The Search for Optimal Antithrombotic Therapy in Transcatheter Aortic Valve Implantation

Facts and Uncertainties

Jurrien ten Berg; Bianca Rocca; Dominick J. Angiolillo; Kentaro Hayashida

Disclosures

Eur Heart J. 2022;43(44):4616-4634.

Abstract and Introduction

Abstract

Graphical Abstract

(Enlarge Image)

Schematic representation of potential haemostatic mechanisms contributing to bleeding and thromboembolic complications peri- and post-transcatheter aortic valve implantation. Left panel: platelet activation/consumption and von Willebrand factor degradation at the valve site induced by local high shear stress, as well as the presence of angiodysplasia may contribute to the high bleeding risk. Right panel: the coagulation cascade can be triggered by abnormal leaflet motion of the native or prosthetic valve, blood slugging in the neo-sinus, heightened presence of Factor XIII in the native aortic valve as well as new-onset atrial fibrillation leading to thromboembolic events. ViV, valve-in-valve procedure; vWF, von Willebrand factor.

Transcatheter aortic valve implantation (TAVI) is a minimally invasive procedure, which is used frequently in patients with symptomatic severe aortic valve stenosis. Most patients undergoing TAVI are over 80 years of age with a high bleeding as well as thrombotic risk. Despite the increasing safety of the procedure, thromboembolic events [stroke, (subclinical) valve thrombosis] remain prevalent. As a consequence, antithrombotic prophylaxis is routinely used and only recently new data on the efficacy and safety of antithrombotic drugs has become available. On the other hand, these antithrombotic drugs increase bleeding in a population with unique aortic stenosis-related bleeding characteristics (such as acquired von Willebrand factor defect and angiodysplasia). In this review, we discuss the impact of thromboembolic and bleeding events, the current optimal antithrombotic therapy based on registries and recent randomized controlled trials, as well as try to give a practical guide how to treat these high-risk patients. Finally, we discuss knowledge gaps and future research needed to fill these gaps.

Introduction

Transcatheter aortic valve implantation (TAVI) is a minimally invasive procedure with outcomes that are at least similar to, but often better than surgical aortic valve replacement (SAVR) with bioprosthesis.^[1,2] As a result, the uptake and use of TAVI have increased exponentially and, although age and the surgical risk of patients undergoing TAVI have decreased over the last decade, most patients are still over 80 and are per se at bleeding as well as thrombotic high risk.^[3–6] Despite the increasing safety of the procedure, thromboembolic events [stroke, valve thrombosis, and myocardial infarction (MI)] remain, unfortunately, fairly stable over time.^[7–9] As a consequence, antithrombotic prophylaxis is routinely used and only recently new data on the efficacy and safety of antithrombotic drugs have become available. In this review, we discuss the current optimal antithrombotic therapy based on recent randomized controlled trials (RCTs), taking into account the unique characteristics of this population, at high-risk for both bleeding and thromboembolic events.^[10,11]

