A Good Shake-up Needed in HF Biomarker Research: Report

June 11, 2014

WASHINGTON, DC — Heart-failure biomarker research needs shaking up, according to a document published this week calling for a more "systematic and collaborative approach" to how clinical trials are designed, conducted, and published that should hasten progress toward the eventual prize: reliable biomarker-guided HF therapy[1].

The report proposes, among other things, that HF biomarker studies follow consistent designs, that even negative trials be published as long as they're high quality, that researchers and statisticians collaborate on "more advanced statistical methodologies into the field of biomarkers," and that the field's disparate groups of professionals form a "heart-failure biomarker consortium" to manage and guide the selection and study of potential molecular markers.

"We envision this being a public-private biomedical research partnership with broad participation from a variety of stakeholders, including government, industry, academia, and potentially patient-advocacy groups," notes the report, published today in JACC: Heart Failure with lead author Dr Tariq Ahmad (Duke Clinical Research Institute, Durham, NC).

"Make no mistake about it, the era of precision medicine in cardiology is upon us. Going into it with a sense of clarity in terms of how to examine research questions is I think very important," the report's senior author, Dr James L Januzzi (Massachusetts General Hospital, Boston), told heartwire .

The new document doesn't condemn the current HF biomarker state of the art, he said. "The biomarker area of research is extraordinarily healthy. It really is a challenge to the very basic nitty-gritty of how the studies are designed and executed and in a larger sense calls attention to the fact that studies of heart-failure biomarkers have grown substantially, implying a large number of people are working in this community, and essentially challenges them to work together. It's very clear that what we can do as a group is much more powerful than what can be achieved if people continue to work individually."

Rare Bench-to-Beside Translations

A lot is known in a narrow sense about natriuretic peptides, galactin-3, and other molecules with prowess or potential as biomarkers in heart failure, but it's a lot less clear whether including them in clinical decision-making algorithms can improve the care of HF patients, according to the report.

A big part of the reason, it states, is the field's overabundance of small, disparately designed, statistically weak trials of various biomarkers that have therefore failed to show relevance to actual practice.

All that has "made bench-to-bedside translations rare, leaving the literature with numerous publications of varied quality," write the authors. "This has led to slow adoption of established biomarkers, debates about the utility of biomarkers in standard clinical care, and delays in approval by regulatory agencies for clinical use."

In order to compare HF biomarker studies, Januzzi said, "there has to be some degree of consistency in concept, design, and execution. The ultimate goal is to facilitate large, highly powered analyses as opposed to the smaller, underpowered analyses that we more often see now. A consortium such as we call for would really help to achieve that dual set of goals of high quality and good execution in large studies."

Proposed changes extend to the publication of those studies: "study quality, rather than results, should determine publication," write the group, which outlines a framework for grading HF-biomarker studies for publication worthiness.

"There's a bias against publishing negative results," Januzzi noted. "The selective publication of overly enthusiastic results often leads to a longer time to gain clarity about the role of a marker and what it might bring to the clinical arena. On the other hand, a well-designed, well-executed study . . .  that shows a marker is not of clinical value is extraordinarily useful." It can help determine where to invest trial efforts and resources and "identify when a marker isn't going to make it."

Natriuretic Peptides at "Maturity" for Diagnosis

The biomarkers furthest along their research journey remain the natriuretic peptides, "which have really reached their maturity with respect to level of acceptance as a marker of diagnosis," Januzzi said. "But the vast majority of studies that we really are speaking of in patients with heart failure are less about diagnosis and more about prognosis."

But studies of prognosis alone aren't necessarily going to affect what clinicians do for patients, he said, and so should be considered a means for research on biomarker-guided therapeutics.

The idea of natriuretic-peptide–guided therapy was first published 14 years ago, but only now is "the pivotal trial to examine this question," the multicenter Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT] trial, being conducted, he noted.

"In the interim, multiple smaller studies were performed to examine the question." Given their limited populations and varying methodologies and biomarker target values, "one can now, after the fact, [see] why some were successful and some were not," according to Januzzi.

"This transition from prognosis to management is really, I would suggest, where a large focus needs to be placed. But before we get there we have to optimize how we establish prognosis, and that's where there's a lot of heterogeneity in how things are done," he said.

"We are lagging behind in cardiology with respect to the concept of precision medicine, which is so widely used in oncology, for example. And to get there with a more rapid pace, we need these kinds of high-quality studies" that could emerge from the process outlined in the new document.

Januzzi discloses serving as an advisor or consultant to Critical Diagnostics and receiving research funding from Critical Diagnostics, Roche Diagnostics, BG Medicine, Thermo Fisher, Singulex, and Siemens. Ahmed had no disclosures; those for the other coauthors are listed in the report.


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