Xarelto Drug Information
Generic name: RIVAROXABAN
Factor Xa Inhibitor [EPC]
Uses of Xarelto
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
XARELTO is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled.
Treatment of Deep Vein Thrombosis
XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
Treatment of Pulmonary Embolism
XARELTO is indicated for the treatment of pulmonary embolism (PE).
Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary
Embolism XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery.
Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for
Thromboembolic Complications Not at High Risk of Bleeding XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding .
Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery
Disease (CAD) XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease.
Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral
Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD XARELTO, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.
Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism
in Pediatric Patients XARELTO is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment. 1.10 Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure XARELTO is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.
Dosage & Administration of Xarelto
| CrCl >50 mL/min | |
| CrCl ≤50 mL/min | 15 mg once daily |
| CrCl ≥15 mL/min | |
| CrCl <15 mL/min | Avoid Use |
| CrCl ≥15 mL/min | |
| CrCl <15 mL/min | Avoid Use |
| CrCl ≥15 mL/min |
| CrCl <15 mL/min | Avoid Use |
| CrCl ≥15 mL/min |
| CrCl <15 mL/min | Avoid Use |
| CrCl ≥15 mL/min | |
| CrCl <15 mL/min | Avoid Use |
| No dose adjustment needed based on CrCl | |
| No dose adjustment needed based on CrCl | |
Side Effects of Xarelto
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. During clinical development for the approved indications, 34,947 adult patients were exposed to XARELTO. Hemorrhage The most common adverse reactions with XARELTO were bleeding complications . Nonvalvular Atrial Fibrillation In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.
Table 5 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial. Table 5: Bleeding Events in ROCKET AF Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. - On Treatment Plus 2 Days Parameter XARELTO N=7111 n (%/year) Warfarin N=7125 n (%/year) XARELTO vs.
Warfarin HR (95% CI) Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. Major Bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 395 386 1.04 Intracranial Hemorrhage (ICH) Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. 55 84 0.67 Hemorrhagic Stroke Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. 36 58 0.63 Other ICH 19 26 0.74 Gastrointestinal (GI) Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. 221 140 1.61 Fatal Bleeding Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 27 55 0.50 ICH 24 42 0.58 Non-intracranial 3 13 0.23 Figure 1 shows the risk of major bleeding events across major subgroups. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors.
Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN DVT and EINSTEIN PE Studies In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.
Table 6 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. Table 6: Bleeding Events Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Parameter XARELTO Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA N=4130 n (%) Enoxaparin/VKA N=4116 n (%) Major bleeding event 40 72 Fatal bleeding 3 (<0.1) 8 Intracranial 2 (<0.1) 4 (<0.1) Non-fatal critical organ bleeding 10 29 Intracranial Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group 3 (<0.1) 10 Retroperitoneal 1 (<0.1) 8 Intraocular 3 (<0.1) 2 (<0.1) Intra-articular 0 4 (<0.1) Non-fatal non-critical organ bleeding Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥2 units of whole blood or packed red blood cells 27 37 Decrease in Hb ≥ 2 g/dL 28 42 Transfusion of ≥2 units of whole blood or packed red blood cells 18 25 Clinically relevant non-major bleeding 357 357 Any bleeding 1169 1153 Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg.
The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients. Table 7 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study. Table 7: Bleeding Events Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug.
Although a patient may have had 2 or more events, the patient is counted only once in a category. in EINSTEIN CHOICE Parameter XARELTO Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily. 10 mg N=1127 n (%) Acetylsalicylic Acid (aspirin) 100 mg N=1131 n (%) Major bleeding event 5 3 Fatal bleeding 0 1 (<0.1) Non-fatal critical organ bleeding 2 1 (<0.1) Non-fatal non-critical organ bleeding Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. 3 1 (<0.1) Clinically relevant non-major (CRNM) bleeding Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 22 20 Any bleeding 151 138 In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 8. Table 8: Bleeding Events Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1–3) XARELTO 10 mg Enoxaparin Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) Total treated patients N=4487 n (%) N=4524 n (%) Major bleeding event 14 9 Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 2 (<0.1) 3 Bleeding that required re-operation 7 5 Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 4 1 (<0.1) Any bleeding event Includes major bleeding events 261 251 Hip Surgery Studies N=3281 n (%) N=3298 n (%) Major bleeding event 7 3 Fatal bleeding 1 (<0.1) 0 Bleeding into a critical organ 1 (<0.1) 1 (<0.1) Bleeding that required re-operation 2 1 (<0.1) Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 3 1 (<0.1) Any bleeding event 201 191 Knee Surgery Study N=1206 n (%) N=1226 n (%) Major bleeding event 7 6 Fatal bleeding 0 0 Bleeding into a critical organ 1 2 Bleeding that required re-operation 5 4 Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells 1 0 Any bleeding event 60 60 Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.
Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events. Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Patients with bronchiectasis/pulmonary cavitation, active cancer (i.e., undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 9. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo.
Table 9 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study. Table 9: Bleeding Events in MAGELLAN Patients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. Study–Safety Analysis Set - On Treatment Plus 2 Days MAGELLAN Study Patients received either XARELTO or placebo once daily for 35 ±4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 ±4 days in the hospital.
XARELTO 10 mg N=3218 n (%) Enoxaparin 40 mg /placebo N=3229 n (%) Major bleeding Defined as clinically overt bleeding associated with a drop in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. 22 15 Critical site bleeding 7 4 Fatal bleeding Fatal bleeding is adjudicated death with the primary cause of death from bleeding. 3 (<0.1) 1 (<0.1) Clinically relevant non-major bleeding events (CRNM) 93 34 Reduction of Risk of Major Cardiovascular Events in Patients with CAD In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily.
