XARELTO® to Treat Thrombosis and Reduce Thrombotic Risknevadaosteopathic.org/attachments/article/60/Xarelto and Thrombosis.pdfA. PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE

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Please see the full Prescribing Information, including Boxed WARNINGS, available at this event.

Nonvalvular Atrial Fibrillation (AF)

Deep Vein Thrombosis (DVT)

Pulmonary Embolism (PE)

XARELTO® to Treat Thrombosis and Reduce Thrombotic Risk

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This promotional educational activity is brought to you

by Janssen Pharmaceuticals, Inc., and is not certified

for continuing medical education. The consultant is a

paid speaker for Janssen Pharmaceuticals, Inc. The

speaker is presenting on behalf of Janssen and must

present information in compliance with FDA

requirements applicable to Janssen.

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~1/3 excretedunchanged as

active drug in urine

~2/3 excretedas inactive metabolites

in urine and feces

No requirement for routine coagulation monitoring105,111

Predictable pharmacokineticsand pharmacodynamics86,113

♦ Oral dosing

♦ Rapid onset of action

Dual modes of clearance

♦ t1/2 of 5 to 9 hours inhealthy individuals aged

20 to 45 years,11 to 13 hours in the elderly

The clinical significance of pharmacokinetic and pharmacodynamic data has not been established.

XARELTO® Pharmacologic Profile

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WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

A. PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS

Premature discontinuation of any oral anticoagulant, including XARELTO®, increases the risk of thrombotic events. If anticoagulation with XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

XARELTO®: IMPORTANT SAFETY INFORMATION

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B. SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

♦ Use of indwelling epidural catheters

♦ Concomitant use of other drugs that affect hemostasis, such as non-steroidalanti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants,see Drug Interactions

♦ A history of traumatic or repeated epidural or spinal punctures

♦ A history of spinal deformity or spinal surgery

♦ Optimal timing between the administration of XARELTO® and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment.If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

XARELTO®: IMPORTANT SAFETY INFORMATION (cont)

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Nonvalvular AF

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63

23

30

34

8

11

0 20 40 60 80

Patients (%)

Non-AF(n=120)

AF (n=30)

♦ 2.7 to 6.1 million individuals in the United States had AF in 201064

♦ AF increases the risk for stroke ≈5-fold64

– 23.5% of strokes in patients80 to 89 years old are AF related

♦ Strokes in patients with AF tend to be more disabling, recur, orbe fatal91

Mortality

Recurrent

stroke

Severe

disability

1-year Outcomes Following

Ischemic Stroke91

AF and Stroke Are a Significant Healthcare Burden

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WarfarinINR target: 2.0 to 3.0 inclusive

• Prior stroke, TIA, or

non-CNS systemic

embolus

– OR –

• ≥2 of the following*:

−CHF or LVEF ≤35%

−Hypertension

−Aged ≥75 years

−Diabetes mellitus

R

A

N

D

O

M

I

Z

E

Primary efficacy endpoint: Stroke or non-CNS systemic embolism

Principal safety endpoint: Major and CRNM bleeding

XARELTO® 20 mg/d(15 mg/d for CrCl 30 to <50 mL/min)

CRNM = clinically relevant nonmajor.

*Only 10% of patients enrolled without prior stroke, TIA, or systemic embolism and only 2 factors.

N=14,264

ROCKET AF Was a Randomized, Double-blindDouble-dummy Trial of Patients With Nonvalvular AF111,129

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21%

79%

≈1 in 5 patients had a baseline

CrCl <50 mL/min55

30-49 mL/min

≥50 mL/min

63

91

44

40

55

0 20 40 60 80 100

Patients (%)

Series 1CHF

Hypertension

Aged ≥75 years

Diabetes mellitus

Prior Stroke/TIA

Percentage of patients calculated by pooling total patients with noted characteristic in each trial arm.

*ITT population.

The mean CHADS2 score was 3.5 111

Median CHA2DS2-VASc = 5 117

ROCKET AF Enrolled 14,264 PatientsWith Nonvalvular AF*

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ROCKET AF:(N=14,264)111,112

XARELTO®

ARISTOTLE:(N=18,201)67

Eliquis®

RE-LY: (N=18,113)35,121

Pradaxa®

ENGAGE AF: (N=21,105)61

Savaysa®

CHADS2 score (mean) 3.5 2.1 2.1 2.8

CHF, % 63 35 32 57

Hypertension, % 91 87 79 94

Aged ≥75 years, % 44 31 40 40

Diabetes mellitus, % 40 25 23 36

Prior Stroke/TIA/SE, % 55 19 20 28

♦ These trials were conducted with different designs and evaluated different populations, so direct comparisons of their results cannot be made

Indicated trademarks are registered to their respective owners. Proportion of patients calculated by pooling total patients with noted

characteristic in each trial arm.

ROCKET AF Enrolled a Population atModerate to High Risk of Stroke

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Events per 100 PTY

XARELTO® 2.1

Warfarin 2.4

HR (95% CI):

0.88 (0.74-1.03)

♦ Consistent results were seen across secondary endpoints112No. at risk

XARELTO® 7081 6927 6774 6620 6470 5580 4779 3820 2951 2058 1321

Warfarin 7090 6910 6755 6590 6440 5561 4756 3807 2944 2069 1319

Days From Randomization

XARELTO®

Warfarin

Cu

mu

lati

ve E

ven

t R

ate

(%

)

0 90 180 270 360 450 540 6300

1

2

3

4

5

6

900810720

Noninferiority to warfarin for the primary composite endpoint of time to first occurrence of stroke or non–CNS systemic embolism was

demonstrated, but superiority to warfarin was not demonstrated. There are limited data on the relative effectiveness of XARELTO®

and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled. *ITT population.

XARELTO® Was Proven Effective to Reduce the Risk of Stroke and Non-CNS Systemic Embolism*

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FavorsXARELTO®

FavorsWarfarin

0.1 1.0 10

HR (95% CI)

Events per 100 PTY(n/N)

XARELTO® Warfarin

Major bleeding 3.6

(395/7111)

3.5

(386/7125)

GI bleeding 2.0

(221/7111)

1.2

(140/7125)

ICH 0.5

(55/7111)

0.7

(84/7125)

Fatal bleeding0.2

(27/7111)

0.5

(55/7125)

*Safety population on treatment plus 2 days. Major bleeding events within each subcategory were counted once per patient,

but patients may have contributed events to multiple subcategories.

XARELTO® and Warfarin Had ComparableMajor Bleeding Rates*

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Events per 100 PTY(n)

HR (95% CI)XARELTO®

(N=7111)*

Warfarin(N=7125)*

Major GI bleeding2.00

(221)

1.24(140)

1.66 (1.34-2.05)

Hemoglobin drop ≥2 g/dL1.84(204)

1.11(125)

1.69 (1.35-2.12)

Transfusion ≥4 U0.47(52)

0.41(47)

1.19 (0.80-1.77)

Fatal Bleeding0.01(1)

0.04(5)

0.21 (0.02-1.76)

*Safety population on-treatment plus 2 days.

Major GI Bleed Rates in ROCKET AF*139

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CONTRAINDICATIONS

♦ Active pathological bleeding

♦ Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS

♦ Increased Risk of Thrombotic Events After Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.


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WARNINGS AND PRECAUTIONS (cont)

♦ Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO® in patients with active pathological hemorrhage.

– A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.

– Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

♦ Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.


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♦ Spinal/Epidural Anesthesia or Puncture (cont): An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO® is to be delayed for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.


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♦ Use in Patients With Renal Impairment:

• Nonvalvular Atrial Fibrillation: Avoid the use of XARELTO® in patients with creatinine clearance (CrCl) <15 mL/min since drug exposure is increased. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

• Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.

• Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO® in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO® should discontinue the treatment.


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DVT/PE Treatment

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♦ Up to 900,000 people are affected by

DVT/PE annually71

♦ ≈550,000 hospitalizations annually in

the United States for DVT and/or PE28

♦ Healthcare costs associated with

DVT/PE in 2011 were estimated to

be up to $10 billion26

CDC Reported Causes of Annual Deaths in the United States27,147

Breast

Cancer

HIV Traffic

Accidents

DVT/PE

An

nu

al

Death

s (

x10

3)

0

20

40

60

80

100

120Column1

41,557

7216

36,415

100,000

VTE kills more people each year

than breast cancer, HIV, and traffic

accidents…combined27,147

VTE Is a Major Cause of Morbidity and Mortality With a Significant Economic Burden in the United States

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Enoxaparin followed by VKA

• EINSTEIN DVT17

− Objectively confirmed

proximal DVT without

symptomatic PE

• EINSTEIN PE21

− Objectively confirmed

PE with or without DVT

R

A

N

D

O

M

I

Z

E

Primary efficacy outcome: Symptomatic recurrent VTE†

Principal safety outcome: Clinically relevant bleeding‡

XARELTO®

15 mg

twice daily

Treatment period of 3, 6, or 12 months*

Day 1 Day 21

XARELTO®

20 mg

once daily

*Decision to treat for 3, 6, or 12 months made by investigator at time of randomization. †Defined as the composite of recurrent

DVT, nonfatal PE, or fatal PE. ‡Defined as the composite of major and clinically relevant nonmajor bleeding.

The EINSTEIN DVT and PE Trials Evaluateda Single-Agent Regimen for VTE Treatment

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EINSTEIN DVT and PE*

(N=8281)40,125,126

XARELTO®

AMPLIFY(N=5395)4-7

Eliquis®

RE-COVER I and II*

(N=5107)136-138

Pradaxa®

HOKUSAI (N=8240)73,74

Savaysa®

DVT only, n (%) 3389 (40.9) 3532 (65.5) 3499 (68.5) 4921 (59.7)

PE only, n (%) 3597 (43.4) 1359 (25.2) 1136 (22.2) 2505 (30.4)

Unprovoked index event, n (%) 5255 (63.5) 4845 (89.8) 1817 (35.6) 5410 (65.7)

Recent trauma or surgery, n (%) 1486 (17.9) Excluded† Did not specify Did not specify

Cancer at baseline‡, n (%) 462 (5.6) 169 (3.1) 221 (4.3) 208 (2.5)

Elderly§, n (%) 1283 (15.5) 749 (13.9) 529 (10.4) 1104 (13.4)

Previous VTE, n (%) 1610 (19.4) 872 (16.2) 1099 (21.5) 1520 (18.4)

♦ These trials were conducted with different designs and evaluated different populations, so direct comparisons of their results cannot be made

*Pooled analysis. †Patients defined as having head trauma, other major trauma, or major surgery 1 month prior to randomization were excluded

from the trial.7 ‡Hokusai enrolled 771 (9.3%) patients with any history of cancer.74 §Elderly patients were aged >75 years for the EINSTEIN and

RE-COVER trial programs, and aged ≥75 years for AMPLIFY and Hokusai.6,73,126,137

Indicated trademarks are registered to their respective owners. Proportion of patients calculated by pooling total patients with

noted characteristic in each trial arm.

