Trial Outcomes & Findings for Switching Study From Warfarin to Rivaroxaban (NCT NCT01507051)

NCT ID: NCT01507051

Last Updated: 2015-02-09

Results Overview

Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax on PT was measured as the ratio of maximum PT (measured in seconds) divided by PT (measured in seconds) at baseline.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 96 participants
• Primary outcome timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo
• Results posted on: 2015-02-09

Participant Flow

Participants were recruited by 2 centers in Germany: ClinPharmCologne - MEDA Manufacturing GmbH, Neurather Ring 1, 51063 Koeln, and CRS Clinical-Research-Services Moenchengladbach GmbH, Hindenburgstrasse 304-306, 41061 Moenchengladbach. 84 participants were planned to participate (n=28 per group; minimum completion target n=75, n=25 per group).

488 participants were screened, 392 were dropped. 96 participants were included in the study, 55 by Trial Unit 1 ClinPharmCologne, and 41 by Trial Unit 2 CRS Moenchengladbach. 91 participants were included in the safety set, 84 participants were valid for the assessment of pharmacokinetics and pharmacodynamics (PK/PD set).

Participant milestones

Measure	Group A: Warfarin Followed by Rivaroxaban Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Group B: Warfarin Followed by Placebo Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Group C: Rivaroxaban Without Any Pre-treatment With Warfarin Days 0 to 3: 20 mg rivaroxaban once daily	Group D: Warfarin Alone Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR
Overall Study STARTED	29	31	29	7
Overall Study Warfarin run-in Phase	28	28	0	7
Overall Study Received Placebo or Rivaroxaban	28	28	28	0
Overall Study COMPLETED	27	28	28	0
Overall Study NOT COMPLETED	2	3	1	7

Reasons for withdrawal

Measure	Group A: Warfarin Followed by Rivaroxaban Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Group B: Warfarin Followed by Placebo Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Group C: Rivaroxaban Without Any Pre-treatment With Warfarin Days 0 to 3: 20 mg rivaroxaban once daily	Group D: Warfarin Alone Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR
Overall Study Withdrawal by Subject	1	3	1	6
Overall Study Physician Decision	0	0	0	1
Overall Study Adverse Event	1	0	0	0

Baseline Characteristics

Switching Study From Warfarin to Rivaroxaban

Baseline characteristics by cohort

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily	Warfarin Alone n=7 Participants Days -6 to -1 (could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR	Total n=91 Participants Total of all reporting groups
Age, Continuous	31.3 years STANDARD_DEVIATION 7.2 • n=5 Participants	30.7 years STANDARD_DEVIATION 7.5 • n=7 Participants	34.8 years STANDARD_DEVIATION 8.0 • n=5 Participants	34.6 years STANDARD_DEVIATION 6.9 • n=4 Participants	32.4 years STANDARD_DEVIATION 7.6 • n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Sex: Female, Male Male	28 Participants n=5 Participants	28 Participants n=7 Participants	28 Participants n=5 Participants	7 Participants n=4 Participants	91 Participants n=21 Participants

PRIMARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax on PT was measured as the ratio of maximum PT (measured in seconds) divided by PT (measured in seconds) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on Prothrombin Time (PT) (Coagulation Test)	4.393 ratio Geometric Coefficient of Variation 18.03	1.884 ratio Geometric Coefficient of Variation 10.35	1.573 ratio Geometric Coefficient of Variation 9.98

PRIMARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. Emax,BA on PT was measured as maximum PT (measured in seconds) minus PT (measured in seconds) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax,BA (Baseline Adjusted Maximum Effect) on Prothrombin Time (Coagulation Test)	44.98 seconds Geometric Coefficient of Variation 20.84	11.59 seconds Geometric Coefficient of Variation 19.52	7.31 seconds Geometric Coefficient of Variation 23.72

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT was the area under the measurement (PT [measured in seconds] at different time-points divided by PT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)	55.36 ratio*h Geometric Coefficient of Variation 13.36	37.89 ratio*h Geometric Coefficient of Variation 9.92	20.41 ratio*h Geometric Coefficient of Variation 33.52

