|
|
| (2 intermediate revisions by 2 users not shown) |
| Line 1: |
Line 1: |
| __NOTOC__
| | #REDIRECT [[Rivaroxaban#Clinical Studies]] |
| {{Rivaroxaban}}
| |
| {{CMG}}; {{AE}} {{AZ}}
| |
|
| |
|
| == Clinical Studies==
| | [[Category: Cardiovascular Drugs]] |
| | | [[Category: Drug]] |
| === 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:
| |
| **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 9 displays the overall results for the primary composite endpoint and its components.
| |
| {|
| |
| |[[image:riva12.png|600px|thumb]]
| |
| |}
| |
| Figure 1 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
| |
| {|
| |
| |[[image:riva13.png|600px|thumb]]
| |
| |}
| |
| 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), 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.
| |
| {|
| |
| |[[image:riva14.png|600px|thumb]]
| |
| |}
| |
| Figures 2 and 3 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.
| |
| {|
| |
| |[[image:riva15.png|600px|thumb]]
| |
| |}
| |
| {|
| |
| |[[image:riva16.png|600px|thumb]]
| |
| |}
| |
| ====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.
| |
| {|
| |
| |[[image:riva17.png|600px|thumb]]
| |
| |}
| |
| Figure 4 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
| |
| {|
| |
| |[[image:riva18.png|600px|thumb]]
| |
| |}
| |
| === 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 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 12.
| |
| {|
| |
| |[[image:riva19.png|600px|thumb]]
| |
| |}
| |
| 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 13.
| |
| {|
| |
| |[[image:riva20.png|600px|thumb]]
| |
| |}
| |
| | |
| <ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = XARELTO (RIVAROXABAN) TABLET, FILM COATED [JANSSEN PHARMACEUTICALS, INC.] |url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=10db92f9-2300-4a80-836b-673e1ae91610 | publisher = | date = | accessdate = }}</ref>
| |
| | |
| ==References==
| |
| {{Reflist}}
| |
| | |
| {{FDA}}
| |
| | |
| [[Category:Drugs]] | |