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Use of XARELTO in the Elderly

Last Updated: 11/05/2024

Summary

  • In clinical trials, the efficacy of XARELTOin the elderly (≥65 years of age) was similar to that seen in patients <65 years. Both thrombotic and bleeding event rates were higher in these older patients. Elderly subjects exhibited higher XARELTO plasma concentrations than younger subjects, with mean area under the curve (AUC) being ~50% higher. The terminal elimination half-life is 11-13 hours in the elderly.1
  • In the ROCKET AF study, the absolute rate of stroke and systemic embolism and absolute rate of major bleeding were higher in elderly patients ≥75 years compared with those <75 years; however, the overall relative effects of XARELTO vs warfarin for both efficacy and major bleeding were consistent, regardless of age.2
    • In an exploratory analysis with no adjustment for multiplicity, treatment with XARELTO vs warfarin resulted in 60.7 (95% confidence interval [CI], -30.0 to 151.5) fewer cases of the composite “net clinical benefit” in the 65 to 75 years old subgroup, and 150.1 (95% CI, -45.2 to 255.1) fewer cases in the >75 years old subgroup. The composite “net clinical benefit” endpoint was defined as the combination of fatal and irreversibly harmful ischemic and hemorrhagic events (vascular death, stroke, MI, fatal bleeding, critical organ bleeding, and nonCNS systemic embolism).3,4
  • In the J-ROCKET AF study, major and clinically relevant nonmajor (CRNM) bleeding was significantly higher in elderly patients ≥75 years old receiving XARELTO compared with those receiving warfarin. The rate of stroke and systemic embolism in elderly patients was comparable with those <75 years, and the overall efficacy of XARELTO vs warfarin was consistent irrespective of age.5
  • In the EINSTEIN program, age did not have a clinically relevant effect on efficacy or major bleeding and CRNM bleeding when XARELTO was used for the treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE).6-8
    • In an exploratory analysis with no adjustment for multiplicity, a composite NCB endpoint, which combines the primary efficacy endpoint and major bleeding, was evaluated to assess benefit-risk. Per 10,000 patient-years (PY), treatment with XARELTO vs enoxaparin plus vitamin K antagonist (VKA) would result in 3 (95% CI, -90 to 96) more cases of this composite in the <65 years old subgroup, 105 (95% CI, 77 to -287) fewer cases in the 65 to 75 years old subgroup, and 544 (95% CI, -273 to -815) fewer cases in the >75 years old subgroup.3,4
  • A subgroup analysis of the RECORD 1-4 studies9-12 found that XARELTO had consistent effects on symptomatic venous thromboembolism (VTE) plus all-cause mortality (ACM) and major plus CRNM bleeding in patients undergoing total hip or knee arthroplasty, regardless of age.13,14
  • In the COMPASS study, the effects of XARELTO plus aspirin vs aspirin alone on the primary efficacy outcome of cardiovascular (CV) death, stroke, or myocardial infarction (MI) and primary safety outcome of major bleeding were consistent, regardless of age.15
  • In the VOYAGER PAD study, the efficacy and safety of XARELTO plus aspirin vs aspirin alone were consistent, regardless of age (in patients <75 years vs those ≥75 years).16
    • A prespecified subgroup analysis of the VOYAGER PAD study found that absolute 3year Kaplan-Meier (KM) cumulative incidence rates for the primary efficacy and safety outcomes were higher in patients ≥75 years vs those <75 years. Efficacy and safety of XARELTO were consistent regardless of age. In patients ≥75 years of age, overall, benefits associated with low-dose XARELTO plus aspirin exceeded risks.17
  • In ATLAS ACS TIMI-51, the efficacy of XARELTO, as compared with placebo, was not significantly different in patients <65 years vs those >65 years.18
  • In MAGELLAN, the efficacy and safety of XARELTO, as compared with enoxaparin/ placebo, was not significantly different in patients across age groups.19 In the MAGELLAN study, approximately 67% were 65 years and over and about 37% were >75 years.1
    • In the MAGELLAN subpopulation, a benefit-risk analysis of MAGELLAN, patients at the highest risk of major bleeding were excluded based on five risk factors that were identified in the MAGELLAN trial. In this subpopulation (~80% of the total MAGELLAN population), results were also consistent when stratified by age.20
  • In MARINER, the efficacy of XARELTO, as compared with placebo, was not significantly different in patients <65 years vs those ≥65 years. Patients ≥65 years experienced increased rates of bleeding compared to younger patients. Efficacy and safety were not significantly different between treatment groups with patients <75 years vs those ≥75 years.21
    • A prespecified subgroup analysis of the MARINER study found that symptomatic VTE and VTE-related death rates in acutely ill medical patients were 2-fold higher in patients ≥75 years of age vs patients <75 years of age. The incidence of International Society on Thrombosis and Hemostasis (ISTH) major bleeding was low and similar between the 2 age and treatment groups. The benefit-risk profile of XARELTO in patients ≥75 years of age was found to be similar to that observed in the general population.22
  • Several pharmacokinetic (PK) and pharmacodynamic (PD) studies demonstrated that XARELTO was well tolerated and produced a predictable PK and PD response in healthy elderly patients.23-26

