Methods:

The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. It randomized patients with HFrEF (left ventricular EF [LVEF] ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP–guided strategy (n = 446) and had HF therapy titrated with the goal of achieving a target NT-proBNP of <1000 pg/ml, or usual care (n = 448). Patients randomized to usual care had HF care in accordance with published guidelines, with emphasis on titration of proven neuro-hormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group.

The primary endpoint was the composite of time-to-first HF hospitalization or cardiovascular mortality. The secondary endpoints were prespecified and included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary endpoint, and adverse events. A total sample size of 1,100 patients (550 per group) was expected to provide approximately 90% power to detect a difference in the primary endpoint with an assumed type I error rate of 0.05, 2-sided. The study investigators estimated that the annual event rate for the composite endpoint would be 40% in the usual care group. They targeted a 20% decrease in the primary endpoint at 12 months for the biomarker-guided group in the sample size calculation, based on the recognition that this treatment effect would be consistent with other effective HF therapies that have been incorporated into clinical practice.