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A clinical trial has sparked debate over the ability of natriuretic peptide (NP)-guided therapy to improve clinical outcomes in heart failure (HF) patients.

The NPs have grown in importance as biochemical markers for HF severity and for informing HF patients of their prognosis, Clinical Laboratory News reported earlier this year. An expectation has been that NPs levels could serve as useful targets for titrating heart failure medication levels. “Since the Food and Drug Administration (FDA) cleared the first B-type natriuretic peptide (BNP) assay in 2000, natriuretic peptide (NP) testing—including BNP, N-terminal proBNP (NT-proBNP), and mid-region pro-atrial NP—has, in the words of esteemed cardiologist and researcher James Januzzi, MD, ‘revolutionized’ heart failure (HF) care,” according to the CLN article.

However, a study published in the Journal of the American Medical Association (JAMA) that randomized high-risk HF patients to an NP-guided regimen or usual care strategy, found no substantive differences between the two approaches in terms of improving clinical outcomes. The Guiding Evidence-Based Therapy Using Biomarker-Intensified Treatment in Heart Failure (GUIDE-IT) study enrolled 894 high-risk patients with chronic HF, reduced ejection fraction (HFrEF), and recent elevated NP levels from 45 clinical sites in the United States and Canada to see if NT-proBNP-guided treatment would produce better clinical outcomes than more common medical therapies.

BNP and NT-proBNP biomarkers are known to rise in patients facing a poor prognosis, and decline when recommended therapies are administered. “These observational data have led to the hypothesis that serial measurements of natriuretic peptides may be used to guide titration of long-term medical therapy in HF,” the authors explained.

Investigators randomly assigned patients to intervention and control groups. The 448 patients in the control or usual care group received proven neurohormonal HF therapies. In the intervention group, 446 patients received a NT-proBNP-guided therapy, titrating medications to reach a target NT-proBNP of less than 1,000 pg/mL. The investigators found little or no differences in outcomes between the two groups after 15 months of follow-up, prompting an early dismissal of the trial. Cardiovascular death and first hospitalization for heart failure—the study’s two primary endpoints—took place in 164 patients each in the biomarker-guided and usual care groups. Looking specifically at cardiovascular mortality, results differed little among the biomarker group (12%) and usual care group (13%). The groups also didn’t differ significantly in achieved decreases in NT-proBNP levels, or among secondary end points such as total hospitalizations for heart failure, all-cause mortality, or days alive.

The results had some experts questioning the merits of NP-guided therapy. “For years, many have flocked to this test as a way to monitor—now BNP joins many other tests/monitoring methods that have added cost without benefit,” Harlan Krumholz, MD, editor-in-chief of NEJM Journal Watch Cardiology, commented in response to the findings. The question now is “should we start treating testing/monitoring like drugs, insisting on evidence of benefit before widespread adoption?” he speculated.

In a related editorial, Gregg C. Fonarow, MD suggested that NT-proBNP may lack the necessary characteristics to guide medical therapy in high-risk HF patients. “Perhaps the most likely explanation for the outcomes observed in the GUIDE-IT trial is that when clinical care follows guidelines and addresses the key issues, biomarkers do not make a difference and that guideline-directed care, if it can be achieved, is more efficient and can lead to outcomes similar to biomarker-guided care,” Fonarow wrote. Based on the GUIDE-IT trial results, “serial monitoring of natriuretic peptide biomarkers do not appear to add incremental value to such efforts,” he concluded.

Januzzi, a co-author of the GUIDE-IT study, believes these doubts are premature. Hundreds of other papers affirm the value of NP testing and its important role in HF care, he told CLN Stat. “The result of GUIDE-IT is hardly the last word on the topic of biomarker guidance for chronic heart failure. This is a diagnosis in great need of tools to optimize its management,”he said. The study results need to be taken into context, he continued. As an example, those in the usual care arm were seen just 10 times in over a year and had substantial reductions in NT-proBNP—a result that was no different than the NT-proBNP arm. “The question any skeptic must be honest about is whether the ‘usual care’ in GUIDE-IT was really usual care? Would the outcome in the study have differed if a more ‘usual’ approach to care was delivered to that arm? One assumes so,” he offered.

Next steps are to compare NT-proBNP guidance with a “true” usual care population. “One can only speculate on the outcome, but given pilot data suggesting value in this context, it’s reasonable to remain optimistic that we can deliver the right care to the right patient at the right time using biomarkers,” Januzzi said.