AntiCoagulation Versus AcetylSalicylic Acid After Transcatheter Aortic Valve Implantation
Phase: PHASE3
Conditions: Aortic Stenosis
Sponsor: Oslo University Hospital

 
1 
 
 
Title: AntiCoagulation versus AcetylSalicylic Acid after Transcatheter Aortic Valve Implantation 
 
An investigator-sponsored multicentre prospective randomized open-label blinded-endpoint trial 
comparing the effect of anticoagulation treatment after transcatheter aortic valve implantation to 
the standard single anti-platelet treatment 
 
Protocol v. ACASA-TAVI-2.4 
February 12st, 2022 
EudraCT: 2021-001554-61 
 
Sponsor: Oslo University Hospital, Oslo, Norway 
Dr. Øyvind H. Lie 
Section for Interventional Cardiology 
Department of Cardiology 
Oslo University Hospital, Rikshospitalet 
Chief of department: Prof. Thor Edvardsen 
Monitor: Oslo University Hospital, Clinical Trial Unit 
 
 

 
2 
 
Contents 
 
Contents ...................................................................................................................................... 2 
Protocol Synopsis ......................................................................................................................... 7 
Abbreviations ..................................................................................................................... 11 
Disclosures ................................................................................................................................ 11 
Background and rationale .......................................................................................................... 12 
Objective ............................................................................................................................... 13 
Hypothesis ............................................................................................................................. 13 
Study endpoints ......................................................................................................................... 13 
Co-primary endpoints at 12 months ........................................................................................ 13 
Hypo-attenuated leaflet thickening (HALT, first co-primary endpoint) .................................. 13 
Safety Composite (second co-primary endpoint) .................................................................. 14 
Secondary endpoints .............................................................................................................. 15 
Key secondary endpoints (hierarchical) ............................................................................... 15 
Secondary safety endpoints ................................................................................................ 16 
Exploratory secondary endpoints ........................................................................................ 16 
Corresponding objectives and endpoints at 12 months ........................................................ 18 
Primary endpoint at 5 and 10 years ........................................................................................ 20 
Major adverse cardiac events (MACE) ................................................................................. 20 
Secondary endpoints at 5 and 10 years ................................................................................... 20 
Study design .............................................................................................................................. 21 
Population ............................................................................................................................. 21 
Inclusion criteria .................................................................................................................... 22 
Exclusion criteria .................................................................................................................... 22 
Management of patients meeting exclusion criteria ............................................................ 23 
Estimated study period........................................................................................................... 23 
Management of low inclusion rate ...................................................................................... 24 
Intervention ........................................................................................................................... 24 
Treatment ................................................................................................................................. 24 
Acetylsalicylic acid .................................................................................................................. 24 
Direct oral anticoagulant ........................................................................................................ 24 
Apixaban ............................................................................................................................ 25 
Edoxaban ........................................................................................................................... 25 
Rivaroxaban ....................................................................................................................... 26 
Cost .................................................................................................................................... 26 
Duration ............................................................................................................................. 26 

 
3 
 
Compliance ............................................................................................................................ 26 
Cross-over .............................................................................................................................. 26 
Concomitant medication ........................................................................................................ 26 
Consideration of placebo control ............................................................................................ 27 
Study procedure ........................................................................................................................ 27 
Screening ............................................................................................................................... 27 
Informed consent ............................................................................................................... 27 
Physical examination .......................................................................................................... 28 
Medical history ................................................................................................................... 28 
Quality of life ..................................................................................................................... 28 
Concomitant medication ..................................................................................................... 28 
Laboratory analyses ............................................................................................................ 28 
Echocardiography ................................................................................................................... 28 
Quality of life ..................................................................................................................... 28 
Randomisation ....................................................................................................................... 29 
Study drug initiation ............................................................................................................... 29 
Telephone contact or visit at 3, 6 and 9 months ...................................................................... 29 
Subgroup assessment of patients from Sørlandet Hospital ................................................... 29 
Medical history ................................................................................................................... 30 
Concomitant medication ..................................................................................................... 30 
Safety assessment .............................................................................................................. 30 
Drug discontinuation .......................................................................................................... 30 
End of treatment visit ............................................................................................................. 30 
Cardiac CT .......................................................................................................................... 30 
Echocardiography ............................................................................................................... 30 
Quality of life ..................................................................................................................... 30 
Medical history ................................................................................................................... 31 
Physical examination .......................................................................................................... 31 
Concomitant medication ..................................................................................................... 31 
Laboratory analyses ............................................................................................................ 31 
Safety assessment .............................................................................................................. 31 
5-year assessment .................................................................................................................. 31 
Echocardiography ............................................................................................................... 31 
Quality of life ..................................................................................................................... 32 
Medical history ................................................................................................................... 32 
Physical examination .......................................................................................................... 32 
Concomitant medication ..................................................................................................... 32 

 
4 
 
Laboratory analyses ............................................................................................................ 32 
10-year assessment ................................................................................................................ 32 
Echocardiography ............................................................................................................... 32 
Quality of life ..................................................................................................................... 33 
Medical history ................................................................................................................... 33 
Physical examination .......................................................................................................... 33 
Concomitant medication ..................................................................................................... 33 
Laboratory analyses ............................................................................................................ 33 
Table summary ...................................................................................................................... 33 
Patient discontinuation .......................................................................................................... 34 
Procedures for discontinuation ............................................................................................... 34 
Study drug discontinuation ................................................................................................. 34 
Patient discontinuation....................................................................................................... 35 
Trial discontinuation ........................................................................................................... 35 
Assessments .............................................................................................................................. 35 
Cardiac computed tomography ............................................................................................... 35 
Echocardiography ................................................................................................................... 37 
Transoesophageal echocardiography .................................................................................. 39 
Cerebral magnetic resonance imaging ................................................................................. 40 
Clinical events .................................................................................................................... 40 
Bleeding events ...................................................................................................................... 40 
Outcome definition: ........................................................................................................... 41 
Stroke .................................................................................................................................... 41 
Myocardial infarction ............................................................................................................. 42 
Peri-procedural MI ............................................................................................................. 42 
Spontaneous MI ................................................................................................................. 43 
Death ..................................................................................................................................... 43 
Laboratory analyses ............................................................................................................... 44 
Quality of life ......................................................................................................................... 44 
Cognitive function .................................................................................................................. 44 
Safety monitoring and reporting ................................................................................................ 44 
Definitions ............................................................................................................................. 45 
Adverse event (AE) ............................................................................................................. 45 
Adverse events of special interest (AESI) ............................................................................. 45 
Serious adverse event (SAE) ................................................................................................ 45 
Suspected unexpected serious adverse reaction (SUSAR) ..................................................... 46 
Time period for reporting AE and SAE ..................................................................................... 46 

 
5 
 
Recording of adverse events ................................................................................................... 46 
Reporting procedure .............................................................................................................. 48 
Adverse events, adverse events of special interest and serious adverse events .................... 48 
Suspected unexpected serious adverse reactions ................................................................ 48 
Annual safety report ........................................................................................................... 49 
Clinical study report ............................................................................................................ 49 
Safety monitoring ............................................................................................................... 49 
Accountability of investigational products ........................................................................... 49 
Data management and monitoring ............................................................................................. 49 
Electronic case report forms (eCRF)......................................................................................... 50 
Source data ............................................................................................................................ 50 
Study monitoring ................................................................................................................... 51 
Confidentiality ....................................................................................................................... 51 
Database management .......................................................................................................... 51 
Biobank ................................................................................................................................. 51 
Data Sharing .......................................................................................................................... 52 
Potential risks and benefits ........................................................................................................ 52 
Statistical methods and data analysis ......................................................................................... 52 
Determination of sample size ................................................................................................. 52 
Randomisation ....................................................................................................................... 54 
Allocation- sequence generation ......................................................................................... 54 
Allocation- procedure to randomise a patient ..................................................................... 54 
Blinding .............................................................................................................................. 54 
Population for Analysis ........................................................................................................... 55 
Planned analyses .................................................................................................................... 56 
Statistical analysis .................................................................................................................. 56 
Co-primary endpoints ......................................................................................................... 56 
Primary endpoint (MACE) at 5 and 10 years ......................................................................... 57 
Secondary endpoint at 5 and 10 years ................................................................................. 57 
Pre-defined subgroup analyses ........................................................................................... 57 
Key secondary endpoints .................................................................................................... 58 
Secondary safety endpoints ................................................................................................ 58 
Exploratory secondary endpoints ........................................................................................ 58 
Missing data ....................................................................................................................... 58 
Project management .................................................................................................................. 59 
Investigator delegation procedure .......................................................................................... 59 
Protocol adherence ................................................................................................................ 59 

 
6 
 
Study amendments ................................................................................................................ 59 
Audit and inspections ............................................................................................................. 59 
Management ......................................................................................................................... 59 
Ethical and regulatory requirements ........................................................................................... 60 
Ethical considerations for participants .................................................................................... 61 
Ethics committee approval ..................................................................................................... 61 
Trial registration..................................................................................................................... 61 
Informed consent procedure .................................................................................................. 61 
Subject identification ............................................................................................................. 62 
Trial sponsorship and financing .................................................................................................. 62 
Trial insurance ........................................................................................................................... 62 
Cost-benefit considerations ........................................................................................................ 62 
Publication policy....................................................................................................................... 62 
Authorship ............................................................................................................................. 63 
Popular science dissemination ................................................................................................ 63 
User representation ................................................................................................................... 63 
Spin-offs .................................................................................................................................... 64 
Planned spin-off analyses ....................................................................................................... 64 
Partners ..................................................................................................................................... 66 
Section for echocardiography, Oslo University Hospital, Rikshospitalet.................................... 66 
The Intervention Centre, Oslo University Hospital, Rikshospitalet ............................................ 66 
Section for Interventional Cardiology, Oslo University Hospital, Ullevål ................................... 66 
Department of Internal Medicine, Sørlandet Sykehus, Arendal ................................................ 66 
Research Institute for Internal Medicine, Oslo University Hospital ........................................... 66 
References ................................................................................................................................. 68 
Signature Page ........................................................................................................................... 71 
 
 
 

 
7 
 
Protocol Synopsis 
Sponsor 
Oslo University Hospital 
Phase and study type 
Phase III, multicentre prospective randomized open-label blinded 
endpoint (PROBE) trial 
Investigational Medical 
Product (including active 
comparator and placebo) :       
Direct oral anticoagulant-based antithrombotic treatment versus the 
standard acetylsalicylic acid-based antithrombotic treatment 
Centres: 
Oslo University Hospital, Rikshospitalet Hospital, Oslo, Norway 
Oslo University Hospital, Ullevål Hospital, Oslo, Norway 
Study Period: 
 
Actual start December 7th, 2021 
Anticipated recruitment duration 4 years until November 30th, 2025 
Last subject last visit (end-of-trial): November 30th, 2026 
Treatment Duration: 
12 months 
Follow-up: 
12 months, 5 years, and 10 years 
Objectives  
The main goal of this study is to evaluate the effect and safety of direct 
oral anticoagulation versus versus acetylsalicylic acid after 
transcatheter aortic valve implantation 
Co-Primary endpoints 12 months:  
Hypo-attenuated leaflet thickening 
- 
CT evidence of increased hypo-attenuated leaflet thickness 
- 
Intention-to-treat, superiority, at 12 months 
Safety composite, composite of 
- 
VARC-3 bleeding events 
o Type 1, 2, 3 or 4 
- 
Thromboembolic events 

 
8 
 
o Myocardial infarction 
o Stroke of any cause 
- 
All-cause mortality 
- 
Per-protocol, non-inferiority, at 12 months 
Secondary endpoints at 12 months: 
Key secondary endpoints (hierarchical): 
- 
Clinical efficacy, intention-to-treat, superiority, composite of: 
o Freedom from all-cause mortality 
o Freedom from all stroke 
o Freedom from hospitalization for procedure- or valve-
related causes 
o Freedom from KCCQ overall summary score <45 or 
decline from baseline of >10 points 
- 
Safety composite, intention-to-treat, superiority 
- 
Thromboembolic events 
- 
Bleeding events 
- 
All-cause mortality 
Secondary safety endpoints: 
- 
The number of adverse events 
- 
The number of serious adverse events 
- 
Life-threatening or disabling bleeding  
- 
Major bleeding  
- 
Minor bleeding  
Exploratory secondary endpoints: 
- 
CT signs of valve degeneration 

 
9 
 
- 
Echocardiographic signs of valve degeneration 
- 
Non-procedure-related life-threatening or disabling bleeding 
(VARC-3) 
- 
Number of major adverse clinical events, 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 
- 
Quality of life as assessed by the KCCQ and the EQ5D 5L 
EuroQoL questionnaires, and HADS 
- 
Per-protocol primary efficacy endpoint sensitivity analysis  
- 
Intention-to-treat primary safety endpoint sensitivity analysis 
- 
Cognitive function as assessed by the Mini-cog 
- 
N-terminal pro-B-type natriuretic peptide (change) 
- 
Cardiac troponin T (change) 
- 
Infective endocarditis 
Primary endpoint 5 and 10 years 
Rate of MACE, composite of 
- 
Cardiac death 
- 
Aortic valve re-intervention 
- 
Stroke 
- 
Myocardial infarction 
- 
Heart failure hospitalization 
- 
Major, life-threatening, or disabling bleeding 
Secondary endpoints 5 and 10 years 
- 
Individual components of primary composite 
- 
Echocardiography 

 
10 
 
o These 3rd and 4th repeated echocardiographic 
assessments of the implanted valve provide 
information on progression of hemodynamic structural 
valve degeneration 
- 
Clinical efficacy 
- 
NYHA-class trajectory 
- 
Cognitive function as assessed by the Mini-cog 
- 
N-terminal pro-B-type natriuretic peptide (change) 
- 
Cardiac troponin T (change) 
- 
Infective endocarditis 
Study Design: 
Multicentre, dual arm, open label, blinded endpoint, randomised, active 
controlled trial 
Main Inclusion Criteria:    
Successful trans-catheter aortic valve implantation in patients aged >65 
and <80 years old at the time of the procedure 
Main 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 
Sample Size: 
360 patients 
Efficacy Assessments: 
Cardiac CT, echocardiography, clinical assessment 
Safety Assessments: 
Patient interview at 3, 6 and 9 months. Physical examination and 
clinical assessment after 12months. 
 
