(rivaroxaban)
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Last Updated: 11/05/2024
The ROCKET AF trial was a randomized, double-blind, double-dummy, active-controlled, event-driven, noninferiority study to evaluate the efficacy and safety of oral fixed-dose XARELTO 20 mg once daily (15 mg for patients with CrCl 30-49 ml/min) and dose-adjusted warfarin (target international normalized ratio [INR]: 2.0-3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke.27
XARELTO Event/100 PYa | Warfarin Event/100 PYa | Hazard Ratio (95% CI) | Interaction P-value | |
---|---|---|---|---|
Stroke or systemic embolism (primary efficacy endpoint) | ||||
<75 | 2.0 | 2.10 | 0.95 (0.76-1.19) | 0.313 |
≥75 | 2.29 | 2.85 | 0.80 (0.63-1.02) | |
Stroke, systemic embolism, vascular death | ||||
<75 | 3.94 | 4.12 | 0.95 (0.81-1.12) | 0.7441 |
≥75 | 5.27 | 5.74 | 0.92 (0.78-1.09) | |
Stroke, systemic embolism, MI, vascular death | ||||
<75 | 4.61 | 4.89 | 0.94 (0.91–1.09) | 0.7493 |
≥75 | 6.07 | 6.68 | 0.91 (0.78–1.06) | |
Abbreviations: CI, confidence interval; ITT, intention-to-treat; MI, myocardial infarction; PY, patient-years.aEvent rate/100 PY=number of events per 100 PY of follow-up. |
XARELTO Event/100 PYa | Warfarin Event/100 PYa | Hazard Ratio (95% CI) | Interaction Pvalue | |
---|---|---|---|---|
Major Bleeding | ||||
<75 | 2.69 | 2.79 | 0.96 (0.78,1.19) | 0.336 |
≥75 | 4.86 | 4.40 | 1.11 (0.92-1.34) | |
Major or Clinically Relevant Nonmajor Bleeding (Primary Safety Endpoint)b | ||||
<75 | 11.58 | 12.43 | 0.93 (0.84–1.04) | 0.0090 |
≥75 | 19.83 | 17.55 | 1.13 (1.02–1.25) | |
Note: All analyses are based on time to first event. Events occurred while on treatment (up to last dose plus 2 days). Abbreviations: CI, confidence interval; PY, patient-years. aEvent rate/100 PY=number of events per 100 PY of follow-up. bIncreased rates of bleeding driven primarily by gastrointestinal bleeding, which was more frequent among elderly patients in the XARELTO group than in the warfarin group (2.81% vs 1.66%; P=0.0002). |
Benefit-risk assessments were conducted to compare XARELTO to warfarin in the ROCKET AF safety/on-treatment population.
In this assessment, the benefits and risks were assessed as rate differences with 95% CIs per 10,000 PY (due to a relatively long-term study and variable follow-up time of patients), defined as the difference in incidence rate between the 2 treatments scaled to a hypothetical population of 10,000 PY. These rate differences can be interpreted as the number of people per 10,000 PY who would experience the event when treated with XARELTO minus the number in the same sized population treated with warfarin. Since all events are harmful, negative rate differences favor XARELTO, positive rate differences favor warfarin. The 95% CIs shown in the forest plots were calculated to reflect statistical uncertainty only, and no hypothesis tests were conducted or any adjustments for multiplicity applied.
Abbreviations: CNS, central nervous system; MI, myocardial infarction.
*Primary efficacy endpoint: composite of stroke and nonCNS systemic embolism. Major secondary efficacy endpoint 1: composite of stroke, nonCNS systemic embolism, and vascular death. Major secondary efficacy endpoint 2: composite of stroke, nonCNS systemic embolism, MI, and vascular death. Principal safety endpoint: composite of major bleeding and clinically relevant nonmajor bleeding.
Rate Differences for Main Outcomes and Components <65 years from ROCKET AF, Safety/On-Treatment are presented below.
Abbreviations: CNS, central nervous system; MI, myocardial infarction.
*Primary efficacy endpoint: composite of stroke and nonCNS systemic embolism. Major secondary efficacy endpoint 1: composite of stroke, nonCNS systemic embolism, and vascular death. Major secondary efficacy endpoint 2: composite of stroke, nonCNS systemic embolism, MI, and vascular death. Principal safety endpoint: composite of major bleeding and clinically relevant nonmajor bleeding.
