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XARELTO® (rivaroxaban)

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Adverse Event of XARELTO - Intracranial Hemorrhage

Last Updated: 10/24/2024

Summary

  • ROCKET AF: Incidence rates of intracranial hemorrhage (ICH) were significantly lower with XARELTO than warfarin (0.8% vs 1.2% per year, respectively; P=0.02).1
    • A subanalysis evaluated the independent, significant predictors of ICH in 14,264 patients in the ROCKET AF study. The risk of ICH was notably greater among Asian patients, black patients, elderly patients, patients with a prior stroke or transient ischemic attack (TIA), patients with elevated diastolic blood pressure, and patients with lower baseline platelet counts and serum albumin. Conversely, the risk of ICH was significantly lower for individuals with a history of heart failure (HF) and who were randomized to XARELTO rather than warfarin (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.44-0.82; P=0.001).2
  • J-ROCKET AF: ICH occurred in 0.8% of patients in the XARELTO group compared to 1.6% of patients in the warfarin group.3
  • X-VERT: Intracerebral bleeding occurred in 0.2% of patients in both the XARELTO and vitamin K antagonist (VKA) groups.4
  • EINSTEIN-DVT: Fatal intracranial bleeding occurred in 0% of patients in the XARELTO group and in 0.1% of patients in the enoxaparin/VKA group.5
  • EINSTEIN-PE: Fatal intracranial bleeding occurred in <0.1% of patients in both the XARELTO and enoxaparin/VKA groups.6
  • COMPASS: There was no significant difference in nonfatal, symptomatic ICH between XARELTO plus aspirin (ASA) and ASA alone (0.2% incidence for both; P=0.77) or between XARELTO alone and ASA alone (0.4% and 0.2%, respectively; P=0.07).7,8
    • In 2 separate prespecified subgroup analyses of the COMPASS study, which evaluated patients with stable coronary artery disease (CAD) at baseline and patients with stable peripheral artery disease (PAD) at baseline, respectively, ICH safety outcomes were consistent with those observed in the overall COMPASS study.9,10
  • ATLAS ACS-TIMI 51: The incidence rates of ICH were significantly higher in the XARELTO group than in the placebo group (0.6% vs 0.2%, respectively; P=0.009).11
  • Postmarketing data: An analysis of 2-year data from an ongoing, observational, postmarketing safety surveillance study was designed to evaluate the use of XARELTO in patients with nonvalvular atrial fibrillation (NVAF). Of the 970 cases of major bleeding, ICH was the site of bleed in 8.1% of patients (N=79/970).12
  • XANTUS: Incidence rate of treatment-emergent ICH in patients treated with XARELTO was 0.4 per 100 patient-years (PY).
  • MAGELLAN: There were 2 fatal intracranial bleeding events in the extended-duration XARELTO group.13
    • In a MAGELLAN subpopulation, excluding those patients at highest risk of major bleeding, there were 2 fatal bleeding events involving intracranial bleeding in the extended-duration XARELTO group.14
  • MARINER: One patient in the XARELTO group experienced a fatal ICH during the treatment period.15
  • VOYAGER PAD: There was no difference in fatal bleeding or ICH between the XARELTO-plus-ASA group and ASA-alone group (17 vs 19; HR, 0.91; 95% CI, 0.47 to 1.76).16
  • SENTINEL DATABASE: Data from the United States Food and Drug Administration (FDA) Sentinel database evaluated the incidence of major bleeding events in groups of patients stratified by age (<65 years and ≥65 years) receiving various DOACs.17-19
  • For patients aged <65 years17
    • In a comparison of XARELTO vs apixaban, the HR was 1.63 (95% CI 0.99-2.70) for ICH.
    • In a comparison of XARELTO vs dabigatran, the HR was 1.18 (95% CI, 0.52-2.67) for ICH
  • For patients aged ≥65 years18,19
    • In a comparison of XARELTO vs apixaban in 2 different studies, the HR was 1.28 (95% CI, 0.99-1.67) and 1.23 (95% CI, 0.96-1.58) by inverse probability of treatment weighted pairwise comparison (IPTW) for ICH.
    • In a comparison of XARELTO vs dabigatran in 2 different studies, the HR was 1.67 (95% CI, 1.29-2.17) and 1.58 (95% CI, 1.23-2.03) by IPTW for ICH.
  • Additional real world studies20-24 and systematic review and meta analyses25,26 that discuss reports of ICH with XARELTO are summarized below.
  • Additional citations identified during literature search are included in the REFERENCES section for your review.27-45