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Prothrombin time (PT) is a global clotting test assessing the extrinsic pathway of the blood coagulation cascade. The test is sensitive for deficiencies of Factors II, V, VII, and X, with sensitivity being best for Factors V, VII, and X and less pronounced for Factor II. The initial read-out is in seconds. Higher values than the baseline indicate anticoagulant effects. AUCBA(0-tn) of PT was the area under the measurement (PT [measured in seconds] at different time-points minus PT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUCBA(0-tn) (Baseline Adjusted Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Prothrombin Time (Coagulation Test)	413.4 s*h Geometric Coefficient of Variation 19.87	179.9 s*h Geometric Coefficient of Variation 26.58	33.06 s*h Geometric Coefficient of Variation 55.70

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Prothrombin time - INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. Emax on PT (INR) was measured as the ratio of maximum INR divided by baseline INR.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax on PT (Measured as INR=International Normalized Ratio)	6.655 ratio Geometric Coefficient of Variation 23.39	2.250 ratio Geometric Coefficient of Variation 13.19	1.793 ratio Geometric Coefficient of Variation 12.87

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Prothrombin time - INR measured in seconds that is calculated as INR which is a correction for PT assay differences and an optimization to measure vitamin K antagonists. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PT (INR) was the area under the measurement (PT measured as INR at different time-points divided by PT measured as INR at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) for PT (Measured as INR=International Normalized Ratio)	72.30 ratio*h Geometric Coefficient of Variation 17.35	43.60 ratio*h Geometric Coefficient of Variation 12.81	23.21 ratio*h Geometric Coefficient of Variation 30.63

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Test to measure the activity of endogenous Factor Xa. Emax on Factor Xa activity was calculated as 100*(Factor Xa activity at baseline [measured as activity per mL] - minimum of Factor Xa activity [measured as activity per mL]) / Factor Xa activity at baseline [measured as activity per mL].

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax on Factor Xa Activity	75.95 Percentage of inhibition Geometric Coefficient of Variation 6.56	43.41 Percentage of inhibition Geometric Coefficient of Variation 12.67	49.73 Percentage of inhibition Geometric Coefficient of Variation 13.86

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Test to measure the activity of endogenous Factor Xa. AUC(0-tn) of Factor Xa activity was the area under the inverse measurement [100*(Factor Xa activity at baseline (measured as activity per mL) - Factor Xa activity (measured as activity per mL) at different time-points) / Factor Xa activity at baseline (measured as activity per mL)] versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Inverse Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor Xa Activity	1238 Percentage of inhibition*h Geometric Coefficient of Variation 12.28	834.8 Percentage of inhibition*h Geometric Coefficient of Variation 19.44	514.1 Percentage of inhibition*h Geometric Coefficient of Variation 27.90

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set; derived parameter could not be evaluated for all participants.

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. Emax on anti-Factor Xa activity was measured as the ratio of maximum anti-Factor Xa activity (measured in U/L) divided by anti-Factor Xa activity (measured in U/L) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=12 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=27 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on Anti-Factor Xa Activity	15.83 ratio Geometric Coefficient of Variation 56.06	2.281 ratio Geometric Coefficient of Variation 112.7	18.57 ratio Geometric Coefficient of Variation 42.99

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set; derived parameter could not be evaluated for all participants.

This is a method for measuring the inhibition of Factor Xa activity determined by an ex vivo using a photometric method. Higher Values than the baseline indicate a more pronounced inhibition. AUC(0-tn) of anti-Factor Xa activity was the area under the measurement (anti-Factor Xa activity [measured in U/L] at different time-points divided by anti-Factor Xa activity [measured in U/L] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=12 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=27 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Anti-Factor Xa Activity	124.9 ratio*h Geometric Coefficient of Variation 68.84	19.63 ratio*h Geometric Coefficient of Variation 202.0	151.6 ratio*h Geometric Coefficient of Variation 38.88

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. Emax on aPTT was measured as the ratio of maximum aPTT (measured in seconds) divided by aPTT (measured in seconds) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on aPTT (Activated Partial Thromboplastin Time)	1.843 ratio Geometric Coefficient of Variation 10.55	1.304 ratio Geometric Coefficient of Variation 15.07	1.409 ratio Geometric Coefficient of Variation 6.19

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of aPTT was the area under the measurement (aPTT [measured in seconds] at different time-points divided by aPTT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of aPTT (Activated Partial Thromboplastin Time)	32.48 ratio*h Geometric Coefficient of Variation 9.41	22.55 ratio*h Geometric Coefficient of Variation 56.41	21.82 ratio*h Geometric Coefficient of Variation 42.67

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set; derived parameter could not be evaluated for all participants.

