Summary

• On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an antiplatelet regimen.¹
• GALILEO was a randomized, open-label, event-driven, phase 3 trial to assess a XARELTO-based antithrombotic strategy to reduce the risk of thromboembolic complications post-TAVR with an acceptable risk of bleeding compared with antiplatelet therapy-based strategy in subjects without an indication for chronic anticoagulation.²
  • Eligible patients were randomized 1:1 to XARELTO plus aspirin or clopidogrel plus aspirin 1-7 days after successful TAVR and before hospital discharge.²
    • After 90 days, the XARELTO/aspirin group discontinued aspirin, and the clopidogrel/aspirin group discontinued clopidogrel. The protocol also included alternative regimens for patients who developed atrial fibrillation.
  • The trial was prematurely ended (on August 13, 2018) by the data and safety monitoring board due to safety concerns.³
  • The primary efficacy outcome, the composite of all-cause mortality, any stroke, myocardial infarction (MI), symptomatic valve thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and non-central nervous system (CNS) systemic embolism, occurred more frequently in the XARELTO group than the antiplatelet group (105 vs 78 events, respectively; hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.01-1.81).³
  • The primary safety outcome, the composite of life-threatening, disabling, or major bleeding, occurred at a similar rate in the XARELTO group and the antiplatelet group (46 vs 31 events, respectively; HR 1.50, 95% CI 0.95-2.37).³
• The goal of GALILEO-4D, a substudy of GALILEO, was to evaluate the effect of each treatment strategy on leaflet-motion abnormalities and thickening.^3,4
  • The primary endpoint was the percentage of patients with ≥1 prosthetic valve leaflet with reduced motion of grade 3 or higher. Of the 97 patients in the XARELTO group, the primary endpoint occurred in 2 (2.1%) versus 11 of 101 (10.9%) in the antiplatelet group (between group difference -16.5 to -1.9; p=0.01).⁴
• EARTH-TAVR a substudy of GALILEO, evaluated the occurrence and extent of cerebral thromboembolism events in 36 patients. Cerebral magnetic resonance imaging (MRI) was performed pre-TAVR, post-TAVR (24-48 hours) and 90 days after TAVR. Included in the MRI protocol was diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging.⁵
  • An increase of cerebral lesions and volume post-TAVR by a median of 4.75 (95% CI 2.1–8.9) and 0.26 cm³ (95% CI 0.11–0.59) was discovered on the DWI MRI scans.
  • FLAIR imaging revealed lesion number and volume increased by a median of 3 (95% CI 1.5–6) and 0.1 cm³ (95% CI 0.04–0.31).
  • Regardless of the treatment arm, there was no statistically significant change in cerebral lesions at 90 days, compared to the post-TAVR MRI scan.
• Jochheim et al (2019)⁶ conducted a multicenter observational registry study to evaluate the use of treatment with NOACs vs vitamin K antagonists (VKAs) after a TAVR up to one year after the procedure.
  • Of the 962 patients included in the study, 326 patients were taking NOACs. Of those 53.7% were prescribed XARELTO.
  • At 1-year follow up, patients receiving a NOAC were found to have a higher risk of the combined endpoint of all-cause mortality, MI, and any cerebrovascular event (primary outcome) and similar risk of bleeding when compared to those receiving VKAs.
• Additional citations identified during literature search have been included in the REFERENCES section for your review.^7-12

CLINICAL STUDIES

GALILEO

GALILEO (Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy after Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes) was a randomized, open-label, event-driven, phase 3 trial to assess a XARELTO-based antithrombotic strategy to reduce the risk of thromboembolic complications post-TAVR with an acceptable risk of bleeding compared with currently recommended antiplatelet therapy-based strategy.²

Methods

• Patients were included if they were at least 18 years old and had successful completion of a TAVR procedure (correct positioning, proper functioning, absence of complications).
• Patients were excluded if they had an established indication for long-term anticoagulation and any absolute indication for dual antiplatelet therapy.
• Eligible patients were randomized 1:1 to the XARELTO-based strategy or the antiplatelet-based strategy 1-7 days after successful TAVR and before hospital discharge. Patients were stratified by site.²
  • Patients in the XARELTO arm were assigned to XARELTO 10 mg daily and aspirin 75-100 mg daily for 90 days, at which time the patients would discontinue aspirin therapy. The patients continued on XARELTO 10 mg daily until the end of the study.
    • If patients in this group developed atrial fibrillation (AF), they were to receive XARELTO 20 mg daily (or 15 mg daily for those with creatinine clearance 30-50 mL/min).³
  • Patients in the antiplatelet arm were assigned to clopidogrel 75 mg daily and aspirin 75-100 mg daily for 90 days, at which time the patients would discontinue clopidogrel therapy. The patients continued on aspirin 75-100 mg daily until the end of the study. (Patients who had not previously received clopidogrel were recommended to receive a single loading dose of at least 300 mg.)
    • If patients in this group developed AF, they were to receive a VKA daily (target international normalized ratio 2.0-3.0) to replace clopidogrel within 3 months after randomization or aspirin afterwards.³
• The primary analysis was intention-to-treat (ITT) and all components of the primary efficacy and safety endpoints were blindly adjudicated.²
• Noninferiority between treatments was to be initially tested, followed by superiority.²
  • Noninferiority could be claimed if the upper bound of the HR was <1.20 based on the on-treatment analysis set.
  • Superiority could be tested if noninferiority of the XARELTO-based regimen is met. If tested, superiority can be claimed if the one-sided p-value is <0.025.
  • It was estimated that 440 primary outcome events would be needed to provide 80% power to detect a 20% lower relative risk in the XARELTO group.
• The primary endpoint was the composite of all-cause mortality, any stroke, MI, symptomatic valve thrombosis, PE, DVT, and non-CNS systemic embolism.²
  • Secondary efficacy endpoints included:
    • The composite of cardiovascular death, any stroke, MI, symptomatic valve thrombosis, PE, DVT, and non-CNS systemic embolism
    • The net clinical benefit, defined as a composite of the primary efficacy and safety endpoint components
• The primary safety endpoint was the composite of life-threatening, disabling, or major bleeding (according to the Valve Academic Research Consortium-2 criteria).²
  • Secondary safety endpoints included bleeding complications according to the following definitions: a composite of Thrombolysis in Myocardial Infarction major and minor bleeding, International Society on Thrombosis and Haemostasis major bleeding, and a composite of Bleeding Academic Research Consortium 2, 3, or 5 bleeding
• Other endpoints included the individual components of the primary efficacy and safety endpoints, as well as the mean transaortic valve pressure gradient at ~360 days after randomization.²