CLINICAL STUDIES

Stroke Prevention in NVAF

ROCKET AF

ROCKET AF was a phase 3, double-blind, double-dummy, noninferiority study that evaluated the efficacy and safety of XARELTO 20 mg once daily with the evening meal (15 mg once daily for patients with creatinine clearance [CrCl] 30 to <50 mL/min) compared to warfarin (dose-adjusted to international normalized ratio [INR] 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with NVAF at moderate-to-high risk for stroke.1

  • In the as-treated safety population (n=14,143), ICH rates were significantly lower in the XARELTO group than in the warfarin group (0.8% vs 1.2% per year, respectively; HR, 0.67; 95% CI, 0.47-0.93; P=0.02).1 See Table: ROCKET AF: Major Bleeding by Intracranial Site.

ROCKET AF: Major Bleeding by Intracranial Site46,a
Site, n (%)
XARELTO
(N=7111)
Warfarin
(N=7125)
Intracranialb
55 (0.77)
84 (1.18)
   Intraparenchymalb
37 (0.52)
56 (0.79)
   Nontraumaticb
33 (0.46)
54 (1.76)
   Traumatic
4 (0.06)
2 (0.03)
   Intraventricular
2 (0.03)
4 (0.06)
   Subdural hematoma
12 (0.17)
22 (0.31)
   Subarachnoid
4 (0.06)
1 (0.01)
   Epidural hematoma
0
1 (0.01)
aSite based on blinded adjudication.
bP<0.05.

J-ROCKET AF

J-ROCKET AF was a double-blind comparison study designed to confirm noninferiority of XARELTO vs warfarin with regard to major or clinically relevant nonmajor bleeding associated with prevention of stroke in Japanese patients with NVAF. Patients were randomized to either XARELTO 15 mg daily (10 mg in patients with CrCl 30-49 mL/min) or warfarin (target INR 2.0-3.0 for patients aged <70 years, or 1.6-2.6 for age ≥70 years).3

  • In the safety evaluable population, ICH was observed in 5 patients (0.8%) in the XARELTO group and in 10 patients (1.6%) in the warfarin group. The results were not tested for statistical significance.

X-VERT

Cappato et al (2014)4,47 conducted a prospective, randomized, open-label, parallel-group, phase 3b study that compared efficacy and safety of XARELTO vs dose-adjusted VKA for the prevention of cardiovascular (CV) events in patients with NVAF scheduled for cardioversion. The primary safety endpoint was major bleeding.

  • Intracerebral bleeding occurred in 2 patients (0.2%) in the XARELTO group and in 1 patient (0.2%) in the VKA group. Of the 2 patients with an intracerebral bleed in the XARELTO group, 1 had fatal bleeding.4

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

The EINSTEIN program consisted of 3 phase 3, randomized studies of XARELTO. See Table: Rates of Fatal and Nonfatal ICH in the Safety Population of the EINSTEIN Studies.

  • EINSTEIN-DVT48 and EINSTEIN-PE6 - open-label, noninferiority studies 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 (EINSTEIN-DVT) and in patients with acute symptomatic PE with or without DVT (EINSTEIN-PE)
  • EINSTEIN-Extension48 - double-blind, superiority study comparing XARELTO 20 mg once daily to placebo in patients with confirmed symptomatic PE or DVT who have been treated for 6 to 12 months with XARELTO or VKA
  • EINSTEIN-DVT and EINSTEIN-PE Pooled Analysis49 - prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies, which provided more precise estimates and detailed analyses of the safety and efficacy of XARELTO in key clinical subgroups