This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on HepTest was measured as the ratio of maximum HepTest (measured in seconds) divided by HepTest (measured in seconds) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=23 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on HepTest (Coagulation Test)	2.148 ratio Geometric Coefficient of Variation 14.20	1.163 ratio Geometric Coefficient of Variation 19.78	2.009 ratio Geometric Coefficient of Variation 12.13

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set; derived parameter could not be evaluated for all participants.

This coagulation test was developed to monitor heparin and especially low-molecular weight heparins (LMWH). It is sensitive to measure Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of HepTest was the area under the measurement (HepTest [measured in seconds] at different time-points divided by HepTest [measured in seconds] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=20 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of HepTest (Coagulation Test)	27.37 ratio*h Geometric Coefficient of Variation 32.90	15.08 ratio*h Geometric Coefficient of Variation 125.9	28.25 ratio*h Geometric Coefficient of Variation 29.31

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set; derived parameter could not be evaluated for all participants.

This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. Emax on PiCT was measured as the ratio of maximum PiCT (measured in seconds) divided by PiCT (measured in seconds) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=18 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=27 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on PiCT (Prothrombinase-induced Clotting Time)	3.158 ratio Geometric Coefficient of Variation 27.20	1.139 ratio Geometric Coefficient of Variation 21.36	2.723 ratio Geometric Coefficient of Variation 20.69

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set; derived parameter could not be evaluated for all participants.

This coagulation test can be adapted to measure different anticoagulants, including inhibitors of Factor X. Higher values than the baseline indicate anticoagulant effects. AUC(0-tn) of PiCT was the area under the measurement (PiCT [measured in seconds] at different time-points divided by PiCT [measured in seconds] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=12 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=26 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of PiCT (Prothrombinase-induced Clotting Time)	37.36 ratio*h Geometric Coefficient of Variation 38.40	4.221 ratio*h Geometric Coefficient of Variation 429.5	39.20 ratio*h Geometric Coefficient of Variation 8.91

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP AUC was measured as the ratio of ETP AUC (measured in nm*min as integral of fluorescence measurements) at baseline divided by minimum ETP AUC (measured in nm*min as integral of fluorescence measurements).

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) AUC	4.257 ratio Geometric Coefficient of Variation 24.41	2.610 ratio Geometric Coefficient of Variation 22.05	1.813 ratio Geometric Coefficient of Variation 25.45

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP AUC assesses the overall function of the clotting cascade. The AUC assesses the overall ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP AUC was the area under the measurement (ETP AUC [measured in nm*min as integral of fluorescence measurements] at baseline divided by ETP AUC [measured in nm*min as integral of fluorescence measurements] at different time-points) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) AUC	69.69 ratio*h Geometric Coefficient of Variation 25.83	51.28 ratio*h Geometric Coefficient of Variation 17.90	18.06 ratio*h Geometric Coefficient of Variation 78.12

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP lag time was measured as the ratio of maximum ETP lag time (in minutes as measure for the start of coagulation) divided by ETP lag time (in minutes as measure for the start of coagulation) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Lag Time	3.954 ratio Geometric Coefficient of Variation 19.02	1.748 ratio Geometric Coefficient of Variation 18.49	2.569 ratio Geometric Coefficient of Variation 9.83

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP lag time assesses the overall function of the clotting cascade. The lag time assesses the time required until thrombin is generated. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP lag time was the area under the measurement (ETP lag time [in minutes as measure for the start of coagulation] at different time-points divided by ETP lag time [in minutes as measure for the start of coagulation] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Lag Time	63.75 ratio*h Geometric Coefficient of Variation 17.88	34.93 ratio*h Geometric Coefficient of Variation 20.83	42.79 ratio*h Geometric Coefficient of Variation 9.54

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak was measured as the ratio of ETP peak (measured in nm as maximum coagulation activity) at baseline divided by minimum ETP peak (measured in nm as maximum coagulation activity).