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Table 1. Cardiovascular events in transcatheter aortic valve implantation studies (randomized controlled trials and registries) since 2016
Trial	Year	Study Type	Number of patients	STS score	Pre-existing AF	Life-threatening or major bleeding		Stroke/TIA		Myocardial infarction		All-cause death
Trial	Year	Study Type	Number of patients	STS score	Pre-existing AF	30 days	1 year	30 days	1 year	30 days	1 year	30 days	1 year
High surgical risk (STS score >8%)
WIN-TAVI¹⁸	2018	Registry	1019^a	8.3 ± 7.4	20.0%	12.5%	12.8%	1.3%/N/A	2.2%/N/A	0.2%	1.1%	3.9%	12.5%
Intermediate surgical risk (STS score 4–8%)
PARTNER 2A¹⁵	2016	RCT	1011	5.8 ± 2.1	31.0%	10.4%^b	15.2%^b	5.5%/0.9%	8.0%/2.4%	1.2%	2.5%	3.9%	12.3%
SURTAVI¹⁶	2017	RCT	864	4.4 ± 1.5	28.1%	12.2%	N/A	3.4%/1.5%	5.4%/3.2%	0.9%	2.0%	2.2%	6.7%
REPRISE III¹⁹	2018	RCT	912	6.8	33.9%	12.1%	18.0%	4.6%/N/A	7.9%/N/A	0.9%	3.6%	2.2%	12.4%
Swiss TAVI²⁰	2018	Registry	3493	5.8 ± 4.4	N/A	13.4%	15.3%	3.8%^c	4.9%^c	0.6%	1.4%	3.8%	12.8%
FORWARD²¹	2018	Registry	1060	5.5 ± 4.5	34.5%	9.9%	10.7%	2.8%/0.4%	3.4%/1.1%	0.8%	1.8%	1.9%	8.9%
OCEAN-TAVI²²	2019	Registry	1613	6.7 (4.7–9.5)	N/A	N/A	N/A	N/A	N/A	N/A	N/A	1.7%	11.3%
STS/ACC TVT¹⁷	2020	Registry	276 316	5.2 (3.3–8.4)	N/A	6.2%	N/A	2.4%/N/A	N/A	0.5%	—	3.3%	15.6%
Low surgical risk (STS score <4%)
PARTNER 3¹	2019	RCT	496	1.9 ± 0.7	15.7%	3.6%^d	7.7%^d	0.6%/0%	1.2%/1.0%	1.0%	1.2%	0.4%	1.0%
Evolut Low Risk²	2019	RCT	734	1.9 ± 0.7	15.5%	2.4%^b	3.2%^b	3.4%/0.6%	4.1%/1.7%	0.9%	1.7%	0.5%	2.4%
SCOPE 1²³	2019	RCT	739	3.5 (2.6–5.0)	36.4%	13.1%	N/A	2.4%/0.5%	N/A	0.3%	N/A	1.6%	N/A
GARY²⁴	2019	Registry	6062	2.86 ± 0.72	18.8%	N/A	N/A	N/A	N/A	N/A	N/A	1.8%	10.0%
Surgical risk not available
FRANCE-2²⁵	2016	Registry	4201	N/A	26.4%	8.6%^e	10.4%^e	2.3%/N/A	2.9%/N/A	0.9%	1.3%	9.2%	23.2%
SOURCE 3²⁶	2017	Registry	1946	N/A	22.6%	5.0%^b	N/A	1.4%/0.6%	3.1%/1.2%	0.3%	0.9%	2.2%	12.6%
FRANCE TAVI²⁷	2019	Registry	11 469	N/A	33.0%	N/A	N/A	N/A	N/A	N/A	N/A	N/A	9.6%

AF, atrial fibrillation; STS, Society of Thoracic Surgeons Predicted Risk of Mortality; TAVI, transcatheter aortic valve implantation; TIA, transient ischaemic attack; N/A, not available.
^aWomen only.
^bLife-threatening or disabling bleeding.
^cStroke and TIA combined.
^dBleeding events were assessed using the trial criteria.
^eMajor bleeding.

Table 2. Guidelines of the ESC/EACTS and AHA/ACC
	Recommendations	Class^a	Level^b
2021 ESC/EACTS Guidelines for the management of valvular heart disease
Patients without baseline indication for OAC	Lifelong SAPT is recommended after TAVI in patients with no baseline indication for OAC.	I	A
Patients without baseline indication for OAC	Routine use OAC is not recommended after TAVI in patients with no baseline indication for OAC.	III	B
Patients with baseline indication for OAC	OAC is recommended lifelong for TAVI patients who have other indications for OAC.	I	B
Anticoagulation using a VKA and/or UFH is recommended in bioprosthetic valve thrombosis before considering re-intervention.		I	C
Anticoagulation should be considered in patients with leaflet thickening and reduced leaflet motion leading to elevated gradients, at least until resolution.		IIa	B
2020 ACC/AHA Guideline for the Management of Valvular Heart Disease
Patients without baseline indication for OAC	For patients with a bioprosthetic TAVI, aspirin 75–100 mg daily is reasonable in the absence of other indications for oral anticoagulants.	IIa	B-R
	For patients with a bioprosthetic TAVI who are at low risk of bleeding, dual-antiplatelet therapy with aspirin 75–100 mg and clopidogrel 75 mg may be reasonable for 3–6 months after valve implantation.	IIb	B-NR
	For patients with a bioprosthetic TAVI who are at low risk of bleeding, anticoagulation with a VKA to achieve an INR of 2.5 may be reasonable for at least 3 months after valve implantation	IIb	B-NR
	For patients with bioprosthetic TAVI, treatment with low-dose rivaroxaban (10 mg daily) plus aspirin (75–100 mg) is contraindicated in the absence of other indications for oral anticoagulants.	III	B-R
Patients with baseline indication for OAC	For patients with AF and native valve heart disease (except rheumatic mitral stenosis) or who received a bioprosthetic valve >3 months ago, a NOAC is an effective alternative to VKA anticoagulation and should be administered on the basis of the patient's CHA₂DS₂-VASc score.	I	A
Patients with baseline indication for OAC	For patients with new-onset AF ≤3 months after surgical or transcatheter bioprosthetic valve replacement, anticoagulation with a VKA is reasonable.	IIa	B-NR
In patients with suspected or confirmed bioprosthetic valve thrombosis who are haemodynamically stable and have no contraindications to anticoagulation, initial treatment with a VKA is reasonable.		IIa	B-NR