The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar. Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial. Table 10: Major Bleeding Events in COMPASS - On Treatment Plus 2 Days Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.
These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients. Parameter XARELTO Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.
N=9134 n (%/year) Placebo N=9107 n (%/year) XARELTO vs. Placebo HR (95 % CI) CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Modified ISTH Major Bleeding Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization. 263 144 1.8 - Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial 12 (<0.1) 6 (<0.1) 6 (<0.1) 8 (<0.1) 3 (<0.1) 5 (<0.1) 1.5 2.0 1.2 - Symptomatic bleeding in critical organ (non-fatal) - ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH 58 23 18 6 (<0.1) 43 21 13 (<0.1) 9 (<0.1) 1.4 1.1 1.4 0.7 - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) 7 (<0.1) 6 (<0.1) 1.2 - Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) 188 91
Major GI bleeding 117 49 2.4 Reduction of Risk of Major Thrombotic
Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The incidence of premature permanent discontinuation due to bleeding events for XARELTO 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively. Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.
Table 11: Major Bleeding Events Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. in VOYAGER- On Treatment Plus 2 Days XARELTO Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. N=3256 Placebo N=3248 XARELTO vs.
Placebo HR (95 % CI) Parameter n (%) Event rate %/year n (%) Event rate %/year CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria TIMI Major Bleeding (CABG/non-CABG) 62 0.96 44 0.67
Fatal bleeding 6 0.09 6 0.09 1.0 Intracranial bleeding 13 0.20 17
0.26
Clinically overt signs of hemorrhage associated with a drop in hemoglobin of
≥5 g/dL or drop in hematocrit of ≥15% 46 0.71 24 0.36
Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of
XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 12. Table 12: Other Adverse Reactions Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System Adverse Reaction EINSTEIN DVT Study XARELTO 20 mg N=1718 n (%) Enoxaparin/VKA N=1711 n (%) Gastrointestinal disorders Abdominal pain 46 25 General disorders and administration site conditions Fatigue 24 15 Musculoskeletal and connective tissue disorders Back pain 50 31 Muscle spasm 23 13 Nervous system disorders Dizziness 38 22 Psychiatric disorders Anxiety 24 11 Depression 20 10 Insomnia 28 18 EINSTEIN PE Study XARELTO 20 mg N=2412 n (%) Enoxaparin/VKA N=2405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 27 Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in RECORD 1–3 studies are shown in Table 13. Table 13: Other Adverse Drug Reactions Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication Reported by ≥1% of XARELTO-Treated Patients in RECORD 1–3 Studies Body System Adverse Reaction XARELTO 10 mg N=4487 n (%) Enoxaparin Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) N=4524 n (%) Injury, poisoning and procedural complications Wound secretion 125 89 Musculoskeletal and connective tissue disorders Pain in extremity 74 55 Muscle spasm 52 32 Nervous system disorders Syncope 55 32 Skin and subcutaneous tissue disorders Pruritus 96 79 Blister 63 40 Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age. Patients were randomized 2:1 to receive body weight-adjusted doses of XARELTO or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA). Discontinuation due to bleeding events occurred in 6 (1.8%) patients in the XARELTO group and 3 (1.9%) patients in the comparator group. Table 14 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study.
In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the XARELTO group and 5 (10%) female patients in the comparator group. Table 14: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event. Parameter XARELTO Treatment schedule: body weight-adjusted doses of XARELTO; randomized 2:1 (XARELTO: Comparator). N=329 n (%) Comparator Group Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. N=162 n (%) Major bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 0 2 Clinically relevant non-major bleeding Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 10 1 Trivial bleeding 113 44 Any bleeding 119 45 Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 15. Table 15: Other Adverse Reactions Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator.
Reported in XARELTO-Treated Patients by ≥5% in EINSTEIN Junior Study Adverse Reaction XARELTO N=329 n (%) Comparator Group N=162 n (%) Pain in extremity 23 7 Fatigue The following terms were combined: fatigue, asthenia. 23 7 A clinically relevant adverse reaction in XARELTO-treated patients was vomiting (10.6% in the XARELTO group vs 8% in the comparator group). Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of XARELTO for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg). Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the XARELTO group and no patients in the aspirin group. Table 16 shows the number of patients experiencing bleeding events in the UNIVERSE study.
Table 16: Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days Parameter XARELTO Treatment schedule: body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg); randomized 2:1 (XARELTO: Aspirin). N=64 n (%) Aspirin N=34 n (%) Major Bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 1 0 Epistaxis leading to transfusion 1 0 Clinically relevant non-major (CRNM) bleeding Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 4 3 Trivial bleeding 21 12 Any bleeding 23 14 Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 17. Table 17: Other Adverse Reactions Adverse reaction with Relative Risk >1.5 for XARELTO versus aspirin. Reported by ≥5% of XARELTO-Treated Patients in UNIVERSE Study (Part B) Adverse Reaction XARELTO N=64 n (%) Aspirin N=34 n (%) Cough 10 3 Vomiting 9 3 Gastroenteritis The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash 8 1 Rash 6 2 Figure 1
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: hemiparesis Renal disorders: Anticoagulant-related nephropathy Respiratory, thoracic and mediastinal disorders: Eosinophilic pneumonia Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) Injury, poisoning and procedural complications: Atraumatic splenic rupture
Warnings & Cautions for Xarelto
Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any
oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant .
