supported by the evidence in patients without OAC indication or recent PCI (stent deployment). The combination of aspirin and clopidogrel does not improve the thrombotic outcome but increases the risk of major bleeding, mainly periprocedural. Aspirin's preprocedural loading does not show any added benefit, although this is a common practice in many trial designs and is currently endorsed in a European consensus document.

Using OAC to reduce the risk for leaflet thrombosis is fraught with challenges, as the clinical significance of this entity is debated, and the risk associated with routine use may overshadow the benefits if any. Whether selective use of OAC is beneficial in patients at potentially higher risk for valve thrombosis (i. e., those with small annuli or valve-in-valve procedures) is unknown.

For patients who have indications for OAC, the use of OAC alone without an antiplatelet agent may represent reasonable frontline therapy to avoid excessive bleeding while maintaining ischemic and thrombotic protection at the cerebral and myocardial levels.

Given the lack of differences compared with VKA in ATLANTIS and their ease of use, NOACs may represent an option in this context.

Another gap in the evidence associated with the use of NOACs in AF patients before TAVR is the discontinuation of OAC with or without bridging. There is a lack of dedicated studies of double or triple therapy in TAVR patients, which warrants case-by-case decision-making with the understanding that a long period of triple therapy may be particularly detrimental in the elderly cohort and that dual- rather than triple-antithrombotic therapy carries a Class 1A recommendation in recent ESC guidelines on the management of patients with AF.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Ten Berg J, Sibbing D, Rocca B, Van Belle E, Chevalier B, Collet JP, et al. Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: A consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease. Eur Heart J 2021;42:2265-9.  Back to cited text no. 1
    
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Dangas GD, Tijssen JG, Wöhrle J, Søndergaard L, Gilard M, Möllmann H, et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med 2020;382:120-9.  Back to cited text no. 4
    
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16.
Van Mieghem NM, Unverdorben M, Hengstenberg C, Möllmann H, Mehran R, López-Otero D, et al. Edoxaban versus vitamin K antagonist for atrial fibrillation after TAVR. N Engl J Med 2021;385:2150-60.  Back to cited text no. 16
    
17.
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18.
Van Mieghem NM, Unverdorben M, Hengstenberg C, Möllmann H, Mehran R, López-Otero D, et al. ENVISAGE-TAVI AF Investigators. Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR. N Engl J Med. 2021 Dec 2;385:2150-60.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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