Sacubitril/Valsartan Treatment for HFpEF Shown to Reduce NT-proBNP Levels

Wanting more data on the benefits of sacubitril/valsartan vs renin angiotensin system inhibitor background therapy, investigators conducted a large randomized study among persons with heart failure with preserved ejection fraction (HFpEF).

Among several measures evaluated in a 24-week, randomized, double-blind, parallel group clinical trial comparing outcomes among patients with heart failure with preserved ejection fraction (HFpEF; left ventricular ejection fraction > 40%), sacubitril/valsartan resulted in a marked decrease in N-terminal pro–brain natriuretic peptide (NT-proBNP) levels by the 12-week mark vs renin angiotensin system (RAS) inhibitor background therapy.

Findings were published recently in Journal of the American Medical Association.

All patients enrolled in the study (N = 2572) had HFpEF, New York Heart Association (NYHA) functional class II through IV disease, elevated plasma NT-proBNP levels, structural heart disease (left atrial enlargement or left ventricular hypertrophy), and reduced quality of life as measured by Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) below 75. There were screened between August 22, 2017, and May 7, 2019, at 396 centers in 32 countries and randomized 1:1 to sacubitril/valsartan or a background medication–based individualized comparator (ie, enalapril, valsartan, or placebo) stratified by RAS inhibitor history. Their mean (SD) age was 72.6 (8.5) years, and 50.7% were women. Most (87.1%) completed the trial.

The authors were trying to answer this primary question: What is the effect of sacubitril/valsartan compared with standard medical therapy on plasma NT-proBNP concentration and submaximal exercise capacity in patients with HFpEF? Their primary outcome was change in NT-proBNP from baseline at week 12, with secondary end points of 24-week improvement in quality of life and NYHA class. At baseline, median NT-proBNP levels were 786 pg/mL and 760 pg/mL in the sacubitril/valsartan and control groups, respectively.

Their analysis resulted in these outcomes:

  • The adjusted geometric mean ratio of plasma NT-proBNP levels was 0.84 (95% CI, 0.80-0.88; P < .001) by week 12, in favor of the sacubitril/valsartan group
  • By week 4, improvements in plasma NT-proBNP levels were already being seen vs the comparator group, and this was sustained through week 24
  • Treatment history did not have an impact on NT-proBNP reductions in the sacubitril/valsartan group
  • Significant between-group differences were not seen for improvement in the 6-minute walk distance test (6MWD), at 9.7 m for the sacubitril/valsartan group and 12.2 m for the control group (95% CI, –8.5 to 3.5; P = .42)
  • Significant between-group differences were not seen for NYHA class improvement in the sacubitril/valsartan vs the control group, 23.6% vs 24.0% (adjusted odds ratio, 0.98; 95% CI, 0.81-1.18), although the sacubitril/valsartan group had a larger reduction in patients with NYHA class III disease (from 32.5% to 17.3%) vs the control group (from 31.25% to 18.2%) by week 24
  • KCCQ-CSS mean change was slightly higher in the sacubitril/valsartan vs the control group: 12.3 vs 11.8 (95% CI, –0.93 to 1.97)
  • Fewer patients in the sacubitril/valsartan had serious cardiac disorders vs the control group: 5.5% vs 7.3%

The authors findings are significant, especially those on change in plasma NT-proBNP levels, because that result was consistent across 9 prespecified subgroups and echoes similar results from the PARAMOUNT and PARAGON-HF trials of patients with HFpEF. In addition, the 6MWD result has been seen in previous randomized trials, with improvements seen in active intervention and control groups no matter the pharmacotherapy.

“One explanation may be that the 6MWD measure is not sufficiently sensitive to detect differences with pharmacological interventions in heart failure compared with implantable electronic devices or a ventricular assist device,” the authors noted. “Additionally, therapies might reduce heart failure hospitalizations without improving exercise capacity.”

Heart failure is also a very heterogeneous disease, they said, and there are many distinct pathophysiologies that may affect reduced exercise capacity.

Areas for future investigation include better phenotyping to tailor therapy to specific subsets of patients with heart failure, testing various combinations of therapies with beneficial effects on cardiac remodeling with therapies beneficial for quality of life, and more study on potential clinical benefits of sacubitril/valsartan in patients with HFpEF.


Pieske B, Wachter R, Shah SJ, et al. Effect of sacubitril/valsartan vs standard medical therapies on plasma NT-proBNP concentration and submaximal exercise capacity in patients with heart failure and preserved ejection fraction:the PARALLAX randomized clinical trial. JAMA. 2021;326(19):1919-1929. doi:10.1001/jama.2021.18463