Baseline Patient Characteristics in Phase 3 Trials for the Initial Treatment of DVT and PE

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No. at risk

XARELTO® 1731 1668 1648 1635 1424 1412 1369 400 369 364 345 309 266

Enox/VKA 1718 1616 1581 1565 1368 1358 1301 380 362 342 325 297 264

Days From Randomization300 60 90 120 150 180 210 300270240 360330

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Cu

mu

lati

ve E

ven

t R

ate

(%

)

Event Rate, %

XARELTO® 2.1

Enox/VKA 3.0

HR=0.68

(95% CI: 0.44-1.04)

XARELTO®

Enoxaparin/VKA

XARELTO® Was Proven Effective for the Treatment of DVT

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No. at risk

XARELTO® 2419 2350 2321 2311 2180 2167 2133 837 794 785 757 725 672

Enox/VKA 2413 2316 2295 2280 2155 2146 2113 835 787 773 746 722 675


0

0.5

1.0

1.5

2.0

2.5

3.0

Cu

mu

lati

ve E

ven

t R

ate

(%

)

Event Rate, %

XARELTO® 2.1

Enox/VKA 1.8

HR=1.12

(95% CI: 0.75-1.68)

XARELTO®

Enoxaparin/VKA

XARELTO® Was Proven Effective for the Treatment of PE

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No. at risk

XARELTO® 4130 3768 3671 3406 3270 3210 1928 1051 1009 936 878 853 453

Enox/VKA 4116 3738 3618 3330 3186 3125 1711 1025 981 907 857 823 369


0

8

12

14

Cu

mu

lati

ve E

ven

t R

ate

(%

)

Event Rate, %

XARELTO® 9.4

Enox/VKA 10.0

HR=0.93

(95% CI: 0.81-1.06)

2

4

6

10

XARELTO®

Enoxaparin/VKA

*Defined as the composite of major and clinically relevant nonmajor bleeding.

Pooled Analysis:EINSTEIN DVT and PE Principal Safety Outcome*126

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XARELTO® Reduced the Risk of VTE

Recurrence by 82% Relative to Placebo

Risk of Bleeding With XARELTO®

Compared With Placebo

% of Patients No. of Patients (%)

XARELTO®

(n=602)

Placebo

(n=594)

XARELTO®

(n=598)

Placebo

(n=590)

Recurrent VTE 1.3 7.1

HR=0.18

(95% CI: 0.09-0.39)

Psuperiority<0.0001

Major bleeding 4 (0.7) 0

CRNM bleeding 32 (5.4) 7 (1.2)

Any bleeding 104 (17.4) 63 (10.7)

In general, ACCP

recommends84:

♦ 3 months of anticoagulation therapy for patients with VTE

♦ Extended therapy for unprovoked VTE is suggested for patients with low to moderate bleeding risk

♦ Some patients may be candidates for extended treatment due to underlying medical conditions, such as active cancer

The EINSTEIN EXT Trial Established the Risk-Benefit Profile of Continued Anticoagulation With XARELTO®

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XARELTO® has a proven safety and efficacy profile in the treatment of patients with DVT and/or PE

♦ Similar rates of clinically relevant bleeding as enoxaparin/VKA

♦ Lower rates of major bleeding compared with enoxaparin/VKA

♦ Extended treatment with XARELTO® reduced the risk of recurrent DVT and PE

– Major bleeding occurred in 4 (0.7%) patients receiving XARELTO® compared with 0 patients receiving placebo

Proven, single-agent regimen helps protect patients from day one

♦ Fast onset of action with no need for bridging

♦ Oral administration

♦ No need for routine INR monitoring

♦ Limited drug-drug and drug-food interactions

EINSTEIN Trials Summary

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♦ Use in Patients With Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased.

♦ Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan). Avoid concomitant use of XARELTO® with drugs that are P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).


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♦ Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO®

dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

♦ Patients With Prosthetic Heart Valves: The safety and efficacy of XARELTO® have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO® is not recommended in these patients.

♦ Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.


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DRUG INTERACTIONS

♦ Avoid concomitant use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

♦ XARELTO® should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors (eg, diltiazem, verapamil, dronedarone, and erythromycin) unless the potential benefit justifies the potential risk.


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USE IN SPECIFIC POPULATIONS

♦ Pregnancy Category C: XARELTO® should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing.

♦ Labor and Delivery: Safety and effectiveness of XARELTO® during labor and delivery have not been studied in clinical trials.

♦ Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.

♦ Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

♦ Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.


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OVERDOSAGE

♦ Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES

♦ The most common adverse reactions with XARELTO® were bleeding complications.

Please see full Prescribing Information, including Boxed WARNINGS, available at this event.

038573-150812


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XARELTO® Real-World Evidence

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♦ An international, noninterventional, prospective, observational study evaluating safety and efficacy in patients with nonvalvular AF receiving XARELTO® in a real-world clinical setting through 311 clinical centers in Europe, Israel, and Canada

Patients (N=6784)

CHADS2 score, mean 2.0

CHA2DS2-VASc score, mean 3.4

Congestive heart failure, % 18.6

Hypertension, % 74.7

Age >75 y, % 37.2

Diabetes, % 19.6

Prior stroke/TIA/non-CNS systemic embolism, % 19.0

Renal impairment (CrCl 30-49 mL/min) 8.0

XANTUS: XARELTO® in Patients With Nonvalvular AF in a Real-World Setting25

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0.82.1

0.2 0.4 0.9

0

2

4

6

8

Series 1

Even

ts p

er

100 P

TY

Stroke/SE(n=51)

Major bleed*(n=128)

Fatal bleed(n=12)

XANTUS: Real-World Outcomes in Patients Treated With XARELTO®

(N=6784)

♦ XANTUS was a prospective, single-arm observational study

Efficacy Safety

*Major bleeding was defined by the ISTH criteria.

Outcomes from XANTUS are not intended for direct comparison with ROCKET AF.

ICH (n=26)

GI bleed (n=52)

Efficacy and Safety Outcomes in the XANTUS Study25

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♦ An ongoing, 5-year post-marketing safety surveillance study is evaluating major bleeding in patients receiving XARELTO® in a real-world clinical setting

♦ 27,467 patients with nonvalvular AF were identified through EMRs from the US Department of Defense database, from January 1, 2013 to March 31, 2014

Major Bleed (n=478) No Major Bleed (n=26,989)

CHADS2 score, mean 3.0 2.2

CHA2DS2-VASc score, mean 4.8 3.7

Age (mean) y 78.4 75.7

Heart failure, % 48.5 23.7

Hypertension, % 95.6 75.8

Diabetes, % 35.4 29.1

Prior ischemic stroke, % 9.0 4.8

Renal disease, % 38.7 16.7

Post-Marketing Safety Surveillance Study:XARELTO® Real-World Evidence143

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0

2

4

6

8

Series 1

Even

ts p

er

100 P

TY

Major bleed*(n=478)

Fatal bleed(n=14)

PMSS: Real-World Outcomes

in Patients Treated With XARELTO®

(N=27,467)XARELTO®

(N=27,467)

GI bleeding, n (%) 423 (1.5)

ICH, n (%) 36 (0.1)

♦ PMSS was a retrospective, single-arm observational study

Safety

*Major bleeding was defined by the Cunningham algorithm, which identifies bleeding-related hospitalizations from a primary discharge diagnosis.

Safety data from PMSS are not intended for direct comparison with ROCKET AF.

2.86

0.08

Major Bleeding Rates in the XARELTO® PMSS Study143

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♦ An international, noninterventional, prospective, observational study evaluating safety and efficacy of XARELTO® compared with standard anticoagulation therapy in patients with DVT in a real-world clinical setting across clinical centers in 21 countries

*Safety population, which included patients who received at least one dose of the anticoagulant treatment of interest. †Standard therapy consisted of initial treatment with UFH, LMWH, or fondaparinux, which could overlap with and be followed by a VKA. ‡Cancer was not considered when defining DVT as provoked or unprovoked.

XARELTO® (n=2619*) Standard therapy† (n=2149*)

Age, (median) y 59 66

DVT only, % 92 88

DVT and PE, % 8 12

Previous VTE, % 24 22

Provoked DVT‡, % 34 38

Unprovoked DVT‡, % 65 61

Active cancer, % 6 19

XALIA: XARELTO® in Patients With DVT in a Real-World Setting3

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0

2

4

6E

ven

t R

ate

s,

% (

n/N

)

Recurrent VTE Major bleed

XALIA: Real-World Outcomes in Patients With DVT

Treated With XARELTO®

XARELTO®

Standard therapy*

♦ The XALIA study was a prospective, two-arm observational study

*Standard therapy consisted of initial treatment with UFH, LMWH, or fondaparinux, which could overlap with and be followed by a VKA.

HR (95% CI)

0.91 (0.54, 1.54)HR (95% CI)

0.77 (0.40, 1.50)

1.4(36/2505)

2.3(47/2010)

0.8(19/2505)

2.1(43/2010)

Outcomes from XALIA are not intended for direct comparison with EINSTEIN studies.

Efficacy and Safety Outcomes in the XALIA Study3

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♦ Due to differences in study design, patient populations, definitions of safety outcomes, and data collection methods, the results of real-world studies are not intended for direct comparisons with clinical trials

♦ Real-world observational studies demonstrated safety and efficacy profiles that were generally consistent with pivotal trials3,25,126,143

– More than 35,000 patients treated with XARELTO® were evaluated in XANTUS, PMSS, and XALIA3,25,143

♦ These data provide additional safety data associated with XARELTO® use in a real-world setting

XARELTO® Real-World Evidence: Summary


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Patients With Nonvalvular AF and Diabetes

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0 20 40 60 80

Series 1Heart

Failure

Hypertension

Aged

≥75 Years

Diabetes

Cerebrovascular

Disease

0 20 40 60 80

Series 1

Patients, % Patients, %

Patients With AF Typically Have Multiple

Chronic Comorbid Conditions*115

Heart

Failure

Hypertension

Aged

≥75 Years

Diabetes

Cerebrovascular

Disease

*Based on 2007 data of 5% sample size of Medicare beneficiaries.

Patients in ROCKET AF Had Multiple

Chronic Comorbid Conditions111

36%

84%

74%

34%

30%

63%

91%

44%

40%

55%

ROCKET AF Enrolled Patients With Multiple Chronic Comorbid Conditions

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♦ Diabetes is a strong independent risk factor for stroke in patients with nonvalvular AF108

♦ Life expectancy can be reduced by ≈12 years in patients aged 60 years with diabetes and a history of stroke*47

Patients with AF and diabetes are

≈2 times as likely to experience

a thromboembolic event94

0

1

2

3

4

5

Diabetes No Diabetes

1-y

ear

Even

t R

ate

, %

(n

/N) 4.3

(8/187)

1.9

(17/897)

Patients with diabetes have a ≈40%

increased risk of having AF77

*Based on data from the Emerging Risk Factors Collaboration (n=689,300) and the UK Biobank (n=499,808).

Diabetes Increases Stroke Risk in Patients With AF

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1.5

1.3

1.2

0 1 2

Series 1

Major bleeding

Hemorrhagic stroke

Intracranial hemorrhage

N-Fold Increase in Bleeding Risk in Patients With Diabetes

*Data represent predicted 2-year rates with actual covariate values, using Cox regression modeling.

