Page 61 - Biomarkers for risk stratification and guidance in heart failure

Chapter 3
DISCUSSION
The PRIMA study is a prospective randomized study to address whether HF therapy, guided by an individualized NT-proBNP level, improves outcome in HF patients. The PRIMA study randomized 345 patients to HF therapy guided by an individually set NT-proBNP target level in addition to clinical signs, or by clinical signs only. It addressed the benefit of selective intensification of therapy only when NT-proBNP increases beyond the individually defined “optimal” NT-proBNP level. Assessing the optimum natriuretic peptide target level is most challenging.12 As such, the PRIMA study complements the recent studies on the benefits of a more general intensification of therapy by aiming for absolute NT-proBNP targets.7, 8 PRIMA showed that selective intensification by an individualized NT- proBNP target did not significantly improve any of the pre-specified primary or secondary outcome measures. Although treatment guided by an individualized NT-proBNP target slightly improved the number of days alive outside the hospital, and improved overall mortality, these changes were not statistically significant. Individualized NT-proBNP-guided therapy resulted in significantly intensified pharmacological HF therapy reflected by an increased use of diuretics and ACE inhibitors or angiotensin II receptor antagonists in the NT-proBNP-guided group. We hypothesized that individualized NT-proBNP-guided treatment would improve outcome.
Our first assumption was that stability of NT-proBNP would portend an improved prognosis, even when the stable NT-proBNP level is well above normal. This first assumption was confirmed in this study. Patients who maintained their individual NT-proBNP target level indeed had a highly significantly better outcome. Most events occur in patients with an unstable NT-proBNP. Indeed, increases of NT-proBNP level above each individual optimum was a strong predictor of HF- related events with hazard ratios up tot 4.17, p < 0.001.
Our second assumption was that treatment of HF guided by an individualized target NT-proBNP level could avert HF events. Despite the ability to detect 64% of the imminent events, and despite the subsequent intensification of HF medication, events were not significantly averted. This suggests that although NT-proBNP measurement can help detect worsening HF, current standard-of- care HF therapy is unable to avert subsequent events. NT-proBNP levels react upon ventricular wall stretch.13 Therefore, deterioration of HF is needed before levels rise. Elevated marker levels before an increase in cardiac pressures takes
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