CLINICAL STUDIES

Stroke Prevention in NVAF

ROCKET AF

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

  • The median age was 73 years, and a quarter of the patients were 78 years or older. Patients ranged in age from 25-97 years.28

Halperin et al (2014)2 conducted a prespecified analysis of the ROCKET AF study to determine the efficacy and safety of XARELTO compared with warfarin among elderly patients (≥75 years).

  • A total of 44% (N=6229/14,264) were ≥75 years. The mean INR in the warfarin group was within target range for 56.9% of elderly patients compared to 53.9% in younger patients. The absolute rate of stroke and systemic embolism was higher in elderly patients compared with those patients <75 years.
  • Overall relative efficacy of XARELTO vs warfarin was consistent among elderly patients ≥75 years compared to those <75 years (see Table: Primary and Secondary Efficacy Endpoints by Age for ITT Population).

Primary and Secondary Efficacy Endpoints by Age for ITT Population2
Age, Years
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.
  • The absolute rate of major bleeding was higher in elderly patients ≥75 years compared with those patients <75 years; however, the rates of major bleeding were comparable between XARELTO and warfarin (see Table: Incidence of Major Bleeding Events by Age in Safety Population). The relative risk of major bleeding in the 2 treatment groups was comparable among older and younger patients (interaction P-value=0.336).
  • Older patients receiving XARELTO had higher rates of major and CRNM bleeding compared to the warfarin group, whereas there was no difference in rates of bleeding in younger patients. This was driven primarily by higher rates of GI bleeding, which was found to be higher in the XARELTO group compared to warfarin (2.81 events/100 PY) vs 1.66 events/100 PY; P=0.0002).

Incidence of Major Bleeding Events by Age in Safety Population2
Age, Years
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 Assessment of XARELTO from ROCKET AF3,4

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.

  • In the safety/on-treatment analysis set, treatment with XARELTO compared to warfarin was associated with 44.3 (95% CI, 8.0-80.6) fewer cases of the primary efficacy endpoint (composite of stroke and nonCNS systemic embolism) and 72.0 (95% CI, 17.8126.2) fewer cases of the composite outcome of stroke, nonCNS systemic embolism, MI, and vascular death (major secondary efficacy outcome 2) per 10,000 PY and 41.3 (95% CI, 17.8-126.2) fewer cases of the composite of fatal or critical organ bleeding (See: Rate Differences for Main Outcomes and Components for All Patients from ROCKET AF, Safety/On-Treatment).  

Rate Differences* for Main Outcomes and Components for All Patients from ROCKET AF, Safety/On-Treatment


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.

Rate Differences* for Main Outcomes and Components <65 years from ROCKET AF, Safety/On-Treatment

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.

Rate Differences* for Main Outcomes and Components 65-75 Years from ROCKET AF, Safety/On-Treatment

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.

Rate Differences* for Main Outcomes and Components >75 Years from ROCKET AF, Safety/On-Treatment

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).

  • Per 10,000 PY, treatment with XARELTO vs warfarin resulted in 60.7 (95% CI, 30.0151.5) fewer cases of the composite “net clinical benefit” in the 65 to 75 years old subgroup, and 150.1 (95% CI, -45.2 to 255.1) fewer cases in the >75 years old subgroup.