Diabetes Increases Bleeding Risk in Patients With AF*16

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Metformin

Metformin + 1 below:

SU, TZD, DPP-4-i,

SGLT2-i, GLP-1-RA, or insulin

Metformin + 2 below:

SU, TZD, DPP-4-i, SGLT2-i, GLP-1-RA,

or insulin

Metformin + basal insulin + mealtime insulin or GLP-1-RA

Mono

Dual

Triple

Combination Injectable

DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLP-1-RA = glucagon-like peptide-1-receptor agonist; SGLT2-i = sodium-glucose co-transporter 2 inhibitor; SU = sulfonylurea;

TZD = thiazolidinedione.

♦ An anticoagulant that requires multiple pills many times a day can add to the pill burden patients with diabetes already face145

♦ Patients with diabetes may have to watch their diets more closely with the use of warfarin9,37

Dietary Restrictions and Multiple MedicationsMay Increase the Complexity of Diabetes Management9,145

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36%

64%

Sales

60%

40%

Sales

75%

25%

Sales

Sales

23%

77%

No diabetes

♦ These trials were conducted with different designs and evaluated different populations,so direct comparisons of their results cannot be made

Indicated trademarks are registered to their respective owners. Proportion of patients calculated by pooling total patients with noted

characteristic in each trial arm.

ROCKET AF:(N=14,264)111

XARELTO®

ARISTOTLE:(N=18,201)67

Eliquis®

RE-LY: (N=18,113)35

Pradaxa®

ENGAGE AF: (N=21,105)61

Savaysa®

Diabetes

40% of Patients in ROCKET AF Had Diabetes

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With Diabetes Without Diabetes

Characteristic

XARELTO®

(N=2878)

Warfarin

(N=2817)

XARELTO®

(N=4253)

Warfarin

(N=4316)

Median age (25th, 75th), y 71 (64, 77) 71 (64, 77) 74 (66, 79) 74 (66, 79)

Median BMI (25th, 75th), kg/m2 30.0 (26.6, 34.2) 29.8 (26.4, 34.2) 27.3 (24.4, 30.7) 27.2 (24.4, 30.4)

Mean CHADS2 score (SD) 3.7 (1.0) 3.7 (1.0) 3.3 (0.9) 3.3 (0.9)

Congestive HF, n (%) 1893 (65.8) 1899 (67.4) 2574 (60.5) 2542 (58.9)

Hypertension, n (%) 2738 (95.1) 2695 (95.7) 3698 (87.0) 3779 (87.6)

Prior stroke/TIA, n (%) 922 (32.0) 884 (31.4) 2832 (66.6) 2830 (65.6)

♦ Patients with diabetes had a higher mean CHADS2 score vs those without diabetes

Baseline Characteristics of PatientsWith and Without Diabetes in ROCKET AF16

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FavorsXARELTO®

FavorsWarfarin

0.1 1.0 10

HR (95% CI)

Major/CRNM Bleeding

Diabetes

No diabetes

14.8

15.0

15.4

13.9

Events per 100 PTY

XARELTO® Warfarin

Diabetes

No diabetes

Intracranial Hemorrhage

0.5

0.5

0.8

0.7

Major Bleeding

Diabetes

No diabetes

3.8

3.5

3.9

3.2

Diabetes

No diabetes

Hemorrhagic Stroke

0.2

0.3

0.5

0.4

Safety Outcomes of XARELTO® Were Generally ConsistentAmong Patients With and Without Diabetes in ROCKET AF16

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♦ Diabetes is a common comorbidity in patients with nonvalvular AF that increases the risks for stroke and bleeding16,78,94

♦ XARELTO® was evaluated in a higher percentage of patients with nonvalvular AF and diabetes in ROCKET AF than any other NOAC16

– 40% of the patients in ROCKET AF had diabetes as a comorbidity

– In ROCKET AF, patients with diabetes had a higher mean CHADS2 score than those without diabetes

♦ Efficacy and safety results of XARELTO® were generally consistent in patients with diabetes and those without diabetes in ROCKET AF16

♦ 1 pill, once-daily with evening meal regimen with no known dietary restrictions113

Generally Consistent Efficacy and Safety Outcomes Regardless of Diabetes Status in ROCKET AF

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6 #1indications approved

by the FDAPrescribed NOAC in the US*41

Salesof commercial and Medicare patients

covered at the lowest branded co-pay43+90%

+18M US prescriptions across

multiple indications42

+15M patients have been prescribed

XARELTO® worldwide39

+55K# of patients who have been studied

in the XARELTO® clinical development

program17,21,34,49,76,81,88,101,111 +1300 publications to date

NOAC = non-vitamin K antagonist oral anticoagulant.

*Among Factor Xa inhibitors and direct thrombin inhibitors.

XARELTO® Is Leading the Way Among Non-vitamin K Antagonist Oral Anticoagulants

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www.xarelto-us.com/xarelto-carepath

1-888-XARELTO (1-888-927-3586)

Live Dedicated Care Coordinators Available

Monday – Friday, 8:00 AM - 8:00 PM ET

♦ XARELTO® CarePath™ is a comprehensive support program to help your patients start and stay on therapy

♦ Access tools support patients from day one and every step of the way

♦ Educational tools keep patients informed about their disease and their treatment to help support their success

♦ Adherence tools help patients stay on therapy through useful resources and reminders

Comprehensive Support for You and Your Patients Tools to Support Treatment Success

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♦ The XARELTO® DocCenter App is a one-stop anticoagulation resource center providing you with access to the latest prescribing tools and XARELTO® product information

♦ Available across iPhones, iPads, Android phones and tablets

To download the XARELTO® app,

visit www.appstore.com/XareltoDocCenter

Comprehensive Set of Resources and Tools to Support You and Your Patient

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Abbreviations

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♦ ACCP = American College of Chest Physicians

♦ ACEI = angiotensin-converting enzyme inhibitor

♦ AF = atrial fibrillation

♦ aPCC = activated prothrombin complex concentrate

♦ ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation

♦ ARR = absolute risk reduction

♦ AUC = area under the curve

♦ bid = twice daily

♦ BMI = body mass index

♦ BP = blood pressure

♦ CAD = coronary artery disease

♦ CBC = complete blood count

♦ CCUS = complete compression ultrasound

♦ CDC = United States Centers for Disease Control and Prevention

♦ CHADS2 = congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, stroke or transient ischemic attack

♦ CHA2DS2-VASc = congestive heart failure, hypertension, age 75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex category

♦ CHF = congestive heart failure

♦ Cmax = maximum concentration

♦ Ctrough = trough concentration

♦ CMS = US Centers for Medicare and Medicaid

♦ CNS = central nervous system

♦ COPD = chronic obstructive pulmonary disease

♦ CrCl = creatinine clearance

♦ CRNM = clinically relevant nonmajor (bleeding)

♦ CT = computed tomography

♦ CXR = chest x-ray

♦ CVA = cerebrovascular accident

♦ CYP = cytochrome P450

♦ D/C = discontinue

♦ DM = diabetes mellitus

♦ DURAC = Duration of Anticoagulation (Trial Study Group)

♦ DPP-4-i = dipeptidyl peptidase-4-inhibitor

Abbreviations

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♦ DVT = deep vein thrombosis

♦ EACA = epsilon-aminocaproic acid

♦ ECV = electrical cardioversion

♦ EKG = electrocardiogram

♦ EF = ejection fraction

♦ EHR = electronic health record

♦ EXT = extension

♦ FFP = fresh frozen plasma

♦ GERD = gastroesophageal reflux disease

♦ GI = gastrointestinal

♦ GLP-1-RA = glucagon-like peptide-1-receptor agonist

♦ GOS = Glasgow Outcomes Scale

♦ Hb = hemoglobin

♦ HCP = healthcare professional

♦ HF = heart failure

♦ HIV = human immunodeficiency virus

♦ HMO = health management organization

♦ HR = hazard ratio

♦ ICH = intracranial hemorrhage

♦ INR = international normalized ratio

♦ ITT = intent to treat

♦ IV = intravenous

♦ LMWH = low-molecular-weight heparin

♦ LOS = length of stay

♦ LTC = long-term care

♦ LVEF = left ventricular ejection fraction

♦ MI = myocardial infarction

♦ N/E = nonestimable

♦ NG = nasogastric

♦ NOAC = non-vitamin antagonist K anticoagulant

♦ NSAIDs = nonsteroidal anti-inflammatory drugs

♦ NSR = normal sinus rhythm

♦ NYHA = New York Heart Association

♦ PCC = prothrombin complex concentrate

♦ PCV = pharmacologic cardioversion

♦ PD = pharmacodynamic

♦ PE = pulmonary embolism

Abbreviations

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♦ PESI = Pulmonary Embolism Severity Index

♦ P-gp = permeability glycoprotein

♦ PMSS = post-marketing safety surveillance

♦ PK = pharmacokinetic

♦ PRBC = packed red blood cell

♦ PT = prothrombin time

♦ PTS = postthrombotic syndrome

♦ PTY = patient year

♦ PVC = polyvinyl chloride

♦ qd = once daily

♦ RECORD=REgulation of Coagulation in ORthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism

♦ RE-LY = Randomized Evaluation of Long-term anticoagulation therapY

♦ rFVIIa = recombinant factor VIIa

♦ ROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation

♦ RRR = relative risk reduction

♦ SAO2 = oxygen saturation

♦ sc = subcutaneous

♦ SCIP = Surgical Care Improvement Project

♦ SGLT2-i = sodium-glucose co-transporter 2 inhibitor

♦ sPESI = simplified Pulmonary Embolism Severity Index

♦ SU = sulfonylurea

♦ t1/2 = half-life of elimination

♦ THR = total hip replacement

♦ TIA = transient ischemic attack

♦ TKR = total knee replacement

♦ TTR = time in therapeutic range

♦ TZD = thiazolidinedione

♦ UFH = unfractionated heparin

♦ VKA = vitamin K antagonist

♦ VTE = venous thromboembolism

♦ WBC = white blood cell

♦ WNL = within normal limits

Abbreviations

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References


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2. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903-1912.

3. Ageno W, Mantovani LG, Haas S, et al. Safety and effectiveness of oral rivaorxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. [Published online December 7, 2015]. Lancet Haematol. doi:10.1016/S2352-3026(15)00257-4.

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6. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism—Supplementary Appendix. N Engl J Med. 2013;369(9):799-808. doi:10.1056/NEJMoa1302507.

7. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism—Supplementary Protocol. N Engl J Med. 2013;369(9):799-808. doi:10.1056/NEJMoa1302507.

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8. Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation. 2007;116(2):180-187.

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16. Bansilal S, Bloomgarden Z, Halperin JL, et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular a trial fibrillation: the rivaroxaban once-daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention ofstroke and embolism trial in atrial fibrillation (ROCKET AF trial). Am Heart J. 2015;170(4):675-682.e8.

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19. Boccalon H, Elias A, Chale JJ, Cadene A, Gabriel S. Clinical outcome and cost of hospital vs home treatment of proximal deep vein thrombosis with a low-molecular-weight heparin: the Vascular Midi-Pyrenees study. Arch Intern Med. 2000;160(12):1769-1773.

20. Büller HR, Lensing AW, Prins MH, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood. 2008;112(6):2242-2247.

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66. Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke. 2006;37(1):151-155.

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67. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.

68. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin Kantagonism for prevention of stroke and embolism trial in Atrial Fibrillation (ROCKET AF). Circulation. 2014;130(2):138-146.

