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  • PARAGON-HF Original

    • PARAGON-HF

    "Sacubitril-Valsartan in Heart Failure with Preserved Ejection Fraction". The New England Journal of Medicine. 2019.

    Clinical Question


    Does sacubitril-valsartan reduce hospitalizations for heart failure and cardiovascular death in patients with heart failure with preserved ejection fraction?

    Bottom Line


    Sacubitril-valsartan did not lead to a statistically significant reduction in total hospitalizations for heart failure and cardiovascular death compared to valsartan alone in patients with heart failure with preserved ejection fraction.

    Major Points




    Guidelines



    Guidelines have not yet reflected the results of this trial as of the knowledge cutoff date.



    Design


    - Multicenter, double-blind, parallel-group, randomized, active-comparator trial.
    - Patients were assigned to sacubitril-valsartan (n=2419; target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (n=2403; target dose, 160 mg twice daily).
    - The median follow-up duration was 35 months.

    Population


    - Enrolled 4822 patients with NYHA class II-IV heart failure, ejection fraction ≥ 45%, elevated levels of natriuretic peptides, and structural heart disease.
    - Median age: 73 years, 52% female, median ejection fraction 57%.

    Interventions


    - After a single-blind run-in period with half-target doses, participants who tolerated both drugs without issues were randomized to either sacubitril-valsartan or valsartan.

    Outcomes


    - Primary outcome: Composite of total hospitalizations for heart failure and death from cardiovascular causes.
    - Secondary outcomes: NYHA class change, worsening renal function, and change in KCCQ clinical summary score.

    Major Points


    The trial did not meet its primary endpoint, with a primary event rate ratio of 0.87 (95% CI, 0.75-1.01; P=0.06) favoring sacubitril-valsartan. Subgroup analyses suggested potential benefit in women and patients with lower ejection fractions. Secondary outcomes showed some improvements in NYHA class and fewer cases of worsening renal function with sacubitril-valsartan versus valsartan.

    Criticisms


    - The trial narrowly missed statistical significance, and multiple secondary analyses suggested potential benefits, generating debate about the clinical application of the findings.
    - Subgroup analyses were not prespecified primary endpoints, limiting the conclusiveness of results for specific patient demographics.

    Funding


    The trial was funded by Novartis.

    Further Reading