Biomarker- vs. Clinically-Guided Heart Failure Care: Where Are The Gains?

With the 2009 publication of the BATTLESCARRED trial (which stood for NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death),(1) it seemed that in the not too distant future, biomarker-guided therapy might allow physicians to personalize HF treatment. The promise was based on the natriuretic peptides, which are excellent surrogates for ventricular stretch and volume overload. They seem ideally suited as a means to drive individual therapy for acute and chronic HF.

More recently, Januzzi and colleagues performed a randomized trial comparing NT-proBNP-guided therapy to standard-of-care (SOC) management.(2) Subjects with systolic dysfunction and elevated NT-proBNP were randomized to SOC or to a targeted NT-proBNP concentration 1,000 pg/ml. There were fewer clinical events in the subjects assigned to the NT-proBNP group, and these patients also had more outpatient visits and more aggressive medication titration. NT-proBNP–guided patients also had greater improvements in QOL and more improvements in left ventricular ejection fraction (LVEF). Thus, NT-proBNP–guided therapy indeed may improve clinical and echocardiographic endpoints compared with SOC.

Results were less impressive for the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF). This was the largest prospective randomized study evaluating an intensified NT proBNP-guided strategy versus standard symptom-guided therapy.(3) BNP-guided therapy did not improve overall 18-month survival free of any hospitalizations or improve QOL more than those receiving standard symptom-guided HF therapy. However, survival free of HF hospitalizations was better among those receiving N-terminal BNP–guided therapy.

The investigators hypothesized that an intensified BNP-guided therapy might be particularly beneficial in older patients who are less physically active and in whom symptoms are less reliable. Yet TIME-CHF showed that guided therapy offered no additional beneficial effect compared to SOC in older patients. Januzzi et al. showed similar results as well.(2) Specifically, HF therapy guided by N-terminal BNP improved outcomes in patients aged 60 to 75 years but not in those aged 75 years or older (p < 0.02 for interaction).

Overall, patient age significantly interacted with the N-terminal BNP-guided treatment; with no benefit in TIME-CHF participants aged 75 years or older. Indeed, the guided-therapy arm showed more clinical events during follow-up. Both treatment strategies improved symptoms and QOL and reduced BNP levels similarly over time, although these effects tended to be lower in patients aged 75 years or older.

Thus, in contrast to the original hypothesis, the TIME-CHF team concluded, the value of BNP levels to guide therapy in addition to clinical symptom-based judgment seems limited despite their undisputed diagnostic and prognostic importance. Not only is it not beneficial, BNP-guided therapy may be harmful.

Theory vs. Practice

So, what’s happening in clinical practice? Recently Clyde W. Yancy, Jr., MD, participated in a study to determine the frequency of BNP assessment and the utilization of guideline-recommended HF therapies by BNP level in outpatients with reduced LVEF.(4)

The IMPROVE HF registry is a prospective cohort study of patients at least 18 years of age with an LVEF of 35% or less and chronic HF or previous MI presenting to cardiology and multispecialty practices. The medical records of 15, 381 patients were reviewed. BNP was measured in only 4,213 (27.4%) patients.

When analyzed by tertile of BNP assessment, elevated BNP levels were not associated with greater use of any quality of care measures. However, patients with a BNP in the top tertile were less likely to be treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or aldosterone antagonists compared with patients with a BNP in the bottom tertile.

Thus, among practices participating in IMPROVE HF, not only was BNP not measured in most outpatients, with few exceptions when it was used, BNP did not impact the utilization of guideline-recommended therapies.


  1. Lainchbury JG, Troughton RW, Strangman KM. N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol 2009;55:53-60.
  2. Januzzi JL Jr, Rehman SU, Mohammed AA, et al. Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction. J Am Coll Cardiol 2011;58:1881-9.
  3. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;301:383-92.
  4. Ambrosy AP, Fonarow GC, Albert NM, et al. B-type natriuretic peptide assessment in ambulatory heart failure patients: insights from IMPROVE HF. J Cardiovasc Med 2012;13:360-367.

Keywords: Biomarkers, Heart Failure, Natriuretic Peptides, Natriuretic Peptide, Brain, Patient Readmission, Peptide Fragments

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