Context:
It is uncertain whether intensified heart failure therapy guided by N-terminal brain natriuretic peptide (BNP) is superior to symptom-guided therapy.

Objective:
To compare 18-month outcomes of N-terminal BNP–guided vs symptom guided heart failure therapy.

Design, Setting, and Patients:
Randomized controlled multicenter Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) of 499 patients aged 60 years or older with systolic heart failure (ejection fraction ≤45%), New York Heart Association (NYHA) class of II or greater, prior hospitalization for heart failure within 1 year, and N-terminal BNP level of 2 or more times the upper limit of normal. The study had an 18-month follow-up and it was conducted at 15 outpatient centers in Switzerland and Germany between January 2003 and June 2008.

Intervention:
Uptitration of guideline-based treatments to reduce symptoms to NYHA class of II or less (symptom-guided therapy) and BNP level of 2 times or less the upper limit of normal and symptoms to NYHA class of II or less (BNP-guided therapy).

Main Outcome Measures:
Primary outcomes were 18-month survival free of all-cause hospitalizations and quality of life as assessed by structured validated questionnaires.

Results:
Heart failure therapy guided by N-terminal BNP and symptom-guided therapy resulted in similar rates of survival free of all-cause hospitalizations (41% vs 40%, respectively; hazard ratio [HR], 0.91 [95% CI, 0.72-1.14]; P=.39). Patients' quality-of life metrics improved over 18 months of follow-up but these improvements were similar in both the N-terminal BNP–guided and symptom-guided strategies. Compared with the symptom-guided group, survival free of hospitalization for heart failure, a secondary end point, was higher among those in the N-terminal BNP–guided group (72% vs 62%, respectively; HR, 0.68 [95% CI, 0.50-0.92]; P=.01). Heart failure 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<.02 for interaction).

Conclusion:
Heart failure therapy guided by N-terminal BNP did not improve overall clinical outcomes or quality of life compared with symptom-guided treatment.

Trial Registration:
isrctn.org Identifier: ISRCTN43596477 (Figs 3,5, and 6.)

Figure 3: Symptoms and N-Terminal Brain Natriuretic Peptide (BNP) Levels at Baseline and Month 6. A, Symptoms expressed as NYHA class. B, N-terminal BNP levels. Boxes indicate interquartile range; horizontal lines, median; error bars, 10th and 90th percentiles. The improvements by both treatment strategies were significant in both age groups (all P<.001). There were no significant differences between the 2 treatment groups by age for symptoms (P=.11 for <75 years vs P=.38 for <75 years) or by N-terminal BNP level (P=.06 vs P=.30). (Reprinted from Pfisterer M, for the TIME-CHF Investigators. 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. Copyright 2009 American Medical Association. All rights reserved.)

Figure 5: Primary and Secondary Outcomes in the 2 Treatment Groups. NT-BNP indicates N-terminal brain natriuretic peptide; CI, confidence interval; HF, heart failure; HR, hazard ratio. (Reprinted from Pfisterer M, for the TIME-CHF Investigators. 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. Copyright 2009 American Medical Association. All rights reserved.)

Figure 6: Treatment Effects on Main Outcomes in Younger Compared With Older Patients. The differences between treatment groups were observed only in younger but not older patients. NT-BNP indicates N-terminal brain natriuretic peptide; CI, confidence interval; HF, heart failure; HR, hazard ratio. (Reprinted from Pfisterer M, for the TIME-CHF Investigators. 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. Copyright 2009 American Medical Association. All rights reserved.)