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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.