Composite of Vascular Death, Stroke, Myocardial Infarction, Fatal Bleeding, Critical Organ Bleeding, and NonCNS Systemic Embolism, XARELTO vs Warfarin, ROCKET AF; Safety/OnTreatment
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.

J-ROCKET AF

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).

  • Of those patients enrolled in the study, 39% (N=498) were ≥75 years, compared with 61% (N=780) that were <75 years. Of the patients aged ≥75 years, 40% had impaired renal function (CrCl<50 ml/min).
  • See Table: Efficacy and Safety Endpoints by Age for efficacy and bleeding event rates.

Efficacy and Safety Endpoints by Age5
Age, 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.

  • The mean INR in the warfarin group was within target range for 69.3% of elderly patients compared to 57.3% in younger patients.

Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and PE

EINSTEIN-DVT

EINSTEIN-DVT was a randomized, open-label, event-driven, noninferiority trial that compared oral XARELTO alone (15 mg twice daily [BID] for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (1.0 mg/kg BID) followed by dose-adjusted oral VKA (warfarin or acenocoumarol) in patients with confirmed symptomatic DVT without symptomatic PE.6 Age ranged from 18-97 years, with a mean age of ~56 years in both groups.30

  • The primary efficacy outcome was symptomatic, recurrent VTE (a composite of DVT or nonfatal or fatal PE). The principal safety outcome was clinically relevant bleeding, which was defined as a composite of major or CRNM bleeding.6

EINSTEIN-PE

EINSTEIN-PE used the same protocol as EINSTEIN-DVT and evaluated patients with acute symptomatic PE with or without DVT.7 Age ranged from 18-97 years in both treatment groups, with a mean age of ~58 years in both groups.31

  • The primary efficacy outcome was symptomatic recurrent VTE, defined as a composite of fatal or nonfatal PE or DVT. The principal safety outcome was clinically relevant bleeding, which was defined as a composite of major or CRNM bleeding.7
  • The effect of age on the primary efficacy endpoint and primary safety endpoint are displayed in Table: Primary Outcomes Stratified by Age in the EINSTEIN-DVT Study and EINSTEIN-PE Study.

Primary Outcomes Stratified by Age in the EINSTEIN-DVT Study and EINSTEIN-PE Study7,32
Age
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.

EINSTEIN-DVT and EINSTEIN-PE Pooled Analysis

A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies was conducted to provide a more detailed analysis of efficacy and safety of XARELTO in key clinical subgroups, including those defined as fragile patients (based on age, moderate or severe renal impairment, or low body weight). Both studies used the same protocol to ascertain outcomes.8

  • In patients >75 years, the rate of recurrent VTE was 2.3% (15/656) in the XARELTO group and 3.7% (23/627) in the standard therapy group. For this subgroup, major bleeding occurred in 1.2% (8/655) of patients treated with XARELTO, and 4.5% (28/624) of patients in the standard therapy group.

Benefit-risk assessment of XARELTO for EINSTEIN-DVT and EINSTEIN-PE Pooled Analysis3,4

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.

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 from Einstein DVT & PE (ITT analysis set)

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.

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 from Einstein DVT & PE (ITT analysis set)

Inserting image...

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.

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.

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 >75 from Einstein DVT & PE (ITT analysis set)

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.


Rates by Arm and Between-Treatment Difference for Age Subgroups for Net Clinical Benefit Composite of Primary Efficacy Endpoint and Major Bleeding, Based on KM Cumulative Incidence Rate at Day 185, from Einstein DVT & PE (ITT analysis set)
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.

EINSTEIN-Extension

EINSTEIN-Extension was a randomized, double-blind, event-driven superiority study comparing XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6-12 months with XARELTO or VKA.6 Age ranged from 18-89 years with XARELTO and from 19-96 years with placebo, with a mean age of ~58 years in both groups.33


Efficacy and Safety Outcomes Stratified by Age in the EINSTEIN-Extension Study32
Age
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)

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

The RECORD clinical trial program included 4 randomized, double-blind, double-dummy, multinational studies, that compared the efficacy and safety of oral XARELTO 10 mg once daily vs subcutaneous enoxaparin 40 mg once daily or 30 mg BID for VTE prophylaxis in patients undergoing elective total hip arthroplasty or total knee arthroplasty.9-12

  • XARELTO was started 6-8 hours after surgery. In the RECORD 1-3 studies, enoxaparin was started 12 hours before surgery and restarted 6-8 hours after wound closure. In RECORD 4, enoxaparin was started 12-24 hours after wound closure.  
  • Efficacy and safety endpoints were similar in all the RECORD trials.  The primary efficacy endpoint was a composite of any DVT (proximal and/or distal); nonfatal, symptomatic, objectively confirmed PE; and ACM. The major safety outcome was the incidence of ontreatment major bleeding, occurring after the first dose of study drug and up to 2 days after the last dose of study drug.

