Summary

• On the basis of the GALILEO trial, the use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an antiplatelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. The use of XARELTO is not recommended in patients with prosthetic heart valves.¹
• In a retrospective analysis of the ROCKET AF trial, the efficacy and safety outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) treated with oral anticoagulants were worse than patients with mitral regurgitation (MR), aortic regurgitation (AR), or no significant valve disease (SVD).²
• A retrospective analysis of ROCKET AF patients with and without SVD showed similar efficacy outcomes with XARELTO and warfarin treatment.³
• In the randomized, open-label, phase 2 RIVER trial, the efficacy outcomes in patients with bioprosthetic mitral valve and AF or flutter were noninferior in the XARELTO group compared with the warfarin group, and the difference in the incidence of bleeding events was similar in the 2 groups.⁴
  • In a prespecified analysis of the RIVER trial evaluating patients according to time of mitral valve implantation (<3 months vs ≥3 months), XARELTO was associated with a lower rate of events compared with warfarin among patients in the first 3 months of valve implantation. Similar event rates were observed for XARELTO and warfarin among patients with ≥3 months of mitral valve implantation.^4,5
• The INVICTUS trial, a randomized, open-label, phase 3 non-inferiority study in patients with AF or atrial flutter and rheumatic heart disease, found a higher rate for the composite of stroke, systemic embolism, myocardial infarction (MI), or death due to vascular or unknown causes in the XARELTO group than the vitamin K antagonist group, with no significant difference in major bleeding outcomes.⁶
• Additional citations identified during a literature search have been included in the REFERENCES section for your review.^7-13

CLINICAL STUDIES

ROCKET AF Trial

The ROCKET AF trial evaluated the efficacy and safety of XARELTO and warfarin for the prevention of stroke and systemic embolism (SSE) in patients with nonvalvular AF at moderate-to-high risk for stroke.¹⁴

In ROCKET AF, nonvalvular AF was defined as AF in the absence of mitral valve stenosis or prosthetic heart valve. Specifically, patients were excluded if they had hemodynamically significant mitral valve stenosis or prosthetic heart valve; however, patients with annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty were permitted.¹⁵

Breithardt et al (2016)² conducted a post hoc analysis of the ROCKET AF trial to compare the outcomes of patients with AF and AS with patients with AF with MR or AR, and patients without SVD.

• In the intent-to-treat (ITT) population (N=14,171), a total of 214 patients had AS with or without other valve abnormalities, 1726 patients had MR or AR, and 12,179 patients had no SVD.
• In the ITT population, the combined efficacy endpoints (composite of stroke, systemic embolism; or vascular death) increased almost twofold in patients with AS after adjusting for prognostic factors. All-cause death was also significantly increased in patients with AS. Major bleeding occurred more frequently in AS and MR or AR than in patients with no SVD.
• In patients with and without valvular disease, the relative efficacy of XARELTO vs warfarin was consistent. XARELTO was associated with higher rates of major bleeding than warfarin in patients with AR or MR.

Breithardt et al (2014)³ conducted a post hoc analysis of the ROCKET AF trial to compare thromboembolic and bleeding outcomes among patients with AF, and with or without SVD randomized to either XARELTO or warfarin.

• A total of 2003 patients (14.1%) had a history of SVD, including MR, AR, or AS, among the ITT population (N=14,171), which included all patients who underwent randomization and were followed for events during treatment or after discontinuation.

• There was no statistical difference in the CHADS2 (congestive heart failure, hypertension, age ≥75 [doubled], diabetes, stroke [doubled]) scores, the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [age ≥65], drugs/alcohol concomitantly) scores, or the prevalence of diabetes mellitus between the 2 groups.
• In the ITT population, the combined efficacy endpoints (SSE; stroke, systemic embolism, or vascular death; stroke, systemic embolism, vascular death, or MI; or all-cause death) were slightly higher in patients with SVD, but the differences were not statistically significant. The individual endpoint of systemic embolism occurred more frequently in the SVD population. In the safety on-treatment population, major or nonmajor clinically relevant bleeding combined and major bleeding alone occurred more in patients with SVD.
• The rate of SSE in patients treated with XARELTO compared with warfarin was consistent among patients with SVD and without SVD. Patients that received XARELTO were at a higher risk of bleeding events compared to warfarin if they had a previous history of SVD, while there was no difference among the treatment groups in patients without SVD.

RIVER Trial

The RIVER trial was a multicenter, randomized, phase 2, open-label, non-inferiority study that evaluated the efficacy and safety of XARELTO compared with warfarin in patients with bioprosthetic mitral valve and AF or flutter.⁴

Patients with paroxysmal, permanent, or persistent AF or flutter and biological prosthesis of the mitral valve with planned or current use of oral anticoagulants for prophylaxis of thromboembolism were included in the trial. Patients were eligible in the trial 48 hours after the mitral valve surgery.⁴

Guimarães et al (2020)⁴ published the efficacy and safety results of the RIVER trial.

