CLINICAL PHARMACOLOGY
Mechanism Of Action
XARELTO is a selective
inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III)
for activity. Rivaroxaban inhibits free FXa and prothrombinase activity.
Rivaroxaban has no direct effect on platelet aggregation, but indirectly
inhibits platelet aggregation induced by thrombin. By inhibiting FXa,
rivaroxaban decreases thrombin generation.
Pharmacodynamics
Dose-dependent inhibition of FXa activity was observed in
humans. Neoplastin® prothrombin time (PT), activated partial thromboplastin
time (aPTT) and HepTest® are also prolonged dose-dependently. Anti-factor Xa
activity is also influenced by rivaroxaban.
Specific Populations
Renal Impairment
The relationship between systemic exposure and pharmacodynamic
activity of rivaroxaban was altered in subjects with renal impairment relative
to healthy control subjects [see Use In Specific Populations].
Table 9: Percentage Increase in Rivaroxaban PK and PD
Measures in Subjects with Renal Impairment Relative to Healthy Subjects from
Clinical Pharmacology Studies
Measure |
Parameter |
Creatinine Clearance (mL/min) |
50-79 |
30-49 |
15-29 |
ESRD (on dialysis)* |
ESRD (post-dialysis)* |
Exposure |
AUC |
44 |
52 |
64 |
47 |
56 |
FXa Inhibition |
AUEC |
50 |
86 |
100 |
49 |
33 |
PT Prolongation |
AUEC |
33 |
116 |
144 |
112 |
158 |
*Separate stand-alone study.
PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma
concentration-time curve; AUEC = Area under the effect-time curve |
Hepatic Impairment
Anti-Factor Xa activity was
similar in subjects with normal hepatic function and in mild hepatic impairment
(Child-Pugh A class). There is no clear understanding of the impact of hepatic
impairment beyond this degree on the coagulation cascade and its relationship
to efficacy and safety.
Pharmacokinetics
Absorption
The absolute bioavailability of
rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it is estimated
to be 80% to 100% and is not affected by food. XARELTO 10 mg tablets can be
taken with or without food. For the 20 mg dose in the fasted state, the
absolute bioavailability is approximately 66%. Coadministration of XARELTO with
food increases the bioavailability of the 20 mg dose (mean AUC and Cmax
increasing by 39% and 76% respectively with food). XARELTO 15 mg and 20 mg
tablets should be taken with food [see DOSAGE AND ADMINISTRATION].
The maximum concentrations
(Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The
pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH.
Coadministration of XARELTO (30 mg single dose) with the H2-receptor antagonist
ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium
hydroxide (10 mL) or XARELTO (20 mg single dose) with the PPI omeprazole (40 mg
once daily) did not show an effect on the bioavailability and exposure of
rivaroxaban (see Figure 4).
Absorption of rivaroxaban is dependent on the site of
drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared
to tablet was reported when rivaroxaban granulate is released in the proximal
small intestine. Exposure is further reduced when drug is released in the
distal small intestine, or ascending colon. Avoid administration of rivaroxaban
distal to the stomach which can result in reduced absorption and related drug
exposure.
In a study with 44 healthy subjects, both mean AUC and
Cmax values for 20 mg rivaroxaban administered orally as a crushed tablet mixed
in applesauce were comparable to that after the whole tablet. However, for the
crushed tablet suspended in water and administered via an NG tube followed by a
liquid meal, only mean AUC was comparable to that after the whole tablet, and
Cmax was 18% lower.
Distribution
Plasma protein binding of rivaroxaban in human plasma is
approximately 92% to 95%, with albumin being the main binding component. The
steady-state volume of distribution in healthy subjects is approximately 50 L.
Metabolism
Approximately 51% of an orally administered [14C]-rivaroxaban
dose was recovered as inactive metabolites in urine (30%) and feces (21%).
Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the
major sites of biotransformation. Unchanged rivaroxaban was the predominant
moiety in plasma with no major or active circulating metabolites.