Rates of Fatal and Nonfatal ICH in the Safety Population of the EINSTEIN Studies5,6,48,49

Fatal Intracranial Bleeding,
n (%)
Nonfatal Intracranial Bleeding, n (%)
XARELTO
Enoxaparin/VKA
XARELTO
Enoxaparin/VKA
EINSTEIN-DVTa
0
2 (0.1)
2 (0.1)
0
EINSTEIN-PEa
2 (<0.1)
2 (<0.1)
1 (<0.1)
10 (0.4)
EINSTEIN Pooled Analysis
2 (<0.1)
4 (<0.1)
3 (<0.1)
9 (0.2)
 
XARELTO
Placebo
XARELTO
Placebo
EINSTEIN-Extension
0
0
0
0
Abbreviations: DVT, deep vein thrombosis; ICH, intracranial hemorrhage; PE, pulmonary embolism; VKA, vitamin K antagonist. aResults were not tested for statistical significance.

Prevention of Recurrent CV Events in Stable Atherosclerotic Vascular Disease

  • COMPASS was a phase 3, event-driven, double-blind, randomized, multicenter study designed to evaluate 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 myocardial infarction (MI), stroke, or CV death in patients with a history of stable atherosclerotic vascular disease (CAD or PAD).
  • Key inclusion criteria: PAD; CAD with ≥1 of the following: age ≥65 years, or age <65 years and documented atherosclerosis or revascularization involving ≥2 vascular beds or ≥2 additional risk factors: current smoker (within 1 year of randomization), diabetes mellitus, renal dysfunction with estimated glomerular filtration rate (eGFR) <60 mL/min, HF, or nonlacunar ischemic stroke ≥1 month ago.
  • Major bleeding (including fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization [including presentation to an acute care facility without an overnight stay]), the primary safety outcome, was also assessed. The study was not designed to compare the XARELTO treatment arms.7,8
    • There was no significant difference in nonfatal, symptomatic ICH between XARELTO plus aspirin and aspirin alone (0.2% incidence for both; P=0.77) or between XARELTO alone and aspirin alone (0.4% and 0.2%, respectively; P=0.07). See Table: Incidence of ICH in the COMPASS Study8

Incidence of ICH in the COMPASS Study7
Outcome
XARELTO Plus ASA (N=9152)
XARELTO Alone (N=9117)
ASA Alone (N=9126)
XARELTO Plus ASA vs ASA Alone
XARELTO Alone vs ASA Alone
n (%)
HR
(95% CI)
P Value
HR
(95% CI)
P Value
Major bleedinga
288 (3.1)
255 (2.8)
170 (1.9)
1.70
(1.40-2.05)
<0.001
1.51
(1.25-1.84)
<0.001
Nonfatal symptomatic ICHb
21 (0.2)
32 (0.4)
19 (0.2)
1.10
(0.59-2.04)
0.77
1.69
(0.96-2.98)
0.07
Fatal bleeding or symptomatic ICH
36 (0.4)
46 (0.5)
29 (0.3)
1.23
(0.76-2.01)
0.40
1.59
(1.00-2.53)
0.05
Site of major bleeding: intracranial
28 (0.3)
43 (0.5)
24 (0.3)
1.16
(0.67-2.00)
0.60
1.80
(1.09-2.96)
0.02
Abbreviations: ASA, aspirin; CI, confidence interval; HR, hazard ratio; ICH, intracranial hemorrhage. aPrimary safety outcome. bIf a participant had >1 event of major bleeding, only the most serious bleeding event was counted in these analyses.