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.


Efficacy and Safety by Age in the Total Treatment Duration Pool13
Age, Years
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).

Coronary Artery Disease (CAD) and Peripheral Artery Disease (PAD)

COMPASS

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

  • The primary efficacy outcome was the composite of CV death, stroke, and MI and the primary safety outcome was modified ISTH major bleeding (including fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization).15
  • Results were consistent when stratified by age, though patients ≥75 years had a smaller numerical reduction in the primary efficacy outcome and a larger increase in major bleeding. Results are presented in Table: Primary Efficacy and Safety Outcomes for the Comparison of XARELTO plus Aspirin Vs Aspirin Alone, Stratified by Age.15,35

Primary Efficacy and Safety Outcomes for the Comparison of XARELTO plus Aspirin Vs Aspirin Alone, Stratified by Age15,35
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 conducted a prespecified subanalysis of patients in COMPASS that had stable CAD at baseline (N=24,824). Mean age was 68.3 years, 17,028 (69%) patients had a history of previous MI, and 15,469 (62%) patients had multivessel disease.  

  • Primary efficacy and safety outcomes were described above for the COMPASS study.14
  • Results were stratified by age and are presented in Table: Efficacy and Safety Outcomes for the Comparison of XARELTO plus Aspirin Vs Aspirin Alone in CAD Patients, Stratified by Age.
    • Similar to the overall COMPASS population, older patients with CAD treated with XARELTO plus aspirin had a smaller numerical reduction in the primary efficacy outcome and a larger increase in major bleeding. The net clinical benefit was also less favorable in older patients. The interactions were not significant in any of the primary efficacy, primary safety, or net clinical benefit analyses.

Efficacy and Safety Outcomes for the Comparison of XARELTO plus Aspirin Vs Aspirin Alone in CAD Patients, Stratified by Age36
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

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


Primary Efficacy and Safety Outcomes for the VOYAGER PAD Study, Stratified by Age38
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.
  • Krantz et al (2021)17 conducted a prespecified subgroup analysis of the VOYAGER PAD study to assess the efficacy and safety of XARELTO plus aspirin vs aspirin alone in patients <75 years of age vs ≥75 years of age.
  • Primary efficacy and safety outcomes of the VOYAGER PAD study are described above.
  • Of the 6564 patients randomized in the VOYAGER PAD study, 20% (n=1330) were elderly (≥75 years). These patients had a significantly greater prevalence of cardiovascular disease risk factors, including hypertension and chronic kidney disease, as well as a lower median estimated glomerular filtration rate.
  • In patients ≥75 years, the 3-year KM cumulative incidence rates for the primary efficacy outcome were 19.6% and 23.4% in the XARELTO-plus-aspirin and aspirin-alone groups, respectively (hazard ratio [HR], 0.82; 95% CI, 0.64-1.05; P=0.058). In patients <75 years, the 3-year KM cumulative incidence rates for the primary efficacy outcome were 16.7% and 19.0% in the XARELTO-plus-aspirin and aspirin-alone groups, respectively (HR, 0.86; 95% CI, 0.75-0.98; P=0.0265). The interaction P-value was 0.83.
  • In patients ≥75 years, the 3-year KM cumulative incidence rates for the principal safety outcome were 4.3% and 3.5% in the XARELTO-plus-aspirin and aspirin-alone groups, respectively (HR, 1.11; 95% CI, 0.55-2.26; P=0.76). In patients <75 years, the 3-year KM cumulative incidence rates for the principal safety outcome were 2.3% and 1.5% in the XARELTO-plus-aspirin and aspirin-alone groups, respectively (HR, 1.60; 95% CI, 1.01-2.55; P=0.044). The interaction P-value was 0.38.  
  • In patients ≥75 years of age, overall, benefits (absolute risk reduction: 3.8%, number needed to treat: 26 for the primary efficacy endpoint) associated with low-dose XARELTO plus aspirin exceeded risks (absolute risk increase: 0.81%, number needed to harm: 123 for TIMI major bleeding).