Excretion
In a Phase 1 study, following the administration of [14C]-rivaroxaban,
approximately one-third (36%) was recovered as unchanged drug in the urine and
7% was recovered as unchanged drug in feces. Unchanged drug is excreted into
urine, mainly via active tubular secretion and to a lesser extent via
glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of
the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp).
Rivaroxaban's affinity for influx transporter proteins is unknown.
Rivaroxaban is a low-clearance drug, with a systemic
clearance of approximately 10 L/hr in healthy volunteers following intravenous
administration. The terminal elimination half-life of rivaroxaban is 5 to 9
hours in healthy subjects aged 20 to 45 years.
Specific Populations
The effects of level of renal impairment, age, body
weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban
are summarized in Figure 3.
Figure 3: Effect of Specific Populations on the
Pharmacokinetics of Rivaroxaban
Gender
Gender did not influence the
pharmacokinetics or pharmacodynamics of XARELTO.
Race
Healthy Japanese subjects were found to have 20 to 40% on
average higher exposures compared to other ethnicities including Chinese.
However, these differences in exposure are reduced when values are corrected
for body weight.
Elderly
The terminal elimination half-life is 11 to 13 hours in
the elderly subjects aged 60 to 76 years [see Use In Specific Populations].
Renal Impairment
The safety and pharmacokinetics of single-dose XARELTO
(10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min
(n=8)] and in subjects with varying degrees of renal impairment (see Figure 3).
Compared to healthy subjects with normal creatinine clearance, rivaroxaban
exposure increased in subjects with renal impairment. Increases in
pharmacodynamic effects were also observed [see Use In Specific Populations].
Hemodialysis in ESRD subjects: Systemic exposure to rivaroxaban
administered as a single 15 mg dose in ESRD subjects dosed 3 hours after the
completion of a 4-hour hemodialysis session (postdialysis) is 56% higher when
compared to subjects with normal renal function (see Table 9). The systemic
exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis
session with a dialysate flow rate of 600 mL/min and a blood flow rate in the
range of 320 to 400 mL/min is 47% higher compared to those with normal renal
function. The extent of the increase is similar to the increase in patients
with CrCl 15 to 50 mL/min taking XARELTO 15 mg. Hemodialysis had no significant
impact on rivaroxaban exposure. Protein binding was similar (86% to 89%) in
healthy controls and ESRD subjects in this study.
Hepatic Impairment
The safety and pharmacokinetics of single-dose XARELTO
(10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with
varying degrees of hepatic impairment (see Figure 3). No patients with severe
hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects
with normal liver function, significant increases in rivaroxaban exposure were
observed in subjects with moderate hepatic impairment (Child-Pugh B) (see
Figure 3). Increases in pharmacodynamic effects were also observed [see Use In
Specific Populations].
Drug Interactions
In vitro studies indicate that rivaroxaban neither
inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2,
and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates a low
rivaroxaban inhibitory potential for P-gp and ABCG2 transporters.
The effects of coadministered drugs on the
pharmacokinetics of rivaroxaban exposure are summarized in Figure 4 [see DRUG
INTERACTIONS].
Figure 4: Effect of Coadministered Drugs on the
Pharmacokinetics of Rivaroxaban
Anticoagulants
In a drug interaction study,
single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given
concomitantly resulted in an additive effect on anti-factor Xa activity. In
another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in
an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor
warfarin affected the pharmacokinetics of rivaroxaban (see Figure 4).
NSAIDs/Aspirin
In ROCKET AF, concomitant aspirin
use (almost exclusively at a dose of 100 mg or less) during the double-blind
phase was identified as an independent risk factor for major bleeding. NSAIDs
are known to increase bleeding, and bleeding risk may be increased when NSAIDs
are used concomitantly with XARELTO. Neither naproxen nor aspirin affected the
pharmacokinetics of rivaroxaban (see Figure 4).
Clopidogrel
In two drug interaction studies
where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance
dose) and XARELTO (15 mg single dose) were coadministered in healthy subjects,
an increase in bleeding time to 45 minutes was observed in approximately 45%
and 30% of subjects in these studies, respectively. The change in bleeding time
was approximately twice the maximum increase seen with either drug alone. There
was no change in the pharmacokinetics of either drug.