Risk of Bleeding
XARELTO increases the risk of bleeding, including in any organ, and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement.
Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding.
These include aspirin, P2Y 12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk . Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e., undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. XARELTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.
Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not dialyzable . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies.
Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.
Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis . To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO . The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.
Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal
function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly . Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO. Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.
Discontinue XARELTO in patients who develop acute renal failure while on treatment . Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.
Discontinue XARELTO in patients who develop acute renal failure while on treatment. Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients.
There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients. Discontinue XARELTO in patients who develop acute renal failure while on treatment. Pediatric Patients There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ); therefore, avoid the use of XARELTO in these patients.
There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5 th percentile; therefore, avoid the use of XARELTO in these patients .
Use in Patients with Hepatic Impairment No clinical data are available for
adult patients with severe hepatic impairment. Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased . No clinical data are available in pediatric patients with hepatic impairment.
Use with P-gp and Strong
CYP3A Inhibitors or Inducers Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors . Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers .
Risk of Pregnancy-Related Hemorrhage
In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing.
Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) .
Patients with Prosthetic Heart Valves 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 anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves.
Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or
Pulmonary Embolectomy Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. 5.10 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including XARELTO, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive ), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Drug Interactions with Xarelto
General Inhibition and
Induction Properties Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters, the latter also known as breast cancer resistance protein (BCRP). Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.
Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction
with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) . Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk . Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk .
Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems
Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) .
Anticoagulants and
NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding. Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs .
Pregnancy Safety for Xarelto
Pregnancy Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing.
Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman . Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.
Fetal/Neonatal Adverse Reactions Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate. Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.
Data Human Data There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.
Animal Data Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day.
Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).
Pediatric Use of Xarelto
Pediatric Use The safety and effectiveness of XARELTO have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional pharmacokinetic, safety and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. XARELTO was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth; had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg . The safety and effectiveness of XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single- and multiple-dose pharmacokinetic properties of XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure . Clinical studies that evaluated safety, efficacy, pharmacokinetic and pharmacodynamic data support the use of XARELTO 10 mg, 15 mg, and 20 mg tablets in pediatric patients.
For the XARELTO 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients. Therefore, XARELTO 2.5 mg tablets are not recommended for use in pediatric patients. Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.
Contraindications for Xarelto
is contraindicated in patients with: active pathological bleeding severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) Active pathological bleeding Severe hypersensitivity reaction to XARELTO
Overdosage Information for Xarelto
Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.
The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable . Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available.
Clinical Studies of Xarelto
Stroke Prevention in Nonvalvular Atrial Fibrillation
The evidence for the efficacy and safety of XARELTO was derived from R ivaroxaban O nce-daily oral direct factor Xa inhibition C ompared with vitamin K antagonist for the prevention of stroke and E mbolism T rial in A trial F ibrillation (ROCKET AF), a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke: a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or 2 or more of the following risk factors: age ≥75 years, hypertension, heart failure or left ventricular ejection fraction ≤35%, or diabetes mellitus ROCKET AF was a non-inferiority study designed to demonstrate that XARELTO preserved more than 50% of warfarin's effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation. A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS 2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black.
There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, XARELTO was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism, but superiority to warfarin was not demonstrated. There is insufficient experience to determine how XARELTO and warfarin compare when warfarin therapy is well-controlled. Table 19 displays the overall results for the primary composite endpoint and its components.
Table 19: Primary Composite Endpoint Results in ROCKET AF Study (Intent-to-Treat Population) XARELTO Warfarin XARELTO vs. Warfarin Event N=7081 n (%) Event Rate (per 100 Pt-yrs) N=7090 n (%) Event Rate (per 100 Pt-yrs) Hazard Ratio (95% CI) Primary Composite Endpoint The primary endpoint was the time to first occurrence of stroke (any type) or non-CNS systemic embolism. Data are shown for all randomized patients followed to site notification that the study would end. 269 2.1 306 2.4 0.88 Stroke 253 2.0 281
Hemorrhagic Stroke Defined as primary hemorrhagic strokes confirmed by adjudication in all
randomized patients followed up to site notification 33 0.3 57
Non-CNS Systemic Embolism 20 0.2 27 0.2 Figure 4 is a plot
of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms. Figure 4: Time to First Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group (Intent-to-Treat Population) Figure 5 shows the risk of stroke or non-CNS systemic embolism across major subgroups. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors.
Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Figure 5: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF Data are shown for all randomized patients followed to site notification that the study would end. (Intent-to-Treat Population) The efficacy of XARELTO was generally consistent across major subgroups. The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin.
XARELTO patients were generally switched to warfarin without a period of coadministration of warfarin and XARELTO, so that they were not adequately anticoagulated after stopping XARELTO until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking XARELTO vs. 6 in the 4691 patients taking warfarin. Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of XARELTO for preventing post-cardioversion stroke and systemic embolism is unknown.
Figure 4 Figure 5
Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)
EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies XARELTO for the treatment of DVT and/or PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0–3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black.
About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups.
Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study. In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%). In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE. In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0. Table 20 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Table 20: Primary Composite Endpoint Results For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (3, 6 or 12 months) irrespective of the actual treatment duration. If the same patient had several events, the patient may have been counted for several components. in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat Population Event XARELTO 20 mg Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA Enoxaparin/VKA XARELTO vs. Enoxaparin/VKA Hazard Ratio (95% CI) EINSTEIN DVT Study N=1731 n (%) N=1718 n (%) Primary Composite Endpoint 36 51 0.68 Death (PE) 1 (<0.1) 0 Death (PE cannot be excluded) 3 6 Symptomatic PE and DVT 1 (<0.1) 0 Symptomatic recurrent PE only 20 18 Symptomatic recurrent DVT only 14 28 EINSTEIN PE Study N=2419 n (%) N=2413 n (%) Primary Composite Endpoint 50 44 1.12 Death (PE) 3 1 (<0.1) Death (PE cannot be excluded) 8 6 Symptomatic PE and DVT 0 2 (<0.1) Symptomatic recurrent PE only 23 20 Symptomatic recurrent DVT only 18 17 Figures 6 and 7 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.
Figure 6: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study Figure 7: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study Figure 6 Figure 7
Reduction in the Risk of Recurrence of
DVT and/or PE EINSTEIN CHOICE Study XARELTO for reduction in the risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study, a multi-national, double-blind, superiority study comparing XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid (aspirin) once daily in patients who had completed 6 to 12 months of anticoagulant treatment for DVT and/or PE following the acute event. The intended treatment duration in the study was up to 12 months. Patients with an indication for continued therapeutic-dose anticoagulation were excluded.
Because the benefit-risk assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose versus aspirin, only the data concerning the 10 mg dose is discussed below. A total of 2275 patients were randomized and followed on study treatment for a mean of 290 days for the XARELTO and aspirin treatment groups. The mean age was approximately 59 years.
The population was 56% male, 70% Caucasian, 14% Asian and 3% Black. In the EINSTEIN CHOICE study, 51% of patients had DVT only, 33% had PE only, and 16% had PE and DVT combined. Other risk factors included idiopathic VTE (43%), previous episode of DVT/PE (17%), recent surgery or trauma (12%), prolonged immobilization (10%), use of estrogen containing drugs (5%), known thrombophilic conditions (6%), Factor V Leiden gene mutation (4%), or active cancer (3%). In the EINSTEIN CHOICE study, XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE. Table 21 displays the overall results for the primary composite endpoint and its components.
Table 21: Primary Composite Endpoint and its Components Results For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (12 months) irrespective of the actual treatment duration. The individual component of the primary endpoint represents the first occurrence of the event. in EINSTEIN CHOICE Study – Full Analysis Set Event XARELTO 10 mg N=1,127 n (%) Acetylsalicylic Acid (Aspirin) 100 mg N=1,131 n (%) XARELTO 10 mg vs. Aspirin 100 mg Hazard Ratio (95% CI) Primary Composite Endpoint 13 50 0.26 p<0.0001 Symptomatic recurrent DVT 8 29 Symptomatic recurrent PE 5 19 Death (PE) 0 1 (<0.1) Death (PE cannot be excluded) 0 1 (<0.1) Figure 8 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
Figure 8: Time to First Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study Figure 8
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
XARELTO was studied in 9011 patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the RE gulation of C oagulation in OR thopedic Surgery to Prevent D VT and PE, Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement (RECORD 1, 2, and 3) studies. The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug.
The mean age was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively.
In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 22. Table 22: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery - Modified Intent-to-Treat Population RECORD 1 RECORD 2 Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRR Relative Risk Reduction; CI = confidence interval, p-value XARELTO 10 mg once daily Enoxaparin Includes the placebo-controlled period of RECORD 2 40 mg once daily RRR, p-value Number of Patients N=1513 N=1473 N=834 N=835 Total VTE 17 (1.1%) 57 (3.9%) 71% (95% CI: 50, 83), p<0.001 17 (2.0%) 70 (8.4%) 76% (95% CI: 59, 86), p<0.001 Components of Total VTE Proximal DVT 1 (0.1%) 31 (2.1%) 5 (0.6%) 40 (4.8%) Distal DVT 12 (0.8%) 26 (1.8%) 11 (1.3%) 43 (5.2%) Non-fatal PE 3 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%) Death (any cause) 4 (0.3%) 4 (0.3%) 2 (0.2%) 4 (0.5%) Number of Patients N=1600 N=1587 N=928 N=929 Major VTE Proximal DVT, nonfatal PE or VTE-related death 3 (0.2%) 33 (2.1%) 91% (95% CI: 71, 97), p<0.001 6 (0.7%) 45 (4.8%) 87% (95% CI: 69, 94), p<0.001 Number of Patients N=2103 N=2119 N=1178 N=1179 Symptomatic VTE 5 (0.2%) 11 (0.5%) 3 (0.3%) 15 (1.3%) One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin.
In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female.
Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active XARELTO and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 23. Table 23: Summary of Key Efficacy Analysis Results for Patients Undergoing Total Knee Replacement Surgery - Modified Intent-to-Treat Population RECORD 3 Treatment Dosage and Duration XARELTO 10 mg once daily Enoxaparin 40 mg once daily RRR Relative Risk Reduction; CI = confidence interval, p-value Number of Patients N=813 N=871 Total VTE 79 (9.7%) 164 (18.8%) 48% (95% CI: 34, 60), p<0.001 Components of events contributing to Total VTE Proximal DVT 9 (1.1%) 19 (2.2%) Distal DVT 74 (9.1%) 154 (17.7%) Non-fatal PE 0 4 (0.5%) Death (any cause) 0 2 (0.2%) Number of Patients N=895 N=917 Major VTE Proximal DVT, nonfatal PE or VTE-related death 9 (1.0%) 23 (2.5%) 60% (95% CI: 14, 81), p = 0.024 Number of Patients N=1206 N=1226 Symptomatic VTE 8 (0.7%) 24 (2.0%)
Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for
Thromboembolic Complications Not at High Risk of Bleeding The efficacy and safety of XARELTO for prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding was evaluated in the MAGELLAN study ( M ulticenter, r A ndomized, parallel G roup E fficacy and safety study for the prevention of venous thromboembolism in hospitalized medically i LL patients comparing rivaroxab aN with enoxaparin ). MAGELLAN was a multicenter, randomized, double-blind, parallel-group efficacy and safety study comparing XARELTO to enoxaparin, in the prevention of VTE in hospitalized acutely ill medical patients during the in-hospital and post-hospital discharge period. Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk of VTE due to moderate or severe immobility, and had additional risk factors for VTE. The population at risk of VTE was required to have one or more of the following VTE risk factors, i.e. prolonged immobilization, age ≥75 years, history of cancer, history of VTE, history of heart failure, thrombophilia, acute infectious disease contributing to the hospitalization and BMI ≥35 kg/m 2 ). The causes for hospitalization included heart failure, active cancer, acute ischemic stroke, acute infectious and inflammatory disease and acute respiratory insufficiency. Patients were randomized to receive either XARELTO 10 mg once daily for 35 ±4 days starting in hospital and continuing post hospital discharge (n=4050) or enoxaparin 40 mg once daily for 10 ±4 days starting in hospital followed by placebo post-discharge (n=4051). The major efficacy outcome in the MAGELLAN trial was a composite endpoint that included asymptomatic proximal deep venous thrombosis (DVT) in lower extremity, symptomatic proximal or distal DVT in the lower extremity, symptomatic non-fatal pulmonary embolism (PE), and death related to venous thromboembolism (VTE). A total of 6024 patients were evaluable for the major efficacy outcome analysis (2967 on XARELTO 10 mg once daily and 3057 on enoxaparin/placebo). The mean age was 68.9 years, with 37.1% of the subject population ≥ 75 years.
VTE risk factors included severe immobilization at study entry (99.9%), D-dimer > 2× ULN (43.7%), history of heart failure (35.6%), BMI ≥ 35 kg/m 2 (15.2%), chronic venous insufficiency (14.9%), acute infectious disease (13.9%), severe varicosis (12.5%), history of cancer (16.2%), history of VTE (4.5%), hormone replacement therapy (1.1%), and thrombophilia (0.3%), recent major surgery (0.8%) and recent serious trauma (0.2%). The population was 54.7% male, 68.2% White, 20.4% Asian, 1.9% Black and 5.3% Other. Admitting diagnoses for hospitalization were acute infectious diseases (43.8%) followed by congestive heart failure NYHA class III or IV (33.2%), acute respiratory insufficiency (26.4%), acute ischemic stroke (18.5%) and acute inflammatory diseases (3.4%). Table 24 shows the overall results from the prespecified, modified intent-to-treat (mITT) analysis for the efficacy outcomes and their components. This analysis excludes approximately 25% of the patients mainly due to no ultrasonographic assessment (13.5%), inadequate assessment at day 35 (8.1%), or lack of intake of study medication (1.3%). Table 24: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in the MAGELLAN Study mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative Risk Events from Day 1 to Day 35, mITT analysis set XARELTO 10 mg N=2967 n (%) Enoxaparin 40 mg/placebo N=3057 n (%) RR (95% CI) Primary Composite Endpoint at Day 35 131 (4.4%) 175 (5.7%) 0.77 Symptomatic non-fatal PE 10 14 Symptomatic DVT in lower extremity 13 15 Asymptomatic proximal DVT in lower extremity 103 133 VTE related death 19 30 Events from Day 1 to Day 10, PP analysis set XARELTO 10 mg N=2938 n (%) Enoxaparin 40 mg N=2993 n (%) RR (95% CI) Primary Composite Endpoint at Day 10 78 82 0.97 Symptomatic non-fatal PE 6 2 (<0.1) Symptomatic DVT in lower extremity 7 6 Asymptomatic proximal DVT in lower extremity 71 71 VTE related death 3 6 mITT analysis set plus all-cause mortality N=3096 n (%) N=3169 n (%) RR (95% CI) Other Composite Endpoint at Day 35 266 293 0.93 Symptomatic non-fatal PE 10 14 Symptomatic DVT in lower extremity 13 15 Asymptomatic proximal DVT in lower extremity 103 133 All-cause mortality 159 153 Patients with bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months (19.4%) all had an excess of bleeding with XARELTO compared with enoxaparin/placebo.