 
 

 
11 
 
Abbreviations 
AS – aortic stenosis 
ASA – acetylsalicylic acid 
BARC – bleeding academic research consortium consensus 
CT – computed tomography 
DOAC – direct oral anti-coagulation 
eCRF – electronic case report form 
HALT – hypo-attenuated leaflet thickening 
SmPC – summary of product characteristics 
SVD – structural valve degeneration 
TAVI – transcatheter aortic valve intervention 
TIA – transient ischemic attack 
VARC 3 – valve academic research consortium-3 consensus 
 
Disclosures 
The authors have no commercial interests or economic disclosures related to the project. 
 
 
 
 

 
12 
 
Background and rationale 
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 risk1, 2. 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 risk3, 4. This 
practice increases the importance of long-term valve maintenance.  
Observational data have suggested that early signs of valve degeneration are associated with an 
increased risk of embolic events5, 6. 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 effects5, 6.  
The current practice guidelines recommend that oral anticoagulation may be considered for 3 
months after open surgical bioprosthetic valve implantation7. 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 
recommended7. 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 outcomes8. 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. The 
ongoing ATLANTIS trial (clinicaltrials.gov NCT02664649) is the only other trial assessing DOAC after 
TAVI. ATLANTIS trial is not powered for valve degeneration, does not include systematic imaging, is 
not powered for the subgroup of patients without indication for anticoagulation (and thereby also 
not powered for the comparison of DOAC vs single antiplatelet therapy), does not have blinded 
endpoint design, and includes an older population9. 
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 outcomes8, 10, 11. Combined anti-platelet and anti-
coagulation treatment has been shown to reduce valve degeneration at the cost of increased 
bleeding12, 13. Conversely, single anti-platelet therapy and anti-coagulation with a direct oral anti-
coagulant (DOAC) have been associated with similar bleeding risk14. Bleeding rates in patients 

 
13 
 
treated with anti-coagulation after TAVI have been reported to be slightly higher than in patients 
treated with ASA after TAVI8, 10, 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. 
Objective 
The primary objective is to evaluate the efficacy and safety of direct oral anticoagulation (DOAC) 
monotherapy versus acetylsalicylic acid (ASA) monotherapy after transcatheter aortic valve 
implantation. 
Hypothesis 
A DOAC-based strategy is superior to an ASA-based strategy to prevent valve degeneration in 
patients after successful TAVI, and non-inferior to ASA for safety. This advantage translates into 
favourable long-term clinical outcome. 
Study endpoints 
Study endpoints will comply with the updated endpoint definitions for aortic valve clinical research 
in VARC-315. 
Co-primary endpoints at 12 months 
The first objective of ACASA-TAVI is to assess whether 
DOAC can reduce the prevalence of valve degeneration 
after TAVI without imposing worse short-term clinical 
outcome. This study question translates to two co-
primary endpoints, where both null hypotheses must be 
rejected for the intervention to be considered 
successful: 
Hypo-attenuated leaflet thickening (HALT, first co-
primary endpoint) 
- 
Hypo-attenuated leaflet thickening (Figure 1) 
- 
intention-to-treat, superiority, at 12 months 
Figure 1 - Hypo-attenuated leaflet 
thickening. VARC-3, Eur Heart J 2021 00, 
1-31 

 
14 
 
The first co-primary composite study endpoint is “Hypo-attenuated leaflet thickening” (hereafter 
“HALT”). The definition of HALT in ACASA-TAVI will be the rate of patients with at least one 
prosthetic leaflet with hypo-attenuated leaflet thickening (HALT) by cardiac CT as defined by VARC-
315.  
HALT is visually identified increased thickness of the bioprosthetic leaflet on the contrast-enhanced 
CT (see Assessments). This thickening typically extends from the stent frame leaflet origin and tapers 
towards the valve center. Reduced leaflet motion (RLM) was the primary endpoint of the GALILEO-
4D trial13, but it is now recommended to focus on HALT in clinical studies because RLM is subject to 
technical artifacts15. 
Management of valve degeneration observed at 12 months 
Observation of HALT at 12 months can be expected in approximately 20% in the ASA-group, and 
fewer in the DOAC-group. There is currently no scientific indication that SVD Stage 1 represents a 
clinical problem. That question will be further addressed in the 5- and 10-year follow-up. Therefore, 
isolated SVD Stage 1 will not be managed clinically. In patients where a thrombus and/or 
hemodynamic bioprosthetic valve deterioration (Stage 2 or 3) is observed, clinical management will 
be initiated. This may include a course of DOAC. This will be registered in the eCRF. 
Safety Composite (second co-primary endpoint) 
- 
VARC-3 bleeding events 
o Type 1, 2, 3 or 4 
- 
Thromboembolic events 
o Myocardial infarction 
o Stroke from any cause 
- 
Death from any cause 
- 
Per-protocol, non-inferiority, at 12 months 
The second co-primary study endpoint is Safety Composite at 12 months. The rationale for this 
endpoint composition is the acknowledgement that reduction in valve degeneration is only of 
clinical value if the intervention does not worsen clinical outcome. Two main concerns are 
addressed: 
- 
Will the use of DOAC increase bleeding risk? 

 
15 
 
- 
Will the omittance of ASA increase risk of stroke or myocardial infarction? 
This clinical endpoint includes bleeding events according to the Valve Academic Research 
Consortium 3 (VARC-3) criteria15 and thromboembolic events. Contrary to a common assumption, 
the current literature does not suggest that there will be a major difference in bleeding propensity 
between patients randomized to ASA or DOAC14. 
Thromboembolic events will include: Stroke of any cause and myocardial infarction. The inclusion of 
thromboembolic events in this non-inferiority endpoint is not straight forward. On one hand, some 
could argue that DOAC provides stronger protection against thromboembolic events than ASA, and 
therefore could bias a strict safety-endpoint towards non-inferiority. On the other hand, other 
clinicians are reluctant to omit ASA from the anti-thrombotic regime for safety concerns, similar to 
guideline practice after percutaneous coronary intervention. Therefore, the rationale for the non-
inferiority endpoint is justified from a clinical standpoint. Safety Composite will also include death to 
ensure that important events are not missed by the composite. It is suggested by the VARC-3 
consensus that mortality should primarily be assessed as all-cause mortality, and not limited to 
death from cardiac causes15. It will not include venous thromboembolism, because this would likely 
bias towards non-inferiority. 
The clinical applicability compromise is to assess non-inferiority for Safety Composite of the DOAC-
intervention to the active comparator. It is critical that bleeding events are registered without 
knowledge of study drug allocation. Therefore, data will be recorded on the outcome form via 
medical records and patient interviews before adjudication is made by the adjudication committee.  
Secondary endpoints 
Secondary endpoints are categorized as key secondary endpoints (hierarchical testing only), 
secondary safety endpoints (all tested for safety transparency) and exploratory secondary endpoints 
(all tested for hypothesis generation). 
Key secondary endpoints (hierarchical) 
- 
Clinical efficacy, intention-to-treat, superiority, composite of: 
o Freedom from all-cause mortality 
o Freedom from all stroke 
o Freedom from hospitalization for procedure- or valve-related causes 

 
16 
 
o Freedom from KCCQ overall summary score <45 or decline from baseline of >10 
points 
- 
Safety composite (second co-primary endpoint), intention-to-treat, superiority 
- 
Thromboembolic events (stroke or myocardial infarction) 
- 
Bleeding events (VARC-3 type 1, 2, 3 or 4) 
- 
All-cause mortality 
o Sub-classified report of cardiovascular and non-cardiovascular mortality (see 
Assessments; Death) 
Secondary safety endpoints 
- 
The number of adverse events 
- 
The number of serious adverse events 
- 
Lethal bleeding (VARC-3 type 4) (Suspected or confirmed 
- 
Life-threatening or disabling bleeding (VARC-3 type 3) 
- 
Major bleeding (VARC-3 type 2) 
- 
Minor bleeding (VARC-3 type 1) 
Exploratory secondary endpoints 
- 
Biosprosthetic valve deterioration Stage 1, 2 or 3 
- 
CT signs of valve degeneration 
o Hypo-attenuated leaflet thickening by grade at patient level and leaflet level 
o Reduced leaflet opening classified by grade at patient level and leaflet level with and 
without hypo-attenuated leaflet thickening 
o Leaflet sclerosis 
o Leaflet calcification 
o Valve thrombosis 
- 
Echocardiographic signs of valve degeneration 
o Delta value for mean gradient and estimated aortic valve opening area 

 
17 
 
o Delta value for left ventricular ejection fraction 
o Valvular regurgitation grade delta value 
- 
Non-procedure-related type 3 bleeding (VARC-3) 
- 
Number of major adverse clinical events, 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 
- 
Quality of life as assessed by the KCCQ and the EQ 5D 3L EuroQoL questionnaires, and HADS 
- 
Patient-reported outcome 
o Favourable, acceptable or unfavourable according to VARC-315. 
- 
Per-protocol primary efficacy endpoint sensitivity analysis  
- 
Intention-to-treat primary safety endpoint sensitivity analysis 
- 
Cognitive function as assessed by the Mini-cog 
- 
N-terminal pro-B-type natriuretic peptide (change) 
- 
Cardiac troponin T (change) 
- 
Infective endocarditis 
If other secondary endpoints become of interest during the study period, they will be highlighted as 
not pre-defined, and they will comply with the VARC-recommendations at the time. 
Definitions 
Bioprosthetic valve deterioration 
BVD will be defined according to VARC-315. 
- 
 Stage 1 
o Hypo-attenuated leaflet thickening (HALT) with or without reduced leaflet motion 
(RLM) and no new hemodynamic abnormality (mean gradient <20 mmHg and 
valvular regurgitation less than moderate) 
- 
Stage 2  
o Increased mean transvalvular gradient ≥10 mmHg resulting in ≥20 mmHg mean 
gradient with concomitant decrease in EOA ≥0.3cm2 or ≥25% 

 
18 
 
o Decrease in Doppler velocity index ≥0.1 or ≥20% compared with 3 month-control 
o New occurrence or increase of ≥1 grade of intraprosthetic regurgitation resulting in 
≥ moderate aortic valve regurgitation 
- 
Stage 3  
o Increased mean transvalvular gradient ≥20 mmHg resulting in ≥30 mmHg mean 
gradient with concomitant decrease in EOA ≥0.6cm2 or ≥50% 
o Decrease in Doppler velocity index ≥0.2 or ≥40% compared with 3 month-control 
o New occurrence or increase of ≥2 grade of intraprosthetic regurgitation resulting in 
severe aortic valve regurgitation 
The stages of bioprosthetic valve deterioration (BVD) are based on structural and functional 
characteristics of the valve, and not on patient response data, symptoms, or need for re-
intervention. However, patients with symptoms attributable to SVD are likely to be identified by 
these criteria. Antithrombotic medication is also administered in patients after TAVI to lower the risk 
of systemic embolism (stroke or transient ischemic attack [TIA]), and these symptoms will not 
necessarily be captured by the SVD definition. Stroke or TIA will be registered at 12 months by the 
use of a dedicated blinded endpoint eCRF filled in by a study nurse via access to the medical records 
and patient interviews and adjudicated by the adjudication committee.  
Endocarditis 
Meeting at least one of the following criteria: 
- 
Fulfilment of the Duke endocarditis criteria 
- 
Evidence of abscess, pus or vegetation secondary to infection confirmed by histological or 
microbiological studies during surgery 
- 
Evidence of abscess, pus or vegetation by autopsy 
Corresponding objectives and endpoints at 12 months 
 
Objective 
Endpoint 
Primary 
To assess whether DOAC treatment 
can reduce early valve degeneration 
after TAVI without risk of worse 
short-term clinical outcome 
compared to ASA treatment. 
 
 
 
First co-primary endpoint* 
- 
HALT (hypo-attenuated leaflet thickening) on 
cardiac CT, intention-to-treat, superiority 
Second co-primary endpoint* 
- 
Safety Composite (Composite of: bleeding 
events, thromboembolic events, all-cause 
mortality), per protocol, non-inferiority 
 

 
19 
 
 
 
The long-term clinical benefit will 
subsequently be assessed during 
long-time follow-up. 
 
