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COMMANDER HF

Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease

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Year of Publication: 2018

Authors: Zannad F, Anker SD, Byra WM, ..., Greenberg B

Journal: The New England Journal of Medicine

Citation: Zannad F, et al. N Engl J Med. 2018;379(14):1332–1342.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1808848

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

Clinical Question

Does low-dose rivaroxaban reduce the risk of death, myocardial infarction, or stroke in patients with worsening chronic heart failure, reduced ejection fraction, coronary artery disease, and in sinus rhythm?

Bottom Line

Rivaroxaban 2.5 mg BID did not reduce death/MI/stroke in patients with worsening chronic HFrEF (EF≤40%), CAD, sinus rhythm (HR 0.94; 95% CI 0.84-1.05; P=0.27). No individual component significant per hierarchical plan, though stroke was numerically lower (2.0% vs 3.0%; HR 0.66; 0.47-0.95). ISTH major bleeding increased (3.3% vs 2.0%; HR 1.68; 95% CI 1.18–2.39; P=0.003); fatal/critical-space bleeding did not differ (HR 0.80; P=0.48). 5,022 patients, 628 sites, 32 countries.

Major Points

  • Primary endpoint negative: death/MI/stroke 25.0% vs 26.2% (HR 0.94; 95% CI 0.84-1.05; P=0.27).
  • Stroke was the only primary-outcome component whose 95% CI did not cross 1.0 (2.0% vs 3.0%; HR 0.66; 0.47-0.95) — but per the hierarchical analysis plan, secondary/component outcomes were to be reported without claims of statistical significance and no multiplicity adjustment was applied.
  • Composite of CV death or HF rehospitalization: 37.2% vs 36.9% (HR 0.99; 95% CI 0.91-1.09) — thrombin-mediated events not primary driver of HF outcomes.
  • ISTH major bleeding increased: 3.3% vs 2.0% (HR 1.68; 95% CI 1.18–2.39; P=0.003); fatal or critical-space bleeding not significantly different (HR 0.80; 95% CI 0.43–1.49; P=0.48).
  • Same 2.5 mg BID dose that benefited in COMPASS (stable CAD) and ATLAS ACS 2-TIMI 51 — but failed in HF setting.
  • 84.3% of deaths were cardiovascular — yet primary endpoint neutral, confirming HF deaths are not predominantly thrombin-mediated.
  • Near-universal guideline therapy: >92% ACEi/ARB, >92% beta-blockers, 76.5% MRAs.
  • BMI <25 subgroup showed nominally significant interaction (HR 0.76; 95% CI 0.63–0.92; P interaction=0.03) — hypothesis-generating only.
  • Completes evidence base (with WASH, WATCH) against routine anticoagulation in HFrEF + sinus rhythm.
  • 5,022 patients, 628 sites, 32 countries. Industry-funded (Janssen). Median follow-up 21.1 months.

Design

Study Type: Randomized, double-blind, placebo-controlled

Randomization: 1

Blinding: Double-blind

Enrollment Period: 2013–2017

Follow-up Duration: Median 21.1 months

Centers: 628

Countries: 32 countries

Sample Size: 5022

Analysis: Intention-to-treat

Inclusion Criteria

  • Chronic heart failure ≥3 months
  • LVEF ≤40%
  • Coronary artery disease
  • Treated for an episode of worsening heart failure within the previous 21 days (index event)
  • Elevated BNP ≥200 pg/mL or NT-proBNP ≥800 pg/mL (added by protocol amendment after enrollment of 1155 patients [23.0%])

Exclusion Criteria

  • Atrial fibrillation or another condition requiring long-term anticoagulation
  • High risk of bleeding
  • Acute myocardial infarction or surgical/percutaneous coronary artery intervention during the index event
  • Recent stroke or previous intracranial hemorrhage
  • eGFR <20 mL/min/1.73 m²
  • Heart failure due to a cause other than coronary artery disease

Baseline Characteristics

CharacteristicComorbiditiesQualifying Event
Hypertension75.7
Diabetes40.8
Prior Stroke8.3

Arms

FieldRivaroxaban 2.5 mg BIDControl
InterventionRivaroxaban 2.5 mg twice daily + standard carePlacebo + standard care
DurationMedian follow-up 21.1 monthsMedian follow-up 21.1 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Composite of death from any cause, MI, or strokePrimary26.2%25.0%0.940.27
All-cause mortalitySecondary22.1%21.8%0.98
Myocardial infarctionSecondary4.7%3.9%0.83
StrokeSecondary3.0%2.0%0.66
Major Bleeding (ISTH)Adverse2.0%3.3%1.680.003
Fatal or critical-space bleedingAdverse0.9%0.7%0.80.48

Subgroup Analysis

Across prespecified subgroups (sex, region, age, BMI, eGFR, BNP/NT-proBNP, D-dimer, NYHA class, ejection fraction), findings for the primary composite were generally consistent with the neutral overall result. BMI <25 showed a nominally significant interaction (HR 0.76; 95% CI 0.63–0.92; P for interaction=0.03), but no adjustment for multiplicity was performed and statistical power for these analyses was limited. Per the hierarchical analysis plan, secondary efficacy outcomes (including stroke, MI, and all-cause mortality — components of the primary composite) were reported without claims of statistical significance because the primary outcome was not significant.

Criticisms

  • Primary endpoint not met; no overall benefit.
  • Higher ISTH major bleeding with rivaroxaban (HR 1.68; P=0.003).
  • Events not centrally adjudicated.
  • Rate of trial discontinuation higher than expected.
  • Low use of CRT and ICD devices.
  • Baseline natriuretic-peptide enrichment applied only after protocol amendment (77% of cohort).

Funding

Janssen Research and Development

Based on: COMMANDER HF (The New England Journal of Medicine, 2018)

Authors: Zannad F, Anker SD, Byra WM, ..., Greenberg B

Citation: Zannad F, et al. N Engl J Med. 2018;379(14):1332–1342.

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