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak	18.73 ratio Geometric Coefficient of Variation 44.08	2.523 ratio Geometric Coefficient of Variation 44.17	6.758 ratio Geometric Coefficient of Variation 33.31

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP peak assesses the overall function of the clotting cascade. The peak assesses the overall maximal ability to generate thrombin. Decreasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak was the area under the measurement (ETP peak [measured in nm as maximum coagulation activity] at baseline divided by ETP peak measured [in nm as maximum coagulation activity] at different time-points) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak	166.8 ratio*h Geometric Coefficient of Variation 45.97	46.75 ratio*h Geometric Coefficient of Variation 19.22	74.67 ratio*h Geometric Coefficient of Variation 27.40

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. Emax on ETP peak time was measured as the ratio of maximum ETP peak time (measured in minutes as time to reach the maximum coagulation activity) divided by ETP peak time (measured in minutes as time to reach the maximum coagulation activity) at baseline.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on ETP (Endogenous Thrombin Potential) Peak Time	4.164 ratio Geometric Coefficient of Variation 33.95	1.375 ratio Geometric Coefficient of Variation 20.87	3.790 ratio Geometric Coefficient of Variation 15.75

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

ETP peak time assesses the overall function of the clotting cascade. The peak time assesses the time required to reach the maximal thrombin generation. Increasing values compared to baseline indicate an anticoagulant effect. AUC(0-tn) of ETP peak time was the area under the measurement (ETP peak time [measured in minutes as time to reach the maximum coagulation activity] at different time-points divided by ETP peak time [measured in minutes as time to reach the maximum coagulation activity] at baseline) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of ETP (Endogenous Thrombin Potential) Peak Time	49.14 ratio*h Geometric Coefficient of Variation 28.10	19.83 ratio*h Geometric Coefficient of Variation 143.9	55.58 ratio*h Geometric Coefficient of Variation 12.47

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Factor VII is a coagulation factor that is required for the coagulation process. Emax on Factor VIIa activity was measured as the ratio of Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma) at baseline divided by minimum Factor VIIa activity (measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma).

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on Factor VIIa Activity	12.80 ratio Geometric Coefficient of Variation 47.88	6.769 ratio Geometric Coefficient of Variation 53.51	1.346 ratio Geometric Coefficient of Variation 7.51

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Factor VII is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor VIIa activity was the area under the measurement (Factor VIIa activity [measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma] at baseline divided by Factor VIIa activity [measured as percent of actual Factor VIIa activity compared to Factor VIIa activity in reference plasma] at different time-points) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor VIIa Activity	134.2 ratio*h Geometric Coefficient of Variation 44.70	94.83 ratio*h Geometric Coefficient of Variation 41.07	9.283 ratio*h Geometric Coefficient of Variation 70.62

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set

Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. Emax on Factor IIa activity was measured as the ratio of Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma) at baseline divided by minimum Factor IIa activity (measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma).

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days 0 to 3: 20 mg rivaroxaban once daily
Emax (Maximum Effect) on Factor IIa Activity	3.166 ratio Geometric Coefficient of Variation 16.09	2.958 ratio Geometric Coefficient of Variation 12.31	1.126 ratio Geometric Coefficient of Variation 5.08

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban or placebo

Population: PK/PD set; derived parameter could not be evaluated for all participants.

Factor II (Thrombin) is a coagulation factor that is required for the coagulation process. AUC(0-tn) of Factor IIa activity was the area under the measurement (Factor IIa activity [measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma] at baseline divided by Factor IIa activity [measured as percent of actual Factor IIa activity compared to Factor IIa activity in reference plasma] at different time-points) versus time curve from time 0 to the last data point.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) n=26 Participants Days 0 to 3: 20 mg rivaroxaban once daily
AUC(0-tn) (Area Under the Measurement Versus Time Curve From Time 0 to the Last Data Point) of Factor IIa Activity	62.26 ratio*h Geometric Coefficient of Variation 18.20	58.60 ratio*h Geometric Coefficient of Variation 15.18	3.908 ratio*h Geometric Coefficient of Variation 117.7

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

Population: PK/PD set

The AUC is a measure of systemic drug exposure which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample ([AUC(0-24)] is defined as area under the concentration vs. time curve from zero to 24 hours after first (single) dose).

