NT-proBNP as a Prognostic Marker in Heart Failure

Study Questions:

Is a reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) associated with a decrease in heart failure (HF) hospitalization and cardiovascular mortality (primary endpoint) in patients with systolic HF; does sacubitril/valsartan (an angiotensin-receptor/neprilysin inhibitor [ARNI]) therapy lower NT-proBNP below specific partition values more often than enalapril in systolic HF patients; and is the relationship between change in NT-proBNP and change in morbidity and mortality event rates influenced by therapy?


Baseline NT-proBNP was measured in 2,080 HF patients enrolled in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial, of whom 1,292 had baseline values >1000 pg/ml and were re-assessed at 1 and 8 months. The study authors related change in NT-proBNP to outcomes. The association between relative changes in NT-proBNP from baseline (using log2–transformed values) and differences in risk of subsequent events were assessed using Cox proportional hazards models, with and without adjustment for baseline NT-proBNP. The impact of randomized therapy on post-baseline NT-proBNP values was compared using the median (interquartile range [IQR]) for each treatment arm at each time point, with differences assessed for significance by Wilcoxon rank-sum test.


The investigators found that 1 month after randomization, 24% of the baseline NT-proBNP levels >1000 pg/ml had fallen to ≤1000 pg/ml. Risk of the primary endpoint was 59% lower in patients with a fall in NT-proBNP to ≤1000 pg/ml than in those without such a fall (hazard ratio 0.41 [0.29, 0.58], p < 0.0001) than in patients without a fall in NT-proBNP to ≤1000 pg/ml at 1 month. In sacubitril/valsartan-treated patients, median NT-proBNP was significantly lower 1 month after randomization compared with enalapril-treated patients, and fell to ≤1000 pg/ml in 31% versus 17% of sacubitril/valsartan- and enalpril-treated patients, respectively (odds ratio 2.15 [1.64, 2.83], p < 0.0001). Among patients with NT-proBNP reduction to ≤1000 pg/ml at 1 month and available NT-proBNP data at 8 months, NT-proBNP remained ≤1000 pg/ml in 74% of sacubitril/valsartan-treated versus 59% of enalapril-treated patients (p = 0.011). Similar results were seen when the partition value was set at a reduction in NT-proBNP ≤750 and ≤500 pg/ml. Sacubitril/valsartan was nearly twice (~1.8 times) as likely to cause a meaningful reduction in NT-proBNP compared with enalapril. The authors found no significant interaction between treatment and the relationship between change in NT-proBNP and the subsequent risk of the primary endpoint.


The study authors concluded that patients attaining a significant reduction in NT-proBNP had a lower subsequent rate of cardiovascular death or HF hospitalization independent of the treatment group. Therapy with sacubitril/valsartan was nearly twice as likely as enalapril to reduce NT-proBNP to values ≤1000 pg/ml.


This is an important study because it suggests that NT-proBNP is an important marker of cardiovascular mortality or HF hospitalization in systolic HF patients. It also suggests that ARNIs are possibly a better agent to reduce NT-proBNP levels. Prospective studies designed to address the prognostic value of these biomarkers are the next step to confirm these important findings.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Acute Heart Failure, Chronic Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Angiotensin-Converting Enzyme Inhibitors, Biological Markers, Enalapril, Heart Failure, Heart Failure, Systolic, Natriuretic Peptide, Brain, Neprilysin, Peptide Fragments, Receptors, Angiotensin, Risk

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