Long-Term Results of Intensified, N-Terminal-Pro-B-Type Natriuretic Peptide–Guided Versus Symptom-Guided Treatment in Elderly Patients With Heart Failure

Abstract

Background— Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP–guided treatment strategy. Methods and Results— Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged ≥60 years with left ventricular ejection fraction ≤45% to intensified, NT-proBNP–guided versus standard, symptom-guided therapy into prespecified age groups (60–74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP–guided group. During long-term, NT-proBNP–guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71–1.06; P =0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64–1.13; P =0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55–0.90; P =0.005). Patients aged 60 to 74 years had benefit from NT-proBNP–guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged ≥75 years did not ( P <0.10 for interaction). In landmark analysis, there was no regression to the mean after cessation of the NT-proBNP–guided strategy. More intensified HF medication at month 12 was associated with better long-term HF hospitalization-free and overall survival. Conclusions— Intensified, NT-proBNP–guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP–guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP–guided group. Clinical Trial Registration— URL: http://www.isrctn.org . Unique identifier: ISRCTN43596477.

Effectiveness and cost-effectiveness of serum B-type natriuretic peptide testing and monitoring in patients with heart failure in primary and secondary care: an evidence synthesis, cohort study and cost-effectiveness model

“…Long-term follow-up is not available for most RCTs. In the TIME-CHF, 86 BNP-guided therapy ceased at 18 months; over a 5-year follow-up period, the study found a non-significant trend for continued improved survival in younger HFrEF patients with treatment guided by BNP (HR 0.62, 95% CI 0.37 to 1.03). Very few patients were followed up for the full 5 years in TIME-CHF.…”

“…Statistically, there was relatively little variation in the mortality outcomes of RCTs; however, there were important differences in the BNP-guided monitoring protocols used. TIME-CHF, 86 which has provided the best evidence to date of a sustained effect in younger patients with HFrEF, scheduled visits at 1, 3, 6, 12 and 18 months with the aim of rapidly up-titrating therapy within 6 months. However, other protocols may be more cost-effective.…”

Association between matrix metalloproteinase‐9 and worsening heart failure events in patients with chronic heart failure

“…Several potential reasons may explain our observations. BNP‐guided therapy does not always improve clinical outcomes as previously reported 9, 10, 11. The reason for this lack of significant improvement may be that BNP levels only change upon ventricular wall stretching.…”

“…Elevated MMP‐9 levels may help identify patients at risk before an increase occurs in ventricular pressure overload, which reflects ongoing ventricular remodeling. The value of BNP levels for guiding therapy in addition to clinical symptom‐based treatment seems to be limited,9, 10, 11, 21 despite the undisputed diagnostic and prognostic importance of these values 6, 7, 8. The benefits of predicting HF events may be offset by non‐HF events.…”

“…Of these, elevated plasma concentrations of brain natriuretic peptide (BNP) show notable associations with development of left ventricular dysfunction and HF 5. Although elevated BNP concentrations have diagnostic and prognostic importance,6, 7, 8 whether intense therapy for HF guided by BNP values is superior to therapy guided by clinical symptoms is unclear 9, 10, 11. BNP play important roles in maintaining cardiorenal homeostasis under physiological and pathological conditions.…”