New Orleans, LA - Weekly or twice-weekly outpatient infusions of nesiritide (Natrecor, Scios/Johnson & Johnson) do not prolong survival or prevent future hospitalizations in patients with advanced chronic heart failure and a history of acute decompensation, according to the first large, randomized, controlled study to test the regimen's effectiveness [1]. On the other hand, the drug—given as it was in the trial and to patients similar to those in the trial—appears not to be harmful overall or to renal function in particular, according to its investigators.

However, one legacy of the study, the second Follow-Up Serial Infusions of Nesiritide in Advanced Heart Failure (FUSION-2) trial, may turn out to be validation of the kind of highly attentive and clinically effective care of patients with the chronic syndrome that can be provided by organized disease-management programs. The trial was ultimately underpowered to render any firm conclusions about nesiritide's safety and clinical effects, say observers, because clinical events were fewer than anticipated. That, say the FUSION-2 trialists, was probably because all patients—whether they received placebo or nesiritide—received excellent care and state-of -the-art therapies compared with what was standard when the study was designed.

Dr Clyde W Yancy

"In the context of optimal adherence to evidence-based medical and device therapies, avoidance of nonindicated therapies, and in concert with excellent disease management, outpatient serial infusions of nesiritide did not result in demonstrable clinical benefit over intensive outpatient management," Dr Clyde W Yancy (Baylor University Medical Center, Dallas, TX) said when presenting the FUSION-2 results at the American College of Cardiology (ACC) 2007 Scientific Sessions. "The most important clinical message from FUSION-2 is that adherence to guideline-driven therapy and meticulous follow-up defines the benchmark of care for patients with chronic decompensated, or stage D, heart failure."

The trial randomized 911 patients to receive nesiritide as a 2-µg/kg bolus followed by a 0.01-µg/kg/min infusion for four to six hours or a matching placebo regimen, once or twice a week for 12 weeks. Two patients were allocated to nesiritide for every one assigned to the control group.

Inclusion in the trial required being in NYHA class 3 or 4 with an LVEF <40% and a history of at least two prior hospitalizations for HF within the past year, the most recent one within the past two months. Patients entering in NYHA class 3 were allowed only if their creatinine clearance was <60 mL/min. No outpatient IV inotropic or vasodilator therapy was allowed during the study.

At the end of the trial, there were no significant differences in rates of the primary end point of all-cause mortality or cardiovascular or cardiorenal hospitalization or in rates of its individual component events. Nor were there significant outcome differences for any of a long list of subgroups defined by age, sex, comorbidities, renal and LV function, and NYHA functional class.

Primary and secondary three-month outcomes, FUSION-2

Parameter	Nesiritide, n=605 (%)	Placebo, n=306 (%)	p
All cause death or CV or cardiorenal hospitalization (primary end point)	36.7	36.8	0.79
Days alive and out of hospital	72.5	74.8	0.09
CV mortality	8.1	9.2	0.68
Change in quality-of-life scores*	13.0	14.2	0.52

A vasodilator approved solely for and once widely used in patients with acute decompensated heart failure (ADHF), nesiritide is considered effective at alleviating symptoms in the short term but in the ADHF setting has been alleged to cause renal dysfunction and increase mortality [2,3]. As covered by heartwire throughout the past few years, the allegations have had both supporters and detractors, with the controversy culminating in Johnson & Johnson's announcement in June 2006