 
 
 
*both primary endpoints must be met for the trial to declare success 
Secondary 
To assess key signals of favourable 
effects of DOAC treatment 
compared to ASA treatment after 
TAVI. 
Key secondary endpoints (hierarchical): 
- 
Clinical efficacy (Composite 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 
- 
Safety Composite (second co-primary 
endpoint), intention-to-treat, superiority 
- 
Thromboembolic events, intention-to-treat, 
superiority 
- 
Bleeding events, intention-to-treat, superiority 
- 
All-cause mortality, intention-to-treat, 
superiority 
Safety 
To assess the safety profile of DOAC 
treatment after TAVI, compared to 
ASA treatment 
Secondary safety endpoints: 
- 
The number of adverse events, safety 
population 
- 
The number of serious adverse events, safety 
population 
- 
Life-threatening or disabling bleeding, safety 
population 
- 
Major bleeding, safety population 
- 
Minor bleeding, safety population 
Exploratory 
To generate hypotheses of potential 
beneficial effects of DOAC treatment 
compared to ASA treatment after 
TAVI 
Exploratory secondary endpoints: 
- 
CT signs of valve degeneration 
- 
Echocardiographic signs of valve degeneration 
- 
Non-procedure-related life-threatening or 
disabling bleeding (VARC-3) 
- 
Number of major adverse clinical events, 
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 
- 
Quality of life as assessed by the KCCQ and the 
EQ5D 5L EuroQoL questionnaires, and HADS 
- 
Per-protocol primary efficacy endpoint 
sensitivity analysis  
- 
Intention-to-treat primary safety endpoint 
sensitivity analysis 
- 
Cognitive function as assessed by the Mini-cog 
- 
N-terminal pro-B-type natriuretic peptide 
(change) 
- 
Cardiac troponin T (change) 
- 
Infective endocarditis 
 

 
20 
 
Primary endpoint at 5 and 10 years 
The important second objective of ACASA-TAVI is to assess whether a DOAC-based antithrombotic 
regime improves clinical outcome at intermediate and long-term follow-up. This translates into one 
composite primary outcome to be assessed at 5 years and 10 years. 
Major adverse cardiac events (MACE) 
Avoidance of major adverse cardiac events (MACE) is of great importance for the patient after a 
medical intervention. The primary endpoint is the rate of MACE at the 5- and 10-year milestone. We 
define MACE as a composite of one of the following: 
- 
Cardiac death 
- 
Heart failure hospitalization 
- 
Re-intervention with valve-in-valve TAVI 
- 
Stroke 
- 
Myocardial infarction 
- 
VARC-3 type 2 – 4 secondary to or exacerbated by antithrombotic treatment 
The occurrence, number and time from TAVI till occurrence of these events will be registered by a 
study nurse or research fellow at 5 and 10 years and adjudicated in the eCRF by a blinded 
investigator. 
Secondary endpoints at 5 and 10 years 
These secondary endpoints will be exploratory of nature but will provide important information on 
the value of the DOAC intervention. 
- 
Components of the composite endpoint 
o Cardiac death 
o Heart failure hospitalization 
o Re-intervention on aortic valve 
o Stroke 
o Myocardial infarction 
o VARC-3 type 2 – 4 secondary to or exacerbated by antithrombotic treatment 

 
21 
 
- 
Freedom from bioprosthetic valve failure 
o Defined as Valve-related mortality OR re-intervention on aortic valve OR BVD Stage 
3 
- 
Echocardiography 
o These 3rd and 4th repeated echocardiographic assessments of the implanted valve 
provide information on progression of hemodynamic structural valve degeneration 
- 
Clinical benefit 
o NYHA-class trajectory 
o Cognitive function as assessed by the Mini-cog 
o N-terminal pro-B-type natriuretic peptide (change) 
o Cardiac troponin T (change) 
o Infective endocarditis 
We will also assess whether an improvement in MACE was mediated by reduction in SVD at 12 
months. 
Study design 
ACASA-TAVI is an investigator sponsored randomized controlled trial of prospective randomized 
open-label blinded-endpoint (PROBE) design. 
Population 
Patients aged less than 80 years at the time of the procedure who are accepted for TAVI by the heart 
team in two high-volume centres in Norway (Rikshospitalet and Ullevål Hospital) are eligible for 
participation in the trial. All patients who receive TAVI in the two centres during the study period will 
receive information before hospital admission, will be screened for inclusion and approached on day 
one following successful TAVI. Patients will be included in the study only when written informed 
consent is provided. 
Baseline characteristics, including age, sex and body-mass index, will be recorded. Comorbidities will 
be recorded with special attention to coronary artery disease, hypertension, diabetes mellitus, heart 
failure, previous stroke, peripheral artery disease, venous thromboembolism, chronic obstructive 
pulmonary disease or permanent pacemaker. Baseline glomerular filtration rate, cardiac troponin t 

 
22 
 
and NT-proBNP will be recorded. In addition, biobank samples will be obtained and frozen according 
to appropriate procedures. 
Procedural characteristics will be recorded. The valve type and size will be noted, as well as valve-in-
valve procedure and post-implantation dilation. The presence of supra-annular leaflet position will 
be noted, together with any procedural bleeding or thrombotic complications. 
Inclusion criteria 
All patients undergoing TAVI during the study period will be screened. Eligible patients:  
- 
Patients aged >65 and <80 years old after successful TAVI 
o Successful TAVI will be defined as:  
▪ 
Freedom from mortality 
▪ 
Successful access, device delivery, and retrieval of the delivery system 
▪ 
Correct positioning of a single prosthetic heart valve into the proper 
anatomical location 
▪ 
No procedural complications or device related interventions that prevents 
the introduction of a study medication within 72 hours (ongoing 
uncontrolled bleeding, peripheral stent graft demanding antiplatelet drugs, 
coronary intervention, major stroke with risk of haemorrhagic 
transformation etc.) 
- 
Signed informed consent and expected compliance with protocol 
Exclusion criteria 
It is an explicit aim of the study to assess a real-world population, and therefore exclusions criteria 
are established to reflect clinical practice. Patients will not be included if they have: 
- 
Contraindication for DOAC or ASA 
- 
Conventional indication for long-term DOAC 
o Atrial fibrillation 
o Recent or recurrent venous thromboembolism 
o Other 
- 
Conventional indication for anti-platelet therapy 

 
23 
 
o Recent percutaneous coronary intervention for chronic coronary syndrome (last 12 
months) 
o Other 
- 
Are unable to start the study medication within 72 hours after the procedure 
- 
Concomitant use of inhibitors of CYP3A4 and P-glycoprotein (such as the antimycotic agents 
ketoconazole, itraconazole, voriconazole, posaconazole and HIV-protease inhibitors) and 
inducers of CYP3A4 and P-glycoprotein (phenytoin, carbamazepine, phenobarbital or St. 
Johns wort). 
Management of patients meeting exclusion criteria 
Patients who have provided signed consent in which screening reveals one or more exclusion criteria 
will be considered for inclusion in a parallel observational database in which no study related 
assessments are performed. These patients will be managed according to guideline 
recommendations, and the data from clinical follow-up will be registered. 
Estimated study period 
Rikshospitalet Hospital performs approximately 500 TAVI procedures per year, and this figure is 
steadily increasing. We retrospectively assessed study inclusion and exclusion criteria in the patient 
population of 3 months from September to November 2020 prior to performing these calculations 
and observed that 43 of 72 patients (60%, 30% of total population) would have been eligible for 
inclusion. This implies a realistic eligibility of approximately 100-120 patients per year in this centre.  
Ullevål Hospital performs approximately 200 
TAVI procedures per year. From pragmatic 
estimations from clinical practice, it seems 
reasonable to expect that 20% will be eligible 
for inclusion. This translates into 
approximately 30-40 eligible patients per 
year at this centre.  
With an expanding number of procedures 
and some unwilling to participate, it seems 
reasonable to infer that inclusion of the 360 patients will be completed within 4 years. The analysis 
will therefore be performed 5 years after study start. With actual inclusion start on December 7th 

 
24 
 
2021 we estimate complete recruitment by November 30th 2025 and last subject last visit (LSLV) by 
November 30th 2026.  
The time of LSLV will be the end-of-trial. 
Five-year analysis will be performed after November 30th 2030, and ten-year analysis after 
November 30th 2035. The data will be destroyed five years after the concluding publication. 
Management of low inclusion rate 
Every patient undergoing TAVI in the two trial centres will undergo pre-screening. If the average 
quarterly inclusion rate falls below 23 (the number needed to include 360 in 4 years) we will 
approach a third collaborating centre in Haukeland Hospital to widen the inclusion. 
Intervention 
Participants will be randomized on day one post successful TAVI to antithrombotic treatment with 
either DOAC of anti Xa-type for 1 year followed by ASA indefinitely (intervention) or ASA indefinitely 
(control). 
Treatment 
Acetylsalicylic acid 
The control group will receive ASA, the standard of care. The antiplatelet effect of ASA is due to its 
inhibition of cyclooxygenase. The standard dosing is 75 mg QD, and there are no dose adjustments. 
The medication will be managed in agreement with the SmPC (Appendix). 
If patients randomized to ASA strategy do not tolerate the drug, either due to adverse effects or 
unexpected allergy, conversion to clopidogrel is recommended according to current clinical practice. 
The treatment will be started immediately after randomization and will continue indefinitely. 
In cases of ASA intolerance, conversion to clopidogrel, an inhibitor of ADP connection to the P2Y12-
receptor, will be considered. All reference safety information will be based on the SmPC for ASA. 
Direct oral anticoagulant 
The intervention group will receive an anti-Xa type DOAC (apixaban, rivaroxaban or edoxaban). 
DOAC of direct thrombin inhibition type (dabigatran) will be avoided to obtain homogenous 
intervention mechanisms and reduce concerns related to previous experience with surgical 
mechanical valves16. DOAC agents will be tested as monotherapies. This includes rivaroxaban 
which has previously been tested in combination with ASA11. Based on previous data from 

 
25 
 
patients with other clinical indications for DOAC treatment10, it is unlikely that DOAC 
monotherapy will be inferior to standard therapy with ASA. 
The choice of agent will be made after clinical discussion between the patient and the treating 
clinician, in which also possible pharmacological interactions or notes of cautions from the 
corresponding SmPC must be considered. The treatment will be started in a timely manner within 72 
hours after randomization accommodating clinical judgement and any subsequent invasive 
procedures (like pacemaker implantation) and continue for 12 months. Thereafter, treatment will be 
converted to ASA indefinitely. One of the following agents will be used at the choice of the patient 
and clinician: 
Apixaban 
Apixaban is an anti-Xa type DOAC sold under the generic name “Eliquis”, and is the most widely used 
agent in our clinical practice. The standard dosing is 5 mg BID. This dose should be reduced to 2.5 mg 
BID if two or three of the following criteria are present: 
- 
Age > 80 years (not relevant at inclusion in ACASA-TAVI but may occur during follow-up. 
- 
Body weight < 60 kg 
- 
Reduced renal function (ClCR 15-29 ml/min) 
The medication will be managed in agreement with the SmPC (Appendix). All reference safety 
information will be based on the SmPC for apixaban. 
Edoxaban 
Edoxaban is an anti-Xa type DOAC sold under the generic name “Lixiana”. Standard dosing is 60 mg 
QD. This dose should be reduced to 30 mg QD if one of the following criteria are present: 
- 
Reduced renal function (ClCR 15-50 ml/min)  
- 
Low bodyweight ≤60 kg 
- 
Use of the following P-gp-inhibitors: Ciclosporine, dronedarone, erythromycin or 
ketoconazole. 
The medication will be managed in agreement with the SmPC (Appendix). All reference safety 
information will be based on the SmPC for edoxaban. 

 
26 
 
Rivaroxaban 
Rivaroxaban is an anti-Xa type DOAC sold under the generic name “Xarelto”. The standard dosing is 
20 mg QD. This dose should be reduced to 15 mg QD if the patient has reduced renal function 
(ClCR 15-49 ml/min). 
The medication will be managed in agreement with the SmPC (Appendix). All reference safety 
information will be based on the SmPC for rivaroxaban. 
Cost 
Patients randomized to ASA will receive a refunded prescription based on the current approved 
treatment indication. Standard dose DOAC will cost approximately 9.000 NOK for one year 
treatment for one patient. The total cost of DOAC in ACASA-TAVI will be approximately 1.65 MNOK. 
Arrangements for supply of DOAC or financial re-imbursement of DOAC to patients allocated to the 
DOAC group are not finalized. 
Duration 
DOAC will be administered for 12 months. From the 12-month visit, all study participants will receive 
ASA 75 mg QD indefinitely. 
Compliance 
Participant compliance to the investigational products will be self-reported and registered at the 3-, 
6-, 9- and 12-month visits. The data will be reported with the trial results. The batch numbers of 
used study medication will be registered at every time point. 
Cross-over 
If patients in the ASA-group develop an indication for anti-coagulation (i.e. atrial fibrillation or 
venous thromboembolism) during follow-up, they will cross over to the DOAC group. Conversely, 
patients in the DOAC-group who develop an indication for anti-platelet therapy (i.e. percutaneous 
coronary intervention) will cross over to the ASA-based group. The time of cross over will be noted. 
Cross-over patients will remain in their original group for the intention-to-treat analyses, and per-
protocol analyses will be performed as predefined. 
Concomitant medication 
Use of concomitant medication which is not a trial exclusion criterion (i.e. not a known inhibitor og 
inducer of CYP3A4 or P-glycoprotein) is permitted. Starting these medications during the trial period 
is not permitted. For other and permitted concomitant medication, potential interactions and 
notions of care from the SmPC shall be considered and noted at inclusion. 