Results

• The trial was prematurely ended (on August 13, 2018) by the data and safety monitoring board due to safety concerns. Only 42% of the planned 440 events occurred before the trial was terminated.³ See Table: GALILEO Select Baseline Characteristics.
  • The main analyses were performed with the ITT principle and were not adjusted for multiple comparisons.
  • On treatment analyses were also performed (which included outcomes if they occurred before premature permanent discontinuation).

• The median duration for trial subjects was 17 months (interquartile range 13-21 months).³
  • During the trial, 307 patients prematurely discontinued treatment in the XARELTO group versus 194 in the antiplatelet group.
  • New AF developed in 11% of the trial population.
• The primary efficacy outcome occurred consistently across prespecified subgroups.³ See Table: GALILEO Efficacy and Safety Outcomes.

• In the on-treatment analysis also conducted, the primary efficacy and safety outcomes occurred at similar rates in the XARELTO-based treatment group and the antiplatelet-based treatment group.³
• On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had TAVR because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an antiplatelet regimen.¹

GALILEO-4D

GALILEO-4D was a substudy of the larger GALILEO trial, a randomized, open-label, event-driven, phase 3 trial to assess a XARELTO-based antithrombotic strategy to reduce the risk of thromboembolic complications post-TAVR with an acceptable risk of bleeding compared with currently recommended antiplatelet therapy-based strategy. The goal of GALILEO-4D was to evaluate the effect of each treatment strategy on leaflet-motion abnormalities and thickening.^3,4

Methods

Enrollment from the substudy came from 12 sites involved in the GALILEO trial that could perform four-dimensional computed tomography (CT) after TAVR. Eligible patients for the main trial were eligible for this substudy, except for patients with contraindications that prohibited CT imaging or those with severe renal insufficiency.⁴

• Patients completed a contrast-enhanced, electrocardiogram-gated cardiac CT scan with full cardiac-cycle coverage (four-dimensional CT) and a transthoracic echocardiogram at 90 day (±15 days) follow-up visit.⁴
  • CT evaluations were done at independent sites by investigators blinded to the patients and their treatment assignments.
• The primary endpoint was the percentage of patients with ≥1 prosthetic valve leaflet with reduced motion of grade 3 or higher. Secondary endpoints included: the percentage of patients with valve leaflets with reduced motion of grade 3 or higher, the percentage of valve leaflets with thickening, the transprosthetic mean pressure gradient, and safety and efficacy endpoints from the main trial.⁴
• The primary analyses were ITT, with per-protocol analyses also reported.⁴
• The early termination of the main GALILEO trial on August 13, 2018 did not affect the treatment or follow-up of patients in GALILEO-4D, since the last patient was enrolled May 23, 2018.⁴

Results

Of the 231 patients enrolled in the substudy, 115 were randomized to the XARELTO-based treatment and 116 were randomized to the antiplatelet-based treatment. Characteristics of patients in the substudy were similar to those in the overall study (except that there were fewer high-risk patients in the substudy) and well-balanced between groups.⁴ See Table: GALILEO-4D Outcomes for the results of the substudy.⁴

Too few clinical events were seen in the GALILEO-4D substudy to assess the effect of reduced leaflet motion and leaflet thickening on clinical outcomes.⁴

Jochheim et al (2019)⁶ conducted a multicenter observational registry study to evaluate the use of treatment with NOACs vs VKAs after a TAVR up to 1 year after the procedure.

• Of the 962 patients included in the study, 326 patients were taking NOACs. Of those 53.7% were prescribed XARELTO.
• At the 1-year follow-up, patients receiving a NOAC were found to have higher risk of the ischemic events (combined endpoint of all-cause mortality, MI, and any cerebrovascular event; primary outcome) and similar risk of bleeding (defined by Bleeding Academic Research Consortium criteria) compared to those receiving VKAs.
  • This effect remained after inverse probability of treatment weighting (IPTW) adjustment.
    • IPTW-adjusted ischemic events: NOAC 21.2% vs VKA 15.0%; HR: 1.44; 95% CI 1.00 to 2.07; P=0.050
    • IPTW-adjusted BARC bleeding: NOAC 33.9% vs VKA 34.1%; HR: 0.97; 95% CI 0.74-1.26; P=0.838

LiTERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 25 September 2024.