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours [AUC(0-24)] of Rivaroxaban After First Dose	1639 microg*h/L Geometric Coefficient of Variation 29.46	1722 microg*h/L Geometric Coefficient of Variation 26.19	—

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

Population: PK/PD set

Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Maximum Drug Concentration in Plasma (Cmax) of Rivaroxaban After First Dose	219.8 microg/L Geometric Coefficient of Variation 30.94	221.0 microg/L Geometric Coefficient of Variation 26.65	—

SECONDARY outcome

Timeframe: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin

Population: PK/PD set

Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Half Life Associated With Terminal Slope (t1/2) of R-warfarin After the Last Dose of Warfarin	40.08 hours Geometric Coefficient of Variation 19.63	40.24 hours Geometric Coefficient of Variation 29.43	—

SECONDARY outcome

Timeframe: Blood samples taken at 24, 30, 48, 54, 72, 96, and 120 h after the last administration of warfarin

Population: PK/PD set

Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Half Life Associated With Terminal Slope (t1/2) of S-warfarin After the Last Dose of Warfarin	28.24 hours Geometric Coefficient of Variation 17.95	27.08 hours Geometric Coefficient of Variation 22.79	—

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

Population: PK/PD set

The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; [AUC(0-24)norm] is defined as AUC divided by dose per kg body weight from zero to 24 hours after first (single) dose.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Divided by Dose Per kg Body Weight [AUC(0-24)Norm] of Rivaroxaban After First Dose	6.569 Kg*h/L Geometric Coefficient of Variation 27.55	6.901 Kg*h/L Geometric Coefficient of Variation 31.63	—

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

Population: PK/PD set

Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; Cmax,norm is defined as Cmax divided by dose (mg) per kg body weight.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Rivaroxaban After First Dose	0.8812 Kg/L Geometric Coefficient of Variation 27.83	0.8857 Kg/L Geometric Coefficient of Variation 31.79	—

SECONDARY outcome

Timeframe: 0 (predose), 1, 2, 3, 4, 6, 8, 12, and 24 h after first administration of rivaroxaban

Population: PK/PD set

Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Rivaroxaban After First Dose	3.008 hours Interval 1.0 to 4.0	3.000 hours Interval 1.0 to 4.067	—

SECONDARY outcome

Timeframe: Always 3 h after second, third, and fourth dose

Population: PK/PD set

Cpeak refers to the time after dosing when the drug concentration is expected to reach its maximum (peak) concentration.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose second dose	211.2 Microg/L Geometric Coefficient of Variation 28.72	206.7 Microg/L Geometric Coefficient of Variation 35.62	—
Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose third dose	206.1 Microg/L Geometric Coefficient of Variation 30.66	201.0 Microg/L Geometric Coefficient of Variation 30.65	—
Drug Concentration in Plasma at Expected Time of Maximum (Peak) Concentration (Cpeak) of Rivaroxaban After Second to Fourth Dose fourth dose	201.4 Microg/L Geometric Coefficient of Variation 77.43	214.5 Microg/L Geometric Coefficient of Variation 27.35	—

SECONDARY outcome

Timeframe: Always 24 h after the second, third, and fourth dose

Population: PK/PD set

Ctrough refers to the time after dosing when the drug concentration is expected to reach its minimum (trough) concentration.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose second dose	13.06 Microg/L Geometric Coefficient of Variation 50.64	17.07 Microg/L Geometric Coefficient of Variation 45.32	—
Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose third dose	14.34 Microg/L Geometric Coefficient of Variation 54.05	15.85 Microg/L Geometric Coefficient of Variation 47.92	—
Drug Concentration in Plasma at Expected Time of Minimum (Trough) Concentration (Ctrough) of Rivaroxaban After Second to Fourth Dose fourth dose	12.43 Microg/L Geometric Coefficient of Variation 85.96	15.61 Microg/L Geometric Coefficient of Variation 51.52	—

SECONDARY outcome

Timeframe: 3, 24, 48, and 72 h after the last administration of rivaroxaban

Population: PK/PD set; derived parameter could not be evaluated for all participants.

Half-life refers to the elimination of the drug, i.e. the time it takes for the blood plasma concentration to reach half the concentration in the terminal phase of elimination.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=27 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Half Life Associated With Terminal Slope (t1/2) of Rivaroxaban After Last Dose	6.885 hours Geometric Coefficient of Variation 42.48	6.931 hours Geometric Coefficient of Variation 36.70	—

SECONDARY outcome

Timeframe: 0 h (predose) and 24 h after the last administration of warfarin

Population: PK/PD set

Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of R-warfarin After the Last Dose of Warfarin before last administration	754.4 Microg/L Geometric Coefficient of Variation 32.70	721.8 Microg/L Geometric Coefficient of Variation 25.56	—
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of R-warfarin After the Last Dose of Warfarin after last administration	740.2 Microg/L Geometric Coefficient of Variation 25.88	702.8 Microg/L Geometric Coefficient of Variation 28.39	—

