Biomarker-Guided HF Drug Management: No Advantage in Large Randomized Trial

August 25, 2017

DURHAM, NC — Titration of heart-failure (HF) medical therapy according to target levels of natriuretic peptides, compared with a standard empiric approach to drug management, did not improve the risk of HF hospitalization or death in a large controlled trial[1].

No benefit in that primary end point of the trial, nor in a long list of secondary end points, was seen for those of the nearly 900 high-risk patients with HF and reduced ejection fraction (HFrEF) assigned to drug management guided by target levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) vs those receiving guideline-based usual care.

Of note, drug dosages were adjusted more frequently in the biomarker-managed group; however, the two groups did not differ in achieved NT-proBNP levels or in achieved dosages of guidelines-recommended drugs.

"We imagined that medical therapy would be substantially more aggressive in the guided-arm than the usual-care arm," lead author Dr G Michael Felker (Duke Clinical Research Institute, Durham, NC) told theheart.org | Medscape Cardiology.

It was surprising, he said, that "there was no difference in natriuretic peptides at all. So either usual care was better than expected, or guided therapy was less aggressive than expected, or maybe some of both."

One of the few large, randomized, multicenter trials of the many studies that have explored the biomarker guided-therapy strategy in HF, the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was halted early when interim analysis suggested it would be futile to continue.

The study was published August 22, 2017 in the Journal of the American Medical Association.

When Biomarkers May Not Make a Difference

What may be most notable about GUIDE-IT, writes Dr Gregg C Fonarow (Ronald Reagan-University of California, Los Angeles) in an accompanying editorial[2], is that special efforts were made in the control group to optimize medical therapy, "and the demonstration that substantial reductions in NT-proBNP levels can be achieved with empirical adjustment in HFrEF medications."

GUIDE-IT may show "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," according to Fonarow.

There may be some truth to that, said Felker. "The more aggressively you follow the guidelines, the less useful something like natriuretic peptides might be in this context."

Biomarkers may help most, he said, in encouraging clinicians to be more aggressive about drug management, "which the guidelines do already."

The current study follows a decade or more of attempts to compare targeted HF drug therapy with standard care in trials like STOP-HFPROTECT, PRIMA, STARBRITE, and STARS-BNP, all covered by theheart.org | Medscape Cardiology.

Those studies tended to be small with varying designs and diverse patient populations, Felker noted. "Some showed a huge treatment benefit, and some didn't show any benefit at all."

And there have been meta-analyses that have shown a big benefit to the targeted approach, but meta-analyses can be only hypothesis-generating.

So, said Felker, "the guidelines are sort of equivocal about whether this is a good thing to do."

As Fonarow points out in his editorial, the earlier studies "have provided insufficient data to support biomarker-guided therapy as a means to improve clinical outcomes. Reflecting this ambiguity, the 2013 American College of Cardiology/American Heart Association Heart Failure guidelines stated that the usefulness of serial measurements of BNP or NT-proBNP to reduce hospitalization or mortality was not well established (class IIb, level of evidence B)."

Encouraged to Prioritize Neurohormonal Antagonists

The plan was for GUIDE-IT to randomize 1100 patients with HF and LVEF ≤40% and elevated natriuretic peptides and a history of HF hospitalization, emergency-department visit for HF, or outpatient IV diuretics for HF. Patients with end-stage renal disease were excluded.

On the data and safety monitoring board's recommendation, enrollment was halted for futility with 446 patients randomized to the guided-therapy group and 448 to the usual-care group; only one-third of the total cohort were women. Guided therapy consisted of treatment to an NT-proBNP target of <1000 pg/mL. Patients were followed a median of 15 months in both groups. Participating clinicians at all 102 sites were provided with the treatment guidelines and recommended drug dosage targets, according to the group.

For patients managed to the natriuretic-peptide target, "specific adjustments of therapy for individual patients were at the discretion of the treating physician, but sites were encouraged to prioritize titration of neurohormonal antagonists over diuretics unless there was clinical evidence of congestion or volume overload," they write.

Local-laboratory NT-proBNP readings were used to guide therapy, but assays from all patients at prespecified intervals were read blindly at a core lab. 

Adjusted HR (95% CI) for Outcomes in Biomarker-Guided Group vs Usual-Care Group

End points HR (95% CI) P
Primary end point* 0.98 (0.79–1.22) 0.88
CV death 0.94 (0.65–1.37) 0.75
Death by any cause 0.86 (0.62–1.20) 0.37
*First HF hospitalization or CV death
 

Nor were there significant differences in the secondary end points of all-cause death, CV death, total HF hospitalizations, days not hospitalized for CV causes, or adverse events.

Patients in the two groups hit the NT-proBNP target of <1000 pg/mL at 12 months at similar rates, 46% in the guided-therapy group and 40% in the usual-care group (P=0.21).

It's possible the results are not necessarily generalizable to the broad range of clinical centers treating patients with HF. In GUIDE-IT, care was taken to include both academic sites and community hospitals.

"But realistically, even those community sites that participated were sites that had an interest in heart failure and an interest in research," Felker said. "So it wouldn't be right to say they were typical community sites."

A potential advantage of biomarker-guided therapy, he said, is that "it might be an easier strategy for places with less expertise. You just titrate toward this lab test. Whether that's true or not, we can't say from GUIDE-IT because I don't think we had many inexperienced centers in our study."

Especially in retrospect, Felker added, "the control arm in GUIDE-IT in terms of the frequency of visits and frequency of medicine titration ended up being similar to what you'd call disease management in heart failure, where there are specialized clinics and patients are seen fairly frequently."

So maybe usual care "is not exactly the right name for the control arm."

GUIDE-IT was funded by the National Institutes of Health; Roche Diagnostics provided support for NT-proBNP testing. Felker reports receiving grant support from Merck and fees from Medtronic, Bristol-Myers Squibb, Trevena, GlaxoSmithKline, MyoKardia, and Stealth Therapeutics. Disclosures for the other authors are listed in the article. Fonarow reports that he has served as a consultant for Amgen, Janssen, Novartis, Medtronic, St Jude, and ZS Pharma and has grant support pending from the National Institutes of Health.

Follow Steve Stiles on Twitter: @SteveStiles2For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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