Neurohormonal activation in severe heart failure: Relations to patient death and the effect of treatment with flosequinan

Background Flosequinan is a direct-acting vasodilator that exerts beneficia l hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse out come, we conducted a substudy to examine the plasma levels of 3 neurohormon al systems known to have prognostic implications in heart failure. Methods At 20 participating Canadian centers, paired plasma samples at base line and 1 month after randomization for the measurement of N-terminal atri al natriuretic peptide (N-ANP), angiotensin Ii, and norepinephrine were obt ained in 234 patients (114 receiving flosequinan and 120 receiving placebo) . Results Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at base line to 1625 pmol/L at 1 month [P = .0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [P = .27 00]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/ mL [P = .002]). These changes were riot observed in the placebo group. Mult ivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseli ne and 1-month variables indicated that plasma N-ANP level predicted patien ts' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate anal ysis of baseline and 1-month data, the increase in plasma norepinephrine le vel did not predict the increase in heart rate associated with the use of f losequinan, suggesting that the 2 effects might be mediated by separate mec hanisms. Conclusions Results of our study demonstrate that in patients with severe h eart failure, baseline norepinephrine level pre diets death. Flosequinan in creases plasma norepinephrine level and heart rate in these patients throug h mechanisms that override its beneficial hemodynamic effects. Our study re inforces the concept that the direct actions of a pharmacologic agent may h ave a more profound impact on the prognosis of these patients than the hemo dynamic effects.