14 CLINICAL STUDIES

14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation

The evidence for the efficacy and safety of XARELTO was derived from Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonist for the prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [NCT00403767], 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 [HR (95% CI): 0.88 (0.74, 1.03)], 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)
* 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. † Defined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification
Primary Composite Endpoint *	269 (3.8)	2.1	306 (4.3)	2.4	0.88 (0.74, 1.03)
Stroke	253 (3.6)	2.0	281 (4.0)	2.2
Hemorrhagic Stroke †	33 (0.5)	0.3	57 (0.8)	0.4
Ischemic Stroke	206 (2.9)	1.6	208 (2.9)	1.6
Unknown Stroke Type	19 (0.3)	0.2	18 (0.3)	0.1
Non-CNS Systemic Embolism	20 (0.3)	0.2	27 (0.4)	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.

*: Data are shown for all randomized patients followed to site notification that the study would end.

Figure 5: Risk of Stroke or Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF * (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.

14.2 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 [NCT00440193] and EINSTEIN PE [NCT00439777], 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 [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)]. 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 * in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat Population
Event	XARELTO 20 mg †	Enoxaparin/VKA †	XARELTO vs. Enoxaparin/VKA Hazard Ratio (95% CI)
* 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. † 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: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0–3.0)]
EINSTEIN DVT Study	N=1731 n (%)	N=1718 n (%)
Primary Composite Endpoint	36 (2.1)	51 (3.0)	0.68 (0.44, 1.04)
Death (PE)	1 (<0.1)	0
Death (PE cannot be excluded)	3 (0.2)	6 (0.3)
Symptomatic PE and DVT	1 (<0.1)	0
Symptomatic recurrent PE only	20 (1.2)	18 (1.0)
Symptomatic recurrent DVT only	14 (0.8)	28 (1.6)
EINSTEIN PE Study	N=2419 n (%)	N=2413 n (%)
Primary Composite Endpoint	50 (2.1)	44 (1.8)	1.12 (0.75, 1.68)
Death (PE)	3 (0.1)	1 (<0.1)
Death (PE cannot be excluded)	8 (0.3)	6 (0.2)
Symptomatic PE and DVT	0	2 (<0.1)
Symptomatic recurrent PE only	23 (1.0)	20 (0.8)
Symptomatic recurrent DVT only	18 (0.7)	17 (0.7)

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

14.3 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 [NCT02064439], 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 * 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)
* 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.
Primary Composite Endpoint	13 (1.2)	50 (4.4)	0.26 (0.14, 0.47) p<0.0001
Symptomatic recurrent DVT	8 (0.7)	29 (2.6)
Symptomatic recurrent PE	5 (0.4)	19 (1.7)
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

14.4 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 REgulation of Coagulation in ORthopedic Surgery to Prevent DVT 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) [NCT00329628, NCT00332020, NCT00361894] 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 [± standard deviation (SD)] 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 *, p-value	XARELTO 10 mg once daily	Enoxaparin † 40 mg once daily	RRR *, p-value
* Relative Risk Reduction; CI = confidence interval † Includes the placebo-controlled period of RECORD 2 ‡ Proximal DVT, nonfatal PE or VTE-related death
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‡	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 *, p-value
* Relative Risk Reduction; CI = confidence interval † Proximal DVT, nonfatal PE or VTE-related death
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†	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%)

14.5 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 ( Multicenter, r Andomized, parallel Group Efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically i LL patients comparing rivaroxab aN with enoxaparin [NCT00571649]). 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 (0.62, 0.96)
Symptomatic non-fatal PE	10 (0.3)	14 (0.5)
Symptomatic DVT in lower extremity	13 (0.4)	15 (0.5)
Asymptomatic proximal DVT in lower extremity	103 (3.5)	133 (4.4)
VTE related death	19 (0.6)	30 (1.0)
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 (2.7)	82 (2.7)	0.97 (0.71, 1.31)
Symptomatic non-fatal PE	6 (0.2)	2 (<0.1)
Symptomatic DVT in lower extremity	7 (0.2)	6 (0.2)
Asymptomatic proximal DVT in lower extremity	71 (2.4)	71 (2.4)
VTE related death	3 (0.1)	6 (0.2)
mITT analysis set plus all-cause mortality	N=3096 n (%)	N=3169 n (%)	RR (95% CI)
Other Composite Endpoint at Day 35	266 (8.6)	293 (9.2)	0.93 (0.80, 1.09)
Symptomatic non-fatal PE	10 (0.3)	14 (0.4)
Symptomatic DVT in lower extremity	13 (0.4)	15 (0.5)
Asymptomatic proximal DVT in lower extremity	103 (3.3)	133 (4.2)
All-cause mortality	159 (5.1)	153 (4.8)

