AntiCoagulation Versus AcetylSalicylic Acid After Transcatheter Aortic Valve Implantation (ACASA-TAVI)

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.

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.

Transcatheter Aortic Valve Implantation, Transcatheter Aortic Valve Replacement, Antithrombotic therapy, Anticoagulation therapy, Antiplatelet therapy

Separate endpoint adjudication committee blinded to randomized allocation of patients to treatment groups

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.

Acetylsalicylic acid 75 mg once daily is the current standard-of-care in TAVI patients without other indications for anticoagulation therapy.

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.

Second co-primary outcome. Composite of VARC-3 bleeding events, thromboembolic events (myocardial infarction or stroke) and all-cause mortality. Per-protocol, non-inferiority.

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.

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.

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.

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.

Third hierarchical secondary outcome. Composite of myocardial infarction or stroke of any cause. Intention-to-treat population.

Fourth hierarchical secondary outcome. Bleeding events according to VARC-3 definitions. Intention-to-treat population.

Exploratory outcome. Any evidence of reduced leaflet mobility, hypo-attenuated leaflet thickening or thrombus.

Exploratory outcome. Change in left ventricular global longitudinal strain assessed by echocardiography.

Exploratory outcome. Defined as stroke or transient ischemic attack of any cause, myocardial infarction, re-intervention on the aortic valve, death (cardiac, all-cause, non-cardiac) and heart failure hospitalization

Exploratory outcome. Assessed by change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (score 0-100, Higher value indicates better quality of life).

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.

Exploratory outcome. Change in left ventricular global longitudinal strain assessed by echocardiography.

Exploratory outcome. Assessment of the individual components of MACE (the primary outcome at long-term follow-up).

Exploratory outcome. Assessed by change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (score 0-100, Higher value indicates better quality of life).

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.

Exploratory outcome. Change in left ventricular global longitudinal strain assessed by echocardiography.

Exploratory outcome. Assessment of the individual components of MACE (the primary outcome at long-term follow-up).

Exploratory outcome. Assessed by change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (score 0-100, Higher value indicates better quality of life).

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

Will be made available with the publication of the primary analysis and remain available for 1 year. Thereafter, it can be made available upon request.

Researchers and clinicians with valid medical questions to be addressed. The data will not be available for commercial use.

VARC-3 WRITING COMMITTEE; Genereux P, Piazza N, Alu MC, Nazif T, Hahn RT, Pibarot P, Bax JJ, Leipsic JA, Blanke P, Blackstone EH, Finn MT, Kapadia S, Linke A, Mack MJ, Makkar R, Mehran R, Popma JJ, Reardon M, Rodes-Cabau J, Van Mieghem NM, Webb JG, Cohen DJ, Leon MB. Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research. Eur Heart J. 2021 May 14;42(19):1825-1857. doi: 10.1093/eurheartj/ehaa799.