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 (R₀ , 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 (EC₅₀ : 3,880/2,414 pg/mL (1,460-4,355 pg/mL)). Model-based 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.

Figure 1

Flow chart describing the procedure for identification and selection of published clinical studies reporting per strata average (NT‐pro)BNP concentrations and clinical event end‐point rates or hazard ratios. HF, heart failure; BNP, brain natriuretic peptide; wo., without.

Figure 2.

NT‐proBNP dependent risk in RWD and clinical studies. (a) Proportion of patients dying within 2 years after initial HF diagnosis calculated for percentiles of the NT‐proBNP distribution in the population. Data derived from Explorys medical record database (black line: point estimates; gray band: 95% CI). Data is compared with the model prediction obtained from the E_max‐like function (red line: median; dashed line: 95% CI). By design, every NT‐proBNP bin is supported by an even number of patients (one percentile) but spans an NT‐proBNP range of varying width. (b) Hazard ratios (triangles) and annualized event rates (circles) vs. NT‐proBNP concentrations as reported in original publications (see Table  1). (c) Black line: Median of model simulations. Gray area: 95% CI of simulations including uncertainties of all model parameters and interstudy variability of EC₅₀. Symbols: Event rates corrected for interstudy variabilities of R₀ and R_max. Red line: Model simulation from a. The box‐whisker plot depicts the distribution of study‐specific EC₅₀ values and reflects interstudy variability. (d) Model simulations with 95% CI given by the uncertainty of the model parameters. To visualize the effect and extent of interstudy variability, the data points are corrected for interstudy variability of all three parameters. The vertical line depicts the median EC₅₀ of the general model. ${\widehat{R}}_{max}$ represents $R_0+R_{max}(1‐R_0)$. CI, confidence interval; EC₅₀, concentration associated with the half maximal risk; HF, heart failure; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; R_max, NT‐proBNP‐dependent maximum risk; R₀, NT‐proBNP‐independent baseline risk. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Comparison of individual study data and model predictions. Median (black line) and 95% percentile (gray area) show NT‐proBNP response predictions per study based on individual study post hoc parameters. The symbols (point estimates) and vertical lines (confidence intervals) represent the original published data the model was built upon. In the case of Lam et al. rEF (cross), mrEF (square), and pEF (triangle) were handled separately. mrEF, medium‐range ejection fraction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; pEF, preserved ejection fraction; rEF, reduced ejection fraction.

Figure 4

Comparison of predicted and observed risk ratios between control and treatment arms in five phase III heart failure studies (ATMOSPHERE, green symbols; COPERNIKUS, blue symbols; PARADIGM, red symbols; open diamonds represent data from a post hoc stratification of verum arm patients by quartiles of BNP measurements after 8–10 weeks of study drug treatment; BEST, orange symbols; TOPCAT, yellow symbols). The black line is the line of identity. (a) Predictions for study treatments arms and strata in PARADIGM defined by BNP quartiles at visit 7 (open diamonds). (b) Zoom into figure: a lower left corner, on‐treatment arms only. Hazard ratios are calculated relative to control arm and the first quartile of BNP, respectively. BNP, brain natriuretic peptide. [Colour figure can be viewed at wileyonlinelibrary.com]