Study Design/Methods

• Patients were randomized 1:1 to receive either XARELTO 20 mg once daily (those with a creatinine clearance (CrCl) of 30-49 ml/min/1.73 m² received 15 mg once daily) or doseadjusted warfarin (to maintain a target international normalized ratio [INR] of 2.03.0).⁴
• The primary outcome was a composite of all-cause mortality, major cardiovascular events (stroke, transient ischemic attack [TIA], valve thrombosis, systemic embolism not related to the central nervous system [CNS], or hospitalization for heart failure), or major bleeding at 12 months.⁴
• The key secondary efficacy outcome was a composite of death from cardiovascular causes or thromboembolic events (stroke, TIA, deep venous thrombosis, pulmonary embolism, valve thrombosis, or systemic embolism not related to the CNS).⁴
• The secondary safety outcomes were bleeding events (major, clinically relevant nonmajor, minor, and total).⁴

Results

• In the overall population (N=1005), 500 patients received XARELTO and 505 received warfarin. Overall, 76 patients had a history of percutaneous valve intervention, 621 patients had permanent fibrillation, 44 patients had flutter, and 189 patients had an interval of <3 months between mitral-valve implantation and randomization.⁴
• In the ITT analysis, the mean time until the occurrence of primary outcome event in the XARELTO vs warfarin groups was 347.5 vs 340.1 days (restricted mean survival time [RMST] difference, 7.4 days; 95% confidence interval [CI], -1.4 to 16.3; P<0.001 for non-inferiority and P=0.10 for superiority).⁴
• The results of primary outcomes in the XARELTO and warfarin groups were consistent across subgroups, including, age, sex, and CrCl.⁴
• At 12 months, the composite secondary outcome of death from cardiovascular causes or thromboembolic events in the XARELTO vs warfarin group occurred in 17/500 (3.4%) vs 26/505 (5.1%) patients (hazard ratio [HR], 0.65; 95% CI, 0.35 to 1.20).⁴
• In the XARELTO vs the warfarin group, any bleeding events were reported in 65/500 (13.0%) vs 78/505 (15.4%) patients (HR, 0.83; 95% CI, 0.59 to 1.15).⁴

Lopes et al (2022)⁵ conducted a pre-specified analysis from the RIVER trial that evaluated the efficacy and safety of XARELTO compared with warfarin in patients with AF or flutter and bioprosthetic mitral valve according to time from valve implantation.

• The study analyzed the ITT population from the RIVER trial (N=1005: [XARELTO, n=500] and [warfarin, n=505]) and reclassified based on time from mitral-valve implantation to randomization: <3 months (N=189: [XARELTO, n=94] and [warfarin, n=95]) and ≥3 months or unknown (N=816, [XARELTO, n=406] and [warfarin, n=410]).^4,5
• The primary outcome evaluated was the same as that of the main RIVER analysis. It was reported using percentage and the RMST method, the mean time free from an outcome event up to the specific time point.^4,5
• Baseline characteristics for mean age (56.5 vs 59.9 years) and history of hypertension (53.4% vs 62.3%) were significantly different for the patients that were randomized
• <3 months after surgery and those randomized ≥3 months after surgery respectively).^4,5
• For patients that had a time from mitral valve implantation of <3 months, the XARELTO group had a lower rate of the primary outcome (a composite of death, major cardiovascular events, or major bleeding) than the warfarin group (HR, 0.31; 95% CI, 0.12 to 0.79; P=0.01). The RMST difference was 35.2 days (95% CI, 8.6 to 61.7). Please see table: Efficacy and Safety Endpoints.⁵
• For patients that had ≥3 months of mitral valve implantation or an unknown duration, the primary outcome was similar between the XARELTO and warfarin groups (HR, 1.21; 95% CI, 0.77 to 1.90; P=0.416). The RMST difference was 1.0 (95% CI, -8.6 to 9.9). Please see table: Efficacy and Safety Endpoints.⁵

INVICTUS trial

INVICTUS is an international research program that includes both a registry and a trial. The trial was a randomized, open-label, non-inferiority study that evaluated the efficacy and safety of XARELTO 20 mg once daily (those with CrCl <50 ml/min received 15 mg once daily) vs. dose-adjusted vitamin K antagonist (to maintain targeted INR in the range of 2.0 to 3.0) in patients with AF or atrial flutter and echocardiographically documented rheumatic heart disease.⁶

