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15914 Page: 1 Date of study report: 07 MAR 2016 Study title: XANTUS - Xarelto on prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation: A non-interventional study Sponsor s study 15914 (XA1101) number: NCT number: NCT01606995 EudraCT number: Not applicable Sponsor: Bayer HealthCare AG, Leverkusen, Germany Clinical phase: Phase IV, Non-interventional study Study objectives: To validate the safety profile of rivaroxaban for stroke prevention in nonvalvular atrial fibrillation (NVAF) in routine clinical practice use. To estimate incidences of treatment-emergent safety events like major bleeding, adverse events (AEs), serious AEs (SAEs) and all-cause mortality. Test drug: Rivaroxaban ( Xarelto, BAY 59-7939) Name of active Rivaroxaban, BAY 59-7939 ingredient(s): Anatomical Therapeutic Chemical Code: B01AF01 Dose: Xarelto 15 mg film-coated tablets; Xarelto 20 mg film-coated tablets Due to the non-interventional study design, the dose was at the discretion of the attending investigator Route of oral administration: Duration of treatment: Due to the non-interventional study design, the duration of treatment was at the discretion of the attending investigator Reference drug: Not applicable Indication: Prevention of stroke and non-central nervous system systemic embolism in non-valvular atrial fibrillation (NVAF)
15914 Page: 2 Diagnosis and main Consenting female and male patients 18 years of age with a diagnosis of criteria for inclusion: NVAF who start treatment with rivaroxaban for the prevention of stroke or non-cns (Central Nervous System) systemic embolism. Study design: Prospective, international, multi-center, non-interventional, observational cohort study. Post-authorization safety study. Methodology: Patients were followed up for 1 year or until 30 days after end of rivaroxaban therapy in case of earlier permanent discontinuation The visit schedule was at the discretion of the attending investigator, however it was advised to documented patients status every 3 months. Outcome measures were collected as adverse events and included major bleeding, all-cause mortality and thromboembolic events Bleeding events, cause of death, stroke events, transient ischemic attacks (TIA), non-cns systemic embolism (SE) and myocardial infarction (MI) were centrally adjudicated Haemorrhagic strokes were recorded as both, stroke and intracranial bleeding. Haemorrhagic transformations of ischaemic stroke were also reported as intracranial haemorrhage. Study center(s): 308 sites in 21 countries: Austria (11), Belgium (8), Canada (18), Czech Republic (11), Denmark (8), France (63), Germany (53), Hungary (4), Ireland (1), Israel (4), Moldova (4), The Netherlands (23), Norway (3), Poland (10), Portugal (4), Russia (32), Slovakia (15), Slovenia (4), Sweden (11), Ukraine (9), United Kingdom (12) A. John Camm et.al. XANTUS: a real-world, prospective, observational Publication(s) based on study of patients treated with rivaroxaban for stroke prevention in atrial the study fibrillation, European Heart Journal, doi:10.1093/eurheartj/ehv466 (references): Study period: Study Start Date: 12 JUN 2012 (FPFV) Study Completion Date: 31 MAR 2015 (DB clean) Early termination: no Number of subjects: Planned: 6000 Analyzed: 6784
15914 Page: 3 Criteria for evaluation All clinical outcomes were collected as adverse events. Statistical methods: Primary Outcome Measures: Adjudicated major bleeding events defined as overt bleeding associated with: o o o o a fall in haemoglobin (Hb) of 2 g/dl, or a transfusion of 2 units of packed red blood cells (RBCs) or whole blood, or occurrence at a critical site (intra-cranial, intra-spinal, intraocular, pericardial, intra-articular, intra-muscular with compartment syndrome, retroperitoneal), or death. AEs and SAEs. All-cause mortality Secondary Outcome Measures included: Adjudicated symptomatic stroke, TIA, SE, MI Non-major bleeding, defined as all bleeding events that do not fall in the category of major bleedings Persistence with rivaroxaban treatment, Reasons for any switch from or interruption of rivaroxaban AEs were coded using MedDRA version 17.0 based on investigator reports. For adjudicated events including major bleeding and stroke the central adjudication committee was involved in the final determination of the coded preferred term (PT). Statistical analyses were explorative and descriptive. Generally, summary tables were presented as either frequency tables or summary statistics. The main analysis population was the safety analysis set which contained all patients who took at least one dose of rivaroxaban. An AE was considered as treatment-emergent when it started on or after the day of the first dose of rivaroxaban and up to 2 days after the last dose. There were no substantial changes to the study protocol after the start of Substantial protocol changes: data collection. The latest protocol is dated 25 MAR 2015.
