Summary

• In ROCKET AF, there were a total of 4467 (62.6%) patients with congestive heart failure (CHF) randomized to receive XARELTO and a total of 4441 (62.3%) patients with CHF randomized to receive warfarin.¹
• In a post hoc analysis of the ROCKET AF trial, there were 63.7% nonvalvular atrial fibrillation (AF) patients with heart failure (HF; ejection fraction [EF] <40%), with 50.1% randomized to XARELTO and 49.9% randomized to warfarin. This analysis demonstrated that efficacy and safety results between XARELTO and warfarin were consistent in patients with and without HF.²
• A retrospective observational cohort study compared the efficacy and safety of XARELTO, apixaban, and dabigatran in obese and morbidly obese patients with AF and HF.³
• A prospective observational cohort study evaluated the incidence of adverse events (all-cause mortality and hospitalizations, acute decompensated HF), thromboembolic events, acute coronary syndrome, and hemorrhages in patients with AF and HF who were treated with XARELTO.⁴
• A retrospective observational study in patients with AF and HF compared the risk of stroke/systemic embolism (SE), major bleeding (MB), and major adverse cardiac events (MACE) in patients taking direct oral anticoagulants (DOACs) vs warfarin and between DOACs.⁵
• A retrospective claims database analysis comparing the efficacy and safety of XARELTO and warfarin in AF patients with HF, showed on difference in hazard ratios (HRs) for developing stroke/SE, ischemic stroke, and MB.⁶
• Additional citations identified during a literature search are included in the References section for your review.^7-10

CLINICAL STUDIES

Stroke Prevention in Nonvalvular AF

The ROCKET AF trial was a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-center, event-driven, non-inferiority study to evaluate the efficacy and safety of oral fixed-dose XARELTO 20 mg once daily (15 mg for patients with creatinine clearance 30-49 ml/min) and dose-adjusted warfarin (target international normalized ratio [INR]: 2.0 to 3.0) for the prevention of stroke and SE in patients with nonvalvular AF at moderate-to-high risk for stroke. The median duration of treatment exposure was 590 days; the median follow-up period was 707 days.¹

• The primary efficacy endpoint was the composite of stroke (ischemic or hemorrhagic) and SE. The primary safety endpoint was the composite of MB and non-major clinically relevant bleeding.
• The primary objective of the study was to demonstrate the non-inferiority of XARELTO to that of dose-adjusted warfarin (INR, 2.0 to 3.0) in the per-protocol (PP) population during treatment (PP, as-treated population).
• There were a total of 4467 (62.6%) patients with CHF randomized to receive XARELTO and a total of 4441 (62.3%) patients with CHF randomized to receive warfarin.

Van Diepen et al (2013)² conducted a post hoc analysis of the ROCKET AF trial to assess the safety and efficacy of XARELTO in patients with HF.  In the ROCKET AF trial, HF was defined as patients with an EF of <35%. In this analysis, HF was defined as having an EF of <40%.

• There were a total of 9033 (63.7%) patients with HF, with 4530 (50.1%) randomized to XARELTO and 4503 (49.9%) randomized to warfarin.
• Patients with HF had similar rates of persistent AF (83.6% vs. 82.3%), EF less than 40% (33.3% vs 34.5%), previous vitamin K antagonist use (58.7% vs 58.2%), concurrent aspirin use (30.3% vs 31.7%), and mean CHADS₂ (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes mellitus, prior stroke or TIA or thromboembolism [doubled], vascular disease, age 65 to 74 years, sex category) scores (3.7 for both) in the XARELTO and warfarin treatment groups, respectively.
• The overall rates of stroke or SE were similar in patients with and without HF (1.99 vs 2.32 per 100-patient years; adjusted HR, 0.94; 95% confidence interval [CI], 0.78-1.13; P=0.51). Safety endpoints were similar between patients with and without HF.
• See Table: Efficacy and Safety Endpoints by Treatment and Heart Failure (ITT Population).
• The primary safety outcome of major or nonmajor clinically relevant bleeding was similar in XARELTO and warfarin-treated patients with HF and without HF. A lower risk of hemorrhagic stroke was observed with XARELTO in HF patients, but not in patients without HF.

• Primary efficacy and safety outcomes were assessed in the following HF subgroups: EF (≥ or <40%), New York Heart Association (NYHA) class, HF with preserved and reduced EF, CHADS₂ score, CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes mellitus, prior stroke or TIA or thromboembolism [doubled], vascular disease, age 65 to 74 years, sex category) score, and device (implantable cardioverter defibrillator [ICD] or biventricular-ICD.
  • Efficacy rates favored XARELTO therapy for the majority of the subgroups, and no difference in efficacy was noted in patients classified by left ventricular EF < or ≥40% (P=0.38 for interaction), NYHA class I-II vs III-IV (P=0.68 for interaction), HF with preserved or reduced EF (P=0.35 for interaction), device therapy (P=0.11 for interaction), CHADS₂ score 2 vs ≥3 (P=0.48 for interaction), or CHA₂DS₂-VASc score (P=0.19 for interaction).
  • Differences in treatment efficacy were not detected for major or nonmajor clinically relevant bleeding between NYHA class (P=0.19 for interaction), HF with preserved or reduced EF (P=0.23 for interaction), CHADS₂ score (P=0.15 for interaction), or CHA₂DS₂-VASc score (P=0.19 for interaction) subgroups.
  • In the left ventricular EF subgroup, a borderline P-value for interaction was detected (EF ≥40%; HR, 1.00; 95% CI, 0.88-1.13; EF <40%; HR, 1.15; 95% CI, 0.96-1.36; P=0.051 for interaction).