Drug-Disease Interactions With Drugs
That Inhibit Cytochrome P450 3A Enzymes And Drug Transport Systems
In a pharmacokinetic trial,
XARELTO was administered as a single dose in subjects with mild (CrCl = 50 to
79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving
multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor).
Compared to XARELTO administered alone in subjects with normal renal function
(CrCl >80 mL/min), subjects with mild and moderate renal impairment
concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf
and a 56% and 64% increase in Cmax, respectively. Similar trends in
pharmacodynamic effects were also observed.
QT/QTc Prolongation
In a thorough QT study in
healthy men and women aged 50 years and older, no QTc prolonging effects were
observed for XARELTO (15 mg and 45 mg, single-dose).
Clinical Studies
Stroke Prevention In Nonvalvular Atrial Fibrillation
The evidence for the efficacy and safety of XARELTO was
derived from Rivaroxaban Once-daily oral direct factor Xa inhibition Compared
with vitamin K antagonist for the prevention of stroke and Embolism Trial in
Atrial Fibrillation (ROCKET AF) [NCT00403767], a multi-national, double-blind study
comparing XARELTO (at a dose of 20 mg once daily with the evening meal in
patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in
patients with CrCl 30 to 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to
reduce the risk of stroke and non-central nervous system (CNS) systemic
embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to
have one or more of the following additional risk factors for stroke:
- a prior stroke (ischemic or unknown type), transient ischemic
attack (TIA) or non-CNS systemic embolism, or
- 2 or more of the following risk factors:
- age ≥75 years,
- hypertension,
- heart failure or left ventricular ejection fraction
≤35%, or
- diabetes mellitus
ROCKET AF was a non-inferiority study designed to
demonstrate that XARELTO preserved more than 50% of warfarin’s effect on stroke
and non-CNS systemic embolism as established by previous placebo-controlled
studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on
study treatment for a median of 590 days. The mean age was 71 years and the
mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13%
Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic
embolism in 55% of patients, and 38% of patients had not taken a vitamin K
antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of
patients in this study included hypertension 91%, diabetes 40%, congestive
heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of
patients were on aspirin (almost exclusively at a dose of 100 mg or less) and
few patients were on clopidogrel. Patients were enrolled in Eastern Europe
(39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe
(15%); and Latin America (13%). Patients randomized to warfarin had a mean
percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during
the first few months of the study.
In ROCKET AF, XARELTO was demonstrated non-inferior to
warfarin for the primary composite endpoint of time to first occurrence of
stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74,
1.03)], but superiority to warfarin was not demonstrated. There is insufficient
experience to determine how XARELTO and warfarin compare when warfarin therapy
is well-controlled.
Table 10 displays the overall results for the primary
composite endpoint and its components.
Table 10: Primary Composite
Endpoint Results in ROCKET AF Study (Intent-to-Treat Population)
Event |
XARELTO |
Warfarin |
XARELTO vs. Warfarin |
N=7081 n (%) |
Event Rate (per 100 Pt-yrs) |
N=7090 n (%) |
Event Rate (per 100 Pt-yrs) |
Hazard Ratio (95% CI) |
Primary Composite Endpoint* |
269 (3.8) |
2.1 |
306 (4.3) |
2.4 |
0.88 (0.74, 1.03) |
Stroke |
253 (3.6) |
2.0 |
281 (4.0) |
2.2 |
|
Hemorrhagic Stroke† |
33 (0.5) |
0.3 |
57 (0.8) |
0.4 |
|
Ischemic Stroke |
206 (2.9) |
1.6 |
208 (2.9) |
1.6 |
|
Unknown Stroke Type |
19 (0.3) |
0.2 |
18 (0.3) |
0.1 |
|
Non-CNS Systemic Embolism |
20 (0.3) |
0.2 |
27 (0.4) |
0.2 |
|
*The primary endpoint was the time to first occurrence of
stroke (any type) or non-CNS systemic embolism. Data are shown for all
randomized patients followed to site notification that the study would end.