 
27 
 
Consideration of placebo control 
A traditional trial design to minimize bias is the double-blind placebo design. Placebo control was 
discussed during the planning of ACASA-TAVI. The study will assess a new intervention instead of, 
not in addition to, the old standard. The standard is dosed QD and the most common DOAC is BID. 
Production of identical pills containing one of the two agents would be costly. Adequately blinded 
adjudication  of the pivotal study endpoints can be achieved using the PROBE-design. The primary 
endpoints and key secondary endpoints are not likely to be influenced by the lack of patient 
blinding. If anything, any reporting bias resulting from the lack of patient blinding could be expected 
to go in the direction of more bleeding reported in the DOAC group. This would bias the safety signal 
against DOAC, and a result suggesting agreeable safety would inspire more confidence.  
After these thorough discussions we have decided that it is reasonable to utilize a PROBE-study 
design without patient blinding. 
Study procedure 
Study participants will be recruited from the group of patients undergoing TAVI for severe aortic 
stenosis at Oslo University Hospital. The age of all patients undergoing TAVI will be assessed and 
those aged less than 80 years old will be approached for further evaluation. 
 
Screening 
Informed consent 
Voluntary, written informed consent (Appendix A) must have been obtained for each subject before 
any study specific procedure is initiated. At this time, the patient will be registered in the eCRF, and a 
unique identifier will be assigned.  
The following tests will be performed at screening: 

 
28 
 
Physical examination 
A physical examination (including examination of heart, lungs, abdomen, neck and assessment of 
peripheral circulation and oedema) must be performed; vital signs (blood pressure, and heart rate); 
and height and weight must be recorded. 
Medical history 
A medical history must be obtained, and age; gender; NYHA functional status; risk factors 
(hypertension, smoking, and diabetes mellitus); and concomitant disease must be recorded.  
Quality of life 
Self-reported, health-related quality of life will be gauged with the KCCQ and the EQ 5D 3L EuroQoL 
questionnaires, and HADS. We will allow subjects to complete the quality-of-life assessments before 
study procedures are performed. 
Concomitant medication 
All concomitant medication used by the participant within 28 days of the start of treatment must be 
recorded in the eCRF by generic name and dose. 
Laboratory analyses 
Fasting blood samples will be obtained to determine: Haemoglobin; white blood cell count, platelet 
count; serum potassium; serum sodium; glucose, glycosylated haemoglobin (HbA1c); creatinine; 
ALT; bilirubin; albumin; INR; CK; CRP; NT-proBNP; total cholesterol; LDL cholesterol, high density 
lipoprotein cholesterol and triglycerides. Blood for efficacy analyses (specified later) must be 
collected, drawn, and appropriately labelled and stored in a dedicated biobank for later analysis. 
Echocardiography 
A comprehensive echocardiographic exam for study purposes must be performed prior to study drug 
administration. A copy of this exam will be stored in the clinical imaging archive under the patient’s 
real name for reasons of safety. 
Quality of life 
Self-reported, health-related quality of life will be gauged with the KCCQ and the EQ 5D 3L EuroQoL 
questionnaires, and HADS. We will allow subjects to complete the quality-of-life assessments before 
study procedures are performed. 

 
29 
 
Randomisation  
After confirmation of eligibility, baseline measurements can be made, and the online randomisation 
process can be performed. If more than 72 hours have passed since the screening visit, the physical 
exam should be repeated, vital signs recorded anew, and safety blood samples should be repeated.  
The project will utilize a secure eCFR with randomization tool (Viedoc®) for randomization of 
participants. After randomization, the caring cardiologist will enter a statement to the patient’s 
electronic medical record declaring the allocation and treatment duration. This statement will be 
distributed to other physicians caring for the patients and will include a recommendation to only 
alter the study medication if it is critically important. 
Study drug initiation 
In patients randomized to DOAC, the treatment will be prescribed and initiated by the cardiologist 
attending to the patient on day 1 post TAVI. Antiplatelet drugs given prior to the procedure will be 
terminated.  
In patients randomized to ASA, the treatment with 75 mg QD will be continued on day 1 post TAVI. 
Some patients will have received loading dose clopidogrel prior to TAVI. This drug will not be 
continued after inclusion. 
Telephone contact or visit at 3, 6 and 9 months 
These visits are for monitoring and assessing safety and adherence to protocol. Telephone contact 
will be the default, with an option to decide for physical visits according to the feasibility and 
convenience of the patient. 
Subgroup assessment of patients from Sørlandet Hospital 
Subgroup assessments at 3 months have been planned for all patients from one collaborating centre 
(Sørlandet Hospital). This subgroup analysis aims to assess the dynamics of early structural valve 
degeneration. No previous studies have reported the timing of onset of the first co-primary endpoint 
HALT, and this may give insights to the optimal DOAC treatment duration. This will be an exploratory 
subgroup assessment in which the standard clinical follow-up of echocardiography, medical history, 
physical exam and laboratory tests will be recorded and supplemented by a dedicated cardiac CT. 
The analysis will be performed after end-of-trial and the primary analysis, and the early effect of 
DOAC on valve dynamics and morphology will be reported. 
 

 
30 
 
Medical history 
A medical history must be obtained, and NYHA functional status; well-being; adverse events; and 
concomitant disease must be recorded.  
Concomitant medication 
All concomitant medication used by the participant within 28 days of the start of treatment must be 
recorded in the eCRF by generic name and dose. Use of concomitant medication which is not a trial 
exclusion criterion (i.e. not a known inhibitor og inducer of CYP3A4 or P-glycoprotein) is permitted. 
Starting these medications during the trial period is not permitted. For other and permitted 
concomitant medication, potential interactions and notions of care from the SmPC shall be 
considered and noted at inclusion.  
Safety assessment 
Any untoward medical event (i.e. any AE, SAE or SUSAR) since the last visit must be recorded in the 
eCRF and the patient medical record. 
Drug discontinuation 
Discontinuation of the drug from the allocated study arm will be recorded together with the reason 
for the discontinuation. If a drug adverse effect in the DOAC group is the reason for discontinuation 
(i.e. nausea), transfer to another anti-Xa type DOAC will be considered and registered. 
End of treatment visit 
This study visit 12 months after TAVI assesses efficacy and safety. 
Cardiac CT 
A study purpose cardiac CT will be performed at 12 months after TAVI. 
Echocardiography 
A comprehensive echocardiographic exam for study purposes must be performed at the end of 
treatment. A copy of this exam will be stored in the clinical imaging archive under the patient’s real 
name for reasons of safety. 
Quality of life 
Self-reported, health-related quality of life will be gauged with the KCCQ and the EQ 5D 3L EuroQoL 
questionnaires, and HADS. We will allow subjects to complete the quality-of-life assessments before 
study procedures are performed. 

 
31 
 
Medical history 
A medical history must be repeated, and NYHA functional status; any change in risk factors 
(hypertension, smoking, diabetes mellitus), and concomitant disease must be recorded. Any medical 
events since inclusion in trial must be evaluated. Current well-being, symptoms, potential side 
effects and physical capacity must be assessed. 
Physical examination 
A physical examination must be performed, and results (including examination of heart, lungs, 
abdomen, neck and assessment of peripheral circulation and oedema); vital signs (blood pressure, 
and heart rate); and height and weight must be recorded. 
Concomitant medication 
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) 
used by the participant within 28 days of treatment start must be recorded in the eCRF by generic 
name and dose. 
Laboratory analyses 
Fasting blood samples will be obtained to determine: Haemoglobin; white blood cell count, platelet 
count; serum potassium; serum sodium; glucose, glycosylated haemoglobin (HbA1c); creatinine; 
ALT; bilirubin; albumin; INR; CK; CRP; TnT and NT-proBNP; total cholesterol; LDL cholesterol, high 
density lipoprotein cholesterol and triglycerides(safety). Blood for efficacy analyses must be 
collected, appropriately labelled and stored in a dedicated biobank for later analysis. 
Safety assessment 
Any untoward medical event (i.e. any AE, SAE or SUSAR) since the last visit must be recorded in the 
eCRF and the patient medical record. 
 
5-year assessment 
This visit 5 years after TAVI will assess efficacy. 
Echocardiography 
A comprehensive echocardiographic exam for study purposes must be performed at the end of 
treatment. A copy of this exam will be stored in the clinical imaging archive under the patient’s real 
name for reasons of safety. 

 
32 
 
Quality of life 
Self-reported, health-related quality of life will be gauged with the KCCQ and the EQ 5D 3L EuroQoL 
questionnaires, and HADS. We will allow subjects to complete the quality-of-life assessments before 
study procedures are performed. 
Medical history 
A medical history must be repeated, and NYHA functional status; any change in risk factors 
(hypertension, smoking, diabetes mellitus), and concomitant disease must be recorded. Any medical 
events since inclusion in trial must be evaluated. Current well-being, symptoms, potential side 
effects and physical capacity must be assessed. 
Physical examination 
A physical examination must be performed, and results (including examination of heart, lungs, 
abdomen, neck and assessment of peripheral circulation and oedema); vital signs (blood pressure, 
and heart rate); and height and weight must be recorded. 
Concomitant medication 
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) 
used by the participant within 28 days of treatment start must be recorded in the eCRF by generic 
name and dose. 
Laboratory analyses 
Fasting blood samples will be obtained to determine: Haemoglobin; white blood cell count, platelet 
count; serum potassium; serum sodium; glucose, glycosylated haemoglobin (HbA1c); creatinine; 
ALT; bilirubin; albumin; INR; CK; CRP; TnT and NT-proBNP; total cholesterol; LDL cholesterol, high 
density lipoprotein cholesterol and triglycerides(safety).  
 
10-year assessment 
This visit 10 years after TAVI will assess efficacy. 
Echocardiography 
A comprehensive echocardiographic exam for study purposes must be performed at the end of 
treatment. A copy of this exam will be stored in the clinical imaging archive under the patient’s real 
name for reasons of safety. 

 
33 
 
Quality of life 
Self-reported, health-related quality of life will be gauged with the KCCQ and the EQ 5D 3L EuroQoL 
questionnaires, and HADS. We will allow subjects to complete the quality-of-life assessments before 
study procedures are performed. 
Medical history 
A medical history must be repeated, and NYHA functional status; any change in risk factors 
(hypertension, smoking, diabetes mellitus), and concomitant disease must be recorded. Any medical 
events since inclusion in trial must be evaluated. Current well-being, symptoms, potential side 
effects and physical capacity must be assessed. 
Physical examination 
A physical examination must be performed, and results (including examination of heart, lungs, 
abdomen, neck and assessment of peripheral circulation and oedema); vital signs (blood pressure, 
and heart rate); and height and weight must be recorded. 
Concomitant medication 
All concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) 
used by the participant within 28 days of treatment start must be recorded in the eCRF by generic 
name and dose. 
Laboratory analyses 
Fasting blood samples will be obtained to determine: Haemoglobin; white blood cell count, platelet 
count; serum potassium; serum sodium; glucose, glycosylated haemoglobin (HbA1c); creatinine; 
ALT; bilirubin; albumin; INR; CK; CRP; TnT and NT-proBNP; total cholesterol; LDL cholesterol, high 
density lipoprotein cholesterol and triglycerides(safety).  
Table summary 
 
Screening 
Discharge 
3 months 
6 months 
9 months 
1 year 
5 years 
10 years 
Study medication 
 
Randomized after TAVI to DOAC or ASA for 12 months 
 
 
ASA treatment 
 
 
 
 
 
ASA indefinitely from 1 year 
Echocardiography 
X 
X 
X* 
 
 
X 
X 
X 
Carciac CT 
 
 
X* 
 
 
X 
 
 
Medical history 
X 
 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X* 
 
 
X 
X 
X 

 
34 
 
AE/SAE/SUSAR 
 
X 
X 
X 
X 
X 
 
 
Quality of life 
X 
 
 
 
 
X 
X 
X 
Medication 
X 
 
X 
X 
X 
X 
X 
X 
Lab tests 
X 
X 
X* 
 
 
X 
X 
X 
Subgrous assessments at Sørlandet Hospital are marked by *. Screening assessments occur before 
randomization. Assessments in green after randomization will be forwarded for blinded 
adjudication. Echocardiography will include assessment of LV function and quantification of valve 
performance. Cardiac CT will assess signs of structural valve degeneration. All concomitant 
medication will be recorded at every time point. Lab tests will include hematologic cell count and 
biochemistry including NT-proBNP and troponin T. 
Patient discontinuation  
Patients may be discontinued from study treatment and assessments at any time. Specific reasons 
for discontinuing a patient for this study are: 
- 
Voluntary discontinuation: participating patients are free to discontinue his/her participation 
in the study at any point in time, without prejudice to further treatment. 
- 
Major protocol deviation 
- 
Incorrect randomisation, i.e. the patient does not meet the required inclusion/exclusion 
criteria for the study 
- 
Patient lost to follow-up 
- 
Patient’s non-compliance to study treatment and/or procedures 
Procedures for discontinuation 
Study drug discontinuation 
The study participants may discontinue study drug treatment at any time according to their 
preferences. The investigator may also advise study drug discontinuation in case of side effects, if 
adverse effects of the treatment are suspected, or if contraindications to the continued use of DOAC 
or ASA arise. Study drug discontinuation and the reason why must be documented in the eCRF as 
well as in the hospital record. Efforts should be made to make ensure that adherence to the study 
protocol is kept up even though the patient no longer takes the study drug. All available data will be 
used in the intention to treat analysis, unless the patient specifically disagrees to let the investigator 
use his or her data. 