SECONDARY outcome

Timeframe: 0 h (predose) and 24 h after the last administration of warfarin

Population: PK/PD set

Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of R-warfarin After the Last Dose of Warfarin before last administration	0.07154 1/Liter Geometric Coefficient of Variation 40.86	0.07843 1/Liter Geometric Coefficient of Variation 48.55	—
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of R-warfarin After the Last Dose of Warfarin after last administration	0.08633 1/Liter Geometric Coefficient of Variation 44.10	0.07915 1/Liter Geometric Coefficient of Variation 46.50	—

SECONDARY outcome

Timeframe: 0 h (predose) and 24 h after the last administration of warfarin

Population: PK/PD set

Ctrough,ss refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of S-warfarin After the Last Dose of Warfarin before last administration	498.2 Microg/L Geometric Coefficient of Variation 38.93	429.9 Microg/L Geometric Coefficient of Variation 31.14	—
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration (Ctrough,ss) of S-warfarin After the Last Dose of Warfarin after last administration	478.4 Microg/L Geometric Coefficient of Variation 26.17	424.9 Microg/L Geometric Coefficient of Variation 29.78	—

SECONDARY outcome

Timeframe: 0 h (predose) and 24 h after the last administration of warfarin

Population: PK/PD set

Ctrough,ss/D refers to the drug concentration at steady state at the time when it is expected to reach its minimum (trough) concentration, normalized by dose.

Outcome measures

Measure	Warfarin Followed by Rivaroxaban (Xarelto, BAY59-7939) n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily	Warfarin Followed by Placebo n=28 Participants Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily	Rivaroxaban (Xarelto, BAY59-7939) Days 0 to 3: 20 mg rivaroxaban once daily
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of S-warfarin After the Last Dose of Warfarin before last administration	0.04724 1/Liter Geometric Coefficient of Variation 43.96	0.04671 1/Liter Geometric Coefficient of Variation 53.03	—
Drug Concentration in Plasma at Steady State at Expected Time of Minimum (Trough) Concentration, Normalized by Dose (Ctrough,ss/D) of S-warfarin After the Last Dose of Warfarin after last administration	0.05580 1/Liter Geometric Coefficient of Variation 43.11	0.04786 1/Liter Geometric Coefficient of Variation 38.96	—

