Meeting NewsPerspective

GALILEO: Rivaroxaban raises death, thrombotic, bleeding risk vs. antiplatelet therapy after TAVR

George D. Dangas

PHILADELPHIA — Among patients who underwent successful transcatheter aortic valve replacement and were not on chronic oral anticoagulation, rivaroxaban was linked to higher risk for death/thromboembolic complications and bleeding compared with antiplatelet therapy, according to results from the GALILEO trial.

In the GALILEO 4D substudy, rivaroxaban (Xarelto, Janssen/Bayer) was linked to a lower rate of abnormalities related to subclinical leaflet thrombosis compared with antiplatelet therapy.

Both studies were presented at the American Heart Association Scientific Sessions and published in The New England Journal of Medicine.

GALILEO

In the intention-to-treat analysis of GALILEO, at a median follow-up of 17 months, the rivaroxaban group had a higher rate of the primary efficacy outcome of death or first thromboembolic event compared with the antiplatelet group (9.8 per 100 person-years vs. 7.2 per 100 person-years; HR = 1.35; 95% CI, 1.01-1.81), George D. Dangas, MD, PhD, professor of medicine (cardiology) and surgery at Icahn School of Medicine at Mount Sinai, said during a presentation, noting the treatment effect was consistent across subgroups.

He also said, in the intention-to-treat analysis of the primary safety outcome of major, disabling or life-threatening bleeding, the rivaroxaban group had a numerically higher rate compared with the antiplatelet group (4.3 per 100 person-years vs. 2.8 per 100 person-years; HR = 1.5; 95% CI, 0.95-2.37).

In addition, the rate of death was higher in the rivaroxaban group (5.8 per 100 person-years vs. 3.4 per 100 person-years; HR = 1.69; 95% CI, 1.13-2.53), driven by non-CV mortality (2.6 per 100 person-years vs. 1 per 100 person-years; HR = 2.67; 95% CI, 1.33-5.35), according to the researchers.

“The mechanism underlying the higher mortality in the rivaroxaban arm observed in the intention-to-treat analysis in this trial is unclear,” Dangas said during the presentation. “The mortality rate differences were attenuated in the on-treatment analysis and many occurred late after discontinuation of the study drug.”

There were no differences between the groups in death from CV causes or any thromboembolic event, symptomatic valve thrombosis, stroke or MI.

In the on-treatment analysis, the primary efficacy outcome occurred at a rate of 8.1 per 100 person-years in the rivaroxaban group and 6.8 per 100 person-years in the antiplatelet group (HR = 1.21; 95% CI, 0.86-1.7), and the primary safety outcome occurred at a rate of 4.6 per 100 person-years in the rivaroxaban group and 2.7 per 100 person-years in the antiplatelet group (HR = 1.53; 95% CI, 0.94-2.49), and there was no difference between the groups in all-cause mortality (HR = 1.23; 95% CI, 0.71-2.15), according to the researchers.

The rivaroxaban group (n = 826; mean age, 80 years; 52% men) received rivaroxaban 10 mg daily for the duration of the study and aspirin 75 mg to 100 mg daily for the first 3 months. The antiplatelet group (n = 818; mean age, 81 years; 50% men) received aspirin 75 mg to 100 mg daily for the duration of the study and clopidogrel 75 mg daily for the first 3 months. The protocol called for those in the antiplatelet group who had never taken clopidogrel to take a loading dose of at least 300 mg. Operators could use any TAVR valve approved in their country. All patients were not previously taking an anticoagulant for any condition.

Janssen issued a statement to Healio by email after the results were released. It read: “Xarelto (rivaroxaban) has a proven, well-established safety and efficacy profile. Health care professionals performing TAVR worldwide were informed of the GALILEO results more than 1 year ago, and reminded that, like all [direct oral anticoagulants], Xarelto use is not recommended for people with prosthetic heart valves. As the GALILEO population was distinctly different from those participating in other Xarelto trials, the safety and efficacy profile of Xarelto across its eight FDA-approved indications remains positive.”

GALILEO 4D

For the GALILEO-4D substudy, 231 patients who had successful TAVR (mean age, 80 years; 64% men) underwent four-dimensional CT approximately 90 days after randomization. The primary endpoint was percentage of patients with at least one valve leaflet with a reduced motion grade of at least 3, defined as involving more than at least 50% of the leaflet. The researchers also analyzed leaflet thickening.

The primary endpoint occurred in 2.1% of the rivaroxaban group compared with 10.9% of the antiplatelet group (difference, –8.8 percentage points; 95% CI, –16.5 to –1.9), Ole De Backer, MD, PhD, MBA, cardiologist at the Heart Center, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, said during a presentation.