Therefore, patients meeting these criteria were excluded from the following analyses presented below. Table 25 provides the efficacy results for the subgroup of patients not at a high risk of bleeding. Table 25: Efficacy Results at Day 35 (modified Intent-to-Treat) and at Day 10 (per protocol) in patients not at a high risk of bleeding in the MAGELLAN Study Patients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative Risk Events from Day 1 to Day 35, mITT analysis set XARELTO 10 mg N=2419 n (%) Enoxaparin 40 mg/placebo N=2506 n (%) RR (95% CI) Primary Composite Endpoint at Day 35 94 143 0.68 Symptomatic non-fatal PE 7 10 Symptomatic DVT in lower extremity 9 10 Asymptomatic proximal DVT in lower extremity 73 110 VTE related death 15 26 Events from Day 1 to Day 10, PP analysis set XARELTO 10 mg N=2385 n (%) Enoxaparin 40 mg N=2433 n (%) RR (95% CI) Primary Composite Endpoint at Day 10 58 72 0.82 Symptomatic non-fatal PE 5 2 (<0.1) Symptomatic DVT in lower extremity 6 4 Asymptomatic proximal DVT in lower extremity 52 62 VTE related death 2 (<0.1) 6 mITT analysis set plus all-cause mortality N=2504 n (%) N=2583 n (%) RR (95% CI) Other Composite Endpoint at Day 35 184 225 0.84 Symptomatic non-fatal PE 7 10 Symptomatic DVT in lower extremity 9 10 Asymptomatic proximal DVT in lower extremity 73 110 All-cause mortality 107 112
Reduction of Risk of Major Cardiovascular Events in Patients with
CAD The evidence for the efficacy and safety of XARELTO for the reduction in the risk of stroke, myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) was derived from the double-blind, placebo-controlled C ardiovascular O utco M es for P eople using A nticoagulation S trategie S trial (COMPASS). A total of 27,395 patients were evenly randomized to rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone. Because the 5 mg dose alone was not superior to aspirin alone, only the data concerning the 2.5 mg dose plus aspirin are discussed below. Patients with established CAD or PAD were eligible.
Patients with CAD who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate <60 mL per minute, heart failure, or non-lacunar ischemic stroke ≥1 month earlier). Patients with PAD were either symptomatic with ankle brachial index <0.90 or had asymptomatic carotid artery stenosis ≥50%, a previous carotid revascularization procedure, or established ischemic disease of one or both lower extremities. Patients were excluded for use of dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies, ischemic, non-lacunar stroke within 1 month, hemorrhagic or lacunar stroke at any time, or eGFR <15 mL/min. The mean age was 68 years and 21% of the subject population were ≥75 years.
Of the included patients, 91% had CAD (and will be referred to as the COMPASS CAD population), 27% had PAD (and will be referred to as the COMPASS PAD population), and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting (CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic carotid artery stenosis > 50%, and 4% had limb or foot amputation for arterial vascular disease. The mean duration of follow-up was 23 months.
Relative to placebo, XARELTO reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular death: HR 0.76 (95% CI: 0.66, 0.86; p=0.00004). In the COMPASS CAD population, the benefit was observed early with a constant treatment effect over the entire treatment period (see Table 26 and Figure 10 ). A benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of fatal or life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds into a critical organ) in the XARELTO group versus the placebo group. Compared to placebo, during 10,000 patient-years of treatment, XARELTO would be expected to result in 70 fewer CV events and 12 additional life-threatening bleeds, indicating a favorable balance of benefits and risks. The results in the COMPASS CAD population were consistent across major subgroups (see Figure 9 ). Figure 9: Risk of Primary Efficacy Outcome by Baseline Characteristics in the COMPASS CAD Population (Intent-to-Treat Population) All patients received aspirin 100 mg once daily as background therapy.
Table 26: Efficacy results from COMPASS CAD Population intention to treat analysis set, primary analyses. Event XARELTO Treatment schedule: XARELTO 2.5 mg twice daily vs placebo. All patients received aspirin 100 mg once daily as background therapy.
N=8313 Placebo N=8261 Hazard Ratio (95% CI) XARELTO vs. placebo. n (%) Event Rate (%/year) n (%) Event Rate (%/year) CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarction Stroke, MI or CV death 347 2.2 460 2.9 0.74 - Stroke 74 0.5 130 0.8 0.56 - MI 169 1.1 195 1.2 0.86 - CV death 139 0.9 184 1.1 0.75 Coronary heart disease death, MI, ischemic stroke, acute limb ischemia 299 1.9 411 2.6 0.72 - Coronary heart disease death Coronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure. 80 0.5 107 0.7 0.74 - Ischemic stroke 56 0.3 114 0.7 0.49 - Acute limb ischemia Acute limb ischemia is defined as limb-threatening ischemia leading to an acute vascular intervention (i.e., pharmacologic, peripheral arterial surgery/reconstruction, peripheral angioplasty/stent, or amputation). 13 0.1 27 0.2 0.48 CV death, CV death includes CHD death, or death due to other CV causes or unknown death. MI, ischemic stroke, acute limb ischemia 349 2.2 470 3.0 0.73 All-cause mortality 262 1.6 339 2.1 0.77 CI: confidence interval Figure 10: Time to First Occurrence of Primary Efficacy Outcome (Stroke, Myocardial Infarction, Cardiovascular Death) in the COMPASS CAD Population All patients received aspirin 100 mg once daily as background therapy. Figure 9 Figure 10
Reduction of Risk of Major Thrombotic Vascular Events in Patients with
PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The efficacy and safety of XARELTO 2.5 mg orally twice daily versus placebo on a background of aspirin 100 mg once daily in patients with PAD were evaluated in the COMPASS study (n=4996) and will be referred to as the COMPASS PAD population . The efficacy and safety of XARELTO were also evaluated for the reduction in the risk of the composite endpoint of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of a vascular etiology in patients undergoing a lower extremity infrainguinal revascularization procedure due to symptomatic peripheral artery disease (PAD) in the double-blinded, placebo-controlled V ascular O utcomes stud Y of A SA alon G with rivaroxaban in E ndovascular or surgical limb R evascularization for peripheral artery disease (PAD) trial (VOYAGER). A total of 6,564 patients were equally randomized to XARELTO 2.5 mg orally twice daily vs placebo on a background therapy of aspirin 100 mg once daily. Eligible patients included adults who were at least 50 years of age with documented moderate to severe symptomatic lower extremity atherosclerotic PAD who had a successful peripheral surgical procedure and/or endovascular procedure with or without clopidogrel (up to a maximum of 6 months was allowed; median duration of therapy was 31 days). Patients had either a prior history of limb revascularization with ankle brachial index ≤0.85 or no prior history of limb revascularization with ankle brachial index ≤0.80. Patients in need of dual antiplatelet for >6 months, or any additional antiplatelet other than aspirin and clopidogrel, or oral anticoagulant, as well as patients with a history of intracranial hemorrhage, stroke, or transient ischemic attack (TIA), or patients with eGFR <15 mL/min were excluded. The mean age was 67 years and 20% of the subject population was ≥75 years.