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 *
mITT: modified intent-to-treat; PP: per protocol; DVT: Deep vein thrombosis; PE: pulmonary embolism; VTE: venous thromboembolism; CI: Confidence Interval; RR: Relative Risk
* 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.
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 (3.9)	143 (5.7)	0.68 (0.53, 0.88)
Symptomatic non-fatal PE	7 (0.3)	10 (0.4)
Symptomatic DVT in lower extremity	9 (0.4)	10 (0.4)
Asymptomatic proximal DVT in lower extremity	73 (3.0)	110 (4.4)
VTE related death	15 (0.6)	26 (1.0)
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 (2.4)	72 (3.0)	0.82 (0.58, 1.15)
Symptomatic non-fatal PE	5 (0.2)	2 (<0.1)
Symptomatic DVT in lower extremity	6 (0.3)	4 (0.2)
Asymptomatic proximal DVT in lower extremity	52 (2.2)	62 (2.5)
VTE related death	2 (<0.1)	6 (0.2)
mITT analysis set plus all-cause mortality	N=2504 n (%)	N=2583 n (%)	RR (95% CI)
Other Composite Endpoint at Day 35	184 (7.3)	225 (8.7)	0.84 (0.70, 1.02)
Symptomatic non-fatal PE	7 (0.3)	10 (0.4)
Symptomatic DVT in lower extremity	9 (0.4)	10 (0.4)
Asymptomatic proximal DVT in lower extremity	73 (2.9)	110 (4.3)
All-cause mortality	107 (4.3)	112 (4.3)

14.6 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 Cardiovascular Outco Mes for People using Anticoagulation Strategie S trial (COMPASS) [NCT10776424]. 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 [eGFR] <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).

*: All patients received aspirin 100 mg once daily as background therapy.

Figure 9: Risk of Primary Efficacy Outcome by Baseline Characteristics in the COMPASS CAD Population (Intent-to-Treat Population) *

Table 26: Efficacy results from COMPASS CAD Population *
Event	XARELTO † N=8313		Placebo † N=8261		Hazard Ratio (95% CI) ‡
Event	n (%)	Event Rate (%/year)	n (%)	Event Rate (%/year)	Hazard Ratio (95% CI) ‡
CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarction
* intention to treat analysis set, primary analyses. † Treatment schedule: XARELTO 2.5 mg twice daily vs placebo. All patients received aspirin 100 mg once daily as background therapy. ‡ XARELTO vs. placebo. § Coronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure. ¶ 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). # CV death includes CHD death, or death due to other CV causes or unknown death.
Stroke, MI or CV death	347 (4.2)	2.2	460 (5.6)	2.9	0.74 (0.65, 0.86)
- Stroke	74 (0.9)	0.5	130 (1.6)	0.8	0.56 (0.42, 0.75)
- MI	169 (2.0)	1.1	195 (2.4)	1.2	0.86 (0.70, 1.05)
- CV death	139 (1.7)	0.9	184 (2.2)	1.1	0.75 (0.60, 0.93)
Coronary heart disease death, MI, ischemic stroke, acute limb ischemia	299 (3.6)	1.9	411 (5.0)	2.6	0.72 (0.62, 0.83)
- Coronary heart disease death §	80 (1.0)	0.5	107 (1.3)	0.7	0.74 (0.55, 0.99)
- Ischemic stroke	56 (0.7)	0.3	114 (1.4)	0.7	0.49 (0.35, 0.67)
- Acute limb ischemia ¶	13 (0.2)	0.1	27 (0.3)	0.2	0.48 (0.25, 0.93)
CV death, # MI, ischemic stroke, acute limb ischemia	349 (4.2)	2.2	470 (5.7)	3.0	0.73 (0.64, 0.84)
All-cause mortality	262 (3.2)	1.6	339 (4.1)	2.1	0.77 (0.65, 0.90)

CI: confidence interval

*: All patients received aspirin 100 mg once daily as background therapy.

Figure 10: Time to First Occurrence of Primary Efficacy Outcome (Stroke, Myocardial Infarction, Cardiovascular Death) in the COMPASS CAD Population *

14.7 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 [see Clinical Studies (14.6)] .

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 Vascular Outcomes stud Y of ASA alon G with rivaroxaban in Endovascular or surgical limb Revascularization for peripheral artery disease (PAD) trial (VOYAGER) [NCT02504216]. 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.

*: All patients received aspirin 100 mg once daily as background therapy.

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 *

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.

*: All patients received aspirin 100 mg once daily as background therapy.