† Defined as primary hemorrhagic strokes confirmed by adjudication in all
randomized patients followed up to site notification |
Figure 5 is a plot of the time
from randomization to the occurrence of the first primary endpoint event in the
two treatment arms.
Figure 5: Time to First
Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group
(Intent-to-Treat Population)
Figure 6 shows the risk of
stroke or non-CNS systemic embolism across major subgroups.
Figure 6: Risk of Stroke or
Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF*
(Intent-to-Treat Population)
* Data are shown for all
randomized patients followed to site notification that the study would end.
Note: The figure above presents effects in various subgroups all of which are
baseline characteristics and all of which were pre-specified (diabetic status
was not pre-specified in the subgroup, but was a criterion for the CHADS2
score). The 95% confidence limits that are shown do not take into account how
many comparisons were made, nor do they reflect the effect of a particular
factor after adjustment for all other factors. Apparent homogeneity or
heterogeneity among groups should not be over-interpreted.
The efficacy of XARELTO was
generally consistent across major subgroups.
The protocol for ROCKET AF did
not stipulate anticoagulation after study drug discontinuation, but warfarin
patients who completed the study were generally maintained on warfarin. XARELTO
patients were generally switched to warfarin without a period of
coadministration of warfarin and XARELTO, so that they were not adequately
anticoagulated after stopping XARELTO until attaining a therapeutic INR. During
the 28 days following the end of the study, there were 22 strokes in the 4637
patients taking XARELTO vs. 6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF
underwent electrical cardioversion for atrial fibrillation. The utility of
XARELTO for preventing post-cardioversion stroke and systemic embolism is
unknown.
Treatment Of Deep Vein Thrombosis (DVT) And/Or Pulmonary
Embolism (PE)
EINSTEIN Deep Vein Thrombosis And EINSTEIN Pulmonary
Embolism Studies
XARELTO for the treatment of DVT and/or PE was studied in
EINSTEIN DVT [NCT00440193] and EINSTEIN PE [NCT00439777], multi-national,
open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15
mg twice daily with food for the first three weeks, followed by XARELTO 20 mg
once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days
with VKA and then continued with VKA only after the target INR (2.0-3.0) was
reached. Patients who required thrombectomy, insertion of a caval filter, or
use of a fibrinolytic agent and patients with creatinine clearance <30
mL/min, significant liver disease, or active bleeding were excluded from the
studies. The intended treatment duration was 3, 6, or 12 months based on
investigator's assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in
EINSTEIN PE) patients were randomized and followed on study treatment for a
mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group.
The mean age was approximately 57 years. The population was 55% male, 70%
Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated
patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received
initial parenteral anticoagulant treatment for a median duration of 2 days.
Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies
received initial parenteral anticoagulant treatment for a median duration of 8
days. Aspirin was taken as on treatment concomitant antithrombotic medication
by approximately 12% of patients in both treatment groups. Patients randomized
to VKA had an unadjusted mean percentage of time in the INR target range of 2.0
to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the
lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of
patients had an idiopathic DVT/PE at baseline. Other risk factors included
previous episode of DVT/PE (19%), recent surgery or trauma (18%),
immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic
conditions (6%), or active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was
demonstrated to be non-inferior to enoxaparin/VKA for the primary composite
endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE
[EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12
(0.75, 1.68)]. In each study the conclusion of non-inferiority was based on the
upper limit of the 95% confidence interval for the hazard ratio being less than
2.0.