 
35 
 
Patient discontinuation 
Patient withdrawal must be documented in the eCRF as well as in hospital records. If possible, a final 
assessment should be obtained (end of study visit). The reason for discontinuation is recorded. The 
investigator is obliged to follow up any significant adverse events until the outcome either is 
recovered or resolved, recovering/resolving, not recovered/not resolved, recovered/resolved with 
sequelae, fatal or unknown. Patients who withdraw will be included in the intention-to treat 
analysis.  
Trial discontinuation 
The whole trial may be discontinued at the discretion of the primary investigator or the sponsor in 
the event of any of the following: 
- 
Occurrence of AEs unknown to date in respect of their nature, severity and duration 
- 
Medical or ethical reasons affecting the continued performance of the trial 
- 
Difficulties in the 
recruitment of patients 
The sponsor and principal 
investigator will inform all 
investigators, the relevant 
Competent Authorities and Ethics 
Committees of the termination of 
the trial along with the reasons for 
such action. If the study is 
terminated early on grounds of 
safety, the Competent Authorities 
and Ethics Committees will be 
informed within 15 days. 
Assessments 
Cardiac computed 
tomography 
Cardiac imaging is well suited to 
assess valve function and structure. Especially, cardiac CT has been utilized to assess leaflet thickness 
and describe their mobility after TAVI6, 12, 13. Contrast-enhanced, ECG-gated cardiac CT with full 
Cardiac CT assessment of hypoattenuated leaftlet thickening and 
reduced leaflet motion. From De Backer O, Dangas GD, Jilaihawi 
H et al. Reduced Leaflet Motion after Transcatheter Aortic-Valve 
Replacement. NEJM 2020;382:130-139. 

 
36 
 
cardiac cycle coverage will be performed on pre-evaluated CT scanners ensuring the optimal image 
quality. Pilot sets will be assessed by the adjudication committee before study assessments are 
performed. CT scanners must be high-end with >64 detector technology, preferably 260-row 
multidetector scanners. Dedicated 4D CT volume image protocol will be used. Image noise will be 
defined at level 30. The majority of scans will be obtained at a single center. Vendors and models will 
be noted.  
Patients will be pre-treated with betablocker or ivabradine to ensure heart rate below 65 bpm 
during acquisition. Typically, 50 to 150 mg metoprolol will be administered approximately 2 hours 
before the scan. Additional intravenous betablocker may be given to patients with heart rate above 
60 bpm at scan start. Patients who do not tolerate betablockers will receive 15 mg ivabradine 2 
hours before the scan. Local practice for contrast injection site and agent will be noted. Typically 70-
110 ml of Visipaque (GE Healthcare) will be used. Arterial phase trigging covering the whole cardiac 
cycle is needed. Start and end positions of the scan will be defined by the initial scanogram. Start will 
be 20 mm cranial to the metal stent frame and the end 
will be 16 mm caudal. The resulting scan field must be 
at least 1 cm above and 1 cm below the TAVI stent 
frame. Images should be reconstructed at the lowest 
slice thickness at every 5% of the cardiac cycle. 
Radiation doses will be approximately 10 mSv per 
exam. Dose-modulation approach can be used 
(reduced dose in diastole).  
Exams will be de-identified by a research nurse, 
research fellow or principal investigator and uploaded 
in DICOM format for analysis by an expert cardiologist 
who will perform all assessments blinded to the 
intervention. Valve leaflets will be assessed 
systematically by 2D and 3D volume-rendered imaging. 
3D-RV images will be assessed as a cine-loop through 
the cardiac cycle to assess valve opening. Hypo-
attenuated valve leaflet thickening and motion will be 
graded with multiplane reformats. Leaflet mobility is 
graded in agreement with previous trials utilizing this 
method13. The following parameters will be recorded 

 
37 
 
at 12 months: 
- 
Hypo-attenuated leaflet thickening (Figure 1, upper panel) 
o Any thickening a leaflet visible on contrast-enhanced reconstructions with careful 
alignment of the long and short axes of the prosthesis will be registred 
o Any definite leaflet thickening will be defined as “leaflet thickening” 
- 
Leaflet motion (Figure 1, lower panel) 
o Any restriction of leaflet mobility will be noted and graded 
o ≥ Grade 3 will be defined as “reduced leaflet motion” 
- 
Leaflet calcification 
- 
Leaflet sclerosis 
One investigator will perform all analyses. The intra-observer variability will be reported in a 
randomly generated sample of 20 individuals. 
 
Echocardiography 
Echocardiography is the primary imaging modality for assessment of valvular function and is well 
suited to determine the degree of aortic stenosis17. Echocardiographic loops will be obtained on a 
Vivid E95 or newer scanner (GE Vingmed, Horten, Norway) with the patient in the left cubital 
position. A comprehensive baseline echocardiogram including all standard views will be obtained on 
day one after TAVI and again after 12 months by a dedicated echocardiography technician. Exams 
will be de-identified by a study nurse, research fellow or principal investigator and uploaded for 
analysis by a blinded expert cardiologist. The following echocardiographic parameters will be 
recorded before hospital discharge and at 12 months: 
- 
Aortic valve mean gradient 
- 
Aortic valve area 
o Based on measured left ventricular outflow tract dimensions 
- 
Left ventricular ejection fraction by Simpson method from apical four-chamber and two-
chamber views 

 
38 
 
- 
Global longitudinal strain by speckle tracking imaging from apical four-chamber, long-axis 
and two-chamber views using loops with more than 60 frames per second. 
- 
Aortic valve regurgitation 
o Valvular or para-valvular 
o < moderate or ≥ moderate 
- 
Para-valvular regurgitation 
In addition to this, results from a comprehensive echocardiography performed shortly before TAVI 
will be included in the baseline characteristics: 
- 
Aortic valve mean gradient 
- 
Aortic valve area 
- 
Left ventricular ejection fraction 
- 
Left ventricular global longitudinal strain 
- 
Presence of low-flow low-gradient 
- 
Presence of non-tricuspid morphology 

 
39 
 
 
Estimation of aortic stenosis severity. From Baumgartner HC, Hung JC-C, et al. Recommendations on the 
echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of 
Cardiovascular Imaging and the American Society of Echocardiography. European Heart Journal Cardiovascular 
Imaging. 2017;18:254-275. 
 
Echocardiography will be repeated after five years and ten years to assess the trajectory of 
myocardial function and valve hemodynamics. 
One investigator will perform all analyses. The intra-observer variability will be reported in a 
randomly generated sample of 20 individuals. 
Transoesophageal echocardiography 
One in eight randomly selected (stratified from each intervention group) patients will be invited to 
participate in a sub-study where the precision of transoesophageal echocardiography (TEE) to 
identify SVD stage 1 will be assessed. Cardiac CT is the gold standard, but the use of contrast and 
ionizing radiation is a challenge. Also, the availability of the cardiac CT can be a challenge. TEE may 
be an uncomfortable procedure, but complications are uncommon. Patients will be thoroughly 

 
40 
 
informed by the operator before the procedure. The images will be de-identified and read by an 
expert reader blinded to the intervention. 
The TEE will be performed in right cubital position with standard pre-medication with 5 mg 
diazepam and 12.5 mg petidin. The ultrasonoscope will be connected to a Vivid E95 scanner (GE 
Vingmed). The procedure will be performed by a very experienced cardiologist, and will include a 
rapid and focused assessment of leaflet thickness and leaflet mobility 12 months after TAVI. The 
procedure will be interrupted at the patients wish. 
Cerebral magnetic resonance imaging 
One in eight randomly selected patients (stratified from each intervention group) will be invited to 
participate in a sub-study in which the prevalence and intervention effect on cerebral embolization 
will be assessed. Cerebral magnetic resonance (MR) will be performed on a dedicated 3T-scanner. 
The images will be de-identified and interpreted by an expert reader blinded to the intervention. 
Clinical events 
Relevant clinical events occurring after randomization will be registered at the time of the 12-month 
follow-up. These events will include: 
- 
VARC-3 bleeding events 
- 
Life-threatening or disabling events or major events with date 
o Minor bleeding (BARC 2 or 3a), non-procedure related 
- 
Stroke of any cause, with date 
- 
Myocardial infarction, with date 
- 
Ischemia driven coronary vascularization, with date 
- 
Pacemaker or implantable cardioverter defibrillation implantation 
- 
Hospitalization for heart failure, with date 
- 
Re-intervention, post-dilatation, surgical aortic valve replacement or valve-in-valve 
- 
Death (any cause, cardiac non-cardiac), with date 
Bleeding events 
Bleeding events will be recorded at every time point. In cases of major, life-threatening or disabling 
bleeding, time to bleeding from TAVI will be registered. 

 
41 
 
Outcome definition: 
- 
Life-threatening or disabling, major bleeding og minor bleeding according to VARC-3 
definition 
VARC-3 classification of bleeding complications of transcatheter aortic valve implantation 
 
VARC-3 updated endpoint definitions for aortic stenosis, Eur Heart J 2021 00, 1-33 
Stroke 
Time to stroke will be recorded. Stroke will be defined as following: 
- 
Acute episode of a focal or global neurological deficit with at least one of the following: 
change in the level of consciousness, hemiplegia, hemiparesis, numbness, or sensory loss 
affecting one side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other 
neurological signs or symptoms consistent with stroke  
- 
Stroke: duration of a focal or global neurological deficit > 24 h; OR < 24 h if available 
neuroimaging documents a new haemorrhage or infarct; OR the neurological deficit results 
in death  
- 
No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain 
tumour, trauma, infection, hypoglycaemia, peripheral lesion, pharmacological influences), to 

 
42 
 
be determined by or in conjunction with the designated neurologist. (Patients with non-focal 
global encephalopathy will not be reported as a stroke without unequivocal evidence of 
cerebral infarction-based upon neuroimaging studies)  
- 
 Confirmation of the diagnosis by at least one of the following:  
o Neurologist or neurosurgical specialist  
o Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on 
clinical grounds alone  
Stroke outcome definition 
- 
Disabling stroke: a modified Rankin Scale (mRS) score of 2 or more at 90 days and an 
increase in at least one mRS category from pre-stroke baseline  
- 
Non-disabling stroke: an mRS score of < 2 at 90 days or one that does not result in an 
increase of at least on mRS category from pre-stroke baseline 
Stroke classification  
- 
Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by 
infarction of the central nervous system tissue  
- 
Haemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid haemorrhage  
- 
 A stroke may be classified as undetermined if there is insufficient information to allow 
categorization as ischemic or haemorrhagic  
Transient ischemic attack (TIA) will be recorded and defined as duration of a focal or global 
neurological deficit < 24 h, any variable neuroimaging does not demonstrate a new haemorrhage or 
infarct, but not be classified as a stroke. 
Myocardial infarction 
Time to myocardial infarction will be registered at every time point. 
Peri-procedural MI 
Myocardial infarction occurring within 72 hours after TAVI will be classified as peri-procedural MI if: 
- 
New ischemic symptoms (e.g. chest pain or shortness of breath), or new ischemic signs (e.g. 
ventricular arrhythmias, new or worsening heart failure, new ST-segment changes, 

 
43 
 
hemodynamic instability, new pathological Q waves in at least two contiguous leads, 
imaging evidence of new loss of viable myocardium or new wall motion abnormality) 
- 
Elevated cardiac biomarkers (preferable CK-MB) within 72 h after the index procedure, 
consisting of at least one sample post-procedure with a peak value exceeding 15 x as the 
upper reference limit for troponin or 5 x for CK-MB. If cardiac biomarkers are increased at 
baseline (>99th percentile), a further increase in at least 50% post-procedure is required 
- 
the peak value must exceed 99th percentile 
Spontaneous MI  
Myocardial infarction occurring more than 72 h after TAVI will be classified as spontaneous MI if: 
- 
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one 
value above the 99th percentile upper reference limit, together with the evidence of 
myocardial ischemia with at least one sign of ischemia: 
o New ischemic symptoms (e.g. chest pain or shortness of breath) 
o ECG changes indicative of new ischemia: new ST-T changes or new left bundle 
branch block (LBBB) 
o New pathological Q-waves in at least two contiguous leads 
o Imaging evidence of a new loss of viable myocardium or new wall motion 
abnormality 
- 
Sudden, unexpected cardiac death occurring before blood samples could be obtained, or at 
a time before the detection of cardiac biomarkers in the blood, often with antecedent 
symptoms suggestive of myocardial ischemia, and accompanied by presumably new ST 
elevation, or new LBBB, and/ or evidence of fresh thrombus by coronary angiography and/or 
at autopsy  
- 
Pathological findings of an acute myocardial infarction 
Death 
Time to death will be recorded at every time point. Death will be classified as: 
- 
Death due to immediate cardiac cause (e.g. myocardial infarction, cardiac tamponade, 
worsening heart failure)  

 
44 
 
- 
Death caused by non-coronary vascular conditions such as neurological events, pulmonary 
embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular disease  
- 
All procedure-related deaths, including those related to a complication of TAVI or treatment 
for a complication of TAVI  
- 
All valve-related deaths including SVD and other valve-related adverse events  
- 
Sudden or unwitnessed death  
- 
Death of unknown cause 
Laboratory analyses 
Blood samples will be obtained to determine: Hemoglobin, white blood cell count, platelet count, 
serum potassium; serum sodium; glucose, glycosylated hemoglobin (HbA1c); creatinine; ALT; 
bilirubin; albumin; INR; CRP; N-terminal pro-B-type natriuretic peptide (NT-proBNP); total 
cholesterol; ferritin; transferrin, serum iron and total iron binding capacity.  
Extra blood will also be appropriately labelled and stored in a biobank and later analyzed for 
vasoactive peptides such as, ST2 and N-terminal pro-B-type natriuretic peptide. We will also assess 
markers of fibrosis, inflammation and relevant metabolic pathways. 
Quality of life 
Quality of life will be examined at baseline and at the end of the study using standard validated 
questionnaires; the EQ 5D 3L EuroQoL questionnaire, EQ-VAS, HADS and KCCQ questionnaires. The 
EQ 5D 3L EuroQoL questionnaire consists of 2 pages, the EQ-5D descriptive system and the EQ visual 
analogue scale. The Hospital Anxiety and Depression Scale (HADS) measures anxiety and depression 
symptoms. KCCQ is a commonly used 23 item self-administered questionnaire designed to evaluate 
physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self-
efficacy, and quality of life in patients with heart disease. 
Cognitive function 
Cognitive function will be assessed with the miniCog questionnaire. In this test the patient is 
challenged to remember three words and should be able to draw the time on a clock. 
Safety monitoring and reporting 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an adverse event (AE) or serious adverse event (SAE). Each patient will be 