Rate Differences for Main Outcomes and Components 65-75 Years from ROCKET AF, Safety/On-Treatment are presented below.
Abbreviations: CNS, central nervous system; MI, myocardial infarction.
*Primary efficacy endpoint: composite of stroke and nonCNS systemic embolism. Major secondary efficacy endpoint 1: composite of stroke, nonCNS systemic embolism, and vascular death. Major secondary efficacy endpoint 2: composite of stroke, nonCNS systemic embolism, MI, and vascular death. Principal safety endpoint: composite of major bleeding and clinically relevant nonmajor bleeding.
Rate Differences for Main Outcomes and Components >75 Years from ROCKET AF, Safety/On-Treatment are presented below.
Abbreviations: CNS, central nervous system; MI, myocardial infarction.
*Primary efficacy endpoint: composite of stroke and nonCNS systemic embolism. Major secondary efficacy endpoint 1: composite of stroke, nonCNS systemic embolism, and vascular death. Major secondary efficacy endpoint 2: composite of stroke, nonCNS systemic embolism, MI, and vascular death. Principal safety endpoint: composite of major bleeding and clinically relevant nonmajor bleeding.
A composite “net clinical benefit” endpoint that combines the fatal and irreversibly harmful ischemic and hemorrhagic events in the analysis above (vascular death, stroke, MI, fatal bleeding, critical organ bleeding, and nonCNS systemic embolism), is presented below (See: Composite of Vascular Death, Stroke, Myocardial Infarction, Fatal Bleeding, Critical Organ Bleeding, and NonCNS Systemic Embolism, XARELTO vs Warfarin, ROCKET AF; Safety/On-Treatment).
Age Subgroup | XARELTO | Warfarin | Rate Difference (XARELTO - Warfarin) /10,000 person-year (95% CI) |
---|---|---|---|
Rate/10,000 person-year | Rate/10,000 person-year | ||
Overall | 444 | 528 | -83.8 (-141.7, -26.0) |
< 65 | 361 | 386 | -25.3 (-128.0, 77.5) |
65 – 75 | 444 | 505 | -60.7 (-151.5, 30.0) |
> 75 | 499 | 649 | -150.1 (-255.1, -45.2) |
Note: NCB is exploratory.Abbreviations: CI, confidence interval; CNS, central nervous system; NCB, net clinical benefit. |
The J-ROCKET AF trial was a prospective, randomized, double-blind, double-dummy, parallel group, active-controlled clinical trial comparing the efficacy and safety of oral XARELTO 15 mg once daily (10 mg for patients with CrCl 30-49 ml/min) and dose-adjusted warfarin (target INR: 2.0-3.0 for patients <70 years, 1.6–2.6 for patients ≥75 years) for the prevention of stroke in patients in Japan with NVAF.29
Hori et al (2014)5 conducted a prespecified analysis of the J-ROCKET AF study to determine the efficacy and safety of XARELTO vs dose-adjusted warfarin in elderly patients (≥75 years) or nonelderly patients (<75 years).