Subanalyses of the COMPASS trial that discussed reports of ICH with XARELTO are presented in Table: Subanalyses of COMPASS

Subanalyses of COMPASS9,10,50

Study Objective
Patients
Outcomes
Connolly et al (2018)9 Prespecified subanalysis of patients with stable CAD at baseline.
Study Groups
  • Low-dose XARELTO plus ASA (n=8313)
  • XARELTO alone (n=8250)
  • ASA alone (n=8261)
  • No difference in major bleeding at the intracranial site between the XARELTO plus ASA group and the ASA alone group (<1% incidence for both; P=0.69). There was a significant increase in intracranial bleeding with XARELTO alone compared with ASA alone (1% vs <1%, respectively; P=0.013).
  • No differences in nonfatal, symptomatic ICH between the 3 treatment groups (<1% incidence for all 3 groups; XARELTO plus ASA vs ASA alone, P=0.98; XARELTO alone vs ASA alone, P=0.065).
  • Similarly, no differences in fatal bleeding or symptomatic ICH were observed between the 3 treatment groups (<1%, 1%, and <1% incidence in the XARELTO plus ASA group, XARELTO alone group, and ASA alone group, respectively; XARELTO plus ASA vs ASA alone, P=0.54; XARELTO alone vs ASA alone, P=0.058).
Anand et al (2018)10 Prespecified subanalysis of patients who had stable PAD at baseline.
Study groups
  • Low-dose XARELTO plus aspirin (n=2492)
  • XARELTO alone (n=2474)
  • Aspirin alone (n=2504)
  • No differences in major bleeding at the intracranial site were observed between the 3 treatment groups (<1% incidence for all 3 groups).
  • Similarly, no differences in nonfatal, symptomatic ICH were observed between the 3 treatment groups (<1% incidence for all 3 groups).
Hori et al (2022)50 Subgroup analysis of Asian vs non-Asian patients (race was self-reported)
 Study Groups
  • Asian (N=4269)
  • Non-Asian (N=23,126)
  • Asian patients had a higher rate of ICH compared with non-Asian patients (0.63% vs 0.29%; P=0.01a).
Abbreviations: ASA, aspirin; CAD, coronary artery disease; ICH, intracranial hemorrhage; MI, myocardial infarction; PAD, peripheral artery disease.aAdjusted for baseline differences.

Acute Coronary Syndrome (ACS)

ATLAS ACS-TIMI 51 was a randomized, multicenter, double-blind, event-driven study designed to determine whether XARELTO (2.5 mg BID or 5 mg BID), when added to standard care, is safe and reduces the risk of the composite of CV death, MI, or stroke in patients with ACS compared with placebo.11

Standard medical therapy included low-dose aspirin. Patients were stratified by the investigator’s intention to administer a thienopyridine (clopidogrel or ticlopidine) or not at the time of enrollment. A total of 93% of patients received thienopyridine therapy.11


ATLAS ACS 2: Incidence of ICH in the Modified Intent-to-Treat Population11
 
ICH,
n (%)
HR
(95% CI)
P Value
XARELTO 2.5 mg twice daily (N=5114)
14 (0.4)
2.83 (1.02-7.86)
0.04
Placebo (N=5113)
5 (0.2)
XARELTO 5 mg twice daily (N=5115)
18 (0.7)
3.74 (1.39-10.07)
0.005
Placebo (N=5113)
5 (0.2)
XARELTO combined (N=10,229)
32 (0.6)
3.28 (1.28-8.42)
0.009
Placebo (N=5113)
5 (0.2)
Abbreviations: CI, confidence interval; HR, hazard ratio; ICH, intracranial hemorrhage.

Prevention of Venous Thromboembolism (VTE) in Acutely Ill Medical Patients Requiring Hospitalization

MAGELLAN was a phase 3, international, randomized, double-blind, active-comparator-controlled study designed to evaluate efficacy and safety of once-daily, oral XARELTO compared with standard-duration, once-daily, subcutaneous enoxaparin, and to evaluate the role of extended-duration XARELTO (up to 39 days) for the prevention of VTE in acutely ill medical patients who required hospitalization.13,52

  • Patients with a history of fatal bleeding were excluded from MAGELLAN. There were 2 fatal intracranial bleeding events in the extended-duration XARELTO group. No fatal intracranial bleeds were reported in the enoxaparin group.

Spyropoulos et al (2019)53 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.