69. Hankey GJ, Patel MR, Stevens SR, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11(4):315-322.

70. Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med. 2000;160(6):769-774.

71. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28(3):370-372.

72. Heparin Sodium Injection® [prescribing information]. Lake Forest, IL: Hospira, Inc.; 2008.

73. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415.

74. Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism—Supplementary Appendix. N Engl J Med. 2013;369:1406-1415. doi:10.1056/NEJMoa1306638.

75. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.2012;141(suppl 2):e152S-e184S.

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76. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – the J-ROCKET AF study. Circ J. 2012;76(9):2104-2111.

77. Huxley RR, Filion KB, Konety S, Alonso A. Meta-analysis of cohort and case-control studies of type-2 diabetes mellitus and risk of atrial fibrillation. Am J Cardiol. 2011;108(1):56-62.

78. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary. J Am Coll Cardiol. 2014;64(21):e1-e76.

79. Jimenez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170(15):1383-1389.

80. Johanson NA, Lachiewicz PF, Lieberman JR, et al. Prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty. J Am Acad Orthop Surg. 2009;17(3):183-196.

81. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39.

82. Kcentra® [prescribing information]. Kankakee, IL: CSL Behring, LLC.; 2013.

83. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST Guideline. [Published online January 7, 2016]. Chest. doi:10.1016/j.chest.2015.11.026.

84. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e419S-e494S.

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85. Kreutz, R. A clinical and pharmacologic assessment of once-daily versus twice-daily dosing for rivaroxaban. J Thromb Thrombolysis. 2014;38(2):137-149.

86. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412-421.

87. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873-880.

88. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.

89. Levi M, Moore KT, Castillejos CF, et al. Comparison of three- and four-factor prothrombin complex concentrates on the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428-1436.

90. Limone BL, Hernandez AV, Michalak D, Bookhart BK, Coleman CI. Timing of recurrent venous thromboembolism early after the index event: a meta-analysis of randomized controlled trials. Thromb Res. 2013;132(4):420-426.

91. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27(10):1760-1764.

92. Lip GYH, Andreotti F, Fauchier L, et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace. 2011;13(5):723-746.

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93. Lip GYH, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR. elderly, drugs/alcohol concomitantly) score. J Am Coll Cardiol. 2011:57(2):173-180.

94. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach. Chest. 2010;137(2):263-272.

95. Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159(3):331-339.

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97. Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med.2003;163(20):2469-2473.

98. Mahaffey KW, Hellkamp AS, Patel MR, et al. End of study transition from study drug to open-label vitamin K antagonist therapy: the ROCKET AF experience. Circ Cardiovasc Qual Outcomes. 2013;6(4):470-478.

99. Mani H, Hesse C, Stratmann G, Lindhoff-Last E. Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. Thromb Haemost. 2011;106(1):156-164.

100. McCormick D, Gurwitz JH, Goldberg RJ, et al. Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting. Arch Intern Med. 2001;161(20):2458-2463.

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102. Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke.2010;41(9):2108-2129.

103. Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct factor xa inhibitor – in healthy subjects. Int J Clin Pharmacol Ther. 2007;45(6):335-344.

104. Mueck W, Borris LC, Dahl OE, et al. Population pharmacokinetics and pharmacodynamics of once and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008;100(3):453-461.

105. Mueck W, Eriksson BI, Bauer KA, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct factor Xa inhibitor – in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47(3):203-216.

106. Mueck W, Lensing AWA, Agnelli G, et al. Population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50(10):675-686.

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109. Othieno R, Abu AM, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev. 2007(3):CD003076.

110. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol.2013;61(6):651-658.

111. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med.2011;365(10):883-891.

112. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation—Supplementary Appendix. N Engl J Med. 2011;365(10):883-891. doi:10.1056NEJMoa1009638.

113. Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol. 2010;30(3):376-381.

114. Piccini JP, Garg J, Patel MR, et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J. 2014;35(28):1873-1880.

115. Piccini JP, Hammill BG, Sinner MF, Jensen PN, et al. Incidence and Prevalence of Atrial Fibrillation and Associated MortalityAmong Medicare Beneficiaries, 1993-2007. Circ Cardiovasc Qual Outcomes. 2012;5(1):85-93.

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117. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: Validation of the R2CHADS2 index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation. 2013;127(2):224-232.

118. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013;61(19):1998-2006.

119. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-1100.

120. Pollack CV Jr. Managing bleeding in anticoagulated patients in the emergency care setting. J Emerg Med. 2013;45(3):467-477.

121. Pradaxa® [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2015.

122. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):3484-3488.

123. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulationin patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92(2):199-205.

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125. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIn-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol. 2014;1(1):e37-e46.

126. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21.

127. Ramacciotti E, Araujo GR, Lastoria S, et al. An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis. Thromb Res. 2004;114(3):149-153.

128. Reardon G, Nelson WW, Patel AA, Philpot T, Neidecker M. Warfarin for prevention of thrombosis among long-term care residents with atrial fibrillation: evidence of continuing low use despite consideration of stroke and bleeding risk. Drugs Aging. 2013;30(6):417-428.

129. ROCKET Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159(3):340-347.

130. Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Risk-adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation: results of the Veterans Affairs Study to Improve Anticoagulation (VARIA). Circ Cardiovasc Qual Outcomes. 2011;4(1):22-29.

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131. Rose AJ, Hylek EM, Ozonoff, Ash AS, Resiman JI, Berlowitz DR. Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA). J Thromb Haemost. 2010;8(10):2182-2191.

132. Rose AJ, Ozonoff A, Henault LE, Hylek EM. Warfarin for atrial fibrillation in community-based practise. J Thromb Haemost. 2008;6(6):1647-1654.

133. Sarawate C, Sikirica MV, Willey VJ, Bullano MF, Hauch O. Monitoring anticoagulation in atrial fibrillation. J Thromb Thrombolysis. 2006;21(2):191-198.

134. Savaysa® [prescribing information]. Parsippany, NJ: Daiichi-Sankyo, Inc.; 2015.

135. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med. 1997;336(6):393-398.

136. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772.

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138. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352.

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140. Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm. 2007;13(6):475-486.

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144. The Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69(6):546-554.

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148. van Bellen B, Bamber L, Correa de Carvalho F, Prins M, Wang M, Lensing AW. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin. 2014;30(5):829-837.

149. van Diepen S, Hellkamp AS, Patel MR, et al. Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrillation: insights from ROCKET AF. Circ Heart Fail. 2013;6(4):740-747.

150. Vigué B. Bench-to-bedside review: Optimising emergency reversal of vitamin K antagonists in severe haemorrhage – from theory to practice. Crit Care. 2009;13(2):209.

151. Warwick D, Friedman RJ, Agnelli G, et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br. 2007;89(6):799-807.

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References

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Nonvalvular AF Backup

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ROCKET AF Supplemental Data

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ROCKET AF112 ARISTOTLE95 RE-LY36 ENGAGE AF62

AF in the absence of:

◆ Hemodynamically

significant mitral

valve stenosis

◆ A prosthetic heart

valve*

◆ Clinically

significant

(moderate or

severe) mitral

stenosis

◆ A prosthetic

mechanical heart

valve

◆ Hemodynamically

relevant valve

disease

◆ A prosthetic valve

◆ Moderate or

severe mitral

stenosis

◆ Unresected atrial

myxoma

◆ A mechanical

heart valve†

*Annuloplasty with or without prosthetic ring, commissurotomy, and/or valvuloplasty were permitted.†Patients with bioprosthetic heart valves and/or valve repair were allowed.

Phase 3 Trials in AF: Nonvalvular AF Definitions

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♦ Patients with moderate renal impairment at baseline had a different baseline characteristics profile than patients with better renal function

Baseline Patient Characteristics According to Renal Function

Renal Impairment

(CrCl 30-49 mL/min)

(N=2950)

No Renal Impairment

(CrCl ≥50 mL/min)

(N=11,277)

CHADS2 Score, median 3.7 3.4

CHF, % 66 62

Hypertension, % 92 90

Age, median 79 71

Diabetes, % 33 42

Prior stroke/TIA/SE, % 50 56

Comorbidities in Patients With Moderate Renal Impairment in ROCKET AF55

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Events per 100 PTYn (%)


(N=7081)Warfarin(N=7090)

Primary composite endpoint 2.1

269 (3.8)

2.4306 (4.3)

0.88 (0.74-1.03)

Stroke 2.0

253 (3.6)

2.2281 (4.0)

–

Hemorrhagic stroke† 0.333 (0.5)

0.457 (0.8)

–

Ischemic stroke1.6

206 (2.9)

1.6208 (2.9)

–

Unknown stroke type0.2

19 (0.3)

0.118 (0.3)

–

Non-CNS systemic embolism0.2

20 (0.3)

0.227 (0.4)

–

This trial was neither designed nor powered for individual components of the composite endpoints.*ITT population. †Hemorrhagic stroke defined as primary hemorrhagic strokes confirmed by adjudication in all randomized patients followed up to site notification.

ROCKET AF: Primary Endpoint Components*

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FavorsXARELTO®

FavorsWarfarin

0.1 1.0 10

HR (95% CI)

1.8(45/1735)

1.9(53/1746)

1.9(54/1734)

1.3(37/1676)

2.5(62/1689)

2.2(63/1807)

2.1(62/1758)

1.8(55/1826)

0-50.6%

50.7%-58.5%

58.6%-65.7%

65.7%-100.0%

*Safety population on treatment plus 2 days.


XARELTO® WarfarinCenter TTR

Stroke/Non-CNS

Systemic Embolism*

The Treatment Effect of XARELTO® Was Consistent Across Center TTRs*116

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No. of Events(Rate/100 PTY)

XARELTO® Warfarin

269 (2.1) 306 (2.4)

188 (1.7) 240 (2.2)

81 (4.7) 66 (4.3)

2.00.5 1.0

HR

FavorsXARELTO®

FavorsWarfarin

ITT

Study drug

Open-label TxStudy drugEarly D/C

No D/C

ITT On-treatment

Open-label TxStudy drug

Study drug

Early D/C

No D/C

ITT Off-treatment

Study drug

Study drug Open-label TxEarly D/C

No D/C

Pnoninferiority <0.001

Psuperiority =0.12

Psuperiority =0.02

Psuperiority =0.58

Stroke and Non-CNS Systemic Embolismin the ITT On- and Off-Treatment Populations111

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Events per 100 PTYn (%)


(N=7081)Warfarin(N=7090)

Stroke, systemic embolism, and

vascular death 4.5

572 (8.1)

4.8609 (8.6)

0.94 (0.84-1.05)

Stroke, systemic embolism,

MI, and vascular death 5.2

659 (9.3)

5.7709 (10.0)

0.93 (0.83-1.03)

Systemic embolism0.2

20 (0.3)

0.227 (0.4)

0.74 (0.42-1.32)

MI1.0

130 (1.8)

1.1142 (2.0)

0.91 (0.72-1.16)

All-cause mortality4.5

582 (8.2)

4.9632 (8.9)

0.92 (0.82-1.03)

This trial was neither designed nor powered for individual components of the composite endpoints. *ITT population.