Of the included patients, 35% had surgical revascularization, 47% had endovascular revascularization with clopidogrel, and 18% endovascular revascularization without clopidogrel. The median duration of follow-up was 30.8 months. XARELTO 2.5 mg twice daily was superior to placebo in reducing the rate of the primary composite outcome of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of a vascular etiology.
The primary efficacy outcome and its components are provided in Table 27. The Kaplan-Meier plot for the primary efficacy outcome can be seen in Figure 11. The secondary efficacy outcomes were tested for superiority in a prespecified, hierarchical order and the first five of seven endpoints were significantly reduced in the rivaroxaban treatment arm (see Table 27 ). Compared to placebo during 10,000 patient-years of treatment, XARELTO would be expected to result in 181 fewer primary outcome events and 29 more TIMI major bleeding events, indicating a favorable balance of benefits and risks. Figure 11: Time to First Occurrence of Primary Efficacy Outcome (Myocardial Infarction, Ischemic Stroke, Cardiovascular Death, Acute Limb Ischemia, Major Amputation due to Vascular Origins) in VOYAGER All patients received aspirin 100 mg once daily as background therapy. Figure 12 shows the risk of primary efficacy outcome across major subgroups.
Subgroup analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. The primary efficacy endpoint generally shows homogeneous results across subgroups. Figure 12: Risk of Primary Efficacy Outcome by Baseline Characteristics in VOYAGER (Intent-to-Treat Population) All patients received aspirin 100 mg once daily as background therapy.
Table 27 provides the efficacy event rates for the prespecified endpoints in VOYAGER and similar endpoints in the COMPASS PAD population. Table 27: Efficacy Results in VOYAGER (Intent-to-Treat Population) and COMPASS PAD VOYAGER COMPASS PAD XARELTO N=3286 Placebo N=3278 Hazard Ratio (95% CI) XARELTO vs. placebo. p-value Two-sided p-values XARELTO N=2492 Placebo N=2504 Hazard Ratio (95% CI) Outcome Components Event Rate (%/year) Event Rate (%/year) Efficacy endpoints in COMPASS PAD were analysed according to the pre-specified endpoints in VOYAGER when applicable. ALI=acute limb ischemia, CHD=coronary heart disease; CI=confidence interval, CV=cardiovascular; MI=myocardial infarction, VTE=venous thromboembolism. 5-Component Outcome (Major thrombotic vascular events) Major thrombotic vascular event is the composite of MI, ischemic stroke, CV death, ALI, and major amputation of a vascular etiology. 6.8 8.0 0.85 p=0.0085 3.4 4.8 0.71 MI 1.7 1.9 0.88 1.1 1.5 0.76 Ischemic Stroke Ischemic stroke for VOYAGER included stroke of uncertain/unknown etiology whereas COMPASS only included ischemic stroke. 0.9 1.0 0.87 0.5 0.9 0.55 CV death CV death includes Coronary Heart Disease death, or death due to other CV causes or sudden cardiac arrest and unknown death. 2.5 2.2 1.14 1.4 1.7 0.82 ALI 2.0 3.0 0.67 0.4 0.8 0.56 Major amputation of a vascular etiology Adjudicated events in VOYAGER and investigator reported events in COMPASS 1.3 1.5 0.89 0.2 0.6 0.40 VOYAGER Secondary Efficacy Outcomes Secondary outcomes for VOYAGER were tested sequentially.