15914 Page: 4 Subject disposition and baseline Centers were requested to document each patient with NVAF treated to prevent stroke and systemic embolism in an anonymous patient log file regardless of the prescribed treatment. This led to 10 934 patients being screened. 6785 patients were enrolled in the study. Of these, one patient was not valid for the safety analysis set because the subject did not take rivaroxaban, leaving 6784 patients evaluable in the safety analysis set. Demographics: Rivaroxaban (N = 6784) Age (years): mean ± SD 71.5 ± 10.0 Median (Q1 Q3) 72.0 (66.0 78.0) Age >75, n (%) 2524 (37.2) Age 75, n (%) 2809 (41.4) Creatinine clearance, n (%) <15 ml/min 20 (0.3) 15 <30 ml/min 75 (1.1) 30 <50 ml/min 545 (8.0) 50 80 ml/min 2354 (34.7) >80 ml/min 1458 (21.5) Missing 2332 (34.4) Co-morbidities, n (%) Hypertension 5065 (74.7) Diabetes mellitus 1333 (19.6) Prior stroke/non-cns SE/TIA 1291 (19.0) Congestive HF 1265 (18.6) Prior MI 688 (10.1)
15914 Page: 5 Rivaroxaban (N = 6784) Mean CHADS2 score ± SD 2.0 ± 1.3 Mean CHA2DS2-VASc score ± SD 3.4 ± 1.7 Mean HAS-BLED score ± SD 2.0 ± 1.0 Treatment duration: The median (range) duration of treatment was 366 (1 802) days. The mean (SD) duration of treatment 329 (115) days Outcomes: Rivaroxaban (N = 6784) Incidence proportion, n (%) Incidence rate, events per 100 patient years Adjudicated major bleeding 128 (1.9) 2.1 (1.8 2.5) Fatal* 12 (0.2) 0.2 (0.1 0.3) Critical organ bleeding 43 (0.6) 0.7 (0.5 0.9) Intracranial haemorrhage 26 (0.4) 0.4 (0.3 0.6) Haemoglobin decrease 2 g/dl 52 (0.8) 0.9 (0.6 1.1) Transfusion of 2 units of packed red blood cells or whole 53 (0.8) 0.9 (0.6 1.1)
15914 Page: 6 blood Non-major bleeding 878 (12.9) 15.4 (14.4 16.5) All-cause death 118 (1.7) 1.9 (1.6 2.3) Adverse events 2709 (39.9%) 57.3 (55.2 59.5) Serious adverse events 1200 (17.7%) 21.4 (20.2 22.7) Adjudicated thromboembolic events (stroke, SE, TIA, and 108 (1.6) 1.8 (1.5 2.1) MI) Stroke/SE 51 (0.8) 0.8 (0.6 1.1) Stroke 43 (0.6) 0.7 (0.5 0.9) Primary haemorrhagic 11 (0.2) Primary ischaemic 32 (0.5) Haemorrhagic transformation 3 (<0.05) No haemorrhagic transformation 29 (0.4) SE 8 (0.1) 0.1 (0.1 0.3) TIA 32 (0.5) 0.5 (0.4 0.7) MI 27 (0.4) 0.4 (0.3 0.6) Investigator reported thromboembolic events
15914 Page: 7 Investigator- reported deep vein thrombosis 5 (0.1%) 0.1 (0.0-0.2 ) Investigator- reported deep pulmonary embolism 2 (0.0%) 0.0 (0.0-0.1 ) Investigator- reported left atrial thrombus 6 (0.1%) 0.1 (0.0-0.2 ) *Death within 30 days after treatment-emergent adjudicated major bleeding and adjudicated cause of death is bleeding Outcomes by stroke risk factors: By CHADS2 score Score, n n (%) (%) Stroke/SE, Major bleeding, All-cause death, 0 703 (10.4) 0.0 (0.0 0.0) 0.5 (0.1 1.4) 0.2 (0.0 0.9) 1 2061 (30.4) 0.5 (0.3 1.0) 1.1 (0.7 1.7) 1.2 (0.7 1.8) 2 2035 (30.0) 0.6 (0.3 1.1) 2.7 (2.0 3.5) 1.9 (1.4 2.7) 3 1111 (16.4) 1.1 (0.6 2.0) 2.9 (1.9 4.2) 2.9 (1.9 4.2) 4 618 (9.1) 2.1 (1.1 3.7) 2.8 (1.6 4.6) 2.6 (1.5 4.4) 5 222 (3.3) 3.0 (1.1 6.4) 5.4 (2.7 9.7) 7.3 (4.1 12.1) 6 34 (0.5) 0.0 (0.0 0.0) 0.0 (0.0 0.0) 3.1 (0.1 17.10) By CHA2DS2-VASc score Score, n n (%) (%) Stroke/SE, Major bleeding, All-cause death, 0 174 (2.6) 0.0 (0.0 0.0) 0.7 (0.0 3.9) 0 (0.0 0.0) 1 685 (10.1) 0.0 (0.0 0.0) 0.3 (0.0 1.2) 0.2 (0.0 0.9) 2 1313 (19.4) 0.7 (0.3 1.3) 1.1 (0.6 1.8) 1.4 (0.8 2.2)
15914 Page: 8 3 1578 (23.3) 0.7 (0.3 1.3) 2.1 (1.4 3.0) 1.7 (1.1 2.5) 4 1405 (20.7) 0.6 (0.3 1.2) 3.0 (2.1 4.1) 2.0 (1.3 3.0) 5 837 (12.3) 1.1 (0.5 2.1) 2.0 (1.1 3.4) 2.6 (1.6 4.0) 6 9 789 (11.6) 2.4 (1.4 3.8) 4.1 (2.7 5.9) 4.3 (2.9 6.2) Treatment persistence: 5418 patients (79.9%) remained persistent on treatment at 1 year after study start Adverse event pattern: AEs were broadly distributed throughout several system organ classes. The review of AEs did not reveal any particular cluster of non-bleeding events, in particular serious and/or unexpected ones. The AEs with highest incidence were epistaxis (296 patients, 4.4%), dizziness (157 patients, 2.3%), and atrial fibrillation (126 patients, 1.9%). Overall conclusions The incidence rates of and patterns of (serious) adverse events, major and non-major bleeding and thromboembolic events did not indicate a higher than expected safety risk of rivaroxaban therapy in this indication. Death was reported in 1.7% of patients, consistent with the age and underlying conditions of this population. In conclusion, this non-interventional safety study data do not give rise to any new or unexpected safety concerns.
Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Drug Xarelto Xarelto rivaroxaban BAY59-7939 Other Company Code(s) Chemical Description Other Product Aliases IUPAC Name: 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2- thiophenecarboxamide Date of last Update/Change: 04 Mar 2013