GALILEO-4D: Comparison of a Rivaroxaban-based Strategy With an Antiplatelet-based Strategy Following Successful TAVR for the Prevention of Leaflet Thickening and Reduced Leaflet Motion as Evaluated by Four-dimensional, Volume-rendered Computed Tomography (4DCT)

• Sponsor: ECRI bv (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02833948
• Collaborator: Rigshospitalet, Denmark (Other), Bayer (Industry), Cardialysis BV (Industry)
• Enrollment: 231
• Locations: 25
• Arms: 2
• Duration (Months): 34.1
• Patients Per Site: 9.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The aortic valve is located between the left ventricle and the aorta. Patients with symptomatic, severe aortic valve stenosis conventionally have it surgically replaced requiring direct access to the heart through the chest. Transcatheter aortic valve replacement (TAVR) is now a well-established alternative for treating severe aortic valve stenosis. Both types of intervention improve prognosis and alleviate symptoms.

The optimal choice of blood thinning therapy after TAVR is unknown. It has been reported that leaflet thrombosis with reduced leaflet motion can occur and this phenomenon has been suggested to be potentially related with neurological events. In addition, the occurence of this phenomenon can be reduced with anticoagulation blood thinning therapy.

The purpose of this study is to evaluate if anticoagulation compared to the usual double platelet inhibitor therapy after TAVR can reduce the risk of leaflet thrombosis.

Condition or Disease	Intervention/Treatment	Phase
Aortic Valve Stenosis; Cardiovascular Diseases; Heart Valve Diseases; Ventricular Outflow Obstruction; Thrombosis	Drug: Acetylsalicylic acid; Drug: Clopidogrel; Drug: Rivaroxaban	Phase 3

Detailed Description

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become an established therapeutic option for patients with symptomatic, severe aortic valve stenosis, who are ineligible or at high risk for conventional surgical aortic valve replacement (SAVR). It was recently reported that leaflet thickening and reduced leaflet motion, verified by four-dimensional computed tomography (4DCT), was not uncommon after both TAVR and SAVR. It has been emphasized that this phenomenon should be further investigated for its effect on clinical outcomes (e.g. stroke) and valve durability. As this valve leaflet thickening and reduced motion could be reversed by oral anticoagulant (OAC) treatment and was not observed in patients on chronic OAC therapy, it has been hypothesized that this phenomenon could be related to possible leaflet thrombosis or a "thrombotic film" on the leaflets.

AIM: To evaluate whether a rivaroxaban-based strategy, following successful TAVR, compared to an antiplatelet-based strategy, is superior in reducing subclinical valve leaflet thickening and motion abnormalities - as detected by 4DCT-scan.

POPULATION: All patients undergoing successful TAVR by ileofemoral or subclavian access with an approved TAVR device will be screened for eligibility. Included subjects must provide written informed consent. Inclusion and exclusion criteria are listed below.

DESIGN: The GALILEO-4D trial will be conducted as a substudy of the multicenter, open-label, randomized, event-driven, active-controlled GALILEO trial. Patients will be 1:1 randomized to an antiplatelet-based strategy vs. rivaroxaban-based strategy - the randomization will adopt the same 1:1 randomization of the main GALILEO trial. In case the GALILEO-4D trial should still be continued after completion of the main GALILEO trial, this 1:1 randomization will be continued until inclusion of 150 patients in both treatment groups. In total, 300 patients will be randomized in the GALILEO-4D trial.

INTERVENTION: Subjects in the GALILEO-4D substudy will receive the same intervention as in the main GALILEO study. In addition, a 4DCT-scan and echocardiography will be performed at 90 days after randomization.

END POINTS: The primary endpoint constitutes the rate of patients with at least one prosthetic leaflet with > 50% motion reduction as assessed by cardiac 4DCT-scan (total N = 300). The secondary endpoints are listed below.