Table 11 displays the overall results for the primary
composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Table 11: Primary Composite
Endpoint Results* in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat
Population
Event |
XARELTO 20 mg† |
Enoxaparin/ VKA† |
XARELTO vs. Enoxaparin/VKA Hazard Ratio (95% CI) |
EINSTEIN DVT Study |
N=1731 n (%) |
N=1718 n (%) |
|
Primary Composite Endpoint |
36 (2.1) |
51 (3.0) |
0.68 (0.44, 1.04) |
Death (PE) |
1 (<0.1) |
0 |
|
Death (PE cannot be excluded) |
3 (0.2) |
6 (0.3) |
|
Symptomatic PE and DVT |
1 (<0.1) |
0 |
|
Symptomatic recurrent PE only |
20 (1.2) |
18 (1.0) |
|
Symptomatic recurrent DVT only |
14 (0.8) |
28 (1.6) |
|
EINSTEIN PE Study |
N=2419 n (%) |
N=2413 n (%) |
|
Primary Composite Endpoint |
50 (2.1) |
44 (1.8) |
1.12 (0.75, 1.68) |
Death (PE) |
3 (0.1) |
1 (<0.1) |
|
Death (PE cannot be excluded) |
8 (0.3) |
6 (0.2) |
|
Symptomatic PE and DVT |
0 |
2 (<0.1) |
|
Symptomatic recurrent PE only |
23 (1.0) |
20 (0.8) |
|
Symptomatic recurrent DVT only |
18 (0.7) |
17 (0.7) |
|
* For the primary efficacy analysis, all confirmed events
were considered from randomization up to the end of intended treatment duration
(3, 6 or 12 months) irrespective of the actual treatment duration. If the same
patient had several events, the patient may have been counted for several
components.
† Treatment schedule in EINSTEIN DVT and EINSTEIN PE
studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily;
enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated
doses to achieve a target INR of 2.5 (range: 2.0-3.0)] |
Figures 7 and 8 are plots of
the time from randomization to the occurrence of the first primary efficacy
endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE
studies, respectively.
Figure 7: Time to First
Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by
Treatment Group (Intent-to-Treat Population) – EINSTEIN DVT Study
Figure 8: Time to First
Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by
Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study
Reduction In The Risk Of Recurrence
Of DVT And/Or PE
EINSTEIN CHOICE Study
XARELTO for reduction in the
risk of recurrence of DVT and of PE was evaluated in the EINSTEIN CHOICE study
[NCT02064439], a multi-national, double-blind, superiority study comparing
XARELTO (10 or 20 mg once daily with food) to 100 mg acetylsalicylic acid
(aspirin) once daily in patients who had completed 6 to 12 months of
anticoagulant treatment for DVT and/or PE following the acute event. The
intended treatment duration in the study was up to 12 months. Patients with an
indication for continued therapeutic-dose anticoagulation were excluded.
Because the benefit-risk
assessment favored the 10 mg dose versus aspirin compared to the 20 mg dose
versus aspirin, only the data concerning the 10 mg dose is discussed below.
A total of 2275 patients were
randomized and followed on study treatment for a mean of 290 days for the
XARELTO and aspirin treatment groups. The mean age was approximately 59 years.
The population was 56% male, 70% Caucasian, 14% Asian and 3% Black. In the
EINSTEIN CHOICE study, 51% of patients had DVT only, 33% had PE only, and 16%
had PE and DVT combined. Other risk factors included idiopathic VTE (43%),
previous episode of DVT/PE (17%), recent surgery or trauma (12%), prolonged
immobilization (10%), use of estrogen containing drugs (5%), known
thrombophilic conditions (6%), Factor V Leiden gene mutation (4%), or active
cancer (3%).
In the EINSTEIN CHOICE study,
XARELTO 10 mg was demonstrated to be superior to aspirin 100 mg for the primary
composite endpoint of time to first occurrence of recurrent DVT or nonfatal or
fatal PE.
Table 12 displays the overall results for the primary
composite endpoint and its components.
