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PARADIGM-HF Trial: Angiotensin Neprilysin Inhibition vs Enalapril Heart Failure

PICOTS for the Trial:

  • P = Adults with class II - IV heart failure and EF < 40% on standard therapy 
  • I = Angiotensin-neprilysin inhibition(LCZ696) at doses of 200 mg twice a day
  • C = Enalapril 10 mg twice daily
  • O = CV related mortality, all-cause mortality, and hospitalizations for heart failure
  • T = Over a period a median of 27 months
  • S = Outpatient
  • What is PICOTS?  It is an acronym similar to PICO used in evidenced-based medicine and represents the following: (P) for patient population, (I) for the intervention of interest, (C) for comparative intervention, (O) for the outcome, (T) for the timing of the intervention, and (S) for the setting.  EBM Consult uses PICOTS because it is more complete and appropriate.  Every study has a PICO or PICOTS and appropriate application of this content should be compared to the PICO or PICOTS being asked by the clinician.

Trial Summary:

  • This was a prospective, randomized, multicenter, double-blinded clinical trial of 8,442 patients with class II, III, or IV heart failure and with an EF ≤ 40% who received either the angiotensin-neprilysin inhibitor (LCX696 at 200 mg twice daily) vs. enalapril.
  • The trial was stopped early (median follow up of 27 months) due to overwhelming benefit in those receiving angiotensin-neprilysin inhibition in reducing risk of death and hospitalization for heart failure.

PARADIGM-HF Trial Summary

  • McMurray J, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371(11):993-1004. PubMed
    LOE Level 2 using the Oxford Centre for Evidence-Based Medicine Criteria
    Study Design Prospective, randomized, multicenter, international, double-blind clinical trial
    Sample Size n = 8,442 patients with class II, III, or IV HF and EF of < 40%
    Treatment Arms

    In addition to standard therapy:

    • Angiotensin-neprilysin inhibition (LCZ696 at a dose of 200 mg twice daily)
    • Enalapril 10 mg twice daily
    Primary Endpoint Death from CV causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from CV causes
    Follow Up Trial stopped early; median of 27 months
    • The trial was stopped early because the boundary for an overwhelming benefit with LCZ696 was exceeded.
    • The primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (HR in the LCZ696 group, 0.80; 95% CI, 0.73 to 0.87; P<0.001).
    • A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (HR death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (HR, 0.80; 95% CI, 0.71 to 0.89; P<0.001).
    • As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001).
    • The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema, but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
    Conclusions Conclusions angiotensin-neprilysin inhibition with LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure.
    Funding Novartis NCT01035255
    Comments The majority of patients enrolled had NYHA class II heart failure.  If the trial had been able to continue beyond its early stop date, the results may have regressed back to the mean and be less than what was reported. However, this new treatment was able to demonstrate an improvement in clinically relevant and patient-oriented outcomes which is difficult in many current CV clinical trials going head-to-head against the standard of care.