NT‐proBNP Qualifies as a Surrogate for Clinical End Points in Heart Failure

Abstract

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT-proBNP/mortality relationship in real-world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT-proBNP / clinical event end-point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT-proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT-proBNP and clinical outcome is well described by an E max model. The NT-proBNP independent baseline risk (R 0 , RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7-4.9%)) is very low compared with the potential NT-proBNP-associated maximum risk (R max : 55.2%/79.4% (61.5-89.0%)). The NT-proBNP concentration associated with the half-maximal risk is comparable in RWD and across clinical studies (EC 50 : 3,880/2,414 pg/mL (1,460-4,355 pg/mL)). Modelbased predictions of phase III outcomes, relying on short-term NT-proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT-proBNP as a surrogate for clinical outcome in HF trials. NT-proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT-proBNP measurement can therefore enable shorter and smaller but still reliable HF trials. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is an established diagnostic biomarker for the presence of heart failure 1,2 (HF) reflected in diagnostic algorithms of current HF guidelines. 3,4 Over the past decades, a large number of publications investigated the prognostic properties of NT-proBNP for mortality and various cardiovascular events in patients with HF 5 and other cardiovascular (CV) diseases as well as in general elderly populations. 2,6 The association of NT-proBNP elevation with the future occurrence of CV events was shown in several studies. Van Veldhuizen 7 demonstrated

Population Pharmacokinetics and Pharmacodynamics of Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

“…While drug-induced effects on natriuretic peptides may not always reflect effects on clinical endpoints, we have demonstrated that, after short treatment durations of less than 10 weeks, NT-proBNP levels predict hazard ratios with confidence levels comparable to the final trial readout [39]. Interestingly, the effect of vericiguat on top of SoC was not linear, but dependent on [NT-proBNP] baseline as an indicator of disease severity and cardiac wall stress (Fig.…”

“…While drug-induced effects on natriuretic peptides may not always reflect effects on clinical endpoints, we have demonstrated that, after short treatment durations of less than 10 weeks, NT-proBNP levels predict hazard ratios with confidence levels comparable to the final trial readout [ 39 ].…”

N-Terminal Pro-B-Type Natriuretic Peptide in Risk Stratification of Heart Failure Patients With Implantable Cardioverter-Defibrillator

“…Consequently, there is an urgent need to find a new risk stratification marker in addition to LVEF and NYHA. Since published data have shown that NT-proBNP has a close relationship with all-cause mortality (15,16), pump failure death (15,16), and sudden death in a variety of populations (21)(22)(23)(24)(25)(26)(27), it is also expected to be a promising marker for HF with ICD.…”

“…It is an established biomarker of HF diagnosis and prognosis (15,16). Moreover, it is recognized as a surrogate indicator for all-cause mortality, HF hospitalization, and HF death (16). In addition, it is associated with myocardial fibrosis (17), which is a wellestablished arrhythmogenic substrate (18)(19)(20).…”

“…N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a hormone secreted primarily by the ventricular myocardium in response to increased wall stress due to volume expansion and/or pressure overload in heart failure (HF) patients ( 15 ). It is an established biomarker of HF diagnosis and prognosis ( 15 , 16 ). Moreover, it is recognized as a surrogate indicator for all-cause mortality, HF hospitalization, and HF death ( 16 ).…”