Study Design

• Study Type: Interventional
• Actual Enrollment: 231 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: Randomized Comparison of a Rivaroxaban-based Strategy With an Antiplatelet-based Strategy Following Successful TAVR for the Prevention of Leaflet Thickening and Reduced Leaflet Motion as Evaluated by Four-dimensional, Volume-rendered Computed Tomography (4DCT) - Substudy of the GALILEO-trial
• Study Start Date: May 1, 2016
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Mar 6, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ASA + Clopidogrel ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy	Drug: Acetylsalicylic acid; Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1); Other Names: Asprin ; Drug: Clopidogrel; Drug: Clopidogrel 75 mg OD for first 90 days; Other Names: Plavix
Experimental: Rivaroxaban + ASA Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy	Drug: Acetylsalicylic acid; Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1); Other Names: Asprin ; Drug: Rivaroxaban; Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily); Other Names: Xarelto

Outcome Measures

Primary Outcome Measures

1. Rate of Patients With at Least One Prosthetic Leaflet With >50% Motion Reduction as Assessed by Cardiac 4DCT-scan [3 months]

   Reduced systolic leaflet excursion is classified as: (I) normal, (II) mildly reduced (<50%), (III) moderate to severely reduced (>50%), and (IV) immobile. Reduced systolic leaflet excursion is considered significant when it is > 50% or immobile. Quantitative assessment of leaflet motion is performed with a blood pool inversion volume rendered cine reconstruction throughout the cardiac cycle evaluating the bioprosthetic leaflets.

Secondary Outcome Measures

1. The Rate of Prosthetic Leaflets With > 50% Motion Reduction as Assessed by Cardiac 4DCT-scan [3 months]

   The rate of prosthetic leaflets with RLM> grade 3 as assessed by cardiac 4DCT

2. The Rate of Patients With at Least One Prosthetic Leaflet With Thickening as Assessed by Cardiac 4DCT-scan [3 months]

   The rate of patients with at least one prosthetic leaflet with hypoattenuated leaflet thickening (HALT) as assessed by cardiac 4DCT.

3. The Rate of Prosthetic Leaflets With Thickening as Assessed by Cardiac 4DCT-scan [3 months]

   The rate of prosthetic leaflet with HALT as assessed by cardiac 4DCT-scan

4. Aortic Transvalvular Mean Pressure Gradient (mmHg) as Determined by Transthoracic Echocardiography. [3 months]

   Transprosthetic mean pressure gradiënt as determined by transthoracic echocardiography at three months after randomization. scale [0-100]

5. Effective Orifice Area (cm^2) as Determined by Transthoracic Echocardiography. [3 months]

   Effective orifice area (cm2) as determined by transthoracic echocardiography at three months after randomization. scale [0.1-4.0]

6. Death Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (HALT) - as Exploratory Analysis. [3 months]

   Death, Dichotomization by HALT

7. Death Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (RLM)- as Exploratory Analysis. [3 months]

   Death, Dichotomization by RLM

8. Thromboembolic Event Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (HALT)- as Exploratory Analysis. [3 months]

   Thromboembolic event, Dichotomization by HALT

9. Thromboembolic Event Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (RLM) - as Exploratory Analysis. [3 months]

   Thromboembolic event, Dichotomization by RLM

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Successful TAVR of a native aortic valve stenosis

• By iliofemoral or subclavian access

• With any approved/marketed TAVR device

• Written informed consent

Exclusion Criteria:

• Atrial fibrillation (AF), current or previous, with an ongoing indication for oral anticoagulant treatment

• Any other indication for continued treatment with any oral anticoagulant

• Known bleeding diathesis (such as but not limited to platelet count ≤ 50,000/mm3 at screening, hemoglobin level < 8.5 g/dL or < 5.3 mmol/l, history of intracranial hemorrhage, or subdural hematoma)

• Any indication for dual antiplatelet therapy (DAPT) for more than three months after randomization (such as coronary, carotid, or peripheral stent implantation)

• Clinically overt stroke within the last three months

• Planned coronary or vascular intervention or major surgery

• Severe renal insufficiency (eGFR < 30 mL/min/1.73 m2) or on dialysis, or post-TAVR unresolved acute kidney injury with renal dysfunction ≥ stage 2

• Moderate and severe hepatic impairment (Child-Pugh Class B or C) or any hepatic disease associated with coagulopathy

