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)

Cardiovascular Diseases Clinical Trial

— GALILEO-4D  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02833948
• Other study ID #: ECRI 006 - H-15016807
• Status: Completed
• Phase: Phase 3
• Start date: May 2016
• Est. completion date: March 6, 2019

Study information

• Verified date: January 2020
• Source: ECRI bv
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 231
• Est. completion date: March 6, 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aortic Valve Stenosis
• Cardiovascular Diseases
• Heart Valve Diseases
• Thrombosis
• Ventricular Outflow Obstruction

Intervention

Drug:
• 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
• Rivaroxaban
Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily)

Locations

Country	Name	City	State
Canada	University of Alberta Hospital	Edmonton
Canada	Providence Health Care	Vancouver
Denmark	Aarhus university hospital	Aarhus
Denmark	Rigshospitalet	Copenhagen
Denmark	Odense University Hospital	Odense
Germany	Kerckhoff Klinik GmbH	Bad Nauheim
Germany	Charité- Universitätsmedizin Berlin - Campus Mitte	Berlin
Germany	Deutsches Herzzentrum Berlin	Berlin
Germany	St. Johannes Hospital	Dortmund
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	Medicin Herzzentrum Lahr/Baden	Lahr
Germany	Herzzentrum Leipzig - Universitätsklinik	Leipzig
Germany	Deutsches Herzzentrum München	München
Netherlands	Academic Medical Center	Amsterdam
Netherlands	Amphia Zienkenhuis	Breda
Netherlands	Erasmus M.C	Rotterdam
Sweden	Skåne University Hospital	Lund
Sweden	Karolinska University Hospital	Stockholm
Switzerland	University Hospital Basel	Basel
Switzerland	Inselspital	Bern
United States	University of Texas, Health Science Center	Houston	Texas
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Mount Sinai M.C	New York	New York
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (4)

Lead Sponsor	Collaborator
ECRI bv	Bayer, Cardialysis BV, Rigshospitalet, Denmark

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  Germany,  Netherlands,  Sweden,  Switzerland, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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