TIME-CHF: Future of Biomarker-Guided Heart-Failure Meds Still Uncertain

Steve Stiles

January 28, 2009

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January 28, 2009 (Basel, Switzerland) — 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.

Hazard Ratio (95% CI) for Mortality End Points at 18 Months, Therapy Guided by NT-Probnp Levels vs Symptoms, in TIME-CHF

End point HR (95% CI) p
Hospitalization-free survival* 0.91 (0.72–1.14) 0.39
Overall survival 0.68 (0.45–1.02) 0.06
Survival free of HF hospitalization 0.68 (0.50–0.92) 0.01
size="1">*Primary end point

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.

  1. 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.

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

face="Verdana" size="1">The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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