  • There were 2 fatal intracranial bleeding events in the extended-duration XARELTO group. There were no fatal intracranial bleeding events reported in the enoxaparin/placebo group.14
  • There were also 3 nonfatal intracranial bleeds in the XARELTO group and two in the enoxaparin/placebo group.14

MARINER54,55 was a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven study that evaluated the efficacy and safety of XARELTO 10 mg once daily (7.5 mg once daily if CrCl ≥30 to <50 mL/min) vs placebo in the prevention of symptomatic VTE and VTE-related death in high-risk, medically ill patients for a period of 45 days post-hospital discharge.

  • In the XARELTO group, one patient experienced a fatal ICH during the treatment period. No patients in the placebo group experienced fatal ICH during this period.15

Risk Reduction of Major Thrombotic Vascular Events in Patients with Symptomatic PAD Undergoing Lower Extremity Revascularization

VOYAGER PAD was a phase 3, multicenter, randomized, placebo-controlled, double-blind, international study designed to evaluate whether XARELTO 2.5 mg BID plus aspirin 100 mg once daily is more effective than aspirin 100 mg once daily alone for the risk reduction of major atherothrombotic vascular outcomes consisting of both CV and limb events in patients with symptomatic PAD undergoing lower extremity revascularization.16 See Table: Incidence of ICH in the VOYAGER PAD Study.

  • There was no difference in fatal bleeding or ICH between the XARELTO-plus-aspirin group and aspirin-alone group (17 vs 19; HR, 0.91; 95% CI, 0.47 to 1.76).

Incidence of ICH in the VOYAGER PAD Study16,a
Outcome
XARELTO
(N=3256)
Placebo
(N=3248)
HR
(95% CI)
Patients With Events,
n (%)
K-M Estimate at 3 Years (%)
Patients With Events,
n (%)
K-M Estimate at 3 Years (%)
ICH
13 (0.40)
0.60
17 (0.52)
0.90
0.78
(0.38-1.61)
Abbreviations: CI, confidence interval; HR, hazard ratio; ICH, intracranial hemorrhage; K-M, Kaplan-Meier.aSafety analyses included all patients who underwent randomization and had received at least 1 dose of trial medication (on-treatment).

A pre-specified analysis was conducted to examine the benefit-risk profile of XARELTO 2.5 mg BID versus placebo on top of background antiplatelet therapy in patients undergoing surgical lower extremity revascularization.56

  • The incidence of ICH was 2 (0.19%) in the XARELTO group (n=1072) and 3 (0.27%) in the placebo group (n=1099).56

FDA SENTINEL REPORTS

  • As part of its pharmacovigilance Sentinel Initiative, the United States Food and Drug Administration (FDA conducts retrospective analyses of safety data collected from electronic health records of patients receiving FDA-regulated drugs. The results of these analyses are published in Sentinel reports.57
  • Data from the FDA Sentinel database has evaluated the incidence of major bleeding events in groups of patients stratified by age (<65 years and ≥65 years) receiving various DOACs.17-19
    • Each study evaluated new users of standard-dose apixaban, dabigatran, and XARELTO with a diagnosis of NVAF in the preceding 183 days.
  • For patients aged <65 years, the HR (95% CI) for ICH was17
    • XARELTO vs apixaban, 1.63 (0.99-2.70)
    • XARELTO vs dabigatran, 1.18 (95% CI, 0.52-2.67)
  • For patients aged ≥65 years, the HR (95% CI) for ICH in 2 different studies and by inverse probability of treatment weighted pairwise comparison (IPTW) was18,19
    • XARELTO vs apixaban, 1.28 (0.99-1.67); and 1.23 (0.96-1.58) by IPTW
    • XARELTO vs dabigatran, 1.67 (1.29-2.17); and 1.58 (1.23-2.03) by IPTW

POSTMARKETING STUDIES

Pharmacovigilance Study

Postmarketing Safety Surveillance

An ongoing, 5-year, observational, postmarketing safety surveillance study will provide longitudinal safety data on XARELTO in patients with NVAF.12

Peacock et al (2015)12 published data collected between January 1, 2013 and December 31, 2014. Electronic medical records from the U.S. Department of Defense database were reviewed to assess major bleeding-related hospitalizations for 39,052 patients on XARELTO therapy. Bleeding events considered serious included GI bleeding, hemorrhagic strokes and other intracranial bleeds, genitourinary bleeding, and bleeding at other sites. Major bleeding events were included if they occurred during and up to 7 days postdiscontinuation of XARELTO.