Acute Coronary Syndrome

ATLAS ACS TIMI-51

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

  • Of the 15,526 patients enrolled, the mean age was 61 years. Patients ranged from 2298 years.39 Approximately 35% of patients were >65 years and 9% were ≥75 years.
  • The overall study results showed that XARELTO significantly reduced the primary efficacy endpoint of CV death, MI, or stroke compared with placebo (8.9% vs 10.7%; HR, 0.84; 95% CI, 0.74-0.96; P=0.008 for modified intent-to-treat). The efficacy of XARELTO, compared with placebo, was not significantly different in patients <65 years and those >65 years.
  • In the overall study, the rate of TIMI major bleeding not related to coronary artery bypass grafting (CABG) was significantly increased with XARELTO compared with placebo (2.1% vs 0.6%; HR, 3.96; 95% CI, 2.46-6.38; P<0.001). The results for TIMI major bleeding not related to CABG for XARELTO compared to placebo was consistent across the prespecified subgroups (including age) and was similar to the overall safety results.

VTE Prophylaxis in Acutely Ill Medical Patients

MAGELLAN

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.40,41

  • Of the 8101 patients randomized in MAGELLAN, 38% were ≥75 years. The median age was 71 years.41
  • The primary efficacy outcome was the composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic nonfatal PE, and VTE-related death at days 10 and 35. The primary safety outcome was clinically relevant bleeding (major bleeding or CRNM bleeding) at days 10 and 35.41
  • Results were consistent between the two treatment arms when stratified by age. See Table: Primary Efficacy and Safety Outcomes in MAGELLAN, Stratified by Age.

Primary Efficacy and Safety Outcomes in MAGELLAN, Stratified by Age19
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)

MAGELLAN Subpopulation

Spyropoulos et al (2019)42 conducted a retrospective analysis in a subpopulation of the MAGELLAN study.

  • Five risk factors for major bleeding were identified and applied as exclusion criteria to the MAGELLAN study to identify a subpopulation (~80% of the overall population) with potentially improved benefit-risk balance. The exclusion criteria were: active cancer, dual antiplatelet therapy at baseline, any bleeding within 3 months prior or during hospitalization, active gastroduodenal ulcer within 3 months or currently symptomatic, and bronchiectasis or pulmonary cavitation.
  • Of the 6447 patients included in the MAGELLAN subpopulation, ~40% were ≥75 years. The median age was 70 years.
  • Results were consistent when stratified by age. See Table: Efficacy and Safety Outcomes in the MAGELLAN Subpopulation, Stratified by Age.

Efficacy and Safety Outcomes in the MAGELLAN Subpopulation, Stratified by Age20
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)

MARINER

The MARINER43,44 study was a phase 3, randomized, double-blind, study that evaluated the efficacy and safety of XARELTO 10 mg once daily (7.5 mg once daily if creatinine clearance [CrCl] ≥30 to <50 mL/min) vs placebo in the prevention of symptomatic VTE and VTErelated death in high-risk, medically ill patients for a period of 45 days post-hospital discharge.

  • Of the 12,019 patients in MARINER, ~36% were ≥75 years, with mean age ~70 years.43
  • The overall study showed that there was not a significant difference between XARELTO and placebo for the primary efficacy endpoint (0.83% vs 1.10%; HR, 0.76; 95% CI, 0.52-1.09). The efficacy of XARELTO, compared with placebo, was not significantly different in patients <65 years and those ≥65 years, nor between those <75 years and ≥75 years.21,43
  • The overall study showed that there was not a significant difference between XARELTO and placebo for the primary safety endpoint (0.28% vs 0.15%; HR, 1.88; 95% CI, 0.844.23). The safety of XARELTO, compared with placebo, was not significantly different in patients <75 years and ≥75 years. However, in another analysis, patients ≥65 years experienced increased rates of major bleeding compared to patients <65 years.21,43

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.