XARELTO Event/100 PYa | Warfarin Event/100 PYa | Hazard Ratio (95% CI) | Interaction P-value | |
---|---|---|---|---|
Primary Efficacy Endpoint: Composite of Stroke and NonCNS Systemic Embolism | ||||
<75 | 0.72 | 1.67 | 0.44 (0.23–1.42) | 0.82 |
≥75 | 2.18 | 4.25 | 0.51 (0.20–1.27) | |
Principal Safety Outcome: Composite of Major and Nonmajor Clinically Relevant Bleeding | ||||
<75 | 14.18 | 16.13 | 0.89 (0.64–1.23) | 0.04 |
≥75 | 25.05 | 16.95 | 1.49 (1.02–2.16) | |
Note: All analyses are based on the time to the first event. Events occurred up to site notification of primary efficacy endpoint. Abbreviations: CI, confidence interval; CNS, central nervous system; PY, patient-years. aEvent rate/100 PY=number of events per 100 PY of follow-up. |
EINSTEIN-DVT Study32 | EINSTEIN-PE Study7 | |||
---|---|---|---|---|
XARELTO | Enoxaparin/VKA | XARELTO | Enoxaparin/VKA | |
n/N (%) | n/N (%) | n/N (%) | n/N (%) | |
Efficacy | ||||
<65 years | 26/1145 (2.3) | 30/1111 (2.7) | 29/1461 (2.0) | 23/1479 (1.6) |
65-75 years | 6/371 (1.6) | 11/382 (2.9) | 10/517 (1.9) | 8/532 (1.5) |
>75 years | 4/215 (1.9) | 10/225 (4.4) | 11/441 (2.5) | 13/402 (3.2) |
Safety | ||||
<65 years | 86/1134 (7.6) | 79/1107 (7.1) | 132/1458 (9.1) | 136/1472 (9.2) |
65-75 years | 34/369 (9.2) | 39/381 (10.2) | 59/514 (11.5) | 71/532 (13.3) |
>75 years | 19/215 (8.8) | 20/223 (9.0) | 58/440 (13.2) | 67/401 (16.7) |
Abbreviations: VKA, vitamin K antagonist. |
The following benefit-risk assessments compare XARELTO to enoxaparin and VKA based on an intention-to-treat (ITT) analysis. For the EINSTEIN studies, the between-treatment differences in KM rates at day 185 were used for benefit-risk assessment due to the design of a relatively short and fixed treatment duration. These risk differences can be interpreted as the number of people per 10,000 patients who would experience the event by day 185 when treated with XARELTO minus the number in the same sized population treated with the comparator treatment. Negative rate differences favor XARELTO, positive rate differences favor warfarin. The 95% CIs shown in these plots were calculated to reflect statistical uncertainty only, and no hypothesis tests were conducted or any adjustments for multiplicity applied. The 95% CI for some endpoints were wide given the small populations in some of the age groups.
Note: Primary efficacy endpoint: composite of symptomatic recurrent DVT, nonfatal PE, and fatal PE. Secondary efficacy endpoint: composite of symptomatic recurrent DVT, nonfatal PE, fatal PE, and all-cause mortality. Principal safety endpoint: composite of major bleeding and clinically relevant nonmajor bleeding.
Abbreviations: DVT, deep vein thrombosis; ITT, intention-to-treat;
Note: Primary efficacy endpoint: composite of symptomatic recurrent DVT, nonfatal PE, and fatal PE. Secondary efficacy endpoint: composite of symptomatic recurrent DVT, nonfatal PE, fatal PE, and all-cause mortality. Principal safety endpoint: composite of major bleeding and clinically relevant nonmajor bleeding.
Treatment group comparison (XARELTO vs Enoxaparin/VKA) for First Occurrence of Efficacy and Safety Outcome Events based on KM Cumulative Incidence risk at Day 185, Age 65–75, from Einstein DVT & PE (ITT analysis set)
Note: Primary efficacy endpoint: Composite of symptomatic DVT and PE. Secondary efficacy endpoint: Composite of symptomatic DVT, PE, and all-cause mortality. Principal safety endpoint: Composite of major bleeding and clinically relevant nonmajor bleeding.
Abbreviations: DVT, deep vein thrombosis; ITT, intention-to-treat; KM, Kaplan-Meier; PE, pulmonary embolism; VKA, vitamin K antagonist.
Note: Primary efficacy endpoint: composite of symptomatic recurrent DVT, nonfatal PE, and fatal PE. Secondary efficacy endpoint: composite of symptomatic recurrent DVT, nonfatal PE, fatal PE, and all-cause mortality. Principal safety endpoint: composite of major bleeding and clinically relevant nonmajor bleeding.
Abbreviations: DVT, deep vein thrombosis; ITT, intention-to-treat; KM, Kaplan-Meier; PE, pulmonary embolism; VKA, vitamin K antagonist.