Study Design/Methods

• The study recruited a total of 4565 patients, 2292 of which were assigned to the XARELTO group, and 2273 that were assigned to the vitamin K antagonist group. The ITT population consisted of 4,531 patients (XARELTO: n=2275 and vitamin K antagonist: n=2256).⁶
• Key inclusion criteria were AF or atrial flutter patients with echocardiographically documented rheumatic heart disease and ≥1 of the following: a CHA₂DS₂VASc (congestive heart failure, hypertension, age ≥75 [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 and sex category [female]) score ≥2, mitral stenosis with a mitral-valve area <2 cm², or echocardiographic evidence of left atrial spontaneous echo contrast or left atrial thrombus.⁶
• Key exclusion criteria included the presence of a mechanical heart valve or the likelihood of receiving one in the next 6 months, severe renal insufficiency (estimated glomerular filtration rate [eGFR] <15 ml/minute), and the use of dual antiplatelet therapy, strong inhibitors of both cytochrome P450 (CYP) 3A4 and P-glycoprotein.⁶
• In the original study design, the primary efficacy outcome was a composite of total SSE. The steering committee observed a low overall stroke rate and higher than expected overall mortality rate during the trial and decided to change the primary outcome to a composite of stroke, systemic embolism, MI, or death from vascular or unknown causes. The primary outcome was planned as a non-inferiority analysis, with a non-inferiority margin of 1.186.⁶
• Key secondary efficacy outcomes were MI and death from vascular causes (cardiac or non-cardiac).⁶
• The primary safety outcome was major bleeding defined by the International Society of Thrombosis and Hemostasis.⁶

Results

Baseline Characteristics

• Baseline characteristics were balanced between the two groups. The mean age was 50.5 years, 72.3% were women, 56.4% had a history of a CHA₂DS₂VASc score ≥2, 81.9% had a mitral-value area <2 cm², 11.6% had left atrial spontaneous echo contrast, 6.7% had left atrial thrombus on echocardiography, and 52.8% had a history of vitamin K antagonist usage.⁶
• Within the vitamin K antagonist group, warfarin was used in the majority of patients (79-85%, with the percentage varying between visits).⁶

Efficacy/Safety

• In the ITT analysis, the primary efficacy outcome of stroke, systemic embolism, MI, or death from vascular or unknown causes occurred in 560/2275 patients (8.21%/year) and 446/2256 patients (6.49%/year) in the XARELTO and vitamin K antagonist groups, respectively (HR, 1.25; 95% CI, 1.10 to 1.41). Please see table: ITT Analysis of Efficacy Outcomes for detailed efficacy data.⁶
• The RMST of the primary outcome was 1599 days in the XARELTO group and 1675 days in the vitamin K antagonist group (the difference, -76 days; 95% CI, -121 to -31 days; P<0.001 for superiority).⁶
• The permanent discontinuation rate of XARELTO was 22.73% and vitamin K antagonist was 5.98%.¹⁶
• The mean follow-up duration was 3.1±1.2 years.⁶
• The on-treatment safety analysis showed no significant difference in major bleeding events in the Xarelto vs vitamin K antagonist group (40/2265 patients [0.67%/year] vs. 56/2251 patients [0.83%/year], respectively [HR, 0.76; 95% CI, 0.51 to 1.15, P=0.18]). Please see table: On-Treatment Analysis of Safety Outcomes.⁶

reAL WORLD EVIDENCE

Effectiveness and Safety of XARELTO vs. Apixaban

Dawwas et al (2022)¹⁷ conducted a retrospective, active-comparator, target trial to compare the efficacy and safety of apixaban and XARELTO in patients with AF and VHD.

• Used the Optum database to identify adult patients (aged ≥18 years) with a diagnosis of both AF and VHD, including aortic, mitral, tricuspid, or pulmonic valve disease (either stenosis or regurgitation of any severity), through ICD 9/10 codes and Clinical Modification codes.
• The cohort was restricted to new users of apixaban (5 mg and 2.5 mg twice daily) or XARELTO (20 mg and 15 mg once daily) with at least 12 months of continuous enrollment in medical and pharmacy benefits. Patients with bioprosthetic or mechanical heart valve replacements were not included.
• The primary efficacy outcome was the composite of ischemic stroke or systemic embolism. The safety outcome was the composite of gastrointestinal or intracranial bleeding.
• Apixaban (n=9947) users were propensity score matched to XARELTO (n=9947) users; both groups were well balanced (all standardized differences <0.1).
• In the propensity score-matched sample, the primary efficacy composite incidence rate was 5.2 among apixaban users compared to 9.1 among XARELTO users, per 1000 person-years of follow-up (HR, 0.57 [95% CI, 0.40-0.80]). The absolute reduction in the probability of SSE was 0.0026 within 6 months and 0.011 within 1 year with apixaban versus XARELTO.
• The safety composite incidence rate was 14.3 among apixaban users compared to 28.1 among XARELTO users, per 1000 person-years of follow-up (HR, 0.51 [95% CI, 0.41-0.62]). The absolute reduction in the probability of bleeding events was 0.012 within 6 months and 0.019 within 1 year with apixaban versus XARELTO.
• No statistically significant difference in all-cause mortality was observed between apixaban and XARELTO users (HR, 1.10 [CI, 0.97-1.24]).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 26 August 2024.