Thickening of at least one leaflet occurred in 12.4% of the rivaroxaban group and in 32.4% of the antiplatelet group (difference, –20 percentage points; 95% CI, –30.9 to –8.5), he said.

The per-protocol analyses showed similar results, he said.

“The overall proportion of patients with reduced leaflet motion grade 3 or more and leaflet thickening was significantly less frequent with the rivaroxaban-based strategy as compared to the antiplatelet strategy,” De Backer said during the presentation. “Echocardiography was not useful in identifying patients with these valve abnormalities.” – by Erik Swain

References:

Dangas GD, et al.

De Backer O, et al. Late Breaking Science III: Controversies in Contemporary Management of AS. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Dangas GD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911425.

De Backer O, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911426.

Disclosures: The study was funded by Bayer and Janssen Pharmaceuticals. Dangas reports he received grants from Bayer, personal fees from Bayer, Daiichi Sankyo, Janssen and Sanofi Aventis and other fees from Medtronic. De Backer reports he received grants and personal fees from Abbott and personal fees from Boston Scientific. Please see the studies for the other authors’ relevant financial disclosures.

George D. Dangas

PHILADELPHIA — Among patients who underwent successful transcatheter aortic valve replacement and were not on chronic oral anticoagulation, rivaroxaban was linked to higher risk for death/thromboembolic complications and bleeding compared with antiplatelet therapy, according to results from the GALILEO trial.

In the GALILEO 4D substudy, rivaroxaban (Xarelto, Janssen/Bayer) was linked to a lower rate of abnormalities related to subclinical leaflet thrombosis compared with antiplatelet therapy.

Both studies were presented at the American Heart Association Scientific Sessions and published in The New England Journal of Medicine.

GALILEO

In the intention-to-treat analysis of GALILEO, at a median follow-up of 17 months, the rivaroxaban group had a higher rate of the primary efficacy outcome of death or first thromboembolic event compared with the antiplatelet group (9.8 per 100 person-years vs. 7.2 per 100 person-years; HR = 1.35; 95% CI, 1.01-1.81), George D. Dangas, MD, PhD, professor of medicine (cardiology) and surgery at Icahn School of Medicine at Mount Sinai, said during a presentation, noting the treatment effect was consistent across subgroups.

He also said, in the intention-to-treat analysis of the primary safety outcome of major, disabling or life-threatening bleeding, the rivaroxaban group had a numerically higher rate compared with the antiplatelet group (4.3 per 100 person-years vs. 2.8 per 100 person-years; HR = 1.5; 95% CI, 0.95-2.37).

In addition, the rate of death was higher in the rivaroxaban group (5.8 per 100 person-years vs. 3.4 per 100 person-years; HR = 1.69; 95% CI, 1.13-2.53), driven by non-CV mortality (2.6 per 100 person-years vs. 1 per 100 person-years; HR = 2.67; 95% CI, 1.33-5.35), according to the researchers.

“The mechanism underlying the higher mortality in the rivaroxaban arm observed in the intention-to-treat analysis in this trial is unclear,” Dangas said during the presentation. “The mortality rate differences were attenuated in the on-treatment analysis and many occurred late after discontinuation of the study drug.”

There were no differences between the groups in death from CV causes or any thromboembolic event, symptomatic valve thrombosis, stroke or MI.

In the on-treatment analysis, the primary efficacy outcome occurred at a rate of 8.1 per 100 person-years in the rivaroxaban group and 6.8 per 100 person-years in the antiplatelet group (HR = 1.21; 95% CI, 0.86-1.7), and the primary safety outcome occurred at a rate of 4.6 per 100 person-years in the rivaroxaban group and 2.7 per 100 person-years in the antiplatelet group (HR = 1.53; 95% CI, 0.94-2.49), and there was no difference between the groups in all-cause mortality (HR = 1.23; 95% CI, 0.71-2.15), according to the researchers.

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The rivaroxaban group (n = 826; mean age, 80 years; 52% men) received rivaroxaban 10 mg daily for the duration of the study and aspirin 75 mg to 100 mg daily for the first 3 months. The antiplatelet group (n = 818; mean age, 81 years; 50% men) received aspirin 75 mg to 100 mg daily for the duration of the study and clopidogrel 75 mg daily for the first 3 months. The protocol called for those in the antiplatelet group who had never taken clopidogrel to take a loading dose of at least 300 mg. Operators could use any TAVR valve approved in their country. All patients were not previously taking an anticoagulant for any condition.

