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The Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) Randomized Trial

Matthias Pfisterer, MD; Peter Buser, MD; Hans Rickli, MD; Marc Gutmann, MD; Paul Erne, MD; Peter Rickenbacher, MD; André Vuillomenet, MD; Urs Jeker, MD; Paul Dubach, MD; Hansjürg Beer, MD; Se-Il Yoon, MD; Thomas Suter, MD; Hans H. Osterhues, MD; Michael M. Schieber, MD; Patrick Hilti, MD; Ruth Schindler, RN; Hans-Peter Brunner-La Rocca, MD; for the TIME-CHF Investigators

JAMA. 2009;301(4):383-392.

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

Author Affiliations: Department of Cardiology, University Hospital Basel, Basel, Switzerland (Drs Pfisterer, Buser, and Brunner-La Rocca, and Ms Schindler); Department of Cardiology, Kantonsspital St Gallen, St Gallen, Switzerland (Dr Rickli); Department of Internal Medicine, University Hospital Liestal, Liestal, Switzerland (Dr Gutmann); Department of Internal Medicine, Kantonsspital Lucerne, Lucerne, Switzerland (Dr Erne); Department of Internal Medicine, University Hospital Bruderholz, Bruderholz, Switzerland (Dr Rickenbacher); Department of Internal Medicine, Kantonsspital Aarau, Aarau, Switzerland (Dr Vuillomenet); Department of Internal Medicine, Kantonales Spital Wolhusen, Sursee, Switzerland (Dr Jeker); Department of Internal Medicine, Kantonsspital Chur, Chur, Switzerland (Dr Dubach); Department of Internal Medicine, Kantonsspital Baden, Baden, Switzerland (Dr Beer); Department of Internal Medicine, Kantonales Spital Sursee, Sursee, Switzerland (Dr Yoon); Department of Cardiology, University Hospital Berne, Bern, Switzerland (Dr Suter); Department of Internal Medicine, Kreiskrankenhaus Lörrach, Lörrach, Germany (Dr Osterhues); Department of Cardiology, Robert Bosch Krankenhaus, Stuttgart, Germany (Dr Schieber); and Department of Internal Medicine, Kantonsspital Solothurn, Solothurn, Switzerland (Dr Hilti).

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