AntiCoagulation Versus AcetylSalicylic Acid After Transcatheter Aortic Valve Implantation

Study Overview
=================
Brief Summary
-----------------
ACASA-TAVI is a pragmatic randomized controlled trial assessing the value of anticoagulation therapy versus the standard antiplatelet therapy after transcatheter aortic valve implantation in patients with aortic stenosis. The trial will assess the efficacy of direct oral anticoagulation (DOAC) therapy compared to the standard single antiplatelet therapy to prevent degeneration of the valve and its safety in co-primary endpoints with blinded endpoint adjudication. The effect of DOAC therapy on hard clinical outcomes will be assessed during long-term follow-up.

Detailed Description
-----------------
Aortic stenosis is a highly prevalent valvular disease and an important cause of morbidity and mortality in the elderly population. Transcatheter aortic valve implantation (TAVI) is an effective intervention in patients with severe aortic stenosis and low surgical risk. The procedure is highly effective, safe, and widely implemented. Current recommendations support transcatheter treatment of younger patients, including patients from 65 years of age with low surgical risk. This practice increases the importance of long-term valve maintenance. Observational data have suggested that early signs of valve degeneration (i.e. hypo-attenuated leaflet thickening/thrombosis/reduced leaflet motion) are associated with an increased risk of embolic events. This is an increasing problem with emerging indications in younger populations. Because both ischemic and bleeding complications after TAVI can be life-threatening, it is important to establish the optimal anti-thrombotic treatment regime. Use of oral anticoagulation after implantation for bioprosthetic valves have been associated with resolved valve degeneration and possible favourable clinical effects. The current practice guidelines recommend that oral anticoagulation may be considered for 3 months after open surgical bioprosthetic valve implantation. Patients with an independent indication for oral anticoagulation (i.e. atrial fibrillation or venous thromboembolism) are recommended to continue this treatment lifelong, but there is no recommendation for oral anticoagulation following TAVI in patients without other indications. In patients without indication for oral anticoagulation, the use of double anti-platelet therapy for 3-6 months following TAVI is recommended. However, single anti-platelet therapy with acetylsalicylic acid (ASA) without clopidogrel has been reported to improve bleeding outcomes and a composite of bleeding and ischemic outcomes. The effect of on oral anticoagulation-based treatment strategy compared to the standard single anti-platelet treatment strategy for valve maintenance after TAVI is unknown. Increased anti-thrombotic treatment intensity may come at the cost of increased bleeding risk. Dual anti-platelet therapy and combination therapy with anticoagulation and anti-platelet therapy have both been associated with unfavourable outcomes. Combined anti-platelet and anti-coagulation treatment has been shown to reduce valve degeneration at the cost of increased bleeding. Conversely, single anti-platelet therapy and anti-coagulation with a direct oral anti-coagulant (DOAC) have been associated with similar bleeding risk. Bleeding rates in patients treated with anti-coagulation after TAVI have been reported to be slightly higher than in patients treated with ASA after TAVI, but patients with conventional indications for anti-coagulation have higher baseline bleeding risk than those without such indications. Therefore, the risk of bleeding in patients treated with DOAC or ASA following TAVI may be similar, but no randomized trials have been performed. ACASA-TAVI will include 360 patients > 65 years and < 80 years of age who have undergone successful TAVI and have no conventional indication for DOAC in a prospective randomized open-label blinded-endpoint (PROBE) study. The intervention arm will be 12 month therapy with an anti-Xa type DOAC (without antiplatelet therapy) and the active control arm will be standard dose ASA. After 12 months, the intervention group will be switched to ASA maintenance. All patients will undergo clinical assessment, cardiac CT and echocardiography at 12 months with blinded endpoint adjudication by an independent committee. Outcome measures will comply with the Valve Academic Research Consortium 3 (VARC-3) consensus, and are described in detail in the protocol. The co-primary endpoints at 12 months, hypo-attenuated leaflet thickening (HALT) and safety composite, must both be met for the trial to declare success. The effect of the DOAC therapy on long-term major adverse cardiovascular events (MACE) will be assessed after 5 years and 10 years.