Janssen issued a statement to Healio by email after the results were released. It read: “Xarelto (rivaroxaban) has a proven, well-established safety and efficacy profile. Health care professionals performing TAVR worldwide were informed of the GALILEO results more than 1 year ago, and reminded that, like all [direct oral anticoagulants], Xarelto use is not recommended for people with prosthetic heart valves. As the GALILEO population was distinctly different from those participating in other Xarelto trials, the safety and efficacy profile of Xarelto across its eight FDA-approved indications remains positive.”

GALILEO 4D

For the GALILEO-4D substudy, 231 patients who had successful TAVR (mean age, 80 years; 64% men) underwent four-dimensional CT approximately 90 days after randomization. The primary endpoint was percentage of patients with at least one valve leaflet with a reduced motion grade of at least 3, defined as involving more than at least 50% of the leaflet. The researchers also analyzed leaflet thickening.

The primary endpoint occurred in 2.1% of the rivaroxaban group compared with 10.9% of the antiplatelet group (difference, –8.8 percentage points; 95% CI, –16.5 to –1.9), Ole De Backer, MD, PhD, MBA, cardiologist at the Heart Center, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, said during a presentation.

Thickening of at least one leaflet occurred in 12.4% of the rivaroxaban group and in 32.4% of the antiplatelet group (difference, –20 percentage points; 95% CI, –30.9 to –8.5), he said.

The per-protocol analyses showed similar results, he said.

“The overall proportion of patients with reduced leaflet motion grade 3 or more and leaflet thickening was significantly less frequent with the rivaroxaban-based strategy as compared to the antiplatelet strategy,” De Backer said during the presentation. “Echocardiography was not useful in identifying patients with these valve abnormalities.” – by Erik Swain

References:

Dangas GD, et al.

De Backer O, et al. Late Breaking Science III: Controversies in Contemporary Management of AS. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Dangas GD, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911425.

De Backer O, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1911426.

Disclosures: The study was funded by Bayer and Janssen Pharmaceuticals. Dangas reports he received grants from Bayer, personal fees from Bayer, Daiichi Sankyo, Janssen and Sanofi Aventis and other fees from Medtronic. De Backer reports he received grants and personal fees from Abbott and personal fees from Boston Scientific. Please see the studies for the other authors’ relevant financial disclosures.

    Perspective
    B. Hadley Wilson

    B. Hadley Wilson

    We do not know the optimal anticoagulant or antiplatelet regimen for patients who have had TAVR. Aspirin and clopidogrel have been the most common agents prescribed post-TAVR for at least 3 months. However, there have been concerns that a post-TAVR anticoagulation regimen might be more effective.

    The hypothesis in GALILEO was that there would be fewer deaths and thromboembolic events in the rivaroxaban group. But actually, there were more deaths and thromboembolic complications in the rivaroxaban group compared with the standard aspirin and clopidogrel regimen. This study shows the regimen of rivaroxaban plus aspirin after TAVR is not beneficial and is actually quite harmful for patients. Questions must be asked about whether this was the right dose and the right anticoagulant. Further studies could help determine if a lower dose of rivaroxaban may be safer and provide equal or better outcomes than standard care for patients who had TAVR. Right now, the results endorse aspirin plus clopidogrel for at least 3 months post-TAVR.

    GALILEO-4D pushes on the theory of using direct oral anticoagulants in post-TAVR patients. We have observed other recent studies showing there is leaflet thrombus accumulation and leaflet thickening post-TAVR, particularly early on, despite the standard treatment of aspirin plus clopidogrel. Indeed, the study showed there was better leaflet motion and reduced thickening, especially early on, with an oral anticoagulant, but the clinical results from the larger GALILEO study did not support that made a clinical difference in avoidance of more serious complications. And in GALILEO-4D, the leaflet motion and thickening results evened out over time.

    These two studies point in different directions. GALILEO-4D suggests oral anticoagulation will be beneficial to patients post-TAVR, but the larger GALILEO study showed the opposite. It does not necessarily mean we should discard all anticoagulants and all anticoagulant regimens for this population. But right now, we should stick with the standard of care with aspirin and clopidogrel.

    • B. Hadley Wilson, MD, FACC
    • Interventional Cardiologist
      Executive Vice Chair, Atrium Health’s Sanger Heart & Vascular Institute
      Clinical Professor of Medicine
      UNC School of Medicine
      Member, Board of Trustees, American College of Cardiology

    Disclosures: Wilson reports no relevant financial disclosures.

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