Adding to a mixed evidence base regarding the use of natriuretic-
peptide levels as a treatment target in heart failure, a randomized
trial has suggested that the appealing but unproven strategy has
little or no effect on survival overall but also hinted at a possible
benefit in patients younger than 75 [1].

In the Trial of Intensified versus Standard Medical Therapy in
Elderly Patients With Congestive Heart Failure (TIME-CHF), drug
therapy guided by N-terminal brain-type natriuretic-peptide (NT-
proBNP) levels, as compared with conventional symptom-guided
management, made no significant difference to the primary end point
of hospitalization-free survival at 18 months.

The TIME-CHF results now published in the January 28, 2009 Journal of
the American Medical Association are virtually the same as those
presented in August at the European Society of Cardiology Congress
2008, reported then by heartwire.

A handful of prior studies exploring the biomarker-guided approach
produced mixed results, some showing it can improve clinical outcomes
and others showing no such advantages. A few suggested that biomarker-
guided management may tilt toward a clinical benefit in younger
patients, especially in preventing some HF hospitalizations.

That experience is somewhat consistent with TIME-CHF, which
secondarily showed across-the-board improvements in several clinical
end points with NT-proBNP guidance among its younger patients, those
no older than 75 years. Biomarker-guided management also appeared to
improve survival free of heart-failure hospitalization over the
entire study population.

In addition, write the authors, led by Dr Matthias Pfisterer
(University Hospital Basel, Switzerland), "both treatment strategies
improved symptoms and quality of life and reduced [NT-proBNP] levels
similarly over time, although these effects tended to be lower in
patients aged 75 years or older." There were also hints that
biomarker-guided therapy may have caused more "serious adverse
events" in the older group.

The current trial "is quite unique in that we looked at real-world
patients," its principal investigator, Dr Hans-Peter Brunner-La Rocca
(University Hospital Basel), told heartwire. It's the first study of
the natriuretic-peptide-guided strategy in a broad spectrum of heart-
failure patients, including the very elderly and those with multiple
comorbidities, he said. The other trials included patients who
were "at least 10 years younger, on average, than those in TIME-CHF."

The trial and clinical experience suggest that patients younger than
75 can benefit from intensified drug management, whether driven by
natriuretic peptide targets or not, according to Brunner-La
Rocca. "But in the very elderly, especially those with many
comorbidities, it's important to use the medications recommended in
the guidelines without pushing them to the highest level."

TIME-CHF entered 499 patients >60 years of age with heart failure of
at least NYHA class 2, an LVEF <45%, an HF hospitalization within the
previous year, and an NT-proBNP level >400 pg/mL for those <75 years
old or >800 pg/mL for those >75 years despite medical therapy. They
were randomized either to drug therapy aimed at pushing natriuretic-
peptide levels below those thresholds and achieving a NYHA class of 2
or better or to symptom-guided management according to US and
European guidelines and with the same functional-class goal.

Across all patients, the two groups fared similarly with respect to
the primary end point. But those younger than 75 showed a consistent
benefit from the natriuretic-peptide-guided approach. Their hazard
ratios were improved by 30% (p=0.05) for hospitalization-free
survival, 59% (p=0.02) for overall survival, and 58% (p=0.002) for HF-
hospitalization-free survival for biomarker-guided vs symptom-guided
therapy. Patients 75 or older showed no such difference for any of
the end points.

An accompanying editorial agrees that the biomarker-guided
approach "may have limited value" in the oldest patients, whereas--as
TIME-CHF suggests--it may reduce the risk of heart-failure
hospitalization in younger patients who are already well managed
pharmacologically by conventional standards [2].

"Medical therapy, therefore, can usually be further optimized and
uptitrated even in the absence of worsening symptoms--an important
clinical point," write Dr Ileana L Piña (Case Western Reserve
University, Cleveland, OH) and Dr Christopher O'Connor (Duke
University, Durham, NC).

TIME-CHF, according to the editorialists, "points to the fact that
symptom-guided medical therapy can be improved in most patients."
Indeed, "persistence in intensifying medical therapy seems to be the
key for an optimal clinical outcome in patients aged 60 to 74 years."

The reports states that TIME-CHF was 55% sponsored by the nonprofit
Horten Research Foundation; the remainder was supported by
AstraZeneca, Novartis, Menarini, Pfizer, Servier, Roche Diagnostics,
Roche Pharma, and Merck.


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; 301:383-392.
Piña IL, O'Connor C. BNP-guided therapy for heart failure. JAMA 2009;
301:432-434.