 
45 
 
instructed to contact the investigator immediately should they manifest any signs or symptoms they 
perceive as serious. When judging whether an adverse event is unexpected or not, the Summary of 
Product Characteristic (SmPC) for the study drugs apixaban, rivaroxaban and edoxaban will be used 
as reference safety information. 
The methods for the collection of safety data are described below. 
Definitions 
Adverse event (AE) 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product.  
The term AE is used to include both serious and non-serious AEs. 
If an abnormal laboratory value/vital sign are associated with clinical signs and symptoms, the 
sign/symptom should be reported as an AE and the associated laboratory result/vital sign should be 
considered additional information that must be collected on the relevant eCRF.  
Adverse events of special interest (AESI) 
In general, AESIs are AEs that occur in categories of special interest with regard to determining the 
benefit/risk profile and overall safety of a drug. Previous data on antithrombotic treatment in atrial 
fibrillation have suggested that adverse events may be more common in the ASA-group than in the 
DOAC group (22% vs 27%)14. 
Unrecognized pregnancy or risk of pregnancy during the study period is a common area of special 
interest. This study will include elderly patients aged 65 to 80 years old, and we do therefore not 
consider unrecognized pregnancy to be a risk in this situation. 
Serious adverse event (SAE) 
Any untoward medical occurrence that:  
- 
Results in death 
- 
Is immediately life-threatening 
- 
Requires hospitalisation or prolongation of existing hospitalisation  

 
46 
 
- 
Results in persistent or significant disability or incapacity 
- 
Is a congenital abnormality or birth defect 
- 
Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
Medical and scientific judgment will be exercised in deciding on the seriousness of a case. Important 
medical events may not be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the subject or may require intervention to prevent one of the listed outcomes in the 
definitions above. In such situations, or in doubtful cases, the case should be considered as serious. 
Hospitalisation for administrative reason (for observation or social reasons) is allowed at the 
investigator’s discretion and will not qualify as serious unless there is an associated adverse event 
warranting hospitalisation.  
Suspected unexpected serious adverse reaction (SUSAR)  
Adverse Reaction: all untoward and unintended responses to an investigational medicinal product 
related to any dose administered. 
Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not consistent 
with the applicable product information. 
Suspected Unexpected Serious Adverse Reaction: SAE (see above) that is unexpected and possibly 
related to the investigational medicinal products. When judging whether a possibly study drug 
related serious adverse event is unexpected or not, the apixaban, rivaroxaban or edoxaban SmPC 
will be used as reference safety information. 
Time period for reporting AE and SAE  
For each patient the standard time period for collecting and recording AE and SAEs will begin at the 
start of study treatment and will continue for 7 day after end-of treatment. We will proactively 
follow up all AEs and SAEs for each patient during the course of the study; events will be followed up 
to resolution, unless the event is considered to be unlikely to resolve due to the underlying disease. 
Every effort should be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. Mandatory reporting of new AEs ends 7 days after the end-of-
treatment visit. 
Recording of adverse events 
If the patient has experienced adverse event(s), the investigator will record the following 
information in the eCRF: 

 
47 
 
- 
The nature of the event(s) will be described by the investigator in precise standard medical 
terminology (i.e. not necessarily the exact words used by the patient). 
- 
The duration of the event will be described in terms of event onset date and event ended 
data. 
The intensity of the adverse event will be categorised as mild / moderate / severe / life-threatening / 
death according to Common Terminology Criteria for Adverse Events version 4.0: 
- 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated 
- 
Moderate: minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental activities of daily life 
- 
Severe: Severe or medically significant but not immediately life-threatening; hospitalisation 
or prolongation of hospitalisation indicated; disabling; limiting self-care activities of daily life 
- 
Life-threatening consequences: urgent intervention indicated.  
The causal relationship of the event to the study medication will be assessed as one of the following: 
- 
Unrelated: There is not a temporal relationship to investigational product administration 
(too early, or late, or investigational product not taken), or there is a reasonable causal 
relationship between non-investigational product, concurrent disease, or circumstance and 
the AE. 
- 
Unlikely: There is a temporal relationship to investigational product administration, but 
there is not a reasonable causal relationship between the investigational product and the 
AE. 
- 
Possible: There is reasonable causal relationship between the investigational product and 
the AE. Dechallenge information is lacking or unclear. 
- 
Probable: There is a reasonable causal relationship between the investigational product and 
the AE. The event responds to dechallenge. Rechallenge is not required. 
- 
Definite: There is a reasonable causal relationship between the investigational product and 
the AE. Action taken: Which investigations/medical procedures/treatments that are initiated 
as a result of the adverse event. 
The outcome of the adverse event – whether the event is resolved or still ongoing will be registred. 

 
48 
 
It is important to distinguish between seriousness and severity of AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria for SAE. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea but is not an SAE. On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mild stroke but would be an SAE. 
Reporting procedure 
Adverse events, adverse events of special interest and serious adverse events 
All adverse events and serious adverse events that should be reported will be recorded in the 
patient's eCRF. SAEs must be reported by the investigator to the sponsor, Oslo University Hospital, 
within 24 hours after the site has gained knowledge of the SAE. The Serious Adverse Event Report 
Form must be completed, documented in the eCRF, signed and sent to Øyvind H Lie. The initial 
report shall promptly be followed by detailed, written reports if necessary. The initial and follow-up 
reports shall identify the trial subjects by unique trial code numbers assigned to the latter. The 
sponsor keeps detailed records of all SAEs reported by the investigators and performs an evaluation 
with respect to seriousness, causality and expectedness. 
Suspected unexpected serious adverse reactions 
SUSARs will be reported to the Norwegian Medicines Agency and the local Ethics Committee. The 
following timelines should be followed: 
The sponsor will ensure that all relevant information about suspected serious unexpected adverse 
reactions that are fatal or life-threatening is recorded and reported as soon as possible to the 
Norwegian Medicines Agency and the Regional Committee for Medical and Health Research Ethics in 
any case no later than seven (7) days after knowledge by the sponsor of such a case, and that 
relevant follow-up information is subsequently communicated within an additional eight (8) days. 
The sponsor shall ensure that suspected adverse reactions that are serious and unexpected are 
reported to the Norwegian Medicines Agency and the Regional Committee for Medical and Health 
Research Ethics within 15 days of the sponsor after knowledge of the event. The sponsor shall 
inform all investigators and involved clinicians of the trial substance in question of suspected 
adverse reactions that are serious and unexpected. An account of any interruption in treatment, the 
investigator’s assessment of the causal relationship, and consequences for further testing shall 
accompany the notification of suspected adverse reactions pursuant to the first and second 
paragraphs. SUSARs will be reported to the drug manufacturer at time of regulatory submission. 

 
49 
 
The Norwegian Medicines Agency may require that individual reports of adverse events described in 
collective reports should also be submitted. The sponsor shall keep detailed records of all adverse 
events that are reported. The records shall be submitted to the Norwegian Medicines Agency on 
request. 
Annual safety report 
Once a year throughout the clinical trial, the sponsor will provide the Norwegian Medicines Agency 
with an annual safety report. The format will comply with national requirements.  
Clinical study report 
The adverse events and serious adverse events occurring during the study will be discussed in the 
safety evaluation part of the Clinical Study Report. 
Safety monitoring  
A Data Safety Monitoring Board will be appointed to assess trial safety. The committee consist of an 
independent clinician and a statistician. It will receive reports summarising patient recruitment, the 
number of AEs / SAEs and the registered occurrence of the second co-primary endpoint (Safety 
composite) after the first 20 patients have been randomised, and once every year starting 12 months 
after the first 12-month control. They will be encouraged to assess signals of safety without 
hypothesis testing. The committee will have access to the randomisation code, and can, if they find 
it necessary, perform an interim analysis regarding the number of adverse events and serious 
adverse events. The data safety monitoring committee will receive additional information on 
demand and can advise temporary or permanent stop in patient enrolment. In case there is worry of 
a pattern of worse bleeding outcome, a recommendation to abort the study will be given to the 
project leader. The data safety monitoring committee is independent from the sponsor and will be 
composed of individuals with no competing interest with regard to the study investigational 
products or study outcome. 
Accountability of investigational products 
The batch number of every container of investigational products  will be registered at every 
visit, both by telephone and physical visits. The batch information will be systematically stored 
in the eCRF, to enable secure identification of batches involved in any adverse events. 
Data management and monitoring 
Data will be stored and handled according to the given permissions and applicable regulations. The 
data will not be used for economic benefit or be made available for commercial actors. 

 
50 
 
Electronic case report forms (eCRF) 
ACASA-TAVI will use an online electronic Case Report Form (eCRF) on the Viedoc platform. The 
designated investigator staff will enter the data required by the protocol into the eCRF. The Principal 
Investigator is responsible for assuring that data entered into the eCRF are complete, accurate, and 
that entry is performed in a timely manner. If any assessments are omitted, the reason for such 
omissions will be noted in the eCRFs. Corrections, with the reason for the corrections will also be 
recorded. After database lock, the investigator will receive a digital copy of the subject data for 
archiving at the investigational site. 
Source data  
Some data will be recorded directly into the eCRF, which, together with the patient medical record, 
is to be considered the source data. All data important for patient safety and continued care must be 
duplicated in the patient’s medical record as described below. Study-specific imaging data and blood 
analyses are independent source data.  
The medical records of each patient should clearly describe at least: 
- 
That the patient is participating in the study 
- 
Date when the informed consent was obtained from the patient 
- 
Results of all assessments confirming a patient’s eligibility for the study 
- 
Diseases (past and current; both the disease studied and others, as relevant) 
- 
Surgical history, as relevant 
- 
Treatments withdrawn/withheld due to participation in the study 
- 
Results of assessments performed during the study 
- 
Treatments provided, changes in treatments during the study and the time points for the 
changes 
- 
Visits to the clinic / telephone contacts during the study, including those for study purposes 
only 
- 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality 
assessments 
- 
Date of, and reason for, discontinuation from study treatment 

 
51 
 
- 
Date of, and reason for, withdrawal from study 
- 
Date of death and cause of death, if available 
Study monitoring  
The investigator will be visited on a regular basis by the Clinical Study Monitor, who will check that 
the study is conducted as approved by the Ethics committee and adheres to GCP guidelines. 
Sponsor’s representatives (e.g. monitors, auditors) and/or competent authorities will be allowed 
access to source data for source data verification in which case a review of those parts of the 
hospital records relevant to the study may be required.  
Trial monitoring will be performed by the Clinical Trial Unit, Oslo University Hospital. 
Confidentiality 
The investigator shall arrange for the secure retention of the patient identification and the code list. 
This list will be kept in the Medinsight database at Oslo University Hospital, and equivalent solutions 
in potential other sites. Patient files shall be kept for the maximum period of time permitted by each 
hospital. The study documentation (eCRFs, etc.) shall be retained and stored during the study and 
for 15 years after study closure. All information concerning the study will be stored in a safe place 
inaccessible to unauthorised personnel, at Oslo University Hospital this will be the K:sensitiv storage 
solution. 
Database management 
Data will be entered into the eCRF without delay and stored in the dedicated and secured online 
platform (Viedoc®). Data will be extracted from Viedoc for analysis, and the extracted data will be 
stored in dedicated, secure areas. Data will be stored in a de-identified manner, where each study 
participant is recognisable by his/her unique trial subject number. The data will be stored until Aug 
31st, 2041 in compliance with local regulations, or until the patient requires that his/her data are 
deleted. Data in the eCRF will be handled according to GCP. Only the personnel authorised to enter 
and/or analyse data (i.e. investigators) will have access to the database.  
Biobank 
A biobank will be established at the Dept. of Cardiology, Oslo University Hospital, Rikshospitalet for 
the analysis of serum and plasma. The samples will be stored in multiple aliquots and labelled with 
the unique trial subject number, and the letter A signifying baseline, and the letter B signifying the 
visit at end-of-study. The samples will be stored at -80 degrees Celsius in a dedicated research 
freezer. The material is scheduled for destruction by Aug 31st, 2041. Dr. Øyvind H Lie at Oslo 

 
52 
 
University Hospital, Rikshospitalet will be responsible for the biobank. Biochemical analyses may be 
performed at other participating centres, and the samples may be shipped between countries for 
storage and analyses. 
Data Sharing 
In agreement with good research ethics, we will share anonymized data sets with the medical 
community via the medical journal upon submitting the manuscript. 
 