REAL-WORLD eVIDENCE

Chugh et al (2023)³ conducted a retrospective observational cohort study to compare the efficacy and safety of XARELTO, apixaban, and dabigatran in obese and morbidly obese patients with non-valvular AF and/or atrial flutter and concurrent HF using the inpatient records at Montefiore Medical Center from January 1, 2011, to September 1, 2015.

• For efficacy and safety, see Table: Efficacy and Safety of XARELTO, Apixaban, and Dabigatran on Obese and Morbidly Obese Patients.

Gómez Doblas et al (2023)⁴ conducted a prospective observational cohort study to evaluate the incidence of adverse events (all-cause mortality and hospitalizations, acute decompensated HF), thromboembolic events, acute coronary syndrome, and hemorrhages in patients with AF and HF who were treated with XARELTO between March 2018 and July 2019.

• For incidence of hospitalizations and adverse events, see Table: Incidence of Hospitalizations and/or Emergency Visits and Adverse Events.

Amin et al (2019)⁵ conducted a retrospective real-world observational study among AF and HF patients comparing DOACs vs warfarin and between DOACs (apixaban, XARELTO, dabigatran) on the risk of stroke/SE, MB, and MACE. Data was collected from January 2012 – September 2015 using United States (US) fee-for-service Medicare and outcome events used propensity score matching and Cox models. Patients were >65 years old and excluded if diagnosed with valvular heart disease, venous thromboembolism, transient AF, cardiac surgery, anticoagulant use during the 12 months prior to collection start date, pregnancy during the study, or knee/hip replacement within 6 weeks prior to collection start date.

• Propensity score matched pairs identified were 10,570 apixaban-warfarin, 4,297 dabigatran-warfarin, 15,712 XARELTO-warfarin, 4,263 apixaban-dabigatran, 10,477 apixaban-XARELTO, and 4,297 dabigatran-XARELTO. Standard doses were apixaban 5mg, dabigatran 150mg, and XARELTO 20mg. Some patients received reduced dosing, apixaban 2.5mg, dabigatran 75mg, and XARELTO 10mg or 15mg. All patients were followed for a mean of 6-8 months.
• When compared to warfarin, all the DOACs showed a lower rate of MACE and apixaban and XARELTO showed a lower rate of stroke/SE. No significant difference was noted in stroke/SE and MB for dabigatran when compared to warfarin, however apixaban showed a lower rate of MB while XARELTO showed an increase. See Table: DOAC vs Warfarin Patients, Incidence Rates and Hazard Ratio.
• Comparing apixaban to dabigatran or XARELTO showed a lower rate of MB and MACE, and a non-significantly lower rate of stroke/SE when compared to dabigatran and XARELTO. Dabigatran when compared to XARELTO showed a lower rate of MB, a higher rate of stroke/SE, and a similar rate of MACE. See Table: DOAC vs DOAC Patients, Incidence Rates and Hazard Ratio.

• Results of a subgroup analysis per index dose of standard vs lower dose were generally consistent with the main analysis.

Martinez et al (2019)⁶ utilized the US Truven MarketScan and Medicare supplemental claims database from November 2011 to December 2016 to access the efficacy and safety of XARELTO (once daily 20 mg or 15 mg) and warfarin treatments in routine practice for AF patients with HF. Patients were oral anticoagulant naïve and matched 1:1 via propensity-scores (demographics, comorbidities, components of the CHAD2DS-VASc and (hypertension, abnormal liver/renal function, stroke history, bleeding history or predisposition, labile INR, elderly, drug/alcohol usage) HAS-BLED risk scores and concomitant non-oral anticoagulant medications). Stroke/SE and MB rates (events per 100 person-years of follow up) were compared using Cox regression and reported as HRs with 95% CIs.

• A total of 6836 patients were assessed, 3418 XARELTO (reduced dose 15 mg in 32%) users and 3418 warfarin users. Patient characteristics included median age 74 (63, 82) years, median CHAD2DS-VASc score 4 (3, 5) and median HAS-BLED score 2 (2, 3). Concomitant medications prescribed for HF included beta-blockers (64%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (62%), loop diuretics (46%), digoxin (11%), and aldosterone receptor antagonists (10%).
• HRs for developing stroke or SE, ischemic stroke and MB, showed no difference between the XARELTO and warfarin users. See Table: Efficacy and safety event rates, hazard ratios, and 95% confidence intervals for XARELTO vs Warfarin users with AF and HF.

Lu et al (2017)¹¹ conducted a retrospective, cohort study was conducted including veterans with AF and HF that were new users of DOACs (XARELTO (N=1,821), dabigatran (N=3,382), apixaban (N=1,522)) or warfarin (N=31,848) between October 1, 2010 and September 30, 2015. The one year bleeding rates among the new users (mainly elderly males) for XARELTO, warfarin, dabigatran, and apixaban, were 18.8%, 23.1%, 13.8%, and 13.6%, respectively. The primary outcome of major and clinically relevant non-MB compared to warfarin were as follows: XARELTO: 0.87 (0.74-1.02, P=0.09); dabigatran: 0.67 (0.58-0.77, P<0.0001); apixaban: 0.58 (0.48-0.71, P<0.0001).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 November 2024.