Age Subgroup (years) | XARELTO/10,000 patients | Enoxaparin-VKA/10,000 patients | Rate Difference (XARELTO - Enoxaparin/VKA)/10,000 patients (95% CI) |
---|---|---|---|
All | 308 | 411 | -103 (-185, -21) |
<65 | 290 | 286 | 3 (-90, 96) |
65-75 | 338 | 443 | -105 (-287, 77) |
>75 | 341 | 884 | -544 (-815, -273) |
Note: NCB is exploratory.Abbreviations: CI, confidence interval; NCB, net clinical benefit; VKA, vitamin K antagonist. |
XARELTO | Placebo | |
---|---|---|
n/N (%) | n/N (%) | |
Efficacy | ||
<65 years | 4/360 (1.1) | 23/374 (6.2) |
65-75 years | 3/153 (2.0) | 8/121 (6.6) |
>75 years | 1/89 (1.1) | 11/99 (11.1) |
Safety (Major and Clinically Relevant Nonmajor Bleeding) | ||
<65 years | 22/358 (6.2) | 3/373 (0.8) |
65-75 years | 7/152 (4.6) | 1/119 (0.8) |
>75 years | 7/88 (8.0) | 3/98 (3.1) |
Turpie et al (2011)13,14 conducted a pooled analysis of the 4 RECORD studies (randomized, N=12,729) to determine the influence of several factors, including age, on the composite efficacy endpoint of symptomatic VTE (symptomatic DVT and PE) plus ACM, and safety endpoints, such as major plus CRNM bleeding.
XARELTO n/N | % | Enoxaparin n/N | % | Hazard Ratio (95% CI) | Interaction P-value | |
---|---|---|---|---|---|---|
Symptomatic VTE Plus All-Cause Mortalitya | ||||||
<65 | 11/2915 | 0.4 | 29/2905 | 1.0 | 0.38 (0.19-0.76) | 0.251 |
65-75 | 12/2354 | 0.5 | 37/2381 | 1.6 | 0.32 (0.17-0.62) | |
>75 | 12/914 | 1.3 | 16/914 | 1.8 | 0.75 (0.35-1.58) | |
Major Plus Clinically Relevant Nonmajor Bleeding | ||||||
<65 | 78/2915 | 2.7 | 54/2905 | 1.9 | 1.44 (1.02-2.04) | 0.100 |
65-75 | 89/2354 | 3.8 | 66/2381 | 2.8 | 1.35 (0.98-1.86) | |
>75 | 30/914 | 3.3 | 38/914 | 4.2 | 0.78 (0.48-1.26) | |
Abbreviations: CI, confidence interval; VTE, venous thromboembolism. aEvents that occurred during the planned treatment period for the double-blind study medication for each RECORD study (up to day 42 for RECORD 1 and 2 and up to day 17 for RECORD 3 and 4). |
The COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) study was a phase 3, event-driven, double-blind, randomized, controlled study designed to determine whether treatment with XARELTO 2.5 mg BID plus aspirin 100 mg once daily or XARELTO 5 mg BID alone is more effective than aspirin 100 mg once daily alone for prevention of MI, stroke, or CV death in patients with stable CAD or PAD. A total of 27,395 patients were enrolled in the study with a mean age of 68.2 years.15 The largest proportion of patients (55.4%) was between 65 and 74 years, 23.8% of patients were younger than 65 years, and 20.8% of patients were ≥75 years.34
Age, Years | XARELTO + Aspirin, n/N (%) | Aspirin Alone, n/N (%) | Hazard Ratio (95% CI) | Interaction P-value |
---|---|---|---|---|
Composite Endpoint: CV death, stroke, or MI (primary efficacy endpoint) | ||||
<65 | 79/2150 (3.7) | 126/2184 (5.8) | 0.63 (0.48-0.84) | 0.20 |
65-74 | 179/5078 (3.5) | 238/5045 (4.7) | 0.74 (0.61-0.90) | |
≥75 | 121/1924 (6.3) | 132/1897 (7.0) | 0.89 (0.69-1.14) | |
Major Bleeding | ||||
<65 | 31/2150 (1.4) | 27/2184 (1.2) | 1.18 (0.70-1.97) | 0.16 |
65-75 | 156/5078 (3.1) | 96/5045 (1.9) | 1.63 (1.26-2.10) | |
≥75 | 101/1924 (5.2) | 47/1897 (2.5) | 2.12 (1.5-3.00) | |
Abbreviations: CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. |
Connolly et al (2018)36
Age, Years | XARELTO + Aspirin, n/N (%) | Aspirin Alone, n/N (%) | Hazard Ratio (95% CI) | Interaction P-value |
---|---|---|---|---|
Composite Endpoint: CV death, stroke, or MI (primary efficacy endpoint) | ||||