ROCKET AF: Secondary Endpoints*40

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Subgroup Analyses


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Major bleeding†

Stroke/non-CNS systemic embolism*

CHADS2 = 2

CHADS2 ≥ 3

CHADS2 = 2

CHADS2 ≥ 3

*ITT population. †Safety population on treatment plus 2 days.

n

Events per 100 PTY

XARELTO® Warfarin

1.5

2.2

3.4

3.6

1.7

2.6

2.7

3.6

1857

12,311

1855

12,378

FavorsXARELTO®

FavorsWarfarin

0.5 1.0 2

HR (95% CI)

The Results in ROCKET AF Were Generally Consistent Across CHADS2 Stroke Risk Groups

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Major bleeding†

Heart failure

No heart failure

Heart failure

No heart failure


Stroke/non-CNS systemic embolism* n

Events per 100 PTY

XARELTO® Warfarin

2.1

2.2

3.5

3.8

2.2

2.8

3.4

3.5

8851

5318

8894

5340

0.5 1.0 2

FavorsXARELTO®

FavorsWarfarin

HR (95% CI)

The Results in ROCKET AF Were Generally Consistent Among Patients With or Without Heart Failure40

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FavorsXARELTO®

FavorsWarfarin

0.1 1.0 10

HR (95% CI)

Ejection Fraction

≥40 (N=4893)

<40 (N=2497)

2.00

1.34

2.06

1.87

*ITT population.

Events per 100 PTY

XARELTO® Warfarin

2 (N=610)

≥3 (N=8423)

CHADS2 Score

1.30

1.96

1.16

2.18

NYHA Class

I or II (N=6205)

III or IV (N=2645)

1.90

1.88

2.02

2.10

Primary Efficacy Endpoint*

The Efficacy of XARELTO® Was Generally Consistent Across Heart Failure Subgroups in ROCKET AF149

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FavorsXARELTO®

FavorsWarfarin

0.1 1.0 10

HR (95% CI)

Ejection Fraction

≥40 (N=4914)

<40 (N=2521)

14.18

15.34

14.81

14.10


*Safety population on treatment plus 2 days.

Events per 100 PTY

XARELTO® Warfarin

2 (N=610)

≥3 (N=8467)

CHADS2 Score

15.96

14.06

10.02

14.42

NYHA Class

I or II (N=6217)

III or IV (N=2676)

14.83

12.45

14.15

13.54

Major/CRNM Bleeding*

The Safety of XARELTO® Was Generally Consistent Across Heart Failure Subgroups in ROCKET AF149

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FavorsXARELTO®

FavorsWarfarin

0.5 1.0 2

HR (95% CI)

Major bleeding†

Diabetes

No diabetes

Diabetes

No diabetes



Events per 100 PTY

XARELTO® Warfarin

1.9

2.3

3.8

3.5

2.3

2.5

3.9

3.2

5647

8524

5683

8553

The Results in ROCKET AF Were Generally Consistent Among Patients With and Without Diabetes

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Major bleeding†

Prior stroke/TIA

No prior stroke/TIA

Prior stroke/TIA

No prior stroke/TIA



Events per 100 PTY

XARELTO® Warfarin

2.8

1.5

3.1

4.1

3.0

1.9

3.2

3.7

7416

6755

7436

6800

FavorsXARELTO®

FavorsWarfarin

0.5 1.0 2

HR (95% CI)

The Results in ROCKET AF Were Generally Consistent Among Patients With or Without Prior Stroke/TIA69

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FavorsXARELTO®

FavorsWarfarin

0.1 1.0 10

HR (95% CI)

Stroke/non-CNS systemicembolism (n=644)

Major Bleeding

CRNM Bleeding

0.61(4/337)

3.47(22/338)

13.01(74/338)

2.23(13/307)

3.14(18/309)

12.76(65/309)

*Includes all patients with a baseline CrCl ≥50 and 2 consecutive on-study CrCl readings <50 mL/min. This analysis was performed

in the safety population on treatment plus 2 days. The efficacy results of the ITT analysis are the basis for the XARELTO® labeling,

and are the data found in the XARELTO® Prescribing Information.

Bleeding (n=647)

Major and CRNM Bleeding 15.31(85/338)

15.19(76/309)


XARELTO® Warfarin

Results for Patients With Baseline CrCl ≥50 mL/minWho Developed Moderate Renal Impairment*40

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Cardioversion and AF Ablation


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ECV, PCV, or Ablation No ECV, PCV, or Ablation

CharacteristicXARELTO®

(N=160)

Warfarin (N=161)

XARELTO®

(N=6901)

Warfarin (N=6921)

Mean age, y 68.5 71.0 73.0 73.0

Heart rate, beats/min 70.5 72.0 76.0 76.0

History of sleep apnea, % 8.8 7.5 4.4 4.5

Antiarrhythmic drugs, %

Amiodarone 21.9 16.8 7.8 7.8

Digoxin 20.6 22.4 39.0 39.0

Sotalol 11.9 11.2 1.8 1.8

Other 7.5 9.3 2.3 1.8

ECV = electrical cardioversion; PCV = pharmacologic cardioversion.

Baseline Characteristics for Patients Undergoing Cardioversion or Ablation in ROCKET AF118

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ECV, PCV, or Ablation No ECV, PCV, or Ablation

XARELTO®

(N=160)

Warfarin (N=161)

XARELTO®

(N=6901)

Warfarin (N=6921)

Persistent Paroxysmal New onset

49.4% 46.6% 82.0% 81.6%

16.7% 17.0%

47.5% 50.3%

3.1% 3.1% 1.3% 1.4%

ECV = electrical cardioversion; PCV = pharmacologic cardioversion.

More Patients Undergoing Cardioversion or Ablation in ROCKET AF Had Paroxysmal AF118

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♦ Outcomes were similar in the subgroup of patients taking XARELTO®

or warfarin the day of ECV, PCV, or AF ablation

Endpoint Following

ECV, PCV, or Ablation

No. of Events (%)

XARELTO®

(N=160)

Warfarin (N=161)

Stroke or systemic embolism 3 (1.9) 3 (1.9)

CV death 2 (1.3) 4 (2.5)

All-cause death 3 (1.9) 6 (3.7)

Hospitalization 50 (31.3) 48 (29.8)

Major or CRNM bleeding 30 (18.8) 21 (13.0)

CRNM = clinically relevant nonmajor. ECV = electrical cardioversion; PCV = pharmacologic cardioversion.

Outcomes After Cardioversion or Ablation in ROCKET AF for XARELTO® and Warfarin118

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Elderly Patients

040685-151214


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Please see the full Prescribing Information, including Boxed WARNINGS, available at this event.*ITT population. †Safety population on treatment plus 2 days.

Age <65

Age 65 to <75

Major bleeding†

Age ≥75

Age <65

Age 65 to <75

Age ≥75


Events per 100 PTY

XARELTO® Warfarin

1.8

2.2

2.3

2.2

3.0

4.9

1.8

2.3

2.9

2.2

3.2

4.4

3284

4723

6164

3288

4733

6215

FavorsXARELTO®

FavorsWarfarin

0.5 1.0 2

HR (95% CI)

Primary Efficacy and Major Bleeding Results in ROCKET AFWere Generally Consistent Among Elderly and Younger Patients

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Events per 100 PTY

XARELTO®

(N=3111)

Warfarin

(N=3104) HR (95% CI)

Major/CRNM bleeding 19.83 17.55 1.13 (1.02-1.25)

GI bleeding* 2.81 1.66

Major bleeding 4.86 4.40 1.11 (0.92-1.34)

Fatal bleeding 0.28 0.61 0.45 (0.23-0.87)

Critical organ 1.07 1.42 0.75 (0.52-1.08)

ICH 0.66 0.83 0.80 (0.50-1.28)

Transfusion 2.28 1.86 1.23 (0.93–1.64)

Hemoglobin drop 3.85 2.98 1.29 (1.03–1.61)

♦ Elderly patients randomized to XARELTO® had higher rates of the combined endpoint of major or CRNM bleeding

– The interaction was restricted to extracranial bleeding and was driven primarily by GI bleeding

♦ Major bleeding rates were comparable with XARELTO® and warfarin in both age groups

*P=0.0002.

Bleeding Events in Elderly Patients in ROCKET AF68

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Transitions, Interruptions, and Discontinuations With XARELTO®

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2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

63.0%

33.0%

Days After Last Dose

% o

f P

ati

en

ts W

ith

IN

R ≥

2.0

XARELTO®

Warfarin

Patients With at Least 2 INRs ≥2.0

♦ No end-of-study transition

protocol was defined in

ROCKET AF

– There was no coadministration

of warfarin and XARELTO®

♦ This resulted in inadequate

anticoagulation after stopping

XARELTO® until attaining a

therapeutic INR 0

20

40

60

80

Time to Therapeutic INR Was Prolonged in Patients Transitioning From XARELTO® at the End of ROCKET AF98

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0 0

2

0

2 2

0 0

2

5

0

2

1

3 3

0

3

0 0

1

0 0 0 0 0

1

0

2

1 1

0 00

1

2

3

4

5

6

1 2 3 4 5 6 7 8 41893 41987 41987 18-20 21-23 24-26 27-28 30

Days After Last Dose of Study Drug

On

Treatment

Days 3-30

After Last Dose

XARELTO®

Warfarin

Str

oke/N

on

-CN

S S

yste

mic

Em

bo

lism

The Pattern of Excess of Thromboembolic Events at the End of ROCKET AF Is Inconsistent With Rebound98

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Pharmacology and Dosing

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Please see the full Prescribing Information, including Boxed WARNINGS, available at this event.The clinical significance of pharmacokinetics and pharmacodynamics has not been established.

Half-lifeTime to reduce plasma drug concentration by half23

• Effect on pharmacodynamics is variable

Cmax Peak plasma concentration following a single dose23,54

Ctrough (Cmin)Minimum plasma concentration following a single dose23,48,54

• Calculated at the end of a dosing interval at steady state (measured

directly before administration of the next dose)

AUC0-24 Total daily exposure, measured at steady state54

The clinical significance of different dosing regimens on efficacy and safety

may not be accurately predicted by pharmacokinetic parameters23,54,85

Pharmacologic Factors That May Inform Optimal Dosing Frequency

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XARELTO® 20 mg Eliquis®46 Pradaxa®121 Savaysa®134

Oral bioavailability 66%-~100%* ~50% 3%-7% 62%

t1/2 (h)

5-9 (in healthy individuals

aged 20-45 years)

11-13 (in the elderly)

~12

12-17

(in healthy

individuals)

10-14

Unbound fraction in plasma ~5%-8% 13% 65% ~45%

Renal clearance ~36%unchanged

~27%total clearance

80%†

total clearance

~50%unchanged

*Bioavailability is 66% in the fasted state, but administration with food increases the mean AUC by 39%. 15-mg and 20-mg doses of XARELTO®

should be taken with food. †Of an intravenous dose. Bioavailability of an intravenously administered compound is 100%.23

♦ Approximately one-third of the absorbed dose of XARELTO® is excreted unchanged in the urine

♦ Although renal clearance of the total Eliquis® dose is ~27%, this represents ~50% of the absorbed, bioavailable dose85

♦ Similarly, ~55%-60% of the absorbed, active dose of edoxaban is renally eliminated85

Pharmacologic Properties of Non-vitamin K AntagonistOral Anticoagulants

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Administration of XARELTO® via NG or gastric feeding tube

Confirm tube

placement

Suspend crushed

XARELTO® tablet

in 50 mL of water

Administer

immediately

Avoid

administration

distal to stomach

Follow 15- and

20-mg doses

immediately by

enteral feeding

Oral administration of crushed XARELTO® tablets

Crush

XARELTO® tablet

Mix with

applesauce

Administer orally

immediately

Follow 15- and

20-mg doses

immediately with

food

♦ The 10-mg dose of XARELTO® does not require coadministration with food

XARELTO® Can Be Administered to Patients Who Have Difficulty Swallowing

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♦ INR is not an appropriate measure of anticoagulation for XARELTO®120

♦ Factor Xa tests used with LMWHor UFH are not suitable for usewith XARELTO®120

♦ XARELTO® prolongs PT time, with variability between reagents99

– Neoplastin Plus® may be the most sensitive reagent for measuring the anticoagulation effects of XARELTO®

Indicated trademarks are registered to their respective owners.

