By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: Among high-risk patients with heart failure and reduced ejection fraction, a strategy of titrating medical therapy to a target natriuretic peptide level was not associated with improvements in hospitalization or survival.

SOURCE: Felker GM, Anstrom KJ, Adams KF, et al. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: A randomized clinical trial. JAMA 2017;318:713-720.

Cardiac biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), correlate with disease severity and predict adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Several small trials have evaluated the use of serial measurement of biomarkers to guide titration of medical therapy for HFrEF, with mixed results.

The authors of the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study randomized patients with HFrEF to either an NT-proBNP-guided strategy or usual care. All patients were considered “high risk,” defined as baseline NT-proBNP level > 2,000 pg/mL and a history of HF hospitalization or the equivalent. The median left ventricular ejection fraction was 25%. Patients in the NT-proBNP-guided group had HF therapies, titrated with the goal of achieving a level < 1,000 pg/mL. Patients randomized to usual care received HF care in accordance with guidelines, focusing on titration of neurohormonal therapies with proven efficacy in HF. The primary endpoint was a composite of time to first HF hospitalization or cardiovascular mortality.

The trial ended early because of futility after 894 of the planned 1,100 patients had been enrolled. Patients randomized to NT-proBNP-guided therapy logged more clinic visits and more adjustments to HF therapies during the study period. Over a median follow-up of 15 months, the primary outcome occurred in 37% of patients in both the NT-proBNP-guided therapy and usual care groups (hazard ratio, 0.98; P = 0.88). Similarly, there were no observed differences in any of the secondary endpoints, including all-cause mortality or total HF hospitalizations. There was no significant difference in the percentage of patients achieving the target NT-proBNP level of 1,000 pg/mL (46% in the guided-therapy group compared to 40% in the usual care group; P = 0.21). Adverse event rates were similar between the two groups. The authors concluded that among high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy is not more effective than usual care for improving outcomes.


Multiple large, randomized trials have shown that medical therapy substantially improves morbidity and mortality in HFrEF. These trials generally involve strict protocols with clearly specified target doses. Although these target doses subsequently are recommended in practice guidelines, clinicians and patients in the real world often fail to reach them. One aim of natriuretic peptide-guided therapy for HFrEF is to provide an objective metric to assess the adequacy of treatment, thereby encouraging clinicians to titrate medical therapy to higher doses. A recent meta-analysis of 11 trials showed a significant reduction in all-cause mortality with natriuretic peptide-guided therapy, although the individual trial results varied substantially. GUIDE-IT, the largest trial of its kind to date, failed to demonstrate any meaningful advantage to a biomarker-guided management.

There are several possible explanations for the negative result. GUIDE-IT specifically enrolled “high-risk” HFrEF, with more advanced disease than patients enrolled in previous trials of biomarker-guided therapy. With more advanced disease, there may have been higher rates of hypotension, renal failure, and other contraindications to the up-titration of medical therapy. Therefore, providers may have been unable to reach target doses, even when the NT-proBNP level suggested further increases were warranted.

Another important explanation for the negative result is the level of usual care provided to the control group. Clinicians received clear guidelines for use of neurohormonal therapy, and were encouraged to up-titrate to evidence-based doses whenever possible. Thus, patients in the usual care arm of GUIDE-IT likely received more aggressive (and therefore effective) medical therapy compared to control groups in previous studies of biomarker-guided therapy. Patients also logged more frequent clinic visits and medication adjustments than what is seen typically in “usual” clinical care of HFrEF. Because of this more intensive therapy, patients in the control arm of GUIDE-IT saw decreases in NT-proBNP levels, comparable to what was observed in the NT-proBNP-guided arm. By comparison, control groups in prior studies have shown much smaller decreases in biomarker levels. The most recent HF guideline update from the American Heart Association/American College of Cardiology states the evidence base is too discrepant to inform specific guideline recommendations related to the use of serial natriuretic peptide measurement to guide therapy for HFrEF (Class IIb). The strength of this recommendation clearly will not increase based on the results of GUIDE-IT, and at this time the routine use of a biomarker-based approach to medication titration is not advisable. What GUIDE-IT ultimately demonstrates is the absolute importance of target doses when titrating medical therapy of HF. Reaching the doses used in pivotal clinical trials appears to be more important than any specific clinical target or marker of adequate therapy.