• Iodine contrast allergy or other condition that prohibits CT imaging

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
2	Mount Sinai M.C	New York	New York	United States	10029-6574
3	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
4	University of Texas, Health Science Center	Houston	Texas	United States	78229
5	University of Alberta Hospital	Edmonton		Canada	AB T6G 2B7
6	Providence Health Care	Vancouver		Canada	ON M1L 1W1
7	Aarhus university hospital	Aarhus		Denmark	8000
8	Rigshospitalet	Copenhagen		Denmark	2100
9	Odense University Hospital	Odense		Denmark	5000
10	Kerckhoff Klinik GmbH	Bad Nauheim		Germany	61231
11	Charité- Universitätsmedizin Berlin - Campus Mitte	Berlin		Germany	10117
12	Deutsches Herzzentrum Berlin	Berlin		Germany	13353
13	St. Johannes Hospital	Dortmund		Germany	44137
14	Universitätsklinikum Erlangen	Erlangen		Germany	91012
15	Universitätsklinikum Schleswig-Holstein	Kiel		Germany	24105
16	Medicin Herzzentrum Lahr/Baden	Lahr		Germany	77933
17	Herzzentrum Leipzig - Universitätsklinik	Leipzig		Germany	04289
18	Deutsches Herzzentrum München	München		Germany	80636
19	Academic Medical Center	Amsterdam		Netherlands	1105
20	Amphia Zienkenhuis	Breda		Netherlands	4818
21	Erasmus M.C	Rotterdam		Netherlands	3015
22	Skåne University Hospital	Lund		Sweden	SE-205 02
23	Karolinska University Hospital	Stockholm		Sweden	SE-171 76
24	University Hospital Basel	Basel		Switzerland	4056
25	Inselspital	Bern		Switzerland	3010

Sponsors and Collaborators

• ECRI bv
• Rigshospitalet, Denmark
• Bayer
• Cardialysis BV

Investigators

• Principal Investigator: Lars Søndergaard, MD;DMSc, Rigshospitalet, Denmark

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 29, 2017

More Information

Publications

• Makkar RR, Fontana G, Jilaihawi H, Chakravarty T, Kofoed KF, De Backer O, Asch FM, Ruiz CE, Olsen NT, Trento A, Friedman J, Berman D, Cheng W, Kashif M, Jelnin V, Kliger CA, Guo H, Pichard AD, Weissman NJ, Kapadia S, Manasse E, Bhatt DL, Leon MB, Søndergaard L. Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. N Engl J Med. 2015 Nov 19;373(21):2015-24. doi: 10.1056/NEJMoa1509233. Epub 2015 Oct 5.

• Responsible Party: ECRI bv
• ClinicalTrials.gov Identifier: NCT02833948
• Other Study ID Numbers: ECRI 006 - H-15016807
• First Posted: Jul 14, 2016
• Last Update Posted: Jan 18, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by ECRI bv: Heart Valve Disease; Randomized Controlled Trial; Transcatheter Aortic Valve Replacement; TAVR; Valve Thrombosis
• Additional relevant MeSH terms: Cardiovascular Diseases; Thrombosis; Aortic Valve Stenosis; Heart Valve Diseases; Ventricular Outflow Obstruction; Aspirin; Rivaroxaban; Clopidogrel

Study Results

Participant Flow

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
Period Title: Overall Study
STARTED	116	115
COMPLETED	101	97
NOT COMPLETED	15	18

Baseline Characteristics

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA	Total
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.	Total of all reporting groups
Overall Participants	116	115	231
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	80.5 (6.2)	79.7 (7.3)	80.1 (6.7)
Sex: Female, Male (Count of Participants)
Female	42 36.2%	41 35.7%	83 35.9%
Male	74 63.8%	74 64.3%	148 64.1%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Body-mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.8 (5.1)	27.7 (6.5)	27.8 (5.8)
Hypertension (Count of Participants)
Count of Participants [Participants]	95 81.9%	98 85.2%	193 83.5%
Diabetes Mellitus (Count of Participants)
Count of Participants [Participants]	27 23.3%	21 18.3%	48 20.8%
STS risk score (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	3.0 (2.1)	2.8 (1.5)	2.9 (1.8)
STS risk category - High (Count of Participants)
Count of Participants [Participants]	3 2.6%	1 0.9%	4 1.7%
STS risk category - Intemediate (Count of Participants)
Count of Participants [Participants]	35 30.2%	37 32.2%	72 31.2%
STS risk category - low (Count of Participants)
Count of Participants [Participants]	78 67.2%	77 67%	155 67.1%
Congestive Heart Failure (Count of Participants)
Count of Participants [Participants]	52 44.8%	52 45.2%	104 45%
Coronary Artery Disease (Count of Participants)
Count of Participants [Participants]	36 31%	42 36.5%	78 33.8%
Previous stroke (Count of Participants)
Count of Participants [Participants]	6 5.2%	11 9.6%	17 7.4%
Peripheral Artery disease (Count of Participants)
Count of Participants [Participants]	10 8.6%	10 8.7%	20 8.7%
Previous venous thromboembolism (Count of Participants)
Count of Participants [Participants]	1 0.9%	1 0.9%	2 0.9%
Permanent Pacemaker (Count of Participants)
Count of Participants [Participants]	14 12.1%	14 12.2%	28 12.1%
Chronic obstructive pulmonary disease (Count of Participants)
Count of Participants [Participants]	16 13.8%	19 16.5%	35 15.2%
Glomerular filtration rate (ml/min/1.73m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73m2]	76.6 (19.4)	73.6 (19.2)	75.1 (19.3)
Valve type - balloon-expandable (Count of Participants)
Count of Participants [Participants]	54 46.6%	52 45.2%	106 45.9%
Valve type - Self-expandable (Count of Participants)
Count of Participants [Participants]	62 53.4%	63 54.8%	125 54.1%
Valve type - Supra-annular leaflet position (Count of Participants)
Count of Participants [Participants]	46 39.7%	37 32.2%	83 35.9%
Valve-in-valve (Count of Participants)
Count of Participants [Participants]	1 0.9%	3 2.6%	4 1.7%
Post TAVR Echo - Aortic-valve-area (cm2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm2]	1.8 (0.5)	1.8 (0.5)	1.8 (0.5)
Post TAVR Echo - mean aortic-valve gradient (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	11 (4)	11 (5)	11 (4)
Post TAVR Echo - Left Ventricular ejection fraction (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	56 (10)	55 (11)	56 (11)
Paravalvular aortic regurgitation - none or trace (Count of Participants)
Count of Participants [Participants]	96 82.8%	94 81.7%	190 82.3%
Paravalvular aortic regurgitation - Mild (Count of Participants)
Count of Participants [Participants]	19 16.4%	19 16.5%	38 16.5%
Paravalvular aortic regurgitation - moderate or severe (Count of Participants)
Count of Participants [Participants]	1 0.9%	2 1.7%	3 1.3%

Outcome Measures

1. Primary Outcome

Title	Rate of Patients With at Least One Prosthetic Leaflet With >50% Motion Reduction as Assessed by Cardiac 4DCT-scan
Description	Reduced systolic leaflet excursion is classified as: (I) normal, (II) mildly reduced (<50%), (III) moderate to severely reduced (>50%), and (IV) immobile. Reduced systolic leaflet excursion is considered significant when it is > 50% or immobile. Quantitative assessment of leaflet motion is performed with a blood pool inversion volume rendered cine reconstruction throughout the cardiac cycle evaluating the bioprosthetic leaflets.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
Measure Participants	101	97
Count of Participants [Participants]	11 9.5%	2 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ASA + Clopidogrel, Rivaroxaban + ASA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Fisher Exact
	Comments	The Fisher's exact probability test was used to compare the percentages of patients with the primary end point between the treatment groups.

2. Secondary Outcome

Title	The Rate of Prosthetic Leaflets With > 50% Motion Reduction as Assessed by Cardiac 4DCT-scan
Description	The rate of prosthetic leaflets with RLM> grade 3 as assessed by cardiac 4DCT
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
Measure Participants	101	97
Measure leaflets	303	291
Number [leaflets]	14	3

3. Secondary Outcome

Title	The Rate of Patients With at Least One Prosthetic Leaflet With Thickening as Assessed by Cardiac 4DCT-scan
Description	The rate of patients with at least one prosthetic leaflet with hypoattenuated leaflet thickening (HALT) as assessed by cardiac 4DCT.
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
Measure Participants	102	97
Count of Participants [Participants]	33 28.4%	12 10.4%

4. Secondary Outcome

Title	The Rate of Prosthetic Leaflets With Thickening as Assessed by Cardiac 4DCT-scan
Description	The rate of prosthetic leaflet with HALT as assessed by cardiac 4DCT-scan
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
Measure Participants	102	97
Measure Leaflets	306	291
Number [Leaflets]	53	16

5. Secondary Outcome

Title	Aortic Transvalvular Mean Pressure Gradient (mmHg) as Determined by Transthoracic Echocardiography.
Description	Transprosthetic mean pressure gradiënt as determined by transthoracic echocardiography at three months after randomization. scale [0-100]
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
Measure Participants	105	102
Mean (Standard Deviation) [mm Hg]	10 (5)	10 (5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ASA + Clopidogrel, Rivaroxaban + ASA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	Effective Orifice Area (cm^2) as Determined by Transthoracic Echocardiography.
Description	Effective orifice area (cm2) as determined by transthoracic echocardiography at three months after randomization. scale [0.1-4.0]
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population