Figure 12: Risk of Primary Efficacy Outcome by Baseline Characteristics in VOYAGER (Intent-to-Treat Population) *

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) * p-value †	XARELTO N=2492	Placebo N=2504	Hazard Ratio (95% CI) *
Outcome Components	Event Rate (%/year)		Hazard Ratio (95% CI) * p-value †	Event Rate (%/year)		Hazard Ratio (95% CI) *
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.
* XARELTO vs. placebo. † Two-sided p-values ‡ Major thrombotic vascular event is the composite of MI, ischemic stroke, CV death, ALI, and major amputation of a vascular etiology. § Ischemic stroke for VOYAGER included stroke of uncertain/unknown etiology whereas COMPASS only included ischemic stroke. ¶ CV death includes Coronary Heart Disease death, or death due to other CV causes or sudden cardiac arrest and unknown death. # Adjudicated events in VOYAGER and investigator reported events in COMPASS Þ Secondary outcomes for VOYAGER were tested sequentially. ß CHD death includes death due to sudden cardiac death, MI, or coronary revascularization procedure à Unplanned index limb revascularization for recurrent limb ischemia was not captured in COMPASS study. è Investigator reported in VOYAGER and adjudicated events in COMPASS
5-Component Outcome (Major thrombotic vascular events) ‡	6.8	8.0	0.85 (0.76, 0.96) p=0.0085	3.4	4.8	0.71 (0.57, 0.87)
MI	1.7	1.9	0.88 (0.70, 1.12)	1.1	1.5	0.76 (0.53, 1.09)
Ischemic Stroke §	0.9	1.0	0.87 (0.63, 1.19)	0.5	0.9	0.55 (0.33, 0.93)
CV death ¶	2.5	2.2	1.14 (0.93, 1.40)	1.4	1.7	0.82 (0.59, 1.14)
ALI	2.0	3.0	0.67 (0.55, 0.82)	0.4	0.8	0.56 (0.32, 0.99)
Major amputation of a vascular etiology #	1.3	1.5	0.89 (0.68, 1.16)	0.2	0.6	0.40 (0.20, 0.79)
VOYAGER Secondary Efficacy Outcomes Þ
MI, ischemic stroke, CHD death, ß ALI, and major amputation due to vascular etiology	5.8	7.3	0.80 (0.71, 0.91) p=0.0008	2.8	4.2	0.66 (0.53, 0.83)
Unplanned index limb revascularization for recurrent limb ischemia à	8.4	9.5	0.88 (0.79, 0.99) 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 (0.62, 0.85) p<0.0001	1.7	2.9	0.58 (0.44, 0.77)
MI, ischemic stroke, all-cause mortality, ALI, and major amputation due to vascular etiology	8.2	9.3	0.89 (0.79, 0.99) p=0.029	4.8	6.0	0.80 (0.67, 0.96)
MI, all-cause stroke, CV death, ALI, and major amputation due to vascular etiology	6.9	8.1	0.86 (0.76, 0.96) p=0.010	3.4	4.9	0.70 (0.57, 0.86)
All-cause mortality	4.0	3.7	1.08 (0.92, 1.27)	2.8	3.1	0.91 (0.72, 1.16)
VTE events è	0.3	0.5	0.61 (0.37, 1.00)	0.2	0.3	0.67 (0.30, 1.49)

14.8 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 [NCT02234843], 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 * N=335 n (%) (95% CI) †	Comparator Group ‡ N=165 n (%) (95% CI) †	XARELTO vs. Comparator Group Risk Difference (95% CI) §	XARELTO vs. Comparator Group Hazard Ratio (95% CI)
* Treatment schedule: body weight-adjusted doses of XARELTO (exposures to match that of 20 mg daily dose in adults); randomized 2:1 (XARELTO: Comparator). † Confidence intervals for incidence proportion were calculated by applying the method of Blyth-Still-Casella. ‡ Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. § 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: Symptomatic recurrent VTE	4 (1.2) (0.4%, 3.0%)	5 (3.0) (1.2%, 6.6%)	-1.8% (-6.0%, 0.6%)	0.40 (0.11, 1.41)
Secondary efficacy outcome: Symptomatic recurrent VTE or asymptomatic deterioration on repeat imaging	5 (1.5) (0.6%, 3.4%)	6 (3.6) (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.

14.9 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 [NCT02846532]. 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 B †
Event	XARELTO N=12 n (%) (95% CI) ‡	XARELTO § N=64 n (%) (95% CI) ‡	Aspirin § N=34 n (%) (95% CI) ‡	XARELTO vs. Aspirin Risk Difference (95% CI) ¶
* Part A: single arm; not randomized † Part B: randomized 2:1 (XARELTO: Aspirin) ‡ Confidence intervals for incidence proportion were calculated by applying the method of Blyth-Still-Casella. § 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) ¶ 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 (8.3) (0.4%, 34.9%)	1 (1.6) (0.1%, 7.8%)	3 (8.8) (2.4%, 22.2%)	-7.3% (-21.7%, 1.1%)
Ischemic stroke	0 (0.0%, 23.6%)	0 (0.0%, 5.6%)	1 (2.9) 0.2%, 15.1%)	-2.9% (-16.2%, 2.9%)
Pulmonary embolism	0 (0.0%, 23.6%)	1 (1.6) (0.1%, 7.8%)	0 (0.0%, 9.0%)	1.6% (-9.9%, 8.4%)
Venous thrombosis	1 (8.3) (0.4%, 34.9%)	0 (0.0%, 5.6%)	2 (5.9) (1.1%, 18.8%)	-5.9% (-20.6%, -0.1%)