3rd October 2018

Rivaroxaban (Xarelto): Increase in all-cause
mortality, thromboembolic and bleeding events inpatients after transcatheter aortic valve replacement ina prematurely stopped clinical trial.

Dear Healthcare Professional,
Bayer AG, in agreement with the European Medicines Agency and the Health Products Regulatory
Authority (HPRA), would like to inform you of the preliminary results of the GALILEO trial:
Summary•A phase III clinical study, 17938 (GALILEO), in patients after transcatheter aortic valve
replacement (TAVR) has been terminated early based on preliminary results showing an
increase in all-cause mortality, thromboembolic and bleeding events in rivaroxabantreated patients. Analyses are ongoing.

•Rivaroxaban is not approved for thromboprophylaxis in patients with prosthetic heart
valves, including patients who have undergone TAVR, and should not be used in suchpatients.

•Rivaroxaban treatment should be stopped in patients who undergo TAVR and switched tostandard of care.

Background on the safety concern
The study 17938 (GALILEO) is a randomised, open label, active-controlled, multicentre phase III trial
to evaluate clinical outcomes after successful transcatheter aortic valve replacement (TAVR) insubjects randomised to either a rivaroxaban-based anticoagulation strategy or an antiplatelet-based
strategy. The first group received rivaroxaban 10 mg once daily and acetylsalicylic acid (ASA) 75-100
mg once daily for 90 days followed by maintenance with rivaroxaban 10 mg once daily, whereas thecomparator group was given clopidogrel 75 mg and ASA 75-100 mg once daily for 90 days followedby ASA alone.
The primary efficacy endpoint is a composite of all-cause death, stroke, systemic embolism,
myocardial infarction, pulmonary embolism, deep vein thrombosis and symptomatic valvethrombosis and the primary safety endpoint is a composite of life-threatening or disabling (BARC
types 5 and 3b/3c) and major (BARC type 3a) bleeding events. Patients with atrial fibrillation atrandomisation were excluded from this trial.
In August 2018, the independent Data Safety Monitoring Board (DSMB) recommended stopping thetrial, as a preliminary analysis of available data suggested an imbalance between the two study
groups in all-cause mortality, thromboembolic and bleeding events. The incidences in therivaroxaban group (826 patients) and the antiplatelet group (818 patients), respectively, were 11.4%
versus 8.8% for death or first thromboembolic events, 6.8% versus 3.3% for all-cause death and 4.2%
versus 2.4% for primary bleeding events. These results are preliminary and based on incomplete
data collection. The final study data will be assessed by regulatory authorities as soon as they areavailable, including an assessment of any implications for approved indications.
TAVR is performed in patients in need of an aortic valve replacement but at higher risk for standard
open heart valve surgery. Patients undergoing TAVR also present with clinical risk factors pertinent
to the background disease of aortic valve stenosis.
Xarelto is not approved for thromboprophylaxis in patients with prosthetic heart valves, including
patients having undergone TAVR, and should not be used in such patients.
The approved indications for Xarelto are as follows:
Rivaroxaban (Xarelto) 2.5 mg, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus
clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adultpatients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers; and coadministered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic
events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease(PAD) at high risk of ischaemic events.
Xarelto 10 mg is authorised for prevention of venous thromboembolism (VTE) in adult patients
undergoing elective hip or knee replacement surgery.
Xarelto 15 mg and Xarelto 20 mg are authorised for prevention of stroke and systemic embolism inadult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive
heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic
attack.
Xarelto 10 mg, Xarelto 15 mg and Xarelto 20 mg are authorised for treatment of deep veinthrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Call for reportingThis medicinal product is subject to additional monitoring. This will allow quick identification ofnew safety information. Healthcare professionals are asked to report any suspected adverse
reactions to HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax:+353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Reports of suspected adverse
reactions can also be made to Bayer Ltd, contact details below.
Company contact point
If you have any questions, or if you require any further information, please contact themedical information service of Bayer Ltd, The Atrium, Blackthorn Road, Dublin 18; Tel: +353 1216 3300; Fax: +353 1 2061456; E-mail: info.ireland@bayerhealthcare.com.
With kind regards,___________________________
Dr. Tristan P. Cooper
Medical Director