Table 12: Primary Composite
Endpoint and its Components Results* in EINSTEIN CHOICE Study – Full
Analysis Set
Event |
XARELTO 10 mg
N=1,127 n (%) |
Acetylsalicylic Acid (Aspirin) 100 mg
N=1,131 n (%) |
XARELTO 10 mg vs. Aspirin 100 mg Hazard Ratio (95% CI) |
Primary Composite Endpoint |
13 (1.2) |
50 (4.4) |
0.26 (0.14, 0.47) p<0.0001 |
Symptomatic recurrent DVT |
8 (0.7) |
29 (2.6) |
|
Symptomatic recurrent PE |
5 (0.4) |
19 (1.7) |
|
Death (PE) |
0 |
1 (<0.1) |
|
Death (PE cannot be excluded) |
0 |
1 (<0.1) |
|
* For the primary efficacy
analysis, all confirmed events were considered from randomization up to the end
of intended treatment duration (12 months) irrespective of the actual treatment
duration. The individual component of the primary endpoint represents the first
occurrence of the event. |
Figure 9 is a plot of the time
from randomization to the occurrence of the first primary efficacy endpoint
event in the two treatment groups.
Figure 9: Time to First
Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by
Treatment Group (Full Analysis Set) – EINSTEIN CHOICE Study
Prophylaxis Of Deep Vein
Thrombosis Following Hip Or Knee Replacement Surgery
XARELTO was studied in 9011
patients (4487 XARELTO-treated, 4524 enoxaparin-treated patients) in the
REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE,
Controlled, Double-blind, Randomized Study of BAY 59-7939 in the Extended
Prevention of VTE in Patients Undergoing Elective Total Hip or Knee Replacement
(RECORD 1, 2, and 3) [NCT00329628, NCT00332020, NCT00361894] studies.
The two randomized,
double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective
total hip replacement surgery compared XARELTO 10 mg once daily starting at
least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound
closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In
RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received
study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to
93) years with 49% of patients ≥65 years and 55% of patients were female.
More than 82% of patients were White, 7% were Asian, and less than 2% were
Black. The studies excluded patients undergoing staged bilateral total hip
replacement, patients with severe renal impairment defined as an estimated
creatinine clearance <30 mL/min, or patients with significant liver disease
(hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to
active XARELTO and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively.
In RECORD 2, the mean exposure duration to active XARELTO and enoxaparin was
33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was
continued in the enoxaparin group for the remainder of the double-blind study
duration. The efficacy data for RECORD 1 and 2 are provided in Table 13.
Table 13: Summary of Key
Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery
-Modified Intent-to-Treat Population
Treatment Dosage and Duration |
RECORD 1 |
RECORD 2 |
XARELTO 10 mg once daily |
Enoxaparin 40 mg once daily |
RRR*, p-value |
XARELTO 10 mg once daily |
Enoxaparin† 40 mg once daily |
RRR*, p-value |
Number of Patients |
N=1513 |
N=1473 |
|
N=834 |
N=835 |
|
Total VTE |
17 (1.1%) |
57 (3.9%) |
71% (95% CI: 50, 83), p<0.001 |
17 (2.0%) |
70 (8.4%) |
76% (95% CI: 59, 86), p<0.001 |
Components of Total VTE |
Proximal DVT |
1 (0.1%) |
31 (2.1%) |
|
5 (0.6%) |
40 (4.8%) |
|
Distal DVT |
12 (0.8%) |
26 (1.8%) |
|
11 (1.3%) |
43 (5.2%) |
|
Non-fatal PE |
3 (0.2%) |
1 (0.1%) |
|
1 (0.1%) |
4 (0.5%) |
|
Death (any cause) |
4 (0.3%) |
4 (0.3%) |
|
2 (0.2%) |
4 (0.5%) |
|
Number of Patients |
N=1600 |
N=1587 |
|
N=928 |
N=929 |
|
Major VTE‡ |
3 (0.2%) |
33 (2.1%) |
91% (95% CI: 71, 97), p<0.001 |
6 (0.7%) |
45 (4.8%) |
87% (95% CI: 69, 94), p<0.001 |
Number of Patients |
N=2103 |
N=2119 |
|
N=1178 |
N=1179 |
|
Symptomatic VTE |
5 (0.2%) |
11 (0.5%) |
|
3 (0.3%) |
15 (1.3%) |
|
* Relative Risk Reduction; CI =
confidence interval
† Includes the placebo-controlled period of RECORD 2
‡ Proximal DVT, nonfatal PE or VTE-related death |
One randomized, double-blind,
clinical study (RECORD 3) in patients undergoing elective total knee
replacement surgery compared XARELTO 10 mg once daily started at least 6 to 8
hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus
enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12
hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0
(range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight
percent (68%) of patients were female. Eighty-one percent (81%) of patients
were White, less than 7% were Asian, and less than 2% were Black. The study
excluded patients with severe renal impairment defined as an estimated
creatinine clearance <30 mL/min or patients with significant liver disease
(hepatitis or cirrhosis). The mean exposure duration (± SD) to active XARELTO
and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy
data are provided in Table 14.