Before surgery

Before XARELTO®

2 hours after XARELTO®


30

25

20

15

10

5

PT

(sec)

Innovin® RecombiPlastin®

Thromborel S® Neoplastin® Plus

Time-dependent Effect of XARELTO® on PT99

Measuring the Anticoagulant Effect of XARELTO®

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Practical Management

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Switching to XARELTO® From:

WarfarinStop warfarin and start

XARELTO® when INR is <3.0

Unfractionated

heparin

Stop the infusion and start

XARELTO® at the same time

Other

non-warfarin

anticoagulants

Start XARELTO® 0 to 2 hours prior

to the next scheduled evening

administration of the other

anticoagulant (eg, LMWH) and

omit administration of the other

anticoagulant

Switching From XARELTO® to:

Warfarin

No clinical trial data are available

to guide converting patients from

XARELTO® to warfarin*

One approach is to stop XARELTO®

and start parenteral anticoagulant

and warfarin at time of next

scheduled XARELTO® dose

Rapid onset

anticoagulants

Stop XARELTO® and start other

anticoagulant when the next dose of

XARELTO® would have been given

*XARELTO® affects INR, so INR measurements made during coadministration of warfarin and XARELTO® may not be useful for

determining the appropriate dose of warfarin.

Switching Patients to and From XARELTO®

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♦ If anticoagulation must be interrupted to reduce the risk of bleeding, XARELTO® should be stopped at least 24 hours before the procedure

♦ The increased risk of bleeding should be weighed against the urgency of intervention when deciding whether to delay procedure until 24 hours afterthe last dose of XARELTO®

♦ XARELTO® should be restarted after the surgical or other procedures assoon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short

– If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant

♦ Factors such as renal function and risk of bleeding during surgery help guide discontinuation times for XARELTO® before surgery120

Interrupting XARELTO® Prior to Surgery or Intervention

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Drug Class Drugs (examples) PK/PD Effect

Avoid

concomitant

use

Combined P-gp

and strong

CYP3A4 inducers

Carbamazepine, phenytoin,

rifampin, St. John’s wort

Concomitant use may

decrease XARELTO®

exposure and efficacy

Combined P-gp

and strong

CYP3A4 inhibitors

Ketoconazole, itraconazole,

lopinavir/ritonavir, ritonavir,

indinavir, and conivaptan

Concomitant use may

increase XARELTO®

exposure and bleeding

risk

Concomitant Use of XARELTO With Combined P-gp and Strong CYP3A4 Inducers and Inhibitors

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Avoid

concomitant

use unless

benefit

outweighs risk

Anticoagulants Enoxaparin, warfarinConcomitant use may

increase bleeding risk

Use only if

benefit justifies

potential risk

NSAIDs/aspirin Naproxen, aspirinConcomitant use may


Platelet

aggregation

inhibitors

ClopidogrelConcomitant use may


Concomitant Use of XARELTO With Drugs That May Impact Coagulation

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*Combined P-gp and/or weak or moderate CYP3A4 inhibitors permitted in ROCKET AF included:amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin.

Patients with CrCl 30 to <50 mL/min receiving

concomitant XARELTO® with combined P-gp and/or

weak or moderate CYP3A4 inhibitors* in ROCKET AF

For patients with a CrCl 15 to <80 mL/min:

◆ Concomitant use of XARELTO® with

combined P-gp and moderate CYP3A4

inhibitors may increase exposure and

bleeding risk

◆ Drug examples: diltiazem, verapamil,

dronedarone, erythromycin

XARELTO® should not be used with

such drugs in patients with a CrCl

of 15 to <80 mL/min unless potential

benefit justifies potential risk

0.1 1.0 10

HR (95% CI)

Bleeding (Major/CRNM)

FavorsXARELTO®

FavorsWarfarin

Concomitant Use of XARELTO® With Combined P-gp and Moderate CYP3A4 Inhibitors in Patients With a CrCl of 15 to <80 mL/min

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Reversal of anticoagulant effects:

♦ A specific antidote for XARELTO® is not available

♦ XARELTO® is not expected to be dialyzable due to

high plasma protein binding

♦ Protamine sulfate and vitamin K are not expected to

affect the anticoagulant activity of XARELTO®

♦ Partial reversal of PT prolongation has been seen

after administration of PCCs in healthy volunteers

♦ The use of other procoagulant reversal agents like

aPCC or rFVIIa has not been evaluated

This is not intended to replace clinical judgment or determine individual patient care.

Initial strategies:

♦ Promptly evaluate any signs and symptoms of blood loss and consider the need for blood replacement

♦ Discontinue XARELTO® in patients with active pathological hemorrhage

– The terminal elimination half-life of XARELTO® is 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in the elderly

Considerations for Managing Bleeding in Patients Receiving XARELTO®

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DVT/PE Backup

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EINSTEIN ProgramSupplemental Data

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11.9

62.8

25.3

0

20

40

60

80

100 Column1

3 mo 6 mo 12 mo

XARELTO® or enoxaparin/VKA

5.2

57.4

37.4

0

20

40

60

80

100 Column1

Pa

tie

nts

(%

)

EINSTEIN DVT17 EINSTEIN PE21

3 mo 6 mo 12 mo

XARELTO® or enoxaparin/VKA

Treatment Duration in EINSTEIN DVT and PE Was Determined by the Treating Physician40

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EINSTEIN DVT

N=3449 17,40 Male Sex BMI ≥30 kg/m2 Unprovoked VTE

XARELTO®

(N=1731)

Enox/VKA

(N=1718)

Column2

Column2

Column2

Column2

Column2

Column2

61%

63%

30%

28%

57%

56%

EINSTEIN DVT: Baseline Patient Characteristics

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EINSTEIN PE

N=4832 21,40 Male Sex BMI ≥30 kg/m2 Unprovoked VTE

XARELTO®

(N=2419)

Enox/VKA

(N=2413)

Column2

Column2

Column2

Column2

Column2

Column2

65%

64%

31%

31%

54%

52%

EINSTEIN PE: Baseline Patient Characteristics

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Age (y) Weight (kg)

EINSTEIN DVT

N=3449

18 Range 97 33 Range 193

EINSTEIN PE

N=4832


Mean

56

Mean

58

Mean

82

Mean

83

EINSTEIN DVT and PE:Baseline Patient Characteristics40

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XARELTO® 20 mg once daily

Placebo

Completed 6 to 12

months of XARELTO®

or VKA for symptomatic

DVT or PE

Treatment period of 6 or 12 months*

*Decision to treat for 6 or 12 months made by investigator at time of randomization.

R

A

N

D

O

M

I

Z

E

Primary efficacy outcome: Symptomatic recurrent VTE

Principal safety outcome: Major bleeding

The EINSTEIN EXT Trial Evaluated the Benefits of Continuing Anticoagulation17

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Female Sex BMI ≥30 kg/m2

Age (years) Weight (kg)


Column2 Column2

Mean

58

Mean

83

Column2 Column2XARELTO® Placebo XARELTO® Placebo

31% 31%41% 43%

EINSTEIN EXT: Baseline Patient Characteristics40

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Subgroup Analyses

EINSTEIN ProgramSupplemental Data

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Gender Subgroups

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FavorsXARELTO®

FavorsEnox/VKA

Major and CRNM Bleeding

Symptomatic/Recurrent VTE

Female

Male

Female

Male

0.1 1.0 10

HR (95% CI)


Event Rate, % (n/N)

XARELTO® Enox/VKA

2.6 (19/738) 3.6 (27/751)

1.7 (17/993) 2.5 (24/967)

8.8 (64/731) 8.6 (64/748)

7.6 (75/987) 7.7 (74/963)

The Results in EINSTEIN DVT Were Consistent Among Females and Males18

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FavorsXARELTO®

FavorsEnox/VKA



Female

Male

Female

Male

0.1 1.0 10

HR (95% CI)

Event Rate, % (n/N)

XARELTO® Enox/VKA

2.3 (25/1110) 2.0 (23/1166)

1.9 (25/1309) 1.7 (21/1247)

11.9 (132/1105) 12.5 (145/1162)

9.0 (117/1307) 10.4 (129/1243)


The Results in EINSTEIN PE Were Consistent Among Females and Males22

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Female

Male

Female

Male

FavorsXARELTO®

FavorsPlacebo

0.1 1.0 10

HR (95% CI)

Event Rate, % (n/N)

XARELTO® Placebo

1.6 (4/248) 5.1 (13/255)

1.1 (4/354) 8.6 (29/339)

4.5 (11/247) 2.0 (5/252)

7.1 (25/351) 0.6 (2/338)


The Results in EINSTEIN EXT Were Consistent Among Females and Males18

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Age Subgroups

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)



<65 years

65-75 years

<65 years

>75 years

>75 years

65-75 years

Event Rate, % (n/N)

XARELTO® Enox/VKA

2.3 (26/1145) 2.7 (30/1111)

1.6 (6/371) 2.9 (11/382)

1.9 (4/215) 4.4 (10/225)

7.6 (86/1134) 7.1 (79/1107)

9.2 (34/369) 10.2 (39/381)

8.8 (19/215) 9.0 (20/223)


The Results in EINSTEIN DVT Were Consistent Across Age Groups Studied18

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)



<65 years

65-75 years

<65 years

65-75 years

>75 years

>75 years

Event Rate, % (n/N)

XARELTO® Enox/VKA

2.0 (29/1461) 1.6 (23/1479)

1.9 (10/517) 1.5 (8/532)

2.5 (11/441) 3.2 (13/402)

9.1 (132/1458) 9.2 (136/1472)

11.5 (59/514) 13.3 (71/532)

13.2 (58/440) 16.7 (67/401)


The Results in EINSTEIN PE Were Consistent Across Age Groups Studied22

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<65 years

65-75 years

<65 years

65-75 years

>75 years

>75 years

0.1 1.0 10

FavorsXARELTO®

FavorsPlacebo

HR (95% CI)

Event Rate, % (n/N)

XARELTO® Placebo

1.1 (4/360) 6.2 (23/374)

2.0 (3/153) 6.6 (8/121)

1.1 (1/89) 11.1 (11/99)

6.2 (22/358) 0.8 (3/373)

4.6 (7/152) 0.8 (1/119)

8.0 (7/88) 3.1 (3/98)