  • A total of 4294 patients were ≥75 years of age and 7725 patients were <75 years of age. Amongst those ≥75 years of age, there were fewer males (43.5% vs 57.2%, respectively), mean body weight was lower (75.4 kg vs 83.7 kg, respectively), and the percentages of patients with D-dimer >2 times the upper limit of normal (76.7% vs 66.9%, respectively) and with moderate renal insufficiency (38.4% vs 7.1%, respectively) were higher compared to those <75 years of age.
  • The incidence of the primary efficacy outcome (composite of symptomatic VTE and VTErelated death) in patients ≥75 years of age was 2-fold higher than that observed in patients <75 years.
  • The incidence of the primary efficacy outcome in both age groups was numerically lower with XARELTO vs placebo (≥75 years: 1.2% vs 1.6%, respectively; HR, 0.73; 95% CI, 0.43-1.22; <75 years: 0.6% vs 0.8%, respectively; HR, 0.78; 95% CI, 0.46-1.32; interaction P-value for age group=0.85).
  • The incidence of ISTH major bleeding, the primary safety outcome, was low and similar among the 2 age and treatment groups (≥75 years of age: 0.3% vs 0.1% with XARELTO vs placebo, respectively; HR, 3.45; 95% CI, 0.72-16.61; <75 years of age: 0.3% vs 0.2% with XARELTO vs placebo, respectively; HR, 1.44; 95% CI, 0.55-3.77; interaction P-value for age group=0.35).
  • A benefit-risk analysis of patients treated with XARELTO or placebo, who were ≥75 years of age in the overall population and in the 10-mg stratum, found that the benefit-risk profile of XARELTO in patients ≥75 years of age is similar to that observed in the general population.

PK DATA

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

  • In all study groups, the maximum plasma concentration (Cmax) was similar, and the time to Cmax (tmax) and XARELTO half-life (t1/2) were not significantly affected by age or gender. AUC values were significantly higher in elderly subjects compared with young subjects (P=0.0013). In the elderly groups, the maximum effect (Emax) and area under the effect-time curve from the first to the last reading (AUC0-tn) were increased (both with P<0.05) compared to the younger subjects. Age alone did not have a clinically relevant influence on the PK and PD of XARELTO after a single 10 mg dose.26
  • A predictable PK and PD response was observed in elderly subjects who received doses of XARELTO up to 40 mg. XARELTO was rapidly absorbed, with a median tmax of 4 hours in all dose groups.24
  • Age did not have a significant effect on the Cmax of XARELTO. AUC was higher in elderly subjects, possibly due to decreased renal function and, thus, reduced clearance of XARELTO.  Elderly subjects had a significant increase in area under the effect-time curve (AUEC) for both prothrombin time (PT) prolongation and inhibition of factor Xa activity. Maximum effects on PT and factor Xa activity occurred 2-4 hours after administration of XARELTO and were not affected by age.  XARELTO was well tolerated in all groups regardless of patient age.25

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 4 April 2024.

 

References

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27 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.  
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29 Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs warfarin in Japanese patients with atrial fibrillation - the J-ROCKET AF Study. Circ J. 2012;76(9):2104-2111.  
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31 Data on File. EINSTEIN PE Clinical Study Report. Johnson & Johnson Pharmaceutical Research and Development, LLC; 2012.  
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37 Capell W, Bonaca M, Nehler M, et al. Rationale and design for the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD). American Heart Journal. 2018;199:83-91.  
38 Bonaca MP, Bauersachs RM, SAnand S, et al. Supplement to: Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med. 2020;382(21):1994-2004.  
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40 Cohen A, Spiro T, Buller H, et al. Supplement to: Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368(6):513-523.  
41 Cohen A, Spiro T, Buller H, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013;368:513-523.  
42 Spyropoulos AC, Lipardi C, Xu J, et al. Improved Benefit Risk Profile of Rivaroxaban in a Subpopulation of the MAGELLAN Study. Clin Appl ThrombHemost. 2019;25:1076029619886022.  
43 Spyropoulos A, Ageno W, Albers G, et al. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med. 2018;379:1118-1127.  
44 Raskob G, Spyropoulos A, Zrubek J, et al. The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Thromb Haemost. 2016;115(6):1240-1248.