The table depicts in parallel the recommendations from the ESC/EACTS and AHA/ACC in TAVI patients according to the presence or absence of a baseline indication for OAC.
AF, atrial fibrillation; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulation; VKA, vitamin K antagonist; SAP, single antiplatelet therapy; R, randomized; NR, non-randomized; UFH, unfractionated heparin.
^aClass of recommendation.
^bLevel of evidence.

Table 3. Ongoing randomized controlled trials evaluating antithrombotic therapy post-transcatheter aortic valve implantation
Trial	Number of patients	Study population	Intervention arm	Control arm	Primary endpoints	Follow-up	Estimated study completion date
ADAPT-TAVR NCT03284827	220	Successful TAVI without indication for long-term OAC	Edoxaban	ASA + clopidogrel	Leaflet thrombosis on 4D-CT scan	6 months	October 2021
POPular PAUSE TAVI NTC04437303	858	Undergoing TAVI with indication for long-term OAC	Continuation of OAC	interruption of OAC	Composite of cardiovascular mortality, stroke, myocardial infarction, major vascular complications, and major, disabling and life-threatening bleeding at 30 days defined by the VARC-2 criteria	30 days	December 2022
AVATAR NCT02735902	170	Successful TAVI with indication for long-term OAC	VKA monotherapy	VKA + ASA	Death, MI, stroke, valve thrombosis, ISTH major VARC-2 bleeding	1 year	April 2023
TICTAVI NCT02817789	308	All-comers undergoing TAVI without indication for long-term OAC	Ticagrelor	ASA + clopidogrel	VARC-2 safety endpoint: death, stroke, life-threatening or disabling bleeding, Stage 2 or 3 acute kidney injury, major vascular complications, coronary artery obstruction or valve-related dysfunction requiring intervention	30 days	May 2018 (stopped due to low recruitment)
PTOLEMAIOS NCT02989558	90	High operative risk patients undergoing TAVI	ASA + ticagrelor	ASA + clopidogrel	Number of high-intensity transient signals as assessed with transcranial Doppler on middle cerebral arteries	Up to 5 days	Current status completed
LTR 2.0 NCT03557242	200	Low-risk TAVI without indication for long-term OAC	Edoxaban + ASA	ASA	Composite of all-cause death, stroke, life-threatening and major bleeding, major vascular complications, hospitalizations for valve-related symptoms, or worsening heart failure	30–45 days	July 2023

ADAPT-TAVR, Anticoagulant vs. Dual-Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement; AF, atrial fibrillation; ASA, acetylsalicylic acid; AVATAR, Anticoagulation Alone vs. Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions; CLOE, Clopidogrel Omission After Transcatheter Aortic Valve Replacement; DAPT, dual-antiplatelet therapy; ISTH, International Society of Thrombosis and Haemostasis; MI, myocardial infarction; OAC, oral anticoagulant; POPular PAUSE TAVI, Peri-procedural Continuation Versus Interruption of Oral Anticoagulant Drugs During Transcatheter Aortic Valve Implantation; PTOLEMAIOS, A Trial to Assess the Safety and Efficacy of Prophylactic Ticagrelor with Acetylsalicylic Acid vs. Clopidogrel with Acetylsalicylic Acid in the Development of Cerebrovascular Embolic Events During TAVI; LTR, Strategies to Prevent Transcatheter Heart Valve Dysfunction in Low-Risk Transcatheter Aortic Valve Replacement; REDOX-TAVI, Rotterdam EDOXaban Leaflet Evaluation in Patients After Transcatheter Aortic Valve Implantation; RETORIC, Rule Out Transcatheter Aortic Valve Thrombosis With Post-Implantation Computed Tomography; SAPT, single antiplatelet therapy; TAVI, transcatheter aortic valve implantation; TAVR, transcatheter aortic valve replacement; TICTAVI, Safety Profile Evaluation of Ticagrelor Alone Compared with a Combination of Lysine Acetylsalicylate-Clopidogrel in the Context of Transcatheter Aortic Valve Implantation; VARC-2, Valve Academic Research Cosortium-2; VKA, vitamin K antagonist.

