Dallas, TX - The Follow-Up Serial Infusions of Nesiritide in Advanced Heart Failure (FUSION II) study, showing no major benefits of nesiritide (human B-type natriuretic peptide [BNP]) (Natrecor, Scios) in the outpatient treatment of advanced chronic heart failure, has now been published in the inaugural, May 1, 2008 issue of the new journal Circulation: Heart Failure [1].

The study was conducted by a group led by Dr Clyde Yancy (Baylor University Medical Center, Dallas).

They explain that patients with advanced heart failure are at high risk for hospitalization and death, and, other than heart transplantation and left-ventricular support devices, no therapeutic interventions beyond standard therapies have been shown to reduce symptoms or improve outcomes in this population, so palliative care is often the default strategy for these patients.

They note that nesiritide exhibits vasodilatory, natriuretic, and lusitropic activity, has been associated with neurohormonal antagonism and reverse remodeling, and is currently indicated for patients with acute decompensated heart failure to reduce pulmonary wedge pressure and improve short-term dyspnea, but its use remains in question because of safety concerns. A pilot study to evaluate the potential of outpatient, intermittent nesiritide infusions in advanced heart failure patients (FUSION I) showed neutral results, but subgroup analysis suggested a lower rate of all-cause death and hospitalization and more days alive and out of the hospital for high-risk patients and those with reduced renal function randomized to nesiritide than for those randomized to usual care.

The investigators therefore conducted a larger trial (FUSION II) trial to further evaluate the nesiritide outpatient infusions in this population.

The trial included 911 patients with ACC/AHA stage C/D heart failure who had had two recent heart-failure hospitalizations, an ejection fraction of less than 40%, and NYHA class 4 symptoms or NYHA class 3 symptoms with creatinine clearance less than 60 mL/min. They were randomized to nesiritide (2 µg/kg bolus plus 0.01 µg/kg-per-minute infusion for four to six hours) or matching placebo, once or twice weekly for 12 weeks. All patients were treated to optimal goals with evidence-based medical/device therapy facilitated by careful disease management.

The primary end point of all-cause death or cardiovascular or renal hospitalization at 12 weeks was similar in the two groups.

There were no statistically significant differences between groups in any of the secondary end points, including the number of cardiovascular or renal hospitalizations, the number of days alive and out of the hospital, change in Kansas City Cardiomyopathy Questionnaire score, or cardiovascular death. Adverse events were similar between groups; nesiritide was associated with more hypotension but less predefined worsening renal function.

Yancy et al conclude: "Serial outpatient nesiritide infusions do not provide a demonstrable clinical benefit over intensive outpatient management of patients with advanced ACC/AHA stage C/D heart failure."

They note that there was no evidence of worsening renal function with nesiritide and no signal of an adverse mortality effect, although this trial was underpowered to conclusively evaluate clinical outcomes. They add: "These data may serve to diminish the safety concerns associated with nesiritide use, but it is important to note that they do not resolve these concerns."

They point out that the mortality and hospitalization rates in FUSION II were much lower than in similar patients in FUSION I, so the trial was underpowered to evaluate the effect of nesiritide on the primary end point. But they add that the "nearly indistinguishable" event rate between active treatment and placebo makes it unlikely that an important positive effect was missed.

They suggest that the event rates were lower in this trial because of better use of background therapy, with greater use of carvedilol, implantable cardioverter defibrillators (ICDs), and cardiac resynchronization therapy (CRT), and less use of positive inotropic agents in FUSION II compared with FUSION I. In addition, FUSION II included one or two half-days weekly when patients interacted closely with a heart-failure management team, and the authors note that while the potential benefits of this contact are immeasurable, this level of care is beyond what can feasibly be provided in routine care settings.

In an accompanying editorial [2], Drs John Burnett and Josef Korinek (Mayo Clinic, Rochester, MN) suggest that the greater incidence of hypotension in the nesiritide group in FUSION II could possibly have offset any favorable sympatho-inhibiting actions of nesiritide and reduced renal perfusion pressure, thereby limiting the full favorable actions often reported in animal models and in human subjects without CHF. They therefore put forward the idea that a lower dose of nesiritide or a regimen without a bolus could be advantageous. They note that less worsening of renal function was observed with nesiritide in FUSION II, which may indicate that the drug had a renoprotective effect despite induced hypotension. "It is therefore conceivable that had no bolus and/or a lower dose been used, a nesiritide benefit could have been even more obvious," the editorialists add.

They report that a large placebo-controlled trial (ASCEND-HF) is currently under way to further evaluate the safety and efficacy of nesiritide in the acute heart-failure setting, but they call for further trials to be conducted with lower doses. They also suggest that the drug may be best targeted to hypertensive patients or those with preserved ejection fraction, recognizing the vasodilating and prolusitropic properties of nesiritide.

Yancy told heartwire that the FUSION II investigators decided to use the standard dose including the bolus. "In the case of outpatient administration, the bolus is especially important given the short-term nature of the infusion, but clearly administration of the bolus is associated with hypotension. However, this need for the bolus is driven by an intent to effect a hemodynamic change. The more provocative approach would be to seek a biological response and indeed, a no-bolus, low-dose paradigm might be preferable," he commented.

Yancy agrees with Burnett that promise for the therapeutic potential of natriuretic peptides remains, but research in this area is still incomplete. "My greatest curiosity regards a need for a better understanding of the relationship of BNP levels and therapeutic response to natriuretic peptides. There are some data, suggestive only, that elevated BNP levels in chronic heart failure may be indicative of BNP deficiency, as the measured BNP is immunoreactive but may not be biologically active. Thus a 'high' measured BNP level might be a signal of a 'low' physiologically active BNP. This needs to be rigorously proven and tested but may reflect an alternative way of using these agents. There are those patients who respond to this therapy, likely in both the acute and chronic setting, but our ability to anticipate response is absent, and our insight into controlling the adverse influence of drug-induced hypotension needs to increase," he added.