The Results in EINSTEIN EXT Were Consistent Across Age Groups Studied18

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Weight Subgroups

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)



≤70 kg

>70-90 kg

≤70 kg

>70-90 kg

>90 kg

>90 kg

Event Rate, % (n/N)

XARELTO® Enox/VKA

2.4 (12/494) 4.0 (21/524)

1.8 (13/740) 2.7 (19/707)

2.2 (11/491) 2.3 (11/486)

9.8 (48/492) 8.0 (42/522)

8.0 (59/733) 8.1 (57/708)

6.4 (31/488) 8.1 (39/481)


The Results in EINSTEIN DVT Were Consistent Across Weight Groups Studied18

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)

≤70 kg

>70-90 kg

≤70 kg

>70-90 kg

>90 kg

>90 kg



Event Rate, % (n/N)

XARELTO® Enox/VKA

2.6 (17/653) 1.6 (10/621)

1.9 (20/1081) 2.1 (24/1119)

1.9 (13/683) 1.5 (10/672)

10.9 (71/649) 12.8 (79/618)

10.2 (110/1078) 12.0 (134/1116)

10.0 (68/683) 9.1 (61/670)


The Results in EINSTEIN PE Were Consistent Across Weight Groups Studied22

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≤70 kg

>70-90 kg

≤70 kg

>70-90 kg

>90 kg

>90 kg

0.1 1.0 10

FavorsXARELTO®

FavorsPlacebo

HR (95% CI)



Event Rate, % (n/N)

XARELTO® Placebo

2.2 (3/135) 7.0 (11/157)

1.5 (4/264) 4.0 (10/246)

0.5 (1/187) 10.2 (18/177)

3.7 (5/134) 1.3 (2/157)

6.1 (16/263) 1.2 (3/244)

7.6 (14/185) 0.6 (1/176)


The Results in EINSTEIN EXT Were Consistent Across Weight Groups Studied18

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Renal Function Subgroups

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)



CrCl <50 mL/min

CrCl 50 to <80 mL/min

CrCl <50 mL/min


CrCl ≥80 mL/min

CrCl ≥80 mL/min

Event Rate, % (n/N)

XARELTO® Enox/VKA

3.3 (4/121) 4.7 (6/129)

3.1 (12/393) 3.5 (14/399)

1.6 (19/1193) 2.6 (30/1170)

10.8 (13/120) 7.8 (10/128)

9.2 (36/390) 10.3 (41/400)

7.5 (89/1186) 7.4 (86/1166)


The Results in EINSTEIN DVT Were Consistent Across Levels of Renal Function18

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)



CrCl <50 mL/min


CrCl <50 mL/min


CrCl ≥80 mL/min

CrCl ≥80 mL/min

Event Rate, % (n/N)

XARELTO® Enox/VKA

3.3 (7/211) 2.6 (5/193)

1.9 (12/637) 2.7 (16/593)

1.9 (30/1555) 1.4 (22/1617)

12.4 (26/209) 17.7 (34/192)

11.5 (73/634) 13.7 (81/593)

9.6 (149/1553) 9.9 (159/1610)


The Results in EINSTEIN PE Were Consistent Across Levels of Renal Function22

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CrCl <50 mL/min


CrCl <50 mL/min


CrCl ≥80 mL/min

CrCl ≥80 mL/min

0.1 1.0 10

HR (95% CI)

FavorsXARELTO®

FavorsPlacebo

Event Rate, % (n/N)

XARELTO® Placebo

2.7 (1/37) 12.2 (6/49)

1.5 (2/134) 7.4 (9/122)

0.8 (3/373) 5.9 (22/373)

2.7 (1/37) 4.1 (2/49)

6.0 (8/133) 0.8 (1/121)

6.7 (25/371) 0.8 (3/373)


The Results in EINSTEIN EXT Were Consistent Across Levels of Renal Function18,40

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Clot Burden Subgroups

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)



Limited burden

Intermediate burden

Limited burden

Intermediate burden

Extensive burden

Extensive burden

Event Rate, % (n/N)

XARELTO® Enox/VKA

1.3 (10/799) 2.3 (19/815)

2.2 (41/1873) 2.6 (49/1881)

2.6 (35/1364) 2.0 (26/1327)

9.2 (73/796) 9.3 (76/813)

9.7 (181/1864) 10.1 (189/1876)

9.3 (126/1359) 10.1 (134/1326)


The Results in EINSTEIN DVT and PE Were Consistent Irrespective of Clot Size126

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Fragility Subgroups

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Aged

>75 years

Weight

≤50 kg

CrCl

<50 mL/min

EINSTEIN DVT and PE

N=828215% 1.3% 7.8%

19% of the population in EINSTEIN DVT and PE were categorized as fragile because of advanced age (n=1279),

low body weight (n=107), or moderate or severe renal function (n=649)

EINSTEIN DVT and PE Enrolled Fragile Patients126

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)


Fragile

Nonfragile

Fragile

Nonfragile


Event Rate, % (n/N)

XARELTO® Enox/VKA

2.7 (21/791) 3.8 (30/782)

1.9 (65/3359) 1.9 (65/3349)

12.3 (97/788) 14.0 (109/779)

8.7 (291/3342) 9.1 (303/3337)


The Results in EINSTEIN DVT and PE Were Consistent in Fragile and Nonfragile Patients126

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>75 years

CrCl <50 mL/min

>75 years

CrCl <50 mL/min

Body weight <50 kg

Body weight <50 kg

FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)

N/E

Major Bleeding

N/E = nonestimable.

Event Rate, % (n/N)

XARELTO® Enox/VKA

2.3 (15/656) 3.7 (23/627)

3.3 (11/332) 3.4 (11/322)

7.1 (3/42) 3.0 (2/66)

1.2 (8/655) 4.5 (28/624)

0.9 (3/329) 4.1 (13/320)

0 (0/42) 4.6 (3/65)

The Results in EINSTEIN DVT and PE Were Consistent Across Individual Fragility Components126

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>75 years

CrCl <50 mL/min

>75 years

CrCl <50 mL/min

HR (95% CI)

FavorsXARELTO®

FavorsPlacebo

0.1 1.0 10

Event Rate, % (n/N)

XARELTO® Placebo

1.1 (1/89) 11.1 (11/99)

2.7 (1/37) 12.2 (6/49)

8.0 (7/88) 3.1 (3/98)

2.7 (1/37) 4.1 (2/49)


The Results in EINSTEIN EXT Were Consistent in Patients Associated With Fragility18

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Patients at High Risk for VTE Recurrence

EINSTEIN Program Supplemental Data

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Cancer

♦ Patients with cancer are at higher risk of recurrence after DVT or PE70,122

♦ Current guidelines recommend extended therapy with LMWH over warfarin for patients with cancer84

Prior VTE

♦ Patients with prior DVT or PE are at increased risk for recurrence70,123

Unprovoked VTE

♦ Patients with idiopathic DVT/PE are more likely to experience recurrence than patients with provoked events135

Malignancy, Prior Events, and Unprovoked Etiology Are Risk Factors for Recurrent DVT/PE

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Active Cancer125 Prior VTE126 Unprovoked VTE126

Pooled Analysis:

EINSTEIN DVT

and

EINSTEIN PE

N=8281125,126

Column2 Column2 Column2

63%

19%

6%

Proportion of patients calculated by pooling total patients with noted characteristic in each trial arm.

EINSTEIN DVT and PE EnrolledPatients at High Risk of Future Events

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)


Cancer

No cancer

Cancer

No cancer

Major Bleeding


Event Rate, % (n/N)

XARELTO® Enox/VKA

4.5 (16/354) 6.6 (20/301)

1.8 (65/3563) 1.9 (70/3594)

2.3 (8/353) 5.0 (15/298)

0.9 (31/3546) 1.5 (53/3582)

13.6 (48/353) 16.4 (49/298)

8.9 (315/3546) 9.5 (341/3582)

CRNM Bleeding

Cancer

No cancer

The Results in EINSTEIN DVT and PE Were Consistent in Patients With and Without Active Cancer125

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)


Prior DVT/PE

No prior DVT/PE

Prior DVT/PE

No prior DVT/PE


Event Rate, % (n/N)

XARELTO® Enox/VKA

1.4 (11/791) 3.1 (25/819)

2.2 (75/3359) 2.1 (70/3312)

8.9 (70/788) 11.2 (91/813)

9.5 (318/3342) 9.7 (321/3303)


The Results in EINSTEIN DVT and PE Were Consistent in Patients With and Without Prior Events126

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)

EINSTEIN DVT

Unprovoked DVT

Provoked DVT

Unprovoked PE

Provoked PE

EINSTEIN PE

Event Rate, % (n/N)

XARELTO® Enox/VKA

1.7 (18/1055) 2.8 (30/1083)

2.7 (18/676) 3.3 (21/635)

2.0 (32/1566) 1.9 (29/1551)

2.1 (18/853) 1.7 (15/862)


The Results in EINSTEIN DVT and PE Were Consistent in Patients With Unprovoked and Provoked Events18,22

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Bridging and Switchingto XARELTO®

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EINSTEIN DVT17 EINSTEIN PE21

XARELTO®

(N=1731)

Enox/VKA (N=1718)

XARELTO®

(N=2419)

Enox/VKA (N=2413)

Column1 Column1Column1Column1

No pretreatment 1 Day 2 Days

27.0% 29.4%

57.4% 58.0%

33.1% 32.2%

68.9% 66.3%

>2 Days

Patients were ineligible if they had received >48 hours of therapeutic parenteral anticoagulation

0.2% 0.4% 7.5%3.9% 3.9% 1.9% 7.9%1.9%

Most Patients in EINSTEIN DVT and PE Received ≤1 Day of Parenteral Anticoagulation Prior to Randomization17,21

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)


No pretreatment

Pretreatment

No pretreatment

Pretreatment


Event Rate, % (n/N)

XARELTO® Enox/VKA

1.9 (9/467) 2.0 (10/505)

2.1 (27/1264) 3.4 (41/1213)

10.1 (47/465) 9.4 (47/500)

7.3 (92/1253) 7.5 (91/1211)


The Results in EINSTEIN DVT Were Generally Consistent in Patients Not Receiving Parenteral Anticoagulation18

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FavorsXARELTO®

FavorsEnox/VKA

0.1 1.0 10

HR (95% CI)



No pretreatment

1 day

No pretreatment

1 day

2 days

2 days

Event Rate, % (n/N)

XARELTO® Enox/VKA

3.8 (7/182) 3.2 (6/190)

1.9 (34/1754) 1.6 (29/1760)

2.0 (9/460) 2.0 (9/443)

8.3 (15/180) 16.0 (30/188)

10.6 (186/1749) 11.1 (195/1757)

9.8 (45/460) 10.7 (47/441)


The Results in EINSTEIN PE Were Generally Consistent in Patients Not Receiving Parenteral Anticoagulation22,40

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VKA

XARELTO®

VKA

XARELTO®

0.1 1.0 10

HR (95% CI)

FavorsXARELTO®

FavorsPlacebo

Event Rate, % (n/N)

XARELTO® Placebo

1.4 (6/429) 6.5 (28/434)

0.6 (1/171) 8.2 (13/158)

6.1 (26/426) 1.2 (5/430)

5.3 (9/170) 1.3 (2/158)


The Results by Prior Anticoagulant Used Were Generally Consistent in EINSTEIN-EXT18

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Switching to XARELTO®

From warfarin Stop warfarin and start XARELTO® when INR is <3.0

From UFH Stop the infusion and start XARELTO® at the same time

From other

non-warfarin

anticoagulants

Start XARELTO® 0 to 2 hours prior to the next scheduled evening

administration of the other anticoagulant (eg, LMWH) and omit

administration of the other anticoagulant

Guidelines for Switching Patients to XARELTO®

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♦ INR is not an appropriate measure of anticoagulation for XARELTO®120

♦ Factor Xa tests used with LMWHor UFH are not suitable for usewith XARELTO®120

♦ XARELTO® prolongs PT time, with variability between reagents99

– Neoplastin Plus® may be the most sensitive reagent for measuring the anticoagulation effects of XARELTO®

Indicated trademarks are registered to their respective owners.