Official Title
-----------------
AntiCoagulation Versus AcetylSalicylic Acid After Transcatheter Aortic Valve Implantation

Conditions
-----------------
Aortic Stenosis

Intervention / Treatment
-----------------
* Drug: Acetylsalicylic acid
* Drug: Apixaban
* Drug: Rivaroxaban
* Drug: Edoxaban


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Successful trans-catheter aortic valve implantation in patients aged >65 and <80 years old at the time of the procedure. Exclusion Criteria: Strict indication for anticoagulation or anti-platelet drugs Strict contraindication for anticoagulation or anti-platelet drugs Overt cognitive failure Failure to obtain written informed consent Concomitant use of inducers or inhibitors of CYP3A4 or P-glycoprotein

Ages Eligible for Study
-----------------
Minimum Age: 65 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel group prospective randomized open blinded endpoint (PROBE) trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Acetylsalicylic acid<br>Patients in the active control arm will receive 75 mg acetylsalicylic acid once daily indefinitely. | Drug: Acetylsalicylic acid<br>* Acetylsalicylic acid 75 mg once daily is the current standard-of-care in TAVI patients without other indications for anticoagulation therapy.<br>* Other names: B01A C06;|
| Experimental: Direct oral anticoagulation (DOAC)<br>Patients in the experimental arm will receive an anti Xa-type DOAC (apixaban, rivaroxaban or edoxaban) in approved therapeutic dose for 12 months. The choice of DOAC agent will be made by the treating clinician after discussion with the patient. After 12 months, these patients will abort DOAC therapy. Acetylsalicylic acid, 75 mg once daily will be started after DOAC discontinuation and continued indefinitely. | Drug: Apixaban<br>* Standard dose apixaban will be one of the options for the patients in the experimental arm.<br>* Other names: B01A F02;Drug: Rivaroxaban<br>* Standard dose rivaroxaban will be one of the options for the patients in the experimental arm.<br>* Other names: B01A F01;Drug: Edoxaban<br>* Standard dose edoxaban will be one of the options for the patients in the experimental arm.<br>* Other names: B01A F03;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypo-attenuated leaflet thickening | First co-primary endpoint. The presence of hypo-attenuated leaflet thickening on dedicated cardiac CT after 12 months will be registered by a blinded expert reader. Intention-to-treat, superiority. | 12 months | 
| Safety composite - Incidence of Treatment Emergent Adverse Clinical Outcome | Second co-primary outcome. Composite of VARC-3 bleeding events, thromboembolic events (myocardial infarction or stroke) and all-cause mortality. Per-protocol, non-inferiority. | 12 months | 
| Major adverse cardiovascular events (MACE) | Primary outcome during long-term follow-up. The rate of the composite of Cardiac death, Aortic valve re-intervention, Stroke, Myocardial infarction, Heart failure hospitalization and Major, life-threatening, or disabling bleeding. | 5 years | 
| Major adverse cardiovascular events (MACE) | Primary outcome during long-term follow-up. The rate of the composite of Cardiac death, Aortic valve re-intervention, Stroke, Myocardial infarction, Heart failure hospitalization and Major, life-threatening, or disabling bleeding. | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy | First hierarchical secondary outcome. Composite of of Freedom from all-cause mortality, Freedom from all stroke, Freedom from hospitalization for procedure- or valve-related causes, Freedom from KCCQ overall summary score <45 or decline from baseline of >10 points. Intention-to-treat, superiority. | 12 months | 
| Safety composite, superiority | Second hierarchical secondary outcome. Composite of VARC-3 bleeding events, thromboembolic events (myocardial infarction or stroke) and all-cause mortality. Same endpoint as second co-primary outcome, but intention-to-treat, superiority. | 12 months | 
| Thromboembolic events | Third hierarchical secondary outcome. Composite of myocardial infarction or stroke of any cause. Intention-to-treat population. | 12 months | 
| Bleeding events | Fourth hierarchical secondary outcome. Bleeding events according to VARC-3 definitions. Intention-to-treat population. | 12 months | 
| All-cause mortality | Fifth hierarchical secondary outcome. Intention-to-treat population. | 12 months | 
| The number of adverse events | First secondary safety endpoint. Safety population. | 12 months | 
| The number of serious adverse events | Second secondary safety endpoint. Safety population. | 12 months | 
| Life-threatening or disabling bleeding | Third secondary safety endpoint. Safety population. VARC-3 definition. | 12 months | 
| Major bleeding | Fourth secondary safety endpoint. Safety population. VARC-3 definition. | 12 months | 
| Minor bleeding | Fifth secondary safety endpoint. Safety population. VARC-3 definition. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Transcatheter Aortic Valve Implantation, Transcatheter Aortic Valve Replacement, Antithrombotic therapy, Anticoagulation therapy, Antiplatelet therapy