  • A total of 970 patients experienced at least 1 major bleed event, representing an incidence of 2.89 per 100 person-years.
    • Of the total major bleeds, ICH was the second most common site of bleeding (8.1%, n=79) after GI hemorrhage.
    • Of the 35 patients that died during hospitalization, 26 (74.3%) had an ICH.

REAL-WORLD STUDIES


Summary of ICH Events in Select Real-World Studies
Study Objective
Patients
Outcomes
Simon et al (2024)21 New-user, population-based cohort study evaluated the effectiveness and safety of apixaban vs XARELTO vs warfarin in patients with cirrhosis and AF using the Medicare database and Optum's de-identified Clinformatics Data Mart Database from January 1, 2013, to December 31, 2022.
Study Groups
Standard dose:
  • XARELTO (n=2785)
  • Apixaban (n=2785)

Reduced dose:
  • XARELTO (n=753)
  • Apixaban (n=753)
Pooled PS-Matched Population
Intracranial Bleeding
XARELTO (n=2785)a
Apixaban (n=2785)a
Events, n
14
10
Incidence rate per 1000 PY
8.6
6.1
Rate difference (95% CI)
2.4 (-4.2 to 9.0)
0 (reference)
HR (95% CI)
1.31 (0.55-3.13)
1 (reference)
Reduced Doses of XARELTO and Apixaban
Intracranial Bleeding
XARELTO (n=753)b
Apixaban (n=753)b
Events, n
<11
<11
Incidence rate per 1000 PY
11.1
12.4
Rate difference (95% CI)
-1.3 (-18.9 to 16.2)
0 (reference)
HR (95% CI)
0.81 (0.18-3.63)
1 (reference)
Rodríguez et al (2023)20 Four observational cohort studies using data from the UK, the PHARMO database network in the Netherlands, the German Pharmacoepidemiological Research Database, and Sweden to evaluate the safety and effectiveness of XARELTO vs VKAs (SOC) for stroke prevention in patients with NVAF.
Study Groups
  • UK
    • XARELTO N=12,929
    • SOC N=15,475
  • The Netherlands
    • XARELTO N=2909
    • SOC N=9123
  • Germany
    • XARELTO N=127,743
    • SOC N=88,655
  • Sweden
    • XARELTO N=19,338
    • SOC N=64,505
Unadjusted ICHc
XARELTO
SOC
UK
Events, n/N
44/12,929
80/15,475
PY
17,577
26,252
Incidence (95% CI)
0.25 (0.18-0.34)
0.30 (0.24-0.38)
The Netherlands
Events, n/N
17/2909
45/9123
PY
5064
10,486
Incidence (95% CI)
0.34 (0.19-0.52)
0.43 (0.31-0.57)
Germany
Events, n/N
938/127,743
946/88,655
PY
175,578
194,599
Incidence (95% CI)
0.53(0.50-0.57)
0.49 (0.46-0.52)
Sweden
Events, n/N
115/19,338
1080/64,505
PY
18,328
135,126
Incidence (95% CI)
0.63 (0.61-0.85)
0.80 (0.75-0.85)
Grymonprez et al (2023)22
Belgian nationwide cohort study that evaluated the long-term effectiveness and safety of dabigatran, XARELTO, apixaban and edoxaban in OAC-naive patients with AF using the InterMutualistic Agency (IMA) database and Minimal Hospital Dataset—from January 1, 2013, to January 1, 2019.
Study Groups
  • Dabigatran (n=28,144)
  • XARELTO (n= 74,421)
  • Apixaban (n=66,925)
  • Edoxaban (n= 23,582)
  • VKAs (n= 61,406)
Study Group
ICH Events, n (per 100 PY)
XARELTO
1443 (1.20)
VKA
791 (1.55)
NOAC
3,011 (1.10)
Dabigatran
476 (1.06)
Apixaban
915 (1.00)
Edoxaban
177 (1.05)
There were no significant differences in ICH risk between individual NOACs, except for a significantly lower risk with apixaban compared with XARELTO (aHR, 0.88; 95% CI, 0.80-0.97).
XANTUS24 Prospective, international, observational study that assesed the safety and efficacy of XARELTO for stroke prevention in NVAF in routine clinical practice.
Study Groups
  • XARELTO 20 mg once daily (N=5336)
  • XARELTO 15 mg once daily (N=1410)
  • XARELTO dose information not reported (N=38)
  • Adjudicated all-cause death occurred in 118 patients
    • 7 (5.9%) deaths were due to ICH
  • Treatment-emergent ICH occurred in 26 (0.4%) of the patients treated with XARELTO (incidence rate 0.4 per 100 PY [95% CI, 0.3-0.6]). Causes of treatment-emergent adjudicated ICH are presented in the table below.
Cause, n (%)
XARELTO (N=6784)
Treatment emergent ICH
26 (0.4)
