GALILEO Clinical Trial Details

Purpose: To evaluate the efficacy and safety of a rivaroxaban-based strategy to an antiplatelet strategy in patients after TAVR who had no ongoing indication for oral anticoagulation.

Trial Design: N=1644. Multicenter (136 centers, 16 countries), open-label, randomized, controlled, event-driven phase 3 trial. Within a week after TAVR, patients with no ongoing indication for oral anticoagulation were randomized to rivaroxaban 10 mg once-daily + ASA 75-100 mg once-daily for 90 days followed by rivaroxaban 10 mg once-daily alone versus clopidogrel 75 mg once-daily + ASA 75-100 mg once-daily for 90 days followed by ASA alone. Average patient age 80-81 years.

Primary Composite Efficacy Endpoint: Time to all-cause death, stroke, MI, or thromboembolic events.

Primary Composite Safety Endpoint: Major, disabling or life-threatening bleeding events.

Results: The trial was stopped early (August 2018) safety concerns after DSMB recommendation. More complications (death, thromboembolic and bleeding complications) were seen with rivaroxaban-based vs antiplatelet-based approach. Future trials are needed.

Recommended

• GALILEO Abstract
• George Dangas's presentation slides (PDF)
• Discussant slides (PDF)
• Published in NEJM: A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement

The trial was terminated on August 13, 2018 (efficacy cut-off date) after the DSMB recommendation of 7 August 2018, due to safety concerns. Only 183 patients had reached the primary efficacy outcome (42% of planned 440).

• In patients without an indication for oral anticoagulation after TAVR, a 10mg daily rivaroxaban-based antithrombotic strategy was associated with higher risk of death or thromboembolic events and bleeding compared to an antiplatelet-based antithrombotic strategy
• The higher number of deaths observed could not be directly attributed to the higher bleeding in the rivaroxaban arm. Among patients randomized to rivaroxaban who died, only a minority developed a significant bleeding event, heart attack or stroke within 30 days prior to death. Most of the adjudicated causes of death in the rivaroxaban arm were sudden or from unknown reasons, or due to non-cardiovascular causes. Hence, the mechanism underlying the higher mortality in the rivaroxaban arm observed in this trial remains unclear.
• The mortality differences were attenuated when we compared patients who stayed on the assigned study drugs all-along.
• These results of GALILEO main trial are irrespective of potential effects on valve imaging findings (GALILEO 4D-CT Ancillary Study). In the CT-scan imaging sub-study of GALILEO, rivaroxaban was able to decrease clots on top of the valve leaflets to a substantial degree and this is presented and published separately at AHA conference and NEJM

Primary Efficacy Endpoints Results (Intention-to-treat): Time to death, stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis or systemic embolism

Rivaroxaban arm: 105 events (9.8 per 100 person-years)
Antiplatelet arm: 78 events (7.2 per 100 person-years)

Rivaroxaban arm vs. Antiplatelet arm
Hazard ratio, 1.35 (95% CI: 1.01-1.81); p=0.04

Secondary Endpoints Results: All-Cause Mortality (Intention-to-treat)

Rivaroxaban arm: 64 events (5.8 per 100 person-years)
Antiplatelet arm: 38 events (3.4 per 100 person-years)

Rivaroxaban arm vs. Antiplatelet arm
Hazard ratio, 1.69 (95% CI: 1.13-2.53); p=0.009

Safety Endpoints Results: Composite of major, disabling or life-threatening bleeding events according to the VARC-2 criteria

Rivaroxaban arm: 46 events (4.3 per 100 person-years)
Antiplatelet arm: 31 events (2.8 per 100 person-years)

Rivaroxaban arm vs. Antiplatelet arm
Hazard ratio, 1.50 (95% CI: 0.95-2.37); p=0.08

On-Treatment Analysis: Time-to-Event Kaplan-Meier Curves for All-Cause Mortality

Rivaroxaban arm vs. Antiplatelet arm
Hazard ratio, 1.23 (95% CI: 0.71-2.15)

Impression:

