Clinical trial NCT05035277: AntiCoagulation Versus AcetylSalicylic Acid After Transcatheter Aortic Valve Implantation
Official title: AntiCoagulation Versus AcetylSalicylic Acid After Transcatheter Aortic Valve Implantation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Aortic Stenosis
Keywords: Transcatheter Aortic Valve Implantation
Transcatheter Aortic Valve Replacement
Antithrombotic therapy
Anticoagulation therapy
Antiplatelet therapy
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: University of Oslo
First posted: 2021-09-05
Enrollment: 360
Sex: ALL
Minimum age (years): 65
Maximum age (years): 80
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel group prospective randomized open blinded endpoint (PROBE) trial
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Hypo-attenuated leaflet thickening
timeFrame: 12 months
measure: Safety composite - Incidence of Treatment Emergent Adverse Clinical Outcome
timeFrame: 12 months
measure: Major adverse cardiovascular events (MACE)
timeFrame: 5 years
measure: Major adverse cardiovascular events (MACE)
timeFrame: 10 years
Secondary outcomes:
measure: Clinical efficacy
timeFrame: 12 months
measure: Safety composite, superiority
timeFrame: 12 months
measure: Thromboembolic events
timeFrame: 12 months
measure: Bleeding events
timeFrame: 12 months
measure: All-cause mortality
timeFrame: 12 months
measure: The number of adverse events
timeFrame: 12 months
measure: The number of serious adverse events
timeFrame: 12 months
measure: Life-threatening or disabling bleeding
timeFrame: 12 months
measure: Major bleeding
timeFrame: 12 months
measure: Minor bleeding
timeFrame: 12 months
Other outcomes:
measure: CT signs of valve degeneration
timeFrame: 12 months
measure: Echocardiographic signs of valve degeneration
timeFrame: 12 months
measure: Cardiac function
timeFrame: 12 months
measure: Non-procedure-related life-threatening or disabling bleeding
timeFrame: 12 months
measure: Number of major adverse clinical events
timeFrame: 12 months
measure: Troponin T
timeFrame: 12 months
measure: N-terminal pro-B-type natriuretic peptide
timeFrame: 12 months
measure: Infective endocarditis
timeFrame: 12 months
measure: Change in quality of life - Kansas City Cardiomyopathy Questionnaire
timeFrame: 12 months
measure: Cognitive function
timeFrame: 12 months
measure: Clinical efficacy
timeFrame: 5 years
measure: All-cause mortality
timeFrame: 5 years
measure: Echocardiographic signs of valve degeneration
timeFrame: 5 years
measure: Cardiac function
timeFrame: 5 years
measure: N-terminal pro-B-type natriuretic peptide
timeFrame: 5 years
measure: Troponin T
timeFrame: 5 years
measure: Individual components of MACE
timeFrame: 5 years
measure: Change in quality of life - Kansas City Cardiomyopathy Questionnaire
timeFrame: 5 years
measure: Cognitive function
timeFrame: 5 years
measure: Infective endocarditis
timeFrame: 5 years
measure: Clinical efficacy
timeFrame: 10 years
measure: All-cause mortality
timeFrame: 10 years
measure: Echocardiographic signs of valve degeneration
timeFrame: 10 years
measure: Cardiac function
timeFrame: 10 years
measure: N-terminal pro-B-type natriuretic peptide
timeFrame: 10 years
measure: Troponin T
timeFrame: 10 years
measure: Individual components of MACE
timeFrame: 10 years
measure: Change in quality of life - Kansas City Cardiomyopathy Questionnaire
timeFrame: 10 years
measure: Cognitive function
timeFrame: 10 years
measure: Infective endocarditis
timeFrame: 10 years
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo Univesity Hospital - Ullevål
city: Oslo
country: Norway
facility: Oslo University Hospital - Rikshospitalet
Study officials:
affiliation: Oslo University Hospital
name: Øyvind H Lie, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.