   Intraparenchymal
6 (0.1)
   Subarachnoid
5 (0.1)
   Intraventricular
6 (0.1)
   Subdural hematoma
6 (0.1)
   Epidural hematoma
1 (<0.05)
   Hemorrhagic transformation of
   ischemic stroke
3 (<0.05)
   Missing
2 (<0.05)
Wong et al (2020)23 Analyzed bleeding rates in patients with AF or atrial flutter across oral anticoagulants identified from the PINNACLE (Practice Innovation and Clinical Excellence) registry between 2013 to 2015.
Study Groups
  • No OAC (n=154,430)
  • Warfarin (n=177,318)
  • XARELTO (n=40,994)
  • Dabigatran (n=32,737)
  • Apixaban (n=17,971)
  • Risk of ICH was lower in patients taking XARELTO (HR, 0.73; 95% CI, 0.64-0.84), dabigatran (HR, 0.56; 95% CI, 0.48-0.65), and apixaban (HR, 0.70; 95% CI, 0.55-0.90) compared with warfarin.
  • The outcome of ICH was analyzed for age (≥75 vs < 75 years) and was found to interact with XARELTO (age ≥75 years: HR, 0.81; 95% CI, 0.69-0.96 vs age <75 years: HR, 0.53; 95% CI, 0.40-0.70) and dabigatran (age ≥75 years: HR, 0.59; 95% CI, 0.49-0.71 vs age <75 years: HR, 0.46; 95% CI, 0.34-0.62) but not with apixaban.
Fralick et al (2020)58 New-user, active-comparator cohort study compared the safety and efficacy of XARELTO vs apixaban for patients with NVAF or atrial flutter using the Optum claims database between December 28, 2012, and January 1, 2019.
Study Groups
After 1:1 propensity score matching:
  • XARELTO (n=39,351)
  • Apixaban (n=39,351)
Outcomed
Propensity Matched
XARELTO (N=39,351)
Apixaban (N=39,351)
ICH
   PY
31,406
31,085
   Events, n
124
113
   Rate per 1000 PY
3.95
3.64
   Rate difference per
   1000 PY (95% CI)
-0.31 (-1.28 to 0.65)
   HR (95% CI)
0.91 (0.71-1.18)
  • The rate of ICH per 1000 PY in patients older than 70 years was 5.93 and 5.07 in the XARELTO and apixaban groups, respectively (HR, 0.85; 95% CI, 0.63-1.15).
XANTUS24 Prospective, international, observational study that assesed the safety and efficacy of XARELTO for stroke prevention in NVAF in routine clinical practice.
Study Groups
  • XARELTO 20 mg once daily (N=5336)
  • XARELTO 15 mg once daily (N=1410)
  • XARELTO dose information not reported (N=38)
  • Adjudicated all-cause death occurred in 118 patients; 7 (5.9%) deaths were due to ICH
  • Treatment-emergent ICH occurred in 26 (0.4%) of the patients treated with XARELTO (incidence rate 0.4 per 100 PY [95% CI, 0.3-0.6]). Causes of treatment-emergent adjudicated ICH are presented in the table below.
Cause, n (%)
XARELTO (N=6784)
Treatment emergent ICH
26 (0.4)
   Intraparenchymal
6 (0.1)
   Subarachnoid
5 (0.1)
   Intraventricular
6 (0.1)
   Subdural hematoma
6 (0.1)
   Epidural hematoma
1 (<0.05)
   Hemorrhagic transformation of
   ischemic stroke
3 (<0.05)
   Missing
2 (<0.05)
Abbreviations: AF, atrial fibrillation; CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; ICH, intracranial hemorrhage; NOAC, new oral anticoagulant; NVAF, nonvalvular atrial fibrillation; OAC, oral anticoagulant; OR, odds ratio; PY, patient-years; SE, systemic embolism; SOC, standard of care; UK, United Kingdom; VKA, vitamin K antagonist.aThe pooled cohort included all eligible, propensity score-matched patients with cirrhosis and NVAF from the Medicare database and Optum’s de-identified Clinformatics Data Mart Database.bFor 2 of the secondary outcomes (intracranial bleeding and ischemic stroke), <11 total events were recorded in the exposure groups. Therefore, the absolute event numbers are not presented, per medicare reporting requirements.cPatients were censored at whichever came first of treatment switching/discontinuation (30-day grace period), occurrence of the outcome of interest, date of last available information, end of study period, or death.
dHRs and rate differences are for apixaban relative to XARELTO. Rate differences were calculated using a Poisson model.