• There is no need to routinely use anticoagulation with rivaroxaban after TAVR if another specific indication for this type of medical therapy is absent.
• The findings from this trial supersedes any possible benefit of routine anticoagulation with rivaroxaban in “clearing up” valve leaflets from any clotting as suggested from valve imaging studies.
• Given many concerns about valve leaflet clotting from early imaging, observational (not randomized) studies, anticoagulation with rivaroxaban was considered by several doctors empirically after TAVR. Our study results indicate that the use of anticoagulation after TAVR is not useful at all in patients who do not have any specific indication for such treatment.
• Other ongoing clinical trials compare various types of blood thinners among patients with TAVR requiring anticoagulation. A different set of future trials is required to compare antiplatelet drugs among TAVR patients not requiring anticoagulation.

Related Science

• Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, O’Gara PT, Rigolin VH, Sundt TM, Thompson A. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines.Circulation. 2017; 135:e1159–e1195. doi: 10.1161/CIR.000000000000050
• Nombela-Franco L, Webb JG, de Jaegere PP, Toggweiler S, Nuis RJ, Dager AE, Amat-Santos IJ, Cheung A, Ye J, Binder RK, van der Boon RM, Van Mieghem N, Benitez LM, Pérez S, Lopez J, San Roman JA, Doyle D, Delarochellière R, Urena M, Leipsic J, Dumont E, Rodés-Cabau J. Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation.Circulation. 2012; 126:3041–3053. doi: 10.1161/CIRCULATIONAHA.112.110981
• Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, Derumeaux G, Anselme F, Laborde F, Leon MB. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description.Circulation. 2002; 106:3006–3008

Trial Design — Phase 3, multicenter, open-label, randomized, event-driven, active-controlled trial.1644 patients randomized to rivaroxaban-based strategy (rivaroxaban 10 mg once-daily plus ASA 75-100 mg once-daily for 90 days followed by rivaroxaban 10 mg once-daily alone) versus an antiplatelet-based strategy (clopidogrel 75 mg once-daily plus ASA 75-100 mg once-daily for 90 days followed by ASA alone) after successful TAVR in patients without an ongoing indication for oral anticoagulation.

Trial Population: — 1644 patients having undergone successful TAVR (placement of single transcatheter balloon-expandable or self-expanding bioprosthetic aortic valve into the proper anatomical location) with:

• Intended optimal performance of the valves: mean aortic valve gradient <20 mm Hg or peak transvalvular velocity <3.0 m/s, without moderate/severe aortic regurgitation.
• Absence of periprocedural complications, including any type of stroke, life-threatening bleeding according to the Valvular Academic Research Consortium definitions, acute coronary artery obstruction requiring intervention, major vascular complication requiring unplanned intervention, unresolved acute valve thrombosis, or any requirement of a repeat transcatheter or surgical procedure.
• Patients with atrial fibrillation before or at the time of randomization with an ongoing indication for anticoagulant therapy, any other indication for chronic oral anticoagulation and an absolute indication to dual antiplatelet therapy were excluded.

Primary Endpoint(s):

• The primary efficacy endpoint was the composite of all-cause death, any stroke, myocardial infarction, symptomatic valve thrombosis, non-central nervous system, systemic embolism, deep venous thrombosis or pulmonary embolism. The primary safety endpoint was the composite of major or life-threatening bleeding.

Secondary Endpoint(s):

• Composite of cardiovascular death, any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, or non-CNS systemic embolism; the composite of all-cause death, any stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep vein thrombosis, non-CNS systemic embolism or VARC life-threatening or major bleeding
• Individual components of the primary efficacy and safety endpoints
• Bleeding events assessed with the TIMI and BARC scales
• Mean transaortic valve gradient at 360 days assessed with echocardiography

Sponsor(s)/Collaborator(s): Bayer, Janssen Research & Development, LLC

TAVR, Aortic Stenosis, Direct Oral Anticoagulants, Dual Antiplatelet, Stroke, Myocardial Infarction, Bleeding, Thrombosis, Embolism, Echocardiograph

Rivaroxaban, Clopidogrel, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Purinergic P2 Receptor Antagonists, Purinergic Antagonists, Purinergic Agents, Neurotransmitter Agents, NSAIDs