Before surgery

Before XARELTO®



30

25

20

15

10

5

PT

(sec)

Innovin® RecombiPlastin®

Thromborel S® Neoplastin® Plus

Time-dependent Effect of XARELTO® on PT99

Measuring the Anticoagulant Effect of XARELTO®

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Pharmacology and Dosing

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Please see the full Prescribing Information, including Boxed WARNINGS, available at this event.The clinical significance of pharmacokinetics and pharmacodynamics has not been established.

Half-lifeTime to reduce plasma drug concentration by half23

• Effect on pharmacodynamics is variable

Cmax Peak plasma concentration following a single dose23,54

Ctrough (Cmin)Minimum plasma concentration following a single dose23,48,54

• Calculated at the end of a dosing interval at steady state (measured

directly before administration of the next dose)

AUC0-24 Total daily exposure, measured at steady state54

The clinical significance of different dosing regimens on efficacy and safety

may not be accurately predicted by pharmacokinetic parameters23,54,85

Pharmacologic Factors That May Inform Optimal Dosing Frequency

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0

1000

2000

3000

4000

5000

20 mg OD 10 mg BID

0

100

200

300

400

500

20 mg OD 10 mg BID

Cmax

Ctrough

AUC0-24

Me

dia

n C

on

ce

ntr

ati

on

, m

g/L

(90

% R

an

ge

)

Me

dia

n C

on

ce

ntr

ati

on

, m

g●h/L

(90

% R

an

ge

)

n=362n=396 n=362n=396

Cmax and Ctrough were similar for once- and

twice-daily dosing regimens

Total daily exposure was approximately

18%-30% higher in patients receiving

once-daily XARELTO®

XARELTO® Exposure Is Consistent for Once-Daily and Twice-Daily Dosing in VTE Prophylaxis104

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XARELTO® 20 mg Eliquis®46 Pradaxa®121 Savaysa®134

Oral bioavailability 66%-~100%* ~50% 3%-7% 62%

t1/2 (h)

5-9 (in healthy individuals

aged 20-45 years)

11-13 (in the elderly)

~12

12-17

(in healthy

individuals)

10-14

Unbound fraction in plasma ~5%-8% 13% 65% ~45%

Renal clearance ~36%unchanged

~27%total clearance

80%†

total clearance

~50%unchanged

*Bioavailability is 66% in the fasted state, but administration with food increases the mean AUC by 39%. 15-mg and 20-mg doses of XARELTO®

should be taken with food. †Of an intravenous dose. Bioavailability of an intravenously administered compound is 100%.23

♦ Approximately one-third of the absorbed dose of XARELTO® is excreted unchanged in the urine

♦ Although renal clearance of the total Eliquis® dose is ~27%, this represents ~50% of the absorbed, bioavailable dose85

♦ Similarly, ~55%-60% of the absorbed, active dose of edoxaban is renally eliminated85

Pharmacologic Properties of Non-vitamin K AntagonistOral Anticoagulants

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Administration of XARELTO® via NG or gastric feeding tube

Confirm tube

placement

Suspend crushed

XARELTO® tablet

in 50 mL of water

Administer

immediately

Avoid

administration

distal to stomach

Follow 15- and

20-mg doses

immediately by

enteral feeding

Oral administration of crushed XARELTO® tablets

Crush

XARELTO® tablet

Mix with

applesauce

Administer orally

immediately

Follow 15- and

20-mg doses

immediately with

food

♦ The 10-mg dose of XARELTO® does not require coadministration with food

XARELTO® Can Be Administered to Patients Who Have Difficulty Swallowing

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Dosing in DVT/PE

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♦ Phase 2 trials informed the phase 3 EINSTEIN dosing regimen8,20

53.0 59.2 56.943.8 45.9

0

20

40

60

80

100

10 mgbid

20 mgbid

30 mgbid

40 mgqd

Enox/VKA

Patients with improved thrombus burden 71.0 71.4 73.4

68.8 71.6

0

20

40

60

80

100

10 mgbid

20 mgbid

30 mgbid

40 mgqd

Enox/VKA

Patients with improved thrombus burden

*Reduction in thrombus burden defined as an improvement of ≥4 points in thrombus score.

Pati

en

ts W

ith

Im

pro

ved

Th

rom

bu

s B

urd

en

(%

)* Day 21 Day 84

(100) (98) (109) (112) (109)n= (100) (98) (109) (112) (109)

Phase 2 Data Suggested Reduced Thrombus Burden With XARELTO® Twice-daily Dosing During the High-Risk Period8

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No. at risk

XARELTO® 4150 4018 3969 3924 3604 3579 3283 1237 1163 1148 1102 1034 938

Enox/VKA 4131 3932 3876 3826 3523 3504 3236 1215 1149 1109 1071 1019 939

0 30 60 90 120 150 180 2100

0.5

300270240 360330

1.0

1.5

2.0

2.5

3.0

Days From Randomization

Cu

mu

lati

ve E

ven

t R

ate

(%

)

Event Rate, %

XARELTO® 2.1

Enox/VKA 2.3

HR=0.89

(95% CI: 0.66-1.19)

Pnoninferiority<0.001

XARELTO®

Enoxaparin/VKA

The XARELTO® Dosing Regimen Was Proven Effective for the Treatment of DVT and PE126

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No. at risk

XARELTO® 4130 3921 3862 3611 3479 3433 2074 1135 1095 1025 969 947 499

Enox/VKA 4116 3868 3784 3525 3394 3348 1835 1109 1065 990 950 916 409


Cu

mu

lati

ve E

ven

t R

ate

(%

)

Event Rate, %

XARELTO® 1.0

Enox/VKA 1.7

HR=0.54

(95% CI: 0.37-0.79)

P=0.002*

0

1.5

2.0

2.5

0.5

1.0

XARELTO®

Enoxaparin/VKA *Not adjusted for multiplicity.

XARELTO® Reduced the Rate of Major Bleeding Compared With Enoxaparin/VKA126

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Practical Management

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Switching to XARELTO® From:

WarfarinStop warfarin and start

XARELTO® when INR is <3.0

Unfractionated

heparin

Stop the infusion and start

XARELTO® at the same time

Other

non-warfarin

anticoagulants

Start XARELTO® 0 to 2 hours prior

to the next scheduled evening

administration of the other

anticoagulant (eg, LMWH) and

omit administration of the other

anticoagulant

Switching From XARELTO® to:

Warfarin

No clinical trial data are available

to guide converting patients from

XARELTO® to warfarin*

One approach is to stop XARELTO®

and start parenteral anticoagulant

and warfarin at time of next

scheduled XARELTO® dose

Rapid onset

anticoagulants

Stop XARELTO® and start other

anticoagulant when the next dose of

XARELTO® would have been given

*XARELTO® affects INR, so INR measurements made during coadministration of warfarin and XARELTO® may not be useful for

determining the appropriate dose of warfarin.

Switching Patients to and From XARELTO®

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♦ If anticoagulation must be interrupted to reduce the risk of bleeding, XARELTO® should be stopped at least 24 hours before the procedure

♦ The increased risk of bleeding should be weighed against the urgency of intervention when deciding whether to delay procedure until 24 hours afterthe last dose of XARELTO®

♦ XARELTO® should be restarted after the surgical or other procedures assoon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short

– If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant

♦ Factors such as renal function and risk of bleeding during surgery help guide discontinuation times for XARELTO® before surgery120

Interrupting XARELTO® Prior to Surgery or Intervention

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Avoid

concomitant

use

Combined P-gp

and strong

CYP3A4 inducers

Carbamazepine, phenytoin,

rifampin, St. John’s wort

Concomitant use may

decrease XARELTO®

exposure and efficacy

Combined P-gp

and strong

CYP3A4 inhibitors

Ketoconazole, itraconazole,

lopinavir/ritonavir, ritonavir,

indinavir, and conivaptan

Concomitant use may

increase XARELTO®

exposure and bleeding

risk

Concomitant Use of XARELTO With Combined P-gp and Strong CYP3A4 Inducers and Inhibitors

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Avoid

concomitant

use unless

benefit

outweighs risk

Anticoagulants Enoxaparin, warfarinConcomitant use may


Use only if

benefit justifies

potential risk

NSAIDs/aspirin Naproxen, aspirinConcomitant use may


Platelet

aggregation

inhibitors

ClopidogrelConcomitant use may


Concomitant Use of XARELTO With Drugs That May Impact Coagulation

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*Combined P-gp and/or weak or moderate CYP3A4 inhibitors permitted in ROCKET AF included:amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin.

Patients with CrCl 30 to <50 mL/min receiving

concomitant XARELTO® with combined P-gp and/or

weak or moderate CYP3A4 inhibitors* in ROCKET AF

For patients with a CrCl 15 to <80 mL/min:

◆ Concomitant use of XARELTO® with

combined P-gp and moderate CYP3A4

inhibitors may increase exposure and

bleeding risk

◆ Drug examples: diltiazem, verapamil,

dronedarone, erythromycin

XARELTO® should not be used with

such drugs in patients with a CrCl

of 15 to <80 mL/min unless potential

benefit justifies potential risk

0.1 1.0 10

HR (95% CI)

Bleeding (Major/CRNM)

FavorsXARELTO®

FavorsWarfarin

Concomitant Use of XARELTO® With Combined P-gp and Moderate CYP3A4 Inhibitors in Patients With a CrCl of 15 to <80 mL/min

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Reversal of anticoagulant effects:

♦ A specific antidote for XARELTO® is not available

♦ XARELTO® is not expected to be dialyzable due to

high plasma protein binding

♦ Protamine sulfate and vitamin K are not expected to

affect the anticoagulant activity of XARELTO®

♦ Partial reversal of PT prolongation has been seen

after administration of PCCs in healthy volunteers

♦ The use of other procoagulant reversal agents like

aPCC or rFVIIa has not been evaluated

This is not intended to replace clinical judgment or determine individual patient care.

Initial strategies:

♦ Promptly evaluate any signs and symptoms of blood loss and consider the need for blood replacement

♦ Discontinue XARELTO® in patients with active pathological hemorrhage

– The terminal elimination half-life of XARELTO® is 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in the elderly

Considerations for Managing Bleeding in Patients Receiving XARELTO®

Documents

XARELTO® to Treat Thrombosis and Reduce Thrombotic Risknevadaosteopathic.org/attachments/article/60/Xarelto and Thrombosis.pdfA. PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE