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) (GALILEO-4D)

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Thrombosis; Aortic Valve Stenosis; Heart Valve Diseases; Ventricular Outflow Obstruction
• Intervention / Treatment: Drug: Acetylsalicylic acid; Drug: Clopidogrel; Drug: Rivaroxaban

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 Type: Interventional
• Enrollment (Actual): 231
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Edmonton, Canada, AB T6G 2B7
    • University of Alberta Hospital
  • Vancouver, Canada, ON M1L 1W1
    • Providence Health Care
• Denmark
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
  • Odense, Denmark, 5000
    • Odense University Hospital
• Germany
  • Bad Nauheim, Germany, 61231
    • Kerckhoff Klinik GmbH
  • Berlin, Germany, 13353
    • Deutsches Herzzentrum Berlin
  • Berlin, Germany, 10117
    • Charité- Universitätsmedizin Berlin - Campus Mitte
  • Dortmund, Germany, 44137
    • St. Johannes Hospital
  • Erlangen, Germany, 91012
    • Universitätsklinikum Erlangen
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein
  • Lahr, Germany, 77933
    • Medicin Herzzentrum Lahr/Baden
  • Leipzig, Germany, 04289
    • Herzzentrum Leipzig - Universitätsklinik
  • München, Germany, 80636
    • Deutsches Herzzentrum München
• Netherlands
  • Amsterdam, Netherlands, 1105
    • Academic Medical Center
  • Breda, Netherlands, 4818
    • Amphia Zienkenhuis
  • Rotterdam, Netherlands, 3015
    • Erasmus M.C
• Sweden
  • Lund, Sweden, SE-205 02
    • Skåne University Hospital
  • Stockholm, Sweden, SE-171 76
    • Karolinska University Hospital
• Switzerland
  • Basel, Switzerland, 4056
    • University Hospital Basel
  • Bern, Switzerland, 3010
    • Inselspital
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
  • New York
    • New York, New York, United States, 10029-6574
      • Mount Sinai M.C
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Texas
    • Houston, Texas, United States, 78229
      • University of Texas, Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Patients With at Least One Prosthetic Leaflet With >50% Motion Reduction as Assessed by Cardiac 4DCT-scan	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.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Rate of Prosthetic Leaflets With > 50% Motion Reduction as Assessed by Cardiac 4DCT-scan	The rate of prosthetic leaflets with RLM> grade 3 as assessed by cardiac 4DCT	3 months
The Rate of Patients With at Least One Prosthetic Leaflet With Thickening as Assessed by Cardiac 4DCT-scan	The rate of patients with at least one prosthetic leaflet with hypoattenuated leaflet thickening (HALT) as assessed by cardiac 4DCT.	3 months
The Rate of Prosthetic Leaflets With Thickening as Assessed by Cardiac 4DCT-scan	The rate of prosthetic leaflet with HALT as assessed by cardiac 4DCT-scan	3 months
Aortic Transvalvular Mean Pressure Gradient (mmHg) as Determined by Transthoracic Echocardiography.	Transprosthetic mean pressure gradiënt as determined by transthoracic echocardiography at three months after randomization. scale [0-100]	3 months
Effective Orifice Area (cm^2) as Determined by Transthoracic Echocardiography.	Effective orifice area (cm2) as determined by transthoracic echocardiography at three months after randomization. scale [0.1-4.0]	3 months
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.	Death, Dichotomization by HALT	3 months
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.	Death, Dichotomization by RLM	3 months
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.	Thromboembolic event, Dichotomization by HALT	3 months
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.	Thromboembolic event, Dichotomization by RLM	3 months

Collaborators and Investigators

• Sponsor: ECRI bv
• Collaborators: Bayer; Rigshospitalet, Denmark; Cardialysis BV
• Investigators: Principal Investigator: Lars Søndergaard, MD;DMSc, Rigshospitalet, Denmark

Publications and helpful links

General 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, Sondergaard 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.
• De Backer O, Dangas GD, Jilaihawi H, Leipsic JA, Terkelsen CJ, Makkar R, Kini AS, Veien KT, Abdel-Wahab M, Kim WK, Balan P, Van Mieghem N, Mathiassen ON, Jeger RV, Arnold M, Mehran R, Guimaraes AHC, Norgaard BL, Kofoed KF, Blanke P, Windecker S, Sondergaard L; GALILEO-4D Investigators. Reduced Leaflet Motion after Transcatheter Aortic-Valve Replacement. N Engl J Med. 2020 Jan 9;382(2):130-139. doi: 10.1056/NEJMoa1911426. Epub 2019 Nov 16.

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): March 6, 2019

Study Registration Dates

• First Submitted: June 24, 2016
• First Submitted That Met QC Criteria: July 12, 2016
• First Posted (Estimate): July 14, 2016

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 9, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Transcatheter Aortic Valve Replacement; TAVR; Heart Valve Disease; Valve Thrombosis
• Additional Relevant MeSH Terms: Heart Diseases; Vascular Diseases; Embolism and Thrombosis; Aortic Valve Disease; Cardiovascular Diseases; Aortic Valve Stenosis; Thrombosis; Heart Valve Diseases; Ventricular Outflow Obstruction; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Clopidogrel; Rivaroxaban
• Other Study ID Numbers: ECRI 006 - H-15016807

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No