Summary

• The COMMANDER-HF^1,2 was a phase 3, randomized, double-blind trial that assessed the efficacy and safety of XARELTO 2.5 mg twice daily compared with placebo in reducing the risk of all-cause mortality (ACM), myocardial infarction (MI), or stroke in participants with chronic heart failure (HF) and significant coronary artery disease (CAD), following a recent exacerbation of HF.
  • XARELTO did not reduce the composite of ACM, MI, or stroke vs placebo (25.0% vs 26.2%, respectively; hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.84-1.05; P=0.27).¹
  • The composite of fatal bleeding or bleeding into a critical space with a potential for disability, occurred in 18 (0.7%) patients treated with XARELTO vs 23 (0.9%) treated with placebo (HR: 0.80; 95% CI: 0.43-1.49; P=0.48).¹
• Additional references identified during a literature search are included in the reference section for your review.^3-5

CLINICAL STUDy

COMMANDER-HF

COMMANDER-HF^1,2 was a phase 3 prospective, randomized, double-blind, event-driven, parallel-group, multicenter trial that assessed the efficacy and safety of XARELTO compared with placebo in reducing the rates of death and cardiovascular (CV) events in patients with worsening chronic HF, reduced left ventricular ejection fraction (LVEF; ≤40%), CAD, and no atrial fibrillation (AF).

Study Design^1,2

• From September 2013 through October 2017, a total of 5022 patients were randomly assigned 1:1 to receive one of the following regimens after treatment for an episode of worsening HF within the previous 21 days:
  • XARELTO 2.5 mg twice daily
  • Matching placebo
• Throughout the study patients received standard of care for HF, CAD, and single or dual antiplatelet therapy as directed by their physician.
• Primary efficacy outcome: composite of ACM, MI, or stroke
• Prespecified secondary efficacy outcomes: composite of CV mortality or rehospitalization for worsening HF, and the separate outcomes of CV mortality, rehospitalization for worsening HF, and rehospitalization for CV events
• Primary safety outcome: composite of fatal bleeding or bleeding into a critical space with a potential for permanent disability.
• Additional safety outcomes: Bleeding events requiring hospitalization and clinically overt major bleeding per the International Society on Thrombosis and Haemostasis (ISTH) criteria.
• Efficacy outcomes were analyzed according to the intention-to-treat (ITT) principle and safety outcomes included patients who took at least one dose of study medication. As per the statistical analysis plan, if the primary efficacy outcome did not meet statistical significance between the treatment and placebo groups, any subsequent efficacy outcomes would be reported without any claims of statistical significance.
• Key Inclusion Criteria:
  • Documented chronic HF for ≥3 months
  • Treatment for an episode of worsening HF (index event) within the previous 21 days
  • A documented LVEF of ≤ 40%
  • Evidence of CAD identified by at least one of the following:
    • Previous MI
    • Angiographic evidence of ≥50% stenosis in one or more coronary artery
    • History of percutaneous coronary artery intervention (PCI)
    • History of coronary artery bypass graft (CABG)
    • Pathological Q waves on electrocardiogram with corresponding wall-motion abnormalities
  • Brain natriuretic peptide (BNP) ≥200 ng/L or N-terminal pro-BNP ≥800 ng/L measured prior to randomization at any time during the screening period
• Key exclusion criteria:
  • High bleeding risk
  • AF or another condition requiring chronic anticoagulation
  • Acute MI or surgical or PCI during the index event
  • Estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m²
  • Recent stroke (within 90 days) or previous intracranial hemorrhage
  • HF due to a cause other than CAD

Results¹

Baseline Characteristics

Patient characteristics and therapies for HF and CAD were similar between the two treatment groups at baseline (see Table: COMMANDER-HF Key Baseline Characteristics). Of the 5022 patients randomized, 53% were in New York Heart Association (NYHA) Functional Class III or IV HF at baseline and >50% of patients were randomized within five days of discharge from the index event. At baseline, 93.1% of patients were taking aspirin and 34.8% were taking dual antiplatelet therapy with aspirin and a thienopyridine.

Efficacy Outcomes

• XARELTO did not significantly reduce the primary efficacy outcome (the composite of ACM, MI, or stroke vs placebo; 626 patients [25.0%] vs 658 patients [26.2%] respectively; HR: 0.94; 95% CI: 0.84-1.05; P=0.27).
• For the secondary and exploratory efficacy outcomes, there was not a significant difference between XARELTO and placebo groups. See Table: COMMANDER HF Efficacy Outcomes.

Safety Outcomes

• For the principal safety outcome of fatal bleeding or bleeding into a critical space with a potential for permanent disability, the difference between treatment groups was not statistically significant (XARELTO, 18 patients [0.7%] vs placebo, 23 patients [0.9%]; HR: 0.80; 95% CI: 0.43-1.49; P=0.48).
• For the safety outcome of ISTH major bleeding, patients in the XARELTO group had a significant increase in risk compared to the placebo group (HR: 1.68; 95% CI: 1.18-2.39; P=0.003). The XARELTO group also experienced more bleeding events requiring hospitalization vs placebo; however, the difference was not significant. See Table: COMMANDER HF Safety Outcomes.

Greenberg (2018)^6,7 conducted a post-hoc analysis of the COMMANDER-HF trial to determine if XARELTO, when added to background antiplatelet therapy, was superior to placebo in reducing thromboembolic events (composite of sudden death, MI stroke, symptomatic pulmonary embolism [PE], and symptomatic deep vein thrombosis [DVT]), in 5,022 patients. After a median follow-up of 19.6 months, the composite thromboembolic event rates were 7.0 and 8.5 per 100 patient-years (PY) for the XARELTO and placebo groups, respectively (HR, 0.83; 95% CI 0.72-0.96; P=0.013). There was a lower event rate per 100 PY for ischemic stroke in the XARELTO group compared with the placebo group (0.9 vs 1.3; HR 0.64; 95% CI 0.43-0.95). There were no significant differences between the XARELTO and placebo groups for the event rate per 100 PY for MI (2.1 vs 2.5), sudden death (4.0 vs 4.5), PE (0.2 vs 0.2), and symptomatic DVT (0.1 vs 0.1).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 20 September 2024.