Table 14: Summary of Key
Efficacy Analysis Results for Patients Undergoing Total Knee Replacement
Surgery -Modified Intent-to-Treat Population
Treatment Dosage and Duration |
RECORD 3 |
XARELTO 10 mg once daily |
Enoxaparin 40 mg once daily |
RRR*, p-value |
Number of Patients |
N=813 |
N=871 |
|
Total VTE |
79 (9.7%) |
164 (18.8%) |
48% (95% CI: 34, 60), p<0.001 |
Components of events contributing to Total VTE |
Proximal DVT |
9 (1.1%) |
19 (2.2%) |
|
Distal DVT |
74 (9.1%) |
154 (17.7%) |
|
Non-fatal PE |
0 |
4 (0.5%) |
|
Death (any cause) |
0 |
2 (0.2%) |
|
Number of Patients |
N=895 |
N=917 |
|
Major VTEt |
9 (1.0%) |
23 (2.5%) |
60% (95% CI: 14, 81), p = 0.024 |
Number of Patients |
N=1206 |
N=1226 |
|
Symptomatic VTE |
8 (0.7%) |
24 (2.0%) |
|
* Relative Risk Reduction; CI =
confidence interval
† Proximal DVT, nonfatal PE or VTE-related death |
Reduction Of Risk Of Major
Cardiovascular Events In Patients With Chronic CAD Or PAD
The evidence for the efficacy
and safety of XARELTO for the reduction in the risk of stroke, myocardial
infarction, or cardiovascular death in patients with coronary artery disease
(CAD) or peripheral artery disease (PAD) was derived from the double-blind
Cardiovascular OutcoMes for People using Anticoagulation StrategieS trial
(COMPASS) [NCT10776424]. A total of 27,395 patients were evenly randomized to
rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily,
rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone.
Because the 5 mg dose alone was not superior to aspirin alone, only the data
concerning the 2.5 mg dose plus aspirin are discussed below.
Patients with established CAD
or PAD were eligible. Patients with CAD who were younger than 65 years of age
were also required to have documentation of atherosclerosis involving at least
two vascular beds or to have at least two additional cardiovascular risk
factors (current smoking, diabetes mellitus, an estimated glomerular filtration
rate [eGFR] <60 mL per minute, heart failure, or non-lacunar ischemic stroke
≥1 month earlier). Patients with PAD were either symptomatic with ankle
brachial index <0.90 or had asymptomatic carotid artery stenosis ≥50%,
a previous carotid revascularization procedure, or established ischemic disease
of one or both lower extremities. Patients were excluded for use of dual
antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies,
ischemic, non-lacunar stroke within 1 month, hemorrhagic or lacunar stroke at
any time, or eGFR <15 mL/min. [see WARNINGS AND PRECAUTIONS].
The mean age was 68 years and 21% of the subject
population were ≥75 years. Of the included patients, 91% had CAD, 27% had
PAD, and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior MI,
60% had prior percutaneous transluminal coronary angioplasty
(PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had
history of coronary artery bypass grafting (CABG) prior to study. Of the
patients with PAD, 49% had intermittent claudication, 27% had peripheral artery
bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had
asymptomatic carotid artery stenosis > 50%, and 4% had limb or foot
amputation for arterial vascular disease.