Potential risks and benefits 
There are certain potential risks associated with participation in the trial. All investigational products 
have potential adverse effects. The risks of bleeding seem to be balanced between the two arms, 
but this is also a matter of trial investigation. The risk of adverse effects like anaemia, gastro-
intestinal events, skin reactions, allergic reactions and increased biochemical liver function tests also 
seem to be balanced between the two randomized groups. However, this has not been tested head-
to-head in this population in previous trials. 
Potential benefits should also be considered. If the trial hypothesis proves to be correct, half of the 
included patients will have access to superior treatment. Trial participants will have close contact 
with the TAVI performing institution and may consider it favourable to have their follow-up at a 
high-volume centre. The follow-up will be closer than standard clinical care. 
Overall, we consider participation in ACASA-TAVI to be of relatively low risk. The balance between 
potential risks, benefits and clinical implications seem to justify the investigation. 
 
Statistical methods and data analysis 
Determination of sample size 
Sample size estimates are calculated based on limited previous data from different populations and 
assumptions. 
Based on previous studies, the first co-primary endpoint (HALT) can be expected to occur in 
approximately 20% of patients treated with ASA12, 13. To obtain 80% power with a two-sided 0.05 
alpha for a 50% reduction in the primary efficacy endpoint in the DOAC group, 310 patients should 

 
53 
 
be randomized 1:1. A 50% reduction is clinically relevant and is a realistic size based on previous 
indirect data12, 13. 
The estimated sample size for the second co-primary endpoint is more complex and relies on 
additional assumptions. There are no placebo-controlled trials of ASA after TAVI, and therefore a 
non-inferiority margin cannot be based on preservation of a previous effect estimate of the active 
comparator. The predefined non-inferiority margin was therefore based on clinical judgement and 
other acknowledged estimates in the field. Previous expected estimates of 1-year rate of the Safety 
Composite endpoint have been presented at 34% in the ASA-group8 and 31% in the DOAC group10. 
The results of those trials are not suited as estimates because they studied to different population 
with vastly different baseline risk. We considered a non-inferiority margin of 35% relative to the 
active comparator to be clinically meaningful and adopted the previous estimates of event rates. 
This relative margin is similar to the non-inferiority margins used in previous trials involving DOAC18, 
19, and gives an absolute margin of (34 x 1.35-34) 11.9 percentage points which should not be 
crossed by the upper boundary of the 95% confidence interval for the rate of the Safety composite 
endpoint in the DOAC group compared to the ASA group. A one-sided 0.025 alpha requires 310 
patients to be randomized 1:1 to obtain 80% power to show non-inferiority. To account for loss to 
follow-up and withdrawal of consent in 10-15% of participants, a total of 360 patients will be 
randomized to ensure power for both the co-primary endpoints (HALT, superiority, and Safety 
composite, non-inferiority). 
To assess whether our estimations are reasonable, we will count the total number of the co-primary 
endpoints when 50% of the 1-year controls have been performed. This number should be 
somewhere around 10-20% for HALT and 30-40% for Safety Composite. Testing between groups will 
not be performed. The steering committee will assemble to assess whether the number of events 
deviates substantially from the anticipated, and whether a revision of the estimated sample size is 
required. 
We do not consider sample size estimations to be relevant for the 5- and 10-years analyses. The data 
will be dependent on the 12-month analysis, and the assessment will be based on these data. It is of 
the greatest clinical and scientific interest to assess the long-term implications of the intervention 
and the interaction with the 12-month first co-primary endpoint.  
- 
If sample sizes were to be considered, one systematic review and meta-analysis estimated the 5-year 
rate of a similar endpoint at 52%20. A Logistic regression assessment for clinically relevant 35% 
reduction in the odds of the primary outcome would require a total of 256 patients randomized 1:1 
for 80% power at 0.05 alpha. The same assumptions and a modest 75% 10-year incidence of the 

 
54 
 
primary endpoint would require a total of 178 patients randomized 1:1 to have power for a 35% 
hazard reduction with the same power and alpha. Considering a diminishing alpha of 0.025 for the 5-
year analysis and 0.01 for the 10-year analysis would still uphold 80% power for 35% hazard reduction 
well within the intended sample size of 360 patients. 
With this sample size it is likely that the research question will be adequately answered. 
Randomisation  
Allocation- sequence generation 
Balanced, permuted block randomisation (in a 1:1: ratio for the two study arms) will be performed 
online in Viedoc™. 
Allocation- procedure to randomise a patient 
We will use a computerised randomisation procedure for treatment allocation. Random treatment 
allocation will be executed on the online, password-protected platform designed for study purposes 
(Viedoc™) once eligibility has been confirmed and the informed consent has been signed.  
Blinding  
It is vital for an open-label blinded-endpoint randomized trial to maintain proper blinding to uphold 
scientific integrity of data and approximate causal inference. Therefore, careful logistic 
arrangements will be made to avoid bias in the endpoint adjudication. Only the investigators 
assessing the outcome measures will be actively blinded for the allocation 
Case report form 
Relevant clinical events may be registered in the electronic medical records or by direct patient 
interview. The clinical event adjudication committee cannot access the electronic records without 
being un-blinded to the randomization. Similarly, they cannot talk directly to the patients without 
risk of un-blinding. Therefore, case report forms (CRF) have been developed by the adjudication 
committee (interview guide, appendix). The clinical CRF will be filled by a research nurse or research 
fellow at 3, 6, 9 and 12 months by telephone interview, direct patient interview and access to the 
electronic medical records. The completed CRF will be made available to the endpoint adjudication 
committee for data entry via the eCRF. To avoid adjudication bias, the clinical endpoint adjudicator 
will not have access to the eCRF of the cardiac CT and echocardiographic adjudication. 
Cardiac CT 
Cardiac CT registrations will be de-identified, undated, and coded with the patient study ID to ensure 
that the reader will not come across details of the treatment. The de-identification will be 
performed by the coordinating investigator who will either be present at the acquisition at the core 

 
55 
 
lab centre or receive transferred acquisitions from collaborating centres. Only de-identified 
acquisitions will be made available to the expert CT reader in the adjudication committee. 
Registration of structural abnormalities will be made on the CT eCRF. To avoid adjudication bias, the 
cardiac CT endpoint adjudicator will not have access to the eCRF of the clinical and 
echocardiographic adjudication. 
A second expert reader will be contacted by a principal investigator if the primary reader finds: 
- 
Blinding is compromised. The primary reader ensures proper blinding and forwards the 
exam for blinded analysis. 
- 
There is uncertainty in the adjudication. Consensus will be achieved. 
Echocardiography 
Echocardiographic recordings will be de-identified, undated, and coded with the patient study ID 
using the dedicated function on the scanners. The study recordings will be performed and coded by 
a coordinating investigator or received from a collaborating centre and coded before it is made 
available to the expert cardiologist in the adjudication committee. Registration of the 
echocardiographic indices in question will be made on the echocardiographic eCRF. To avoid 
adjudication bias, the echocardiographic endpoint adjudicator will not have access to the eCRF of 
the clinical and cardiac CT adjudication. 
A second expert reader will be contacted by a principal investigator if: 
- 
Blinding is compromised. The primary reader ensures proper blinding and forwards the 
exam to a principal investigator for blinded analysis. 
- 
There is uncertainty in the adjudication. Consensus will be achieved. 
Population for Analysis 
 The following populations will be considered for the analyses: 
- 
Intention to treat (ITT) population: All randomised participants, regardless of protocol 
adherence. 
o This population will be used do assess superiority for the first co-primary endpoint 
HALT and all non-safety secondary endpoints. 
- 
Safety population: All patients who have been enrolled in the trial, and who have received at 
least one dose of the investigational medicinal product (DOAC). 

 
56 
 
o This population will be used to assess the secondary safety endpoints. 
- 
Per-protocol population (PP): Includes all subjects who have completed 12 months of 
treatment. 
o This population will be used to assess non-inferiority for the second co-primary 
endpoint Safety Composite. 
Planned analyses 
A separate detailed Statistics Analysis Plan (SAP) will be developed in collaboration with the 
dedicated study statistician Erica Ponzi, PhD, at the Clinical Trial Unit at Oslo University Hospital 
before data lock. 
The first main statistical analysis is planned when the last patient has completed the end-of-
treatment visit 12 months after randomisation. The number and severity of adverse events will be 
assessed consecutively. Deviation from the original statistical plan will be described and justified in 
the Clinical Study Report. Amendments to plan can be done until the day of database lock. 
After the first analysis, the randomization group will be removed from the CFR during the 
adjudication of long-term clinical endpoints. The second planned analysis is after 5 years, and the 
last analysis is planned after 10 years. These two will be analyses of the clinical outcome of the 
patients. 
Statistical analysis 
The preferred statistical analysis software pack of the principal investigator is Stata SE (StataCorp 
LLC, College Station, TX). The active available version at the time of study completion will be used. 
Erica Ponzi, PhD, at the Clinical Trial Unit (CTU) at Oslo University Hospital will be the dedicated trial 
statistician for the entire study period. The final anonymized dataset will be shared with the 
publishing journal to ensure transparency of the results. 
Co-primary endpoints 
The co-primary endpoints at 12 months will be tested using chi-square tests of proportions. The first 
co-primary endpoint will be tested for superiority using a two-sided chi-square test at the 0.05 
significance level, and the second co-primary endpoint Safety Composite will be tested for non-
inferiority using the computed one-sided non-inferiority limit corresponding to an upper end of the 
95% confidence interval of the DOAC group 11.9% above the proportion in the ASA group. 
We have not planned to test for between-group differences in baseline characteristics or to perform 
adjusted analyses of the co-primary endpoints. There will be no statistical correction for the use of 

 
57 
 
co-primary endpoints, but study success will not be declared unless both null hypotheses are 
rejected. 
Primary endpoint (MACE) at 5 and 10 years 
The study will be re-visited after 5 and 10 years to explore the intervention effect on major adverse 
cardiac events/MACE (intention-to-treat and per-protocol; composite of time to stroke, myocardial 
infarction, heart failure hospitalization, redo TAVI, cardiac death, type 3 or 4 bleeding defined by 
VARC-3). The rate of MACE at the 5- and 10-year milestones will be assessed, and the intervention 
effect will be assessed by rate ratios. 
These two analyses will be supplemented by a competing risk-regression to account for the 
competing risk of non-cardiac death. We will also assess the interaction between DOAC intervention 
and SVD at 12 months for reduction in MACE to assess whether a possible favourable signal is 
mediated through SVD. 
Secondary endpoint at 5 and 10 years 
The rate of the individual components of MACE will be assessed, and the rate ratio will explore any 
effect of the intervention. The repeated echocardiographic parameters of left ventricular function 
and aortic valve hemodynamic performance will be entered to a linear mixed model regression to 
assess progression of the valve degeneration. The same will be performed for NYHA class 
deterioration. The randomization group will be entered to this regression as an interaction term with 
time to assess the effect of 12-month DOAC intervention on the development of hemodynamic valve 
degeneration. 
Pre-defined subgroup analyses 
Certain characteristics are associated with increased risk of SVD in previous reports. We trust the 
randomization for balanced allocation, and no stratified randomization is planned. However, 
interaction effects in subgroups of interest will be assessed in the primary study: 
- 
Age <75 and ≥75 years old 
- 
Females and males 
- 
Diabetes mellitus 
- 
Hypertension 
- 
Preserved and impaired renal function 
o Estimated glomerular filtration rate cut-off <30 ml/min 

 
58 
 
- 
Balloon-expanded vs. self-expandable valve 
- 
Post-dilatation vs no post-dilatation 
- 
Supra-valvular prosthesis position  
- 
Ascending aorta diameter > and ≤ 30 millimetres 
- 
High and low frailty index 
Key secondary endpoints 
The rates of the predefined key secondary endpoints (Clinical efficacy, Safety composite superiority, 
Thromboembolic events, Bleeding events, Cardiac death) will be tested in a hierarchical order, 
meaning that hypothesis testing stops at the first non-significant endpoint (p≥0.05). 
Secondary safety endpoints 
Safety analyses will include tabulation of type and frequency of all adverse events. Any serious 
adverse events will be reported with comprehensive narratives. Any value of safety laboratory 
parameters outside normal ranges will be identified. 
Exploratory secondary endpoints 
The secondary endpoints that are defined as “exploratory” in the protocol will be tested and 
interpreted as hypothesis generating. 
Missing data 
Every reasonable effort will be made to minimize missing data, but it is expected that some CT-scans 
will be of insufficient quality and that some of these elderly patients will be unavailable for 1-year 
adjudication of the primary efficacy endpoint HALT. Less, but some, missing data is expected for 
Safety Composite. Some data may be missing completely at random (MCAR) and missing at random 
(MAR), but some instances of data missing not at random (MNAR) may occur if either the therapy 
increases likelihood of being available for 1-year analysis by improving HALT or decreases the 
likelihood for 1-year analysis by increasing incidence of the Safety Composite. Therefore, we will 
take conservative and simplistic measures to handle missing data. Missing data on the primary 
endpoint analysis will be replaced using hot-deck imputation using random allocation with a 5:1 
ratio of failures for the first co-primary endpoint HALT and a 3:1 ratio of failures for the second co-
primary endpoint Safety Composite. These ratios are based on the expected prevalence used in the 
sample size estimations. These imputations will be evenly distributed and therefore bias the 
distribution of HALT towards the null hypothesis.  