Adverse Events

RG1: Warfarin Followed by Rivaroxaban

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

RG2: Warfarin Followed by Placebo

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

RG3: Rivaroxaban

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

RG4: Warfarin Alone

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	RG1: Warfarin Followed by Rivaroxaban n=28 participants at risk All participants received warfarin and later rivaroxaban. Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 20 mg rivaroxaban once daily; Day 5: 10 mg vitamin K once daily. Note: Safety Data presented here include participants listed in Group A of the Participant Flow section.	RG2: Warfarin Followed by Placebo n=28 participants at risk All participants received warfarin and later placebo. Days -6 and -5: 10 mg warfarin once daily or lower depending on INR; Days -4 to -1 (could be prolonged by two days): 2.5, 5, 10, 12.5 or 15 mg warfarin once daily depending on INR; Days 0 to 3: 1 tablet matching placebo once daily; Day 5: 10 mg vitamin K once daily. Note: Safety Data presented here include participants listed in Group B of the Participant Flow section.	RG3: Rivaroxaban n=28 participants at risk All participants received rivaroxaban. Days 0 to 3: 20 mg rivaroxaban once daily. Note: Safety Data presented here include participants listed in Group C of the Participant Flow section.	RG4: Warfarin Alone n=63 participants at risk All participants received warfarin in the Run-In Phase, who either received rivaroxaban or placebo afterwards, or discontinued the study. Days -6 to -1(could be prolonged by 2 days): dose 15 mg to 2.5 mg, dosing depending on INR. Note: Safety Data presented here include participants listed in Groups A, B (warfarin run-in only) and D of the Participant Flow section.
Cardiac disorders Bradycardia	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/63
Eye disorders Dry eye	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Gastrointestinal disorders Abdominal discomfort	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Gastrointestinal disorders Abdominal pain	0.00% 0/28	7.1% 2/28 • Number of events 2	0.00% 0/28	1.6% 1/63 • Number of events 1
Gastrointestinal disorders Diarrhoea	7.1% 2/28 • Number of events 2	3.6% 1/28 • Number of events 1	0.00% 0/28	4.8% 3/63 • Number of events 3
Gastrointestinal disorders Dyspepsia	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Gastrointestinal disorders Eructation	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Gastrointestinal disorders Flatulence	0.00% 0/28	0.00% 0/28	0.00% 0/28	3.2% 2/63 • Number of events 2
Gastrointestinal disorders Gingival bleeding	7.1% 2/28 • Number of events 2	0.00% 0/28	0.00% 0/28	4.8% 3/63 • Number of events 3
Gastrointestinal disorders Lip dry	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Gastrointestinal disorders Nausea	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Gastrointestinal disorders Tongue ulceration	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/63
Gastrointestinal disorders Toothache	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
General disorders Application site erythema	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/63
General disorders Asthenia	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
General disorders Chest pain	3.6% 1/28 • Number of events 2	0.00% 0/28	0.00% 0/28	0.00% 0/63
General disorders Fatigue	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	4.8% 3/63 • Number of events 3
General disorders Injection site haematoma	3.6% 1/28 • Number of events 1	0.00% 0/28	3.6% 1/28 • Number of events 1	1.6% 1/63 • Number of events 1
General disorders Catheter site pain	0.00% 0/28	3.6% 1/28 • Number of events 2	0.00% 0/28	1.6% 1/63 • Number of events 1
Infections and infestations Nasopharyngitis	0.00% 0/28	0.00% 0/28	10.7% 3/28 • Number of events 3	1.6% 1/63 • Number of events 1
Infections and infestations Rhinitis	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/63
Infections and infestations Febrile infection	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/63
Infections and infestations Oral herpes	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/63
Injury, poisoning and procedural complications Muscle strain	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Injury, poisoning and procedural complications Tooth fracture	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Investigations Alanine aminotransferase increased	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/63
Investigations Blood amylase increased	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/63
Investigations Blood bilirubin increased	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Investigations Blood creatine phosphokinase increased	0.00% 0/28	3.6% 1/28 • Number of events 1	3.6% 1/28 • Number of events 1	0.00% 0/63
Investigations C-reactive protein increased	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	1.6% 1/63 • Number of events 1
Investigations Lipase increased	3.6% 1/28 • Number of events 1	0.00% 0/28	7.1% 2/28 • Number of events 2	0.00% 0/63
Investigations Urine output increased	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/63
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/28	3.6% 1/28 • Number of events 1	3.6% 1/28 • Number of events 1	1.6% 1/63 • Number of events 1
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/28	7.1% 2/28 • Number of events 2	0.00% 0/28	0.00% 0/63
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	1.6% 1/63 • Number of events 1
Musculoskeletal and connective tissue disorders Muscle tightness	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/63
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/63
Nervous system disorders Dizziness	3.6% 1/28 • Number of events 1	0.00% 0/28	3.6% 1/28 • Number of events 1	1.6% 1/63 • Number of events 1
Nervous system disorders Headache	7.1% 2/28 • Number of events 2	3.6% 1/28 • Number of events 1	3.6% 1/28 • Number of events 1	6.3% 4/63 • Number of events 4
Nervous system disorders Paraesthesia	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/63
Psychiatric disorders Sleep disorder	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Reproductive system and breast disorders Spontaneous penile erection	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/63
Respiratory, thoracic and mediastinal disorders Cough	3.6% 1/28 • Number of events 1	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/63
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/28	3.6% 1/28 • Number of events 1	3.6% 1/28 • Number of events 1	0.00% 0/63
Respiratory, thoracic and mediastinal disorders Hiccups	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/28	10.7% 3/28 • Number of events 3	0.00% 0/28	0.00% 0/63
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/28	0.00% 0/28	0.00% 0/28	1.6% 1/63 • Number of events 1
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/63
Skin and subcutaneous tissue disorders Rash	0.00% 0/28	0.00% 0/28	3.6% 1/28 • Number of events 1	0.00% 0/63
Vascular disorders Thrombophlebitis	3.6% 1/28 • Number of events 1	0.00% 0/28	0.00% 0/28	0.00% 0/63

Additional Information

Therapeutic Area Head

BAYER

Email: clinical-trials-contact@bayerhealthcare.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any disclosure of study results by the Principal Investigator or investigators has to be in agreement with the sponsor.
• Publication restrictions are in place

Restriction type: OTHER