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NT-proBNP Tx Disappoints for HF Drug Titration

<ѻý class="mpt-content-deck">— No difference in the proportion of GUIDE-IT trial patients who hit target biomarker level
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Natriuretic peptide-guided therapy made no difference in outcomes for patients with heart failure, according to results of the GUIDE-IT randomized trial.

High-risk patients with heart failure and reduced ejection fraction (HFrEF) had over 15 months whether they were treated according to an amino-terminal pro–B-type natriuretic peptide (NT-proBNP)-guided strategy or usual care (adjusted HR 0.98, 95% CI 0.79-1.22).

No differences in any secondary endpoints were found despite the biomarker-guided group having more intense care in the form of more study clinic visits (median 12 versus 10, P=0.002) and more adjustments to heart failure therapy (median six versus four, P<0.001), reported G. Michael Felker, MD, MHS, of Duke Clinical Research Institute in Durham, N.C., and colleagues in the Journal of the American Medical Association.

Even the NT-proBNP levels achieved were indistinguishable between patients who had heart failure therapy adjusted according to natriuretic peptide levels and their peers who had usual guideline-directed care. There was no difference in the proportion of patients achieving the target biomarker level of 1,000 pg/mL at 12 months (46% versus 40%, P=0.21).

"Whether the lack of up-titration of medical therapy observed in this study was related to patient characteristics (e.g., inability to up-titrate due to azotemia or hypotension) or physician behavior (e.g., unwillingness to up-titrate due to concern over adverse effects) in not clear from these data," Felker's group said.

Another reason might explain why natriuretic peptide-guided therapy flopped in the GUIDE-IT trial, according to Gregg C. Fonorow, MD, of UCLA Medical Center in Los Angeles.

"In contrast to a target like systolic blood pressure in hypertension, which is not only a prognostic marker but a mediator for adverse outcomes, NT-proBNP levels are not mediating any outcomes in heart failure and elevated plasma levels can reflect a wide variety of cardiac and noncardiac causes. This biomarker may lack the qualities needed to be a viable target or goal for titrating HFrEF medical therapy," he wrote in an accompanying editorial.

"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," he stated.

Although there may still be some merit in testing other targeted or goal-directed strategies for HFrEF drug titration, this trial bolsters the current guideline-directed approach for titration, he concluded, emphasizing a "critical need" for more guideline-directed therapies in this area of clinical practice.

Felker's group conducted GUIDE-IT at 45 sites in the U.S. and Canada. They hoped to enroll 1,100 patients with HFrEF, but were only able to randomized 446 patients to NT-proBNP-guided treatment and 448 to usual care before the data and safety monitoring board stopped the study for futility.

The overall study population was a median age 63 with 32% women. Participants started with a median NT-proBNP baseline at 2,607 pg/mL, indicating relatively advanced heart failure.

Secondary endpoints turned up no differences between groups:

  • Cardiovascular mortality: 12% for biomarker-guided group versus 13% for usual care (HR 0.94, 95% CI 0.65-1.37)
  • All-cause mortality: 15% versus 17% (HR 0.86, 95% CI 0.62-1.20)
  • First HF hospitalization: 33% versus 32% (HR 1.04, 95% CI 0.82-1.31)

Besides the unblinded nature of GUIDE-IT, the trial suffered from the possibility that the usual care group might have gotten NT-proBNP measurements at non-study sites despite being discouraged from doing so.

  • author['full_name']

    Nicole Lou is a reporter for ѻý, where she covers cardiology news and other developments in medicine.

Disclosures

GUIDE-IT was funded by NIH grants with NT-proBNP tests supported by Roche Diagnostics.

Felker disclosed support from Merck and relevant relationships with Medtronic, Bristol-Myers Squibb, Trevena, GlaxoSmithKline, Myokardia, and Stealth Therapeutics.

Fonarow disclosed pending support from the NIH and relevant relationships with Amgen, Janssen, Novartis, Medtronic, St Jude, and ZS Pharma.

Primary Source

Journal of the American Medical Association

Felker GM, 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; DOI: 10.1001/jama.2017.10565.

Secondary Source

Journal of the American Medical Association

Fonarow GC "Biomarker-guided vs guideline-directed titration of medical therapy for heart failure" JAMA 2017.