MI, ischemic stroke, CHD death, CHD death includes death due to sudden cardiac death, MI, or coronary revascularization procedure ALI, and major amputation due to vascular etiology 5.8 7.3 0.80 p=0.0008 2.8 4.2 0.66 Unplanned index limb revascularization for recurrent limb ischemia Unplanned index limb revascularization for recurrent limb ischemia was not captured in COMPASS study. 8.4 9.5 0.88 p=0.028 N/A N/A N/A Hospitalization for a coronary or peripheral cause of a thrombotic nature 3.5 4.8 0.72 p<0.0001 1.7 2.9 0.58 MI, ischemic stroke, all-cause mortality, ALI, and major amputation due to vascular etiology 8.2 9.3 0.89 p=0.029 4.8 6.0 0.80 MI, all-cause stroke, CV death, ALI, and major amputation due to vascular etiology 6.9 8.1 0.86 p=0.010 3.4 4.9 0.70 All-cause mortality 4.0 3.7 1.08 2.8 3.1 0.91 VTE events Investigator reported in VOYAGER and adjudicated events in COMPASS 0.3 0.5 0.61 0.2 0.3 0.67 Figure 11 Figure 12
Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism
in Pediatric Patients XARELTO for the treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE was evaluated in the EINSTEIN Junior Phase 3 study, a multicenter, open-label, active-controlled, randomized study in 500 pediatric patients from birth to less than 18 years with confirmed VTE. There were 276 children aged 12 to <18 years, 101 children aged 6 to <12 years, 69 children aged 2 to <6 years, and 54 children aged <2 years. Patients <6 months of age were excluded from enrollment if they were <37 weeks of gestation at birth, or had <10 days of oral feeding, or had a body weight of <2.6 kg. Index VTE was classified as either central venous catheter-related VTE (CVC-VTE), cerebral vein and sinus thrombosis (CVST), and all other VTE including DVT and PE (non-CVC-VTE). Patients received initial treatment with therapeutic dosages of unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux for at least 5 days, and were randomized 2:1 to receive either body weight-adjusted doses of XARELTO (exposures to match that of 20 mg daily dose in adults) or comparator group (UFH, LMWH, fondaparinux or VKA) for a main study treatment period of 3 months (or 1 month for children <2 years with CVC-VTE). A diagnostic imaging test was obtained at baseline and at the end of the main study treatment.
When clinically necessary, treatment was extended up to 12 months in total (or up to 3 months in total for children <2 years with CVC-VTE). Table 28 displays the primary and secondary efficacy results. Table 28: Efficacy Results in EINSTEIN Junior Study – Full Analysis Set Event XARELTO Treatment schedule: body weight-adjusted doses of XARELTO (exposures to match that of 20 mg daily dose in adults); randomized 2:1 (XARELTO: Comparator). N=335 n (%) (95% CI) Confidence intervals for incidence proportion were calculated by applying the method of Blyth-Still-Casella. Comparator Group Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. N=165 n (%) (95% CI) XARELTO vs.
Comparator Group Risk Difference (95% CI) Confidence intervals for difference in incidence proportions were calculated by unstratified exact method according to Agresti-Min using the standardized test statistic and inverting a two-sided test. XARELTO vs. Comparator Group Hazard Ratio (95% CI) Primary efficacy outcome: Symptomatic recurrent VTE 4 (0.4%, 3.0%) 5 (1.2%, 6.6%) -1.8% (-6.0%, 0.6%) 0.40 Secondary efficacy outcome: Symptomatic recurrent VTE or asymptomatic deterioration on repeat imaging 5 (0.6%, 3.4%) 6 (1.6%, 7.6%) -2.1% (-6.5%, 0.6%) Complete resolution of thrombus on repeat imaging without recurrent VTE occurred in 128 of 335 children (38.2%, 95% CI 33.0%, 43.5%) in the XARELTO group and 43 of 165 children (26.1%, 95% CI 19.8%, 33.0%) in the comparator group.
Symptomatic recurrent VTE or major bleeding events occurred in 4 of 335 children (1.2%, 95% CI 0.4%, 3.0%) in the XARELTO group and 7 of 165 children (4.2%, 95% CI 2.0%, 8.4%) in the comparator group.
Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure
The efficacy and safety of XARELTO for thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure was evaluated in the UNIVERSE Phase 3 study. UNIVERSE was a prospective, open-label, active controlled, multicenter, 2-part study, designed to evaluate the single- and multiple-dose pharmacokinetic properties of XARELTO (Part A), and to evaluate the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months compared with aspirin (Part B) in children 2 to 8 years of age with single ventricle physiology who had the Fontan procedure. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of XARELTO (exposures to match that of 10 mg daily dose in adults) or aspirin (approximately 5 mg/kg). Patients with eGFR <30 ml/min/1.73 m 2 were excluded.
The median time between Fontan procedure and the first dose of XARELTO was 4 (range: 2–61) days in Part A and 34 (range: 2–124) days in part B. In comparison, the median time to initiating aspirin was 24 (range 2–117) days. Table 29 displays the primary efficacy results. Table 29: Efficacy Results in UNIVERSE Study – Full Analysis Set Part A Part A: single arm; not randomized Part B Part B: randomized 2:1 (XARELTO: Aspirin) Event XARELTO N=12 n (%) (95% CI) Confidence intervals for incidence proportion were calculated by applying the method of Blyth-Still-Casella.
XARELTO Treatment schedule: body weight-adjusted doses of XARELTO (exposures to match that of 10 mg daily dose in adults) or aspirin (approximately 5 mg/kg) N=64 n (%) (95% CI) Aspirin N=34 n (%) (95% CI) XARELTO vs. Aspirin Risk Difference (95% CI) Confidence intervals for difference in incidence proportions were calculated by unstratified exact method according to Agresti-Min using the standardized test statistic and inverting a two-sided test. Primary efficacy outcome: any thrombotic event 1 1 3 -7.3% (0.4%, 34.9%) (0.1%, 7.8%) (2.4%, 22.2%) (-21.7%, 1.1%) Ischemic stroke 0 0 1 -2.9% (0.0%, 23.6%) (0.0%, 5.6%) 0.2%, 15.1%) (-16.2%, 2.9%) Pulmonary embolism 0 1 0 1.6% (0.0%, 23.6%) (0.1%, 7.8%) (0.0%, 9.0%) (-9.9%, 8.4%) Venous thrombosis 1 0 2 -5.9% (0.4%, 34.9%) (0.0%, 5.6%) (1.1%, 18.8%) (-20.6%, -0.1%)
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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