"June 22, 2012 -- The FDA has decided -- for now -- against allowing the new blood thinner Xarelto to be used to treat patients with blocked coronary arteries.
Federal officials issued a complete response letter late Thursday, which me"...
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.
Dose-dependent inhibition of FXa activity was observed in humans and the Neoplastin® prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest® are prolonged dose-dependently. Anti-factor Xa activity is also influenced by rivaroxaban.
The absolute bioavailability of rivaroxaban is dose-dependent. For the 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 2).
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.
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.
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.
Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. In a Phase 1 study, following the administration of a [14C]-rivaroxaban dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). 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.
Gender did not influence the pharmacokinetics or pharmacodynamics of XARELTO.
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.
In clinical studies, elderly subjects exhibited higher rivaroxaban plasma concentrations than younger subjects with mean AUC values being approximately 50% higher, mainly due to reduced (apparent) total body and renal clearance. Age related changes in renal function may play a role in this age effect. The terminal elimination half-life is 11 to 13 hours in the elderly [see Use In Specific Populations].
Extremes in body weight ( < 50 kg or > 120 kg) did not influence (less than 25%) rivaroxaban exposure.
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 Table 7). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.
Table 7: Percent Increase of Rivaroxaban PK and PD
Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated
Renal Impairment Study
|50 to 79
N = 8
|30 to 49
N = 8
|15 to 29
N = 8
|(% increase relative to normal)||C max||28||12||26|
|(% increase relative to normal)||Emax||9||10||12|
|(% increase relative to normal)||Emax max||4||17||20|
|PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance|
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 Table 8). 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). Increases in pharmacodynamic effects were also observed.
Table 8: Percent Increase of
Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic
Insufficiency from a Dedicated Hepatic Impairment Study
|Parameter||Hepatic Impairment Class (Child-Pugh Class)|
|Mild (Child-Pugh A)
N = 8
|Moderate (Child-Pugh B)
N = 8
|(% increase relative to normal)||C max||0||27|
|(% increase relative to normal)||Emax||0||24|
|(% increase relative to normal)||Emax||2||41|
|PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect|
In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A4 nor induces CYP1A2, 2B6, 2C19, or 3A4. 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 2 [see DRUG INTERACTIONS for dosing recommendations].
Figure 2: Effect of
Coadministered Drugs on the Pharmacokinetics of Rivaroxaban
In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in 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 2).
In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as 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 2).
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 3A4 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 CYP3A4 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.
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).
Stroke Prevention In Nonvalvular Atrial Fibrillation
The evidence for the efficacy and safety of XARELTO was derived from ROCKET AF, a multi-national, double-blind study comparing XARELTO (at a dose of 20 mg once daily with the evening meal in patients with CrCl > 50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to < 50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:
- a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or
- 2 or more of the following risk factors:
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 9 displays the overall results for the primary composite endpoint and its components.
Table 9: Primary Composite Endpoint Results in ROCKET
AF Study (Intent-to-Treat Population)
|Event||XARELTO||Warfarin||XARELTO vs. Warfarin|
|N = 7081
(per 100 Pt-yrs)
|N = 7090
(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 3 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
Figure 3: Time to First
Occurrence of Stroke (any type) or Non-CNS Systemic Embolism by Treatment Group
Figure 4 shows the risk of stroke or non-CNS systemic embolism across major subgroups.
Figure 4: Risk of Stroke or
Non-CNS Systemic Embolism by Baseline Characteristics in ROCKET AF*
* Data are shown for all randomized patients followed to site notification that the study would end. 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.
Treatment Of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), And Reduction In The Risk Of Recurrence Of DVT And Of PE
EINSTEIN Deep Vein Thrombosis and EINSTEIN Pulmonary Embolism Studies
XARELTO for the treatment of DVT and/or PE and for the reduction in the risk of recurrence of DVT and of PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing XARELTO (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by XARELTO 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0-3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance < 30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the XARELTO group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilic conditions (6%), or active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, XARELTO was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [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 10 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Table 10: Primary Composite
Endpoint Results* in EINSTEIN DVT and EINSTEIN PE Studies – Intent-to-Treat
|Event||XARELTO 20 mg†||Enoxaparin/VKA†’||XARELTO vs. Enoxaparin/VKA Hazard Ratio (95% CI)|
|EINSTEIN DVT Study||N = 1731
|N = 1718
|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
† 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 5 and 6 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 5: 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 6: Time to First
Occurrence of the Composite of Recurrent DVT or Non-fatal or Fatal PE by
Treatment Group (Intent-to-Treat Population) – EINSTEIN PE Study
EINSTEIN Extension Study
XARELTO for reduction in the risk of recurrence of DVT and of PE was studied in the EINSTEIN Extension study, a multi-national, double-blind, superiority study comparing XARELTO (20 mg once daily with food) to placebo in patients who had completed 6 to 14 months of treatment for DVT and/or PE following the acute event. The intended treatment duration was 6 or 12 months based on investigator's assessment prior to randomization.
A total of 1196 patients were randomized and followed on study treatment for a mean of 190 days for both XARELTO and placebo treatment groups. The mean age was approximately 58 years. The population was 58% male, 78% Caucasian, 8% Asian and about 2% Black. Aspirin was taken as on-treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. In the EINSTEIN Extension study about 60% of patients had a history of proximal index DVT without PE event and 29% of patients had a PE without symptomatic DVT event. About 59% of patients had an idiopathic DVT/PE. Other risk factors included previous episode of DVT/PE (16%), immobilization (14%), known thrombophilic conditions (8%), or active cancer (5%).
In the EINSTEIN Extension study XARELTO was demonstrated to be superior to placebo for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [HR (95% CI): 0.18 (0.09, 0.39)].
Table 11 : displays the overall results for the primary composite endpoint and its components.
Table 11: Primary Composite Endpoint Results* in EINSTEIN Extension Study – Intent-to-Treat Population
|Event||XARELTO 20 mg
N = 602 n (%)
N = 594 n (%)
|XARELTO vs. Placebo Hazard Ratio (95% CI)|
|Primary Composite Endpoint||8 (1.3)||42 (7.1)||0.18 (0.09, 0.39)
p-value = < 0.0001
|Death (PE)||0||1 (0.2)|
|Death (PE cannot be excluded)||1 (0.2)||0|
|Symptomatic recurrent PE||2 (0.3)||13 (2.2)|
|Symptomatic recurrent DVT||5 (0.8)||31 (5.2)|
|* For the primary efficacy analysis, all confirmed events were considered from randomization up to the end of intended treatment duration (6 or 12 months) irrespective of the actual treatment duration.|
Figure 7 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
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 Extension 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 RECORD 1, 2, and 3 studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared XARELTO 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥ 65 years and 55% of patients were fan emale. 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 activan e 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 12.
Table 12: Summary of Key
Efficacy Analysis Results for Patients Undergoing Total Hip Replacement Surgery
- Modified Intent-to-Treat Populationan
|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 =
† 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-an 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 13.
Table 13: 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 VTE†||9 (1.0%)||23 (2.5%)||60% (95% CI: 14, 81),
p = 0.024
|Number of Patients||N = 1206||N = 1226|
|Symptomatic VTE||8 (0.7%)||24 (2.0%)|
|* Relative Risk Reduction; CI =
† Proximal DVT, nonfatal PE or VTE-related death
Last reviewed on RxList: 9/25/2015
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