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.

Study Overview

• Status: Recruiting
• Conditions: Aortic Stenosis
• Intervention / Treatment: Drug: Acetylsalicylic acid; Drug: Apixaban; Drug: Rivaroxaban; Drug: Edoxaban

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.

• Study Type: Interventional
• Enrollment (Anticipated): 360
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Øyvind H Lie, MD, PhD; Phone Number: +4793429011; Email: oyvlie@gmail.com

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Not yet recruiting
    • Haukeland University Hospital
    • Contact: Jon Herstad, MD; Email: jon.herstad@helse-bergen.no
  • Oslo, Norway, 0424
    • Not yet recruiting
    • Oslo Univesity Hospital - Ullevål
    • Contact: Anders Opdahl, MD PhD
  • Oslo, Norway, 0772
    • Recruiting
    • Oslo University Hospital - Rikshospitalet
    • Contact: Øyvind Lie, MD PhD; Phone Number: +4793420911; Email: oyvlie@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 80 years (OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Acetylsalicylic acid; Patients in the active control arm will receive 75 mg acetylsalicylic acid once daily indefinitely.	Drug: Acetylsalicylic acid; Acetylsalicylic acid 75 mg once daily is the current standard-of-care in TAVI patients without other indications for anticoagulation therapy.; Other Names: B01A C06
EXPERIMENTAL: Direct oral anticoagulation (DOAC); 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; Standard dose apixaban will be one of the options for the patients in the experimental arm.; Other Names: B01A F02; Drug: Rivaroxaban; Standard dose rivaroxaban will be one of the options for the patients in the experimental arm.; Other Names: B01A F01; Drug: Edoxaban; Standard dose edoxaban will be one of the options for the patients in the experimental arm.; 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
N-terminal pro-B-type natriuretic peptide	Exploratory outcome. Assessment of blood samples.	12 months
CT signs of valve degeneration	Exploratory outcome. Any evidence of reduced leaflet mobility, hypo-attenuated leaflet thickening or thrombus.	12 months
Echocardiographic signs of valve degeneration	Exploratory outcome. Change in transaortic pressure gradient assessed by echocardiography.	12 months
Cardiac function	Exploratory outcome. Change in left ventricular global longitudinal strain assessed by echocardiography.	12 months
Non-procedure-related life-threatening or disabling bleeding	Exploratory outcome. VARC-3 definition.	12 months
Number of major adverse clinical events	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	12 months
Troponin T	Exploratory outcome. Assessment of blood samples.	12 months
Infective endocarditis	Exploratory outcome. Definition by Duke criteria.	12 months
Change in quality of life - Kansas City Cardiomyopathy Questionnaire	Exploratory outcome. Assessed by change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (score 0-100, Higher value indicates better quality of life).	12 months
Cognitive function	Exploratory outcome. Assessed by change in the Mini-cog score	12 months
Clinical efficacy	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.	5 years
All-cause mortality	Fifth hierarchical secondary outcome. Intention-to-treat population.	5 years
Echocardiographic signs of valve degeneration	Exploratory outcome. Change in transaortic pressure gradient assessed by echocardiography.	5 years
Cardiac function	Exploratory outcome. Change in left ventricular global longitudinal strain assessed by echocardiography.	5 years
N-terminal pro-B-type natriuretic peptide	Exploratory outcome. Assessment of blood samples.	5 years
Troponin T	Exploratory outcome. Assessment of blood samples.	5 years
Individual components of MACE	Exploratory outcome. Assessment of the individual components of MACE (the primary outcome at long-term follow-up).	5 years
Change in quality of life - Kansas City Cardiomyopathy Questionnaire	Exploratory outcome. Assessed by change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (score 0-100, Higher value indicates better quality of life).	5 years
Cognitive function	Exploratory outcome. Assessed by change in the Mini-cog score	5 years
Infective endocarditis	Exploratory outcome. Definition by Duke criteria.	5 years
Clinical efficacy	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.	10 years
All-cause mortality	Fifth hierarchical secondary outcome. Intention-to-treat population.	10 years
Echocardiographic signs of valve degeneration	Exploratory outcome. Change in transaortic pressure gradient assessed by echocardiography.	10 years
Cardiac function	Exploratory outcome. Change in left ventricular global longitudinal strain assessed by echocardiography.	10 years
N-terminal pro-B-type natriuretic peptide	Exploratory outcome. Assessment of blood samples.	10 years
Troponin T	Exploratory outcome. Assessment of blood samples.	10 years
Individual components of MACE	Exploratory outcome. Assessment of the individual components of MACE (the primary outcome at long-term follow-up).	10 years
Change in quality of life - Kansas City Cardiomyopathy Questionnaire	Exploratory outcome. Assessed by change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (score 0-100, Higher value indicates better quality of life).	10 years
Cognitive function	Exploratory outcome. Assessed by change in the Mini-cog score	10 years
Infective endocarditis	Exploratory outcome. Definition by Duke criteria.	10 years

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: University of Oslo
• Investigators: Principal Investigator: Øyvind H Lie, MD, PhD, Oslo University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 4, 2021
• Primary Completion (ANTICIPATED): November 1, 2026
• Study Completion (ANTICIPATED): November 1, 2026

Study Registration Dates

• First Submitted: August 19, 2021
• First Submitted That Met QC Criteria: August 30, 2021
• First Posted (ACTUAL): September 5, 2021

Study Record Updates

• Last Update Posted (ACTUAL): November 14, 2022
• Last Update Submitted That Met QC Criteria: November 10, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Transcatheter Aortic Valve Replacement; Antiplatelet therapy; Antithrombotic therapy; Transcatheter Aortic Valve Implantation; Anticoagulation therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Rivaroxaban; Apixaban; Edoxaban
• Other Study ID Numbers: 247400; 2021-001554-61 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The application to share IPD is pending with the ethical committee.
• IPD Sharing Time Frame: 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.
• IPD Sharing Access Criteria: Researchers and clinicians with valid medical questions to be addressed. The data will not be available for commercial use.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No