Table 4. Studies evaluating antithrombotic strategies after transcatheter aortic valve implantation
Study	Year	Study type	Number of patients	Compared antithrombotic regimen	Endpoints	Follow-up	Main results
Studies including patients without a chronic indication for OAC
Ussia et al.⁹⁷	2011	RCT	79	ASA monotherapy vs. 3 months DAPT	Composite of all-cause mortality, myocardial infarction, major stroke, or life-threatening bleeding or urgent conversion to surgery	6 months	No significant difference in composite endpoint (15 vs. 18%, P = 0.85)
Stabile et al.⁹⁸	2014	RCT	120	ASA monotherapy vs. 6 months DAPT	VARC-2 endpoints	30 days	No significant difference in VARC-2 endpoint. More vascular complications in DAPT compared with ASA monotherapy (13.3 vs. 5%, P < 0.05)
Rodés-Cabau et al.⁸⁸	2017	RCT	222	ASA monotherapy vs. 3 months DAPT	Composite of all-cause mortality, myocardial infarction, stroke or TIA, or major or life-threatening bleeding	3 months	Lower rates of composite endpoint in ASA monotherapy compared with DAPT (7.2 vs. 15.3%, P = 0.065). Less bleeding events in ASA monotherapy compared with DAPT (3.6 vs. 10.8%, P = 0.04)
Mangieri et al.⁹⁵	2017	Observational study	439	SAPT (for patients with contraindication to DAPT) vs. 3 to 6 months DAPT	Composite of all-cause mortality, major bleeding, cerebrovascular events, redo TAVR and valve thrombosis	1 year	No significant difference in composite endpoint
Czerwińska-Jelonkiewicz et al.⁹⁴	2017	Observational study	827	All antithrombotic strategies	VARC-2 endpoints	In-hospital	Lower rates of bleeding (OR 0.176, P = 0.007) and vascular complications in ASA monotherapy (OR 0.068, P = 0.01) after propensity score analysis
D'Ascenzo et al.⁹⁹	2017	Observational study	Total cohort 1364 Propensity score-matched 1210	ASA monotherapy vs. 6 months DAPT and VKA vs. VKA + ASA	Prosthetic heart valve dysfunction at follow-up	45 ± 14 months	No differences in prosthetic heart valve dysfunction. Lower mortality rate in ASA monotherapy compared with DAPT (1.5 vs. 4.5%, P = 0.002). Lower long-term follow-up major bleeding events in ASA monotherapy vs. DAPT (1.4 vs. 4.0%, P < 0.001).
Sherwood et al.¹⁰⁰	2018	Observational study	16 694	SAPT vs. DAPT	Mortality, stroke, major bleeding, or myocardial infarction	1 year	No difference in combined endpoint. Higher risk of major bleeding in DAPT vs. SAPT (HR: 1.48)
Al Halabi et al.¹⁰¹	2018	Meta-analysis of 3 RCTs and 5 observational studies	2439	SAPT vs. DAPT	VARC-2 endpoints	30 days	Lower risk of all-cause mortality (OR 2.06, P = 0.001), major or life-threatening bleeding (OR 2.04, P < 0.001) and major vascular complications (OR 2.15, P < 0–001) in the SAPT compared with DAPT
Maes et al.¹⁰²	2018	Meta-analyses of 3 RCTs	421	SAPT vs. DAPT	Composite of death, major or life-threatening bleedings, and major vascular complications according to VARC-2 classification	30 days	Lower risk of composite endpoint in SAPT vs. DAPT (10.9 vs. 17.6%, OR 1.73, P = 0.05). Higher risk of bleeding in DAPT vs. SAPT (OR 2.24, P = 0.022)
Diaz et al. (unpublished data)	2019	RCT	123	3 months DAPT vs. VKA	New areas of cerebral infarction at MRI	3 months	No difference in new brain lesions between DAPT and VKA at 6 days (66.7 vs. 84.2%, P = 0.15) and between day 6 and 3 months (6.0 vs. 10.4%, P = 0.71)
Dangas et al.³	2020	RCT	1644	Rivaroxaban 10 mg + 3 months aspirin than rivaroxaban 10 mg vs. 3 months DAPT than ASA monotherapy	Composite of death from any cause or first thromboembolic event Composite of life-threatening, disabling or major VARC-2 bleeding	17 months (13–21)	Higher risk of composite endpoint in rivaroxaban + ASA vs. ASA + clopidogrel (incidence rates 9.8 vs. 7.2 per 100 person-years, HR 1.35, P = 0.04) Higher rate of bleeding in rivaroxaban + ASA vs. + clopidogrel (incidence rates 4.3 vs. 2.8 per 100 person-years, HR 1.5, P = 0.08)
Brouwer et al.⁵	2020	RCT	665	Aspirin monotherapy vs. aspirin + 3 months clopidogrel (Cohort A POPular TAVI trial)	Freedom from all VARC-2-defined bleeding complication Composite of cardiovascular mortality, non-procedural bleeding, stroke, or myocardial infarction Composite of cardiovascular mortality, ischaemic stroke, or myocardial infarction	1 year	Lower all bleeding in aspirin monotherapy vs. aspirin + 3 months clopidogrel (15.1 vs. 26.6%, RR 0.57, P = 0.001) Lower rate of composite of cardiovascular mortality, non-procedural bleeding, stroke, or myocardial infarction in aspirin alone arm vs. aspirin + 3 months clopidogrel (23.0 vs. 31.1%, RR 0.74, P = 0.04) No difference in composite of cardiovascular mortality, ischaemic stroke, or myocardial infarction (9.7 vs. 9.9%, RR 0.98, P = 0.93, P = 0.004 for non-inferiority)