Arm/Group Title	ASA + Clopidogrel	Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.	Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
Measure Participants	105	102
Mean (Standard Deviation) [cm2]	1.8 (0.4)	1.8 (0.5)

7. Secondary Outcome

Title	Death Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (HALT) - as Exploratory Analysis.
Description	Death, Dichotomization by HALT
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population, subgroup of patients with analysable scans

Arm/Group Title	HALT (-)	HALT (+)
Arm/Group Description	Hypoattenuated leaflet thickening (-)	Hypoattenuated leaflet thickening (+)
Measure Participants	151	44
Count of Participants [Participants]	0 0%	0 0%

8. Secondary Outcome

Title	Death Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (RLM)- as Exploratory Analysis.
Description	Death, Dichotomization by RLM
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population, subgroup of patients with analysable scans

Arm/Group Title	RLM>2 (-)	RLM(+)
Arm/Group Description	Reduced Leaflet Motion >2 (-)	Reduced Leaflet Motion >2 (+)
Measure Participants	169	25
Count of Participants [Participants]	0 0%	0 0%

9. Secondary Outcome

Title	Thromboembolic Event Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (HALT)- as Exploratory Analysis.
Description	Thromboembolic event, Dichotomization by HALT
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population, subgroup of patients with analysable scans

Arm/Group Title	HALT (-)	HALT (+)
Arm/Group Description	Hypoattenuated leaflet thickening (-)	Hypoattenuated leaflet thickening (+)
Measure Participants	151	44
Count of Participants [Participants]	2 1.7%	0 0%

10. Secondary Outcome

Title	Thromboembolic Event Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (RLM) - as Exploratory Analysis.
Description	Thromboembolic event, Dichotomization by RLM
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Intention-to-treat (ITT) study population, subgroup of patients with analysable scans

Arm/Group Title	RLM>2 (-)	RLM(+)
Arm/Group Description	Reduced Leaflet Motion >2 (-)	Reduced Leaflet Motion >2 (+)
Measure Participants	169	25
Count of Participants [Participants]	2 1.7%	0 0%

Adverse Events

Time Frame	90 days
Adverse Event Reporting Description	Adverse event reporting was captured via the Main Galileo trial (Global Study Comparing a rivAroxaban-based Antithrombotic Strategy to an antipLatelet-based Strategy After Transcatheter aortIc vaLve rEplacement to Optimize Clinical Outcomes) NCT02556203
Arm/Group Title	ASA + Clopidogrel		Rivaroxaban + ASA
Arm/Group Description	ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Clopidogrel: Drug: Clopidogrel 75 mg OD for first 90 days If new-onset atrial fibrillation occurred within three months, clopidogrel was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3 and combined with acetylsalicyclic acid 75mg to 100mg once-daily (which was discontinued at three month post-TAVR); however, if new-onset atrial fibrillation occurred after three months, acetylsalicyclic acid 75mg to 100mg once-daily was replaced by vitamin K antagonist targeting an international normalized ratio of 2 to 3.		Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy Acetylsalicylic acid: Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1) Rivaroxaban: Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily) If new-onset atrial fibrillation occurred within this group, the rivaroxaban drug dose was increased from 10mg once-daily to 20mg once-daily (or 15mg once-daily in patients with moderate renal dysfunction as per drug label) plus acetylsalicyclic acid 75mg to 100mg once-daily; acetylsalicyclic acid was discontinued at three months post-TAVR.
All Cause Mortality
	ASA + Clopidogrel		Rivaroxaban + ASA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/116 (1.7%)		3/115 (2.6%)
Serious Adverse Events
	ASA + Clopidogrel		Rivaroxaban + ASA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/116 (2.6%)		7/115 (6.1%)
Blood and lymphatic system disorders
Major bleeding event	1/116 (0.9%)	1	4/115 (3.5%)	4
Cardiac disorders
Thromboembolic event	2/116 (1.7%)	2	4/115 (3.5%)	4
Other (Not Including Serious) Adverse Events
	ASA + Clopidogrel		Rivaroxaban + ASA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/116 (14.7%)		16/115 (13.9%)
Blood and lymphatic system disorders
minor bleeding	17/116 (14.7%)	17	16/115 (13.9%)	16

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.