The mean duration of follow-up was 23 months. Relative to
aspirin alone, XARELTO plus aspirin reduced the rate of the primary composite
outcome of stroke, myocardial infarction or cardiovascular death. The benefit
was observed early with a constant treatment effect over the entire treatment
period (see Table 15 and Figure 11).
A benefit-risk analysis of the data from COMPASS was
performed by comparing the number of CV events (CV deaths, myocardial
infarctions and non-hemorrhagic strokes) prevented to the number of fatal or
life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds
into a critical organ) in the XARELTO plus aspirin group versus the aspirin
group. Compared to aspirin alone, during 10,000 patient-years of treatment,
XARELTO plus aspirin would be expected to result in 70 fewer CV events and 12
additional life-threatening bleeds, indicating a favorable balance of benefits
and risks.
The results in patients with PAD, CAD, and both CAD and
PAD were consistent with the overall efficacy and safety results (see Figure
10).
Figure 10 shows the risk of primary efficacy outcome
across major subgroups.
Figure 10: Risk of Primary Efficacy Outcome by
Baseline Characteristics in COMPASS (Intent-to-Treat Population)
Table 15: Efficacy results from COMPASS study
Study Population |
Patients with CAD or PAD* |
Event |
Xarelto plus aspirin†
N=9152 |
Aspirin alone†
N=9126 |
Hazard Ratio (95% CI) ‡ |
n (%) |
Event Rate (%/year) |
n (%) |
Event Rate (%/year) |
Stroke, MI or CV death |
379 (4.1) |
2.2 |
496 (5.4) |
2.9 |
0.76 (0.66, 0.86) |
- Stroke |
83 (0.9) |
0.5 |
142 (1.6) |
0.8 |
0.58 (0.44, 0.76) |
- MI |
178 (1.9) |
1.0 |
205 (2.2) |
1.2 |
0.86 (0.70, 1.05) |
- CV death |
160 (1.7) |
0.9 |
203 (2.2) |
1.2 |
0.78 (0.64, 0.96) |
Coronary heart disease death, MI, ischemic stroke, acute limb ischemia |
329 (3.6) |
1.9 |
450 (4.9) |
2.6 |
0.72 (0.63, 0.83) |
- Coronary heart disease death§ |
86 (0.9) |
0.5 |
117 (1.3) |
0. 7 |
0.73 (0.55, 0.96) |
- Ischemic stroke |
64 (0.7) |
0.4 |
125 (1.4) |
0.7 |
0.51 (0.38, 0.69) |
- Acute limb ischemia# |
22 (0.2) |
0.1 |
40 (0.4) |
0.2 |
0.55 (0.32, 0.92) |
CV death¶, MI, ischemic stroke, acute limb ischemia |
389 (4.3) |
2.2 |
516 (5.7) |
3.00 |
0.74 (0.65, 0.85) |
All-cause mortality |
313 (3.4) |
1. 8 |
378 (4.1) |
2.2 |
0.82 (0.71, 0.96) |
Lower extremity amputations for CV reasons |
15 (0.2) |
<0.1 |
31 (0.3) |
0.2 |
0.48 (0.26, 0.89) |
Patients with PAD |
Acute limb ischemia |
19 (0.8) |
0.4 |
34 (1.4) |
0.8 |
0.56 (0.32, 0.99) |
* intention to treat analysis set, primary analyses.
† Treatment schedule: XARELTO 2.5 mg twice daily plus aspirin 100 mg once
daily, or aspirin 100 mg once daily.
‡ vs. aspirin 100 mg
§ Coronary heart disease death: death due to acute MI, sudden cardiac death, or
CV procedure.
¶ CV death includes CHD death, or death due to other CV causes or unknown
death.
# Acute limb ischemia is defined as limb-threatening ischemia leading to an
acute vascular intervention (i.e., pharmacologic, peripheral arterial
surgery/reconstruction, peripheral angioplasty/stent, or amputation).
CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI:
myocardial infarction |
Figure 11: Time to first occurrence of primary
efficacy outcome (stroke, myocardial infarction, cardiovascular death) in
COMPASS