Collet et al.⁵⁴	2021	RCT	1049	Apixaban vs. standard of care Stratum 2: no indication for OAC	Efficacy outcome: composite of death, myocardial infarction, stroke, intracardiac or valve thrombosis, systemic emboli, deep vein thrombosis or pulmonary embolism Safety outcome: life-threatening, disabling or major VARC-2 bleeding	1 year	No difference in efficacy outcome (16.9 vs. 19.3%, HR 0.88) No differences in safety outcome (7.8 vs. 7.3%, HR 1.09) Higher risk of death, stroke/TIA of systemic embolism in apixaban group and a lower risk of valve thrombosis
Studies including patients with a chronic indication for OAC
Abdul-Jawad Altisent et al.¹⁰³	2016	Observational study	621	VKA monotherapy vs. VKA + SAPT/DAPT	Composite of cardiovascular death, myocardial infarction and stroke. Major or life-threatening bleeding events according to BARC and VARC-2 classification	Median follow-up: 13 months	No significant differences in composite endpoint. Lower risk of major or life-threatening bleeding in VKA monotherapy compared with VKA + SAPT/DAPT (adjusted HR 1.05, P = 0.04)
Geis et al.¹⁰⁴	2017	Observational study	167	VKA monotherapy vs. VKA + SAPT/DAPT	Composite of all-cause mortality, stroke, thromboembolism, and major bleeding	6 months	Lower rates of the composite endpoint in VKA monotherapy compared with VKA + SAPT (6.5 vs. 22%, P = 0.02) or to VKA + DAPT (28.6%, P = 0.002)
Seeger et al.¹⁰⁵	2017	Observational study	272	Apixaban vs. VKA	VARC-2 safety endpoint	30 days and 1 year	Lower rates of bleeding in apixaban compared with VKA (13.5 vs. 30.5%, P < 0.01)
D'Ascenzo et al.⁹⁹	2017	Observational study	Total cohort 292 Propensity score-matched 210	ASA monotherapy vs. 6 months DAPT and VKA vs. VKA + ASA	Prosthetic heart valve dysfunction at follow-up	45 ± 14 months	No differences in prosthetic heart valve dysfunction. Less 30-day life-threatening bleeding events in VKA arm compared with VKA + ASA (4.8 vs. 11.4%, P < 0.001).
Geis et al.¹⁰⁶	2018	Observational study	326	NOAC monotherapy vs. VKA monotherapy	VARC-2 endpoints	6 months	No significant difference in VARC-2 endpoints
Jochheim et al.¹⁰⁷	2019	Observational study	962	NOAC vs. VKA	Non-hierarchical combined endpoint of all-cause mortality, myocardial infarction, and any cerebrovascular event	1 year	Higher incidence of the combined endpoint in NOAC vs. VKA (21.2 vs. 15.0%, adjusted HR 1.44, P = 0.05)
Nijenhuis et al.⁴	2020	RCT	313	OAC monotherapy vs. OAC + 3 months clopidogrel (Cohort B POPular TAVI trial)	Freedom from all VARC-2-defined bleeding complication Composite of cardiovascular mortality, non-procedural bleeding, stroke, or myocardial infarction Composite of cardiovascular mortality, ischaemic stroke, or myocardial infarction	1 year	Lower all bleeding in OAC monotherapy vs. OAC + 3 months clopidogrel (21.7% vs. 34.6%, RR 0.63, P = 0.01) Lower rate of composite of cardiovascular mortality, non-procedural bleeding, stroke, or myocardial infarction in OAC monotherapy arm vs. OAC + 3 months clopidogrel (31.2 vs. 45.5%, RR 0.69) No difference in composite of cardiovascular mortality, ischaemic stroke, or myocardial infarction (13.4 vs. 17.3%, RR 0.77)
Kawashima et al.¹⁰⁸	2020	Observational study	403	NOAC vs. VKA	Primary outcome: all-cause mortality after discharge Secondary outcome: bleeding and ischaemic events after discharge	Median follow-up: 568 days	Higher all-cause mortality in VKA group compared with NOAC (adjusted, 20.6 vs. 10.2%, P = 0.036) No differences in bleeding and ischaemic events after discharge
Butt et al.¹⁰⁹	2021	Observational study	735	NOAC vs. VKA	Arterial thromboembolism, bleeding, all-cause mortality	3 years	No difference in arterial thromboembolism (9.6 vs. 7.4%, adjusted HR 1.23), bleeding (14.3 vs. 13.3%, adjusted HR 1.14), and all-cause mortality (32.7 vs. 32.0%, adjusted HR 0.93)
Didier et al.¹¹⁰	2021	Observational study	Total cohort 8962 Propensity score-matched 2471	NOAC vs. VKA	Efficacy outcome: death from any cause Safety outcome: major bleeding	Median follow-up 1.08 year	Less death from any cause in NOAC group vs. VKA group (31.2 vs. 35.6%, P < 0.005) Less major bleeding in NOAC group vs. VKA group (8.4 vs. 12.3%, P < 0.005)
Collet et al.⁵⁴	2021	RCT	451	Apixaban vs. standard of care Stratum 1: indication for OAC	Efficacy outcome: composite of death, myocardial infarction, stroke, intracardiac or valve thrombosis, systemic emboli, deep vein thrombosis or pulmonary embolism Safety outcome: life-threatening, disabling or major VARC-2 bleeding	1 year	No difference in efficacy outcome (21.9 vs. 21.9%, HR 1.02) No differences in safety outcome (10.3 vs. 11.4%, HR 0.92)
Van Mieghem et al.⁶	2021	RCT	1426	Edoxaban vs. VKA	Efficacy outcome: composite of death from any cause, myocardial infarction, ischaemic stroke, systemic thromboembolism, valve thrombosis, or ISTH major bleeding Safety outcome: ISTH major bleeding	Median follow-up: 554 vs. 530 days	Edoxaban was non-inferior to VKA regarding efficacy outcome (17.3 vs. 16.5 per 100 person-years, P = 0.01 for non-inferiority) Higher ISTH major bleeding in edoxaban group vs. VKA group (9.7 vs. 7.0 per 100 person-years, P = 0.93 for non-inferiority)

AF, atrial fibrillation; ASA, acetylsalicylic acid; BARC, Bleeding Academic Research Consortium; DAPT, dual-antiplatelet therapy (aspirin plus clopidogrel); HR, hazard ratio; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; OR, odds ratio; RCT, randomized clinical trial; SAPT, single antiplatelet therapy; TAVI, transcatheter aortic valve implantation; TIA, transient ischaemic attack; VARC-2, Valve Academic Research Consortium-2; VKA, vitamin K antagonist.

Table 5. Gaps in knowledge
• The role of bleeding and thrombotic risk scores in patients undergoing TAVI
• Timing of peri-procedural antithrombotic therapy (pre- or post-TAVI)
• Duration of antiplatelet therapy post-TAVI (lifelong or shorter?)
• The role of NOACs in patients post-TAVI
• The need for antithrombotic treatment of subclinical valve thrombosis
• The role of intensified antithrombotic therapy in lower risk patients
• The effect of cerebral embolic protection devices during TAVI on clinical events
• The role of protamine sulphate reversal when closing the access site
• The role of vWF multimer measurement as biomarker of early post-TAVI bleeding
• The need for routine CT scanning of the bioprosthetic valve

TAVI, transcatheter aortic valve implantation; vWF, von Willebrand factor; NOAC, non-vitamin K antagonist oral anticoagulant; CT, computed tomography.