Natriuretic peptides as a surrogate endpoint in clinical trials\u2009—\u2009a riddle wrapped in an enigma

Abstract

Each year the cost of healthcare rises exponentially. A substantial portion of these rising costs lie in the development of novel therapeutics. Specifically, cardiovascular medication development is one of the costliest. Nearly 85% of early phase clinical development programmes for experimental drugs are terminated at this stage and of those that do progress to phase III testing, only half will go on to receive regulatory approval.1 Considering this, it is imperative that only the most promising compounds/devices be identified prior to moving forward with pivotal cardiovascular (CV) outcomes trials. Natriuretic peptides (NPs) have been shown in numerous observational studies to correlate well with mortality and risk of hospitalization2 and are often used as a surrogate marker in phase II clinical trials to identify candidate drugs and devices that should proceed to definitive phase III clinical trials.3 Thus, in this issue of the Journal, Wessler et al.4 examined the role of NPs as a surrogate endpoint in phase II clinical trials of novel pharmacotherapies for heart failure with a reduced ejection fraction (HFrEF). A systematic review was performed to evaluate the correlation between average change in NP levels and CV outcomes in phase III trials for chronic medications for HFrEF. The authors sought to identify previously completed studies using a comprehensive search strategy. First, looking at large randomized clinical trials (RCTs) of drugs and/or devices examining the effect on outcomes in HFrEF patients (i.e. defined as an ejection fraction < 45%) with at least 6 months of follow-up. Following initial identification of these trials, they searched for corresponding short-term trials evaluating the effect of the same drugs/devices on NP levels vs. placebo. In this second search, the authors included only trials for HFrEF patients lasting at least 4 weeks with either amino terminal pro B-type NP (NT-proBNP) or B-type NP (BNP) for the active treatment and