 
59 
 
Sensitivity analysis for the primary endpoints will be performed on the complete-case data and on 
worst-case imputation data. Additional post-hoc sensitivity analyses will be performed if unexpected 
patterns of missing data are observed. 
Project management 
Investigator delegation procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” listing all 
the involved co-workers and their role in the project. He will ensure that appropriate training 
relevant to the study is given to all of these staff, and that any new information of relevance to the 
performance of this study is forwarded to the staff involved. 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. All significant 
protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
Study amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the 
study protocol (Amended Protocol) must be notified to and approved by the Competent Authority 
and the Ethics Committee according to EU and national regulations. 
Audit and inspections 
Authorised representatives of a Competent Authority and Ethics Committee may visit the centre to 
perform inspections, including source data verification. Likewise, the representatives from sponsor 
may visit the centre to perform an audit. The purpose of an audit or inspection is to systematically 
and independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analysed, and accurately reported according to 
the protocol, Good Clinical Practice (ICH/GCP), and any applicable regulatory requirements. The 
principal investigator will ensure that the inspectors and auditors will be provided with access to 
source data/documents. 
Management 
The project is based in the Section of Interventional Cardiology, Oslo University Hospital.  
- 
Principal Investigator:  
o Dr. Øyvind H Lie, Oslo University Hospital 

 
60 
 
▪ 
+4793420911 / oyvlie@gmail.com  
- 
Medical monitor: 
o Dr. Ketil Lunde, Oslo University Hospital 
▪ 
+4799627913 / ketlun@ous-hf.no  
- 
Steering Committee 
o Dr. Lars Aaberge, Oslo University Hospital 
▪ 
laraab@ous-hf.no  
o Prof. Lars Gullestad, Oslo University Hospital 
▪ 
lars.gullestad@medisin.uio.no  
o Dr. Øyvind H. Lie, Oslo University Hospital 
o Dr. Ketil Lunde, Oslo University Hospital 
- 
Endpoint Adjudication Committee 
o Dr. Kaspar Broch, cardiologist, leader, clinical events 
▪ 
sbbrok@ous-hf.no  
o Dr. Christian H. Eek, cardiologist, valvular cardiac CT expert 
o Dr. Jan Otto Beitnes, cardiologist, echocardiography expert 
- 
Data Safety Monitoring Board 
o Prof. Rune Wiseth, cardiologist, St. Olavs Hospital, Trondheim, Norway 
▪ 
rune.wiseth@stolav.no  
o Dr. Marissa Le Blanc, external statistician, Clinical Trial Unit OUH 
Ethical and regulatory requirements 
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory requirements. 
Registration of patient data will be carried out in accordance with national personal data laws. 

 
61 
 
Ethical considerations for participants 
If the hypothesis of the study is correct, half of the patients will be randomized to a superior 
treatment regimen without increased bleeding risk. This constitutes a significant benefit. The 
uncertainty regarding bleeding rates is a possible risk. Because there is no documentation of 
increased bleeding risk with anticoagulation versus single platelet inhibition, we consider the 
intervention not to impose unjustified risk for the patients.  
The active study protocol will not include study-specific invasive procedures. The additional CT 
assessment after 12 months will expose the patients to an additional contrast and radiation dose 
over the regular clinical course. However, the contrast dose is low and overt kidney damage is very 
uncommon after contrast-enhanced CT. 
Individuals who consent to the study will commit to an additional visit at the academic institution, 
with travel cost and risk. They will also contribute with personal information in a registry, and 
thereby trust the sponsor to treat their data appropriately. 
Ethics committee approval 
The study protocol, including the patient information and informed consent form to be used, must 
be approved by the regional ethics committee before enrolment begins. The investigator is 
responsible for informing the regional ethics committee of any serious and unexpected adverse 
events and/or major amendments to the protocol as per national requirements. 
Trial registration 
To ensure transparency, the protocol is registered in the EudraCT database and will be registered on 
www.clinicaltrials.gov before inclusion of the first patient. 
Informed consent procedure 
The investigator is responsible for giving the patients full and adequate verbal and written 
information about the nature, purpose, and potential risks and benefits of the study. Study 
participants will be informed as to the strict confidentiality of their patient data, but that their 
medical records may be reviewed for trial purposes by authorised individuals other than their 
treating physician.  
It will be emphasised that study participation is voluntary and that the patient is allowed to refuse 
further participation in the protocol whenever she/he wants. This will not prejudice the patient’s 
subsequent care. Written informed consent must be obtained for all study participants before 

 
62 
 
enrolment in the study. This will be done in accordance with the national and local regulatory 
requirements. The investigator is responsible for obtaining signed informed consent. 
A copy of the patient information and consent form will be given to the patients. The signed and 
dated consent forms will be filed in the Investigator Site File binder. 
Subject identification 
The investigator is responsible for keeping a list of all patients (who have received study treatment 
or undergone any study specific procedure) including patient’s date of birth and personal number, 
full names and last known addresses. The patients will be identified in the eCRFs by a study-specific, 
unique identification number. 
Trial sponsorship and financing 
ACASA-TAVI is an investigator-sponsored study (ISS). Funding is not finalized. We will apply for an 
open project support from the public research grants of South-Eastern Norway Health Authorities. 
We will not apply for funding from industry outside of provided tablets. The investigators take sole 
responsibility for the integrity of the data, the writing of the manuscript and the dissemination of the 
results. 
Trial insurance 
The Principal investigator has insurance coverage for this study through the Norwegian 
Pasientskadeloven. Insurance for the intervention will be obtained from Legemiddelforsikringen. 
Cost-benefit considerations 
The project will need considerable funding for thorough and precise execution. Any unforeseen 
events may also impose a cost to the public hospital system. The cost of medication is not negligible. 
On the other side, the potential economic benefits from reduced rate of re-intervention, frequent 
hospitalization and earlier death are substantial. Therefore, our general consideration is that this 
project holds great potential for cost benefit in intermediate and long-term. 
Publication policy 
Upon study completion and finalisation of the study report the results of this study will either be 
submitted for publication and/or posted in a publicly assessable database of clinical study results. 
We will allow for a separate publication of baseline characteristics once all subjects have been 
enrolled. 

 
63 
 
The results of this study will also be submitted to the Competent Authorities and the Regional Ethics 
Committees according to EU and national regulations. All personnel who have contributed 
significantly with the planning and performance of the study (Vancouver convention 1988) may be 
included in the list of authors. The funding sources have had no role in the conception of the study; 
neither will they participate in the implementation of the trial, in the analyses of the results, or in 
the decision to publish. 
Authorship 
All manuscript authorships of the main analysis and spin-off projects must be according to ICMJE 
recommendations and must be approved by the steering committee.  
Popular science dissemination 
We have made arrangements with the national patient organization (LHL, Landsforeningen for 
Hjerte- og Lungesyke) to aid in public science dissemination at the time of the main analyses.  
User representation 
A panel of users has been recruited via the national patient organization (LHL, Landsforeningen for 
Hjerte- og Lungesyke). The user panel has participated in the trial planning. They have emphasized 
the importance of registering quality of life endpoints. The elements highlighted in these discussions 
are all captured in the KCCQ, EQ-5D-5L and HADS questionnaires (especially symptoms like 
breathlessness, anxiety and depression, and apathy or fatigue). Furthermore, they have been 
consulted in establishing the 3-month follow-up intervals during the treatment year, which is aimed 
at creating a compromise between good safety monitoring and individual intrusiveness. The user 
panel also requested routines for interaction between the study centre and the local hospitals with 
regards to clinical information generated from the study follow-up. The panel highlights the 
importance of safety during the treatment period, and have suggested that a contact person in the 
trial (e.g. study nurse or research fellow) will be made available for every-day questions. This person 
should have immediate access to trial management. 
Further user representation is planned at the following time-points (all approximate): 
- 
September 2021 
o Start-up meeting prior to enrolment of first patient, discussions of approved study 
proceedings and incorporations of previous feedback. Discussions of whether 
additional alterations should be made before inclusion starts. 
- 
March 2022 

 
64 
 
o Early evaluation meeting after 6 months of inclusion experience and early telephone 
follow-up. Discussions of challenges. 
- 
October 2022, 2023 and 2024 
o Yearly evaluations and discussions of progression and interaction with trial 
participants. Considerations of remarks to be made in the yearly rapport. 
The user panel will receive re-imbursement for any expenses and will receive a non-monetary 
gratification for their efforts. The user representation panel consists of: 
- 
Anne Grete Funderud 
- 
Per Bøhler 
- 
Irene Steinsvik, user representation coordinator at LHL. 
o irene.steinsvik@lhl.no (telephone 95706313) 
Spin-offs 
Spin-off projects are analyses planned around the primary inclusion database. Projects that are not 
pre-defined must be approved by the Steering Committee and Partners after written project 
proposal. Spin-off projects will have a dedicated supplementary protocol. 
Planned spin-off analyses 
- 
The association between structural valve degeneration/HALT at 12 months and MACE at 5 
and 10 years. 
- 
The association between repeated echocardiographic and CT indices of valve degeneration. 
o Focus on myocardial work index, register blood pressure during echo. 
o 3D volume acquisitions 
- 
Echocardiographic predictors of adverse outcome. Assessment using dedicated 
comprehensive echocardiography prior to TAVI. 
- 
Sub-group with cerebral MR performed before and 6-12 months after TAVI. Stratified 
random selection from both intervention arms. The effect of DOAC related to ASA for 
reduction of subclinical cerebral micro-emboli will be assessed, together with neurological 
exam and cognitive testing. 

 
65 
 
o Primary outcome measure will be cerebral ischemic lesions using diffusion weighted 
imaging and mean diffusivity. Limited data exist, but one abstract suggested a 
remarkably high prevalence after TAVI (92% of 109 patients), mostly sub-clinical. 
Because most of these lesions are sub-clinical, we believe a substantial reduction 
should be seen with DOAC before any clinical benefit can be hypothesized. A 50% 
reduction would mandate 17 patients from each intervention group for an alpha 
value of 0.05 and 80% power. We will include 45 patients (1 of 8 random patients 
from the main trial) to allow for loss to follow-up, coincidental skewed distribution 
between intervention groups and deviation from expected prevalence of outcome. 
- 
Assessment of biomarkers associated with subclinical structural valve degeneration/HALT 
- 
Standard clinical biomarkers after 3 months 
- 
Subgroup analysis with repeated CT at 3 and 12 months to assess dynamic SVD Stage 1. 
- 
Technical optimization of cardiac CT protocol for clinical use 
- 
Arterial elastance as marker of biological age – invasive pressure validation and association 
with clinical outcome (Thomas Helle-Valle and Njord Nordstrand) 
o Ultrasound acquisition during TAVI for invasive pressure validation 
- 
Invasive pressure assessment of aortic valve regurgitation. Datapoints are routinely assessed 
during the clinical procedure. We will use these to explore invasive pressure predictors of 
significant para-valvular regurgitation.  
 
 
 

 
66 
 
Partners  
Partners are collaborating units with their contact person. They have key roles in the main study and 
can propose subsequent spin-off studies. 
Section for echocardiography, Oslo University Hospital, Rikshospitalet 
The section for echocardiography at the Department of Cardiology is the largest echocardiographic 
laboratory in Norway and has international accreditation. More than 10.000 echocardiographic 
exams are performed every year, including on many patients with aortic stenosis before and after 
TAVI. Qualified and dedicated echocardiographers and technicians contribute with acquisitions and 
interpretations of optimal quality. 
- 
Helge Skulstad, MD PhD, Head of Section 
The Intervention Centre, Oslo University Hospital, Rikshospitalet 
The intervention centre at Oslo University Hospital has state-of-the-art hybrid operating theatres 
and modern CT-scanners. They have good accessibility for high-end CT and will perform spin-off 
efforts to optimize cardiac CT protocols, and good availability for cerebral MR. 
- 
Ragnhild Undseth, MD PhD, Head of Radiology 
Section for Interventional Cardiology, Oslo University Hospital, Ullevål 
The section for interventional cardiology at Ullevål Hospital will screen all approximately 200 TAVI-
patients and include all eligible patients. They may also generate projects within the trial in 
collaboration with the steering committee. 
- 
Anders Opdahl, MD PhD, site PI. 
Department of Internal Medicine, Sørlandet Sykehus, Arendal 
The Section for Cardiology at the Department of Internal Medicine at Sørlandet Hospital, Arendal, is 
a key collaborator in the management of patients with aortic stenosis. They have good accessibility 
for repeated CT assessments, and will conduct controls and spin-off analysis with repeated CT at 3 
and 12 months. 
- 
Sverre Høie, MD, Consultant Cardiologist 
Research Institute for Internal Medicine, Oslo University Hospital 
The institute for research in internal medicine specialises in biomarker analyses and will be pivotal in 
the spin-off studies assessing markers of micro-thrombosis and heart failure. 

 
67 
 
- Thor Ueland, MD PhD, Professor 
 

 
68 
 
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71 
 
Signature Page 
I hereby declare that I will conduct the study in compliance with this protocol and the applicable 
regulations: 
Name 
Title 
Role 
Date 
Signature 
Øyvind H Lie 
MD, PhD 
Principal Investigator 
 
 
Ketil Lunde 
MD, PhD 
Steering Committee 
 
 
Lars Gullestad 
MD, PhD 
Steering Committee 
 
 
Lars Aaberge 
MD, PhD 
Steering Committee 
 
 
Kaspar Broch 
MD, PhD 
Adjudication Committee 
 
 
Christian H Eek 
MD, PhD 
Adjudication Committee 
 
 
Jan Otto Beitnes 
MD, PhD 
Adjudication Committee 
 
 
Rune Wiseth 
MD, PhD 
Safety Monitoring Board 
 
 
Marissa Le Blanc 
PhD 
Safety Monitoring Board 
 
 
Erica Ponzi 
PhD 
Trial Statistician 
 
 
Sophie Foss Kløve 
RN 
Study Nurse 
 
 
Christopher Dodgson 
MD 
PhD fellow