Quadruple therapy proposed as therapeutic standard for HFrEF

  • Vaduganathan M & al.
  • Lancet
  • 21 May 2020

  • curated by Emily Willingham, PhD
  • Clinical Essentials
Access to the full content of this site is available only to registered healthcare professionals. Access to the full content of this site is available only to registered healthcare professionals.


  • These authors analyzed data from 3 randomized controlled trials (RCTs) of individual therapies and argue for a quadruple-therapy approach for treating heart failure (HF) with reduced ejection fraction (rEF).
  • The 4 drug classes are mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, beta-blockers, and sodium/glucose cotransporter 2 inhibitors.

Why this matters

  • These authors say that the combination should be a “new therapeutic standard,” given predicted “aggregate treatment effects” on event-free and overall survival with early use of this comprehensive approach.

Key results

  • Median follow-up among the trials was
  • Compared with conventional therapies (renin-angiotensin inhibitors with beta-blockers), use of the combination yielded reduced risks (HRs; 95% CIs) for:
    • Cardiovascular death/HF hospitalization: 0.38 (0.30-0.47).
    • Cardiovascular death: 0.50 (0.37-0.67).
    • HF hospitalization: 0.32 (0.24-0.43).
    • All-cause mortality: 0.53 (0.40-0.70).
  • They estimated that compared with conventional treatment, the quadruple combination could add 2.7 (95% CI, 2.2-3.3) event-free years for someone age 80 years or 8.3 (6.2-10.7) years for someone age 55 years with HFrEF.

Study design

  • Cross-trial analysis of data from EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744) RCTs.
  • The authors projected long-term gains based on assumption of consistent relative treatment effects over time and performed an actuarial analysis.
  • Primary endpoint: composite of cardiovascular death or first HF hospitalization.
  • Funding: None.


  • Underlying assumptions could be wrong, especially with potential for nonadherence.
  • Benefits were assumed to be additive, without overlap.
  • Clinical populations in the trials varied.