<65 | 69/1864 (3.7) | 115/1890 (6.1) | 0.61 (0.45-0.82) | 0.20 |
65-75 | 168/4707 (3.6) | 223/4661 (4.8) | 0.74 (0.61-0.91) | |
≥75 | 110/1742 (6.3) | 122/1710 (7.1) | 0.87 (0.67-1.13) | |
Major Bleeding | ||||
<65 | 25/1864 (1.3) | 23/1890 (1.2) | 1.11 (0.63-1.96) | 0.21 |
65-75 | 146/4707 (3.1) | 90/4661 (1.9) | 1.62 (1.24-2.10) | |
≥75 | 92/1742 (5.3) | 45/1710 (2.6) | 2.02 (1.41-2.88) | |
Abbreviations: CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. |
VOYAGER PAD (Vascular Outcomes Study of ASA alonG with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate XARELTO 2.5 mg BID plus aspirin 100 mg once daily versus aspirin 100 mg in patients with symptomatic PAD undergoing lower extremity revascularization (LER). A total of 6564 patients were randomized in the study with a median age of 67.0 years.16,37
Age, years | XARELTO + Aspirin, n/N (%) | Aspirin Alone, n/N (%) | Hazard Ratio (95% CI) |
---|---|---|---|
Primary Efficacy Endpoint: ALI, major amputation of vascular etiology, MI, ischemic stroke, or CV death | |||
<75 | 391/2613 (14.96) | 446/2621 (17.02) | 0.86 (0.75, 0.98) |
≥75 | 117/673 (17.38) | 138/657 (21.00) | 0.82 (0.64, 1.05) |
Major Bleeding according to TIMI classification | |||
<75 | 46/2595 (1.77) | 29/2598 (1.12) | 1.60 (1.01, 2.55) |
≥75 | 16/661 (2.42) | 15/650 (2.31) | 1.11 (0.55, 2.26) |
Abbreviations: ALI, acute limb ischemia; CI, confidence interval; CV, cardiovascular; MI, myocardial infacrtion; TIMI, thrombolysis in myocardial infarction. |
ATLAS ACS TIMI-51 was a randomized, double-blind, event-driven trial to determine whether XARELTO (2.5 mg BID or 5 mg BID), when added to standard care, was safe and reduced the risk of the composite of CV death, MI, or stroke compared with placebo in stabilized patients after an acute coronary syndrome event.18
MAGELLAN was a phase 3, randomized, double-blind trial designed to evaluate efficacy and safety of extended thromboprophylaxis with XARELTO compared with standard duration enoxaparin for the prevention of VTE in hospitalized acutely ill medical patients during the inpatient and post-discharge periods.40
Age, Years | XARELTO, n/N (%) | Enoxaparin/Placebo, n/N (%) | P-value for heterogeneity |
---|---|---|---|
Primary Efficacy Outcome at Day 35 | |||
<65 | 28/1021 (2.7) | 33/1066 (3.1) | 0.1107 |
65-74 | 43/862 (5.0) | 40/842 (4.8) | |
≥75 | 60/1084 (5.5) | 102/1149 (8.9) | |
Primary Safety Outcome at Day 35 | |||
<65 | 42/1323 (3.2) | 20/1363 (1.5) | 0.8426 |
65-75 | 47/1144 (4.1) | 18/1090 (1.7) | |
≥75 | 75/1530 (4.9) | 29/1548 (1.9) |
Spyropoulos et al (2019)42
Age, Years | XARELTO, n/N (%) | Enoxaparin/Placebo, n/N (%) |
---|---|---|
Primary Efficacy Outcome at Day 35 | ||
<65 | 16/786 (2.0) | 27/834 (3.2) |
65-74 | 31/686 (4.5) | 30/671 (4.5) |
≥75 | 43/872 (4.9) | 80/929 (8.6) |
Major Bleeding at Day 35 | ||
<65 | 5/1011 (0.5) | 5/998 (0.5) |
65-75 | 6/885 (0.7) | 4/846 (0.5) |
≥75 | 10/1197 (0.8) | 6/1229 (0.5) |
The MARINER43
Ageno et al (2021)22 conducted a prespecified subgroup analysis of the MARINER study to compare rates of the efficacy and safety outcomes for XARELTO vs placebo in patients ≥75 years of age with those in patients <75 years of age.
Several PK and PD studies showed that XARELTO was well tolerated and produced a predictable response in healthy elderly subjects. Doses studied ranged from 5-50 mg.23-26
A literature search of MEDLINE®
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