SystematiC review and META-ANALYSes

Study Objective
Patients
Outcomes
Chan et al (2023)25 Systematic review and network meta-analysis of real-world studies compared the safety and clinical effectiveness of XARELTO, apixaban, dabigatran, and edoxaban with VKAs in patients with NVAF.
Inclusion Criteria
  • Studies reporting any of the following outcomes: major bleeding, ischemic stroke, myocardial infarction, ICH, and all-cause mortality
Pairwise Comparison of the Risk of ICH
HR
95% CI
XARELTO vs apixaban
1.13
0.78-1.63
XARELTO vs dabigatran
1.53
1.05-2.22
XARELTO vs edoxaban
1.48
0.94-2.33
XARELTO vs warfarin
0.40
0.28-0.58
Lv et al (2022)26
Network meta-analysis of 82,404 patients from 19 RCTs compared the risk of ICH between VKAs and different oral anticoagulants in patients with NVAF.
Inclusion Criteria
  • Compared DOACs and VKAs
  • ICH data reported in 2 groups
  • For trials comparing DOACs with control, only regular-dose arms were included.
  • Dabigatran 110 mg was the safest DOAC in terms of ICH risk, and XARELTO 20 mg was the least safe DOAC. VKAs were deemed the least safe among all studied oral anticoagulants.
  • Dabigatran 110 mg and edoxaban 30 mg showed a reduced relative risk of ICH of 53% (OR, 0.47; 95% CI, 0.27-0.82) and 52% (OR, 0.48; 95% CI, 0.30-0.79), respectively, compared with XARELTO 20 mg.
  • In a subgroup meta-analysis of DOACs vs VKAs, XARELTO (n=8915) showed a lower risk of ICH compared with VKAs (n=8439; OR, 0.63; 95% CI, 0.46-0.87). The other studied DOACs also showed a lower risk of ICH compared to VKAs.
Abbreviations: CI, confidence interval; DOAC, direct oral anticoagulant; HR, hazard ratio; ICH, intracranial hemorrhage; NOAC, new oral anticoagulant; NVAF, nonvalvular atrial fibrillation; RCT, randomized controlled trial; SE, systemic embolism; VKA, vitamin K antagonist.

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 29 July 2024.

References

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