14.1Stroke 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.
| XARELTO | Warfarin | XARELTO vs. Warfarin | |||
|---|---|---|---|---|---|
| Event | 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 | |
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) |
|
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.
14.2Treatment 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.
| 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) | |
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
14.3Reduction 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 non-fatal or fatal PE.
Table 12 displays the overall results for the primary composite endpoint and its components.
| 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) | |
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
14.4Prophylaxis 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.
| RECORD 1 | RECORD 2 | |||||
|---|---|---|---|---|---|---|
| Treatment Dosage and Duration | 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%) | ||
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.
| RECORD 3 | |||
|---|---|---|---|
| Treatment Dosage and Duration | 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%) | |
14.5Reduction 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 (5.2)].
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)
| 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) | ||
| CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarction | |||||
| |||||
| 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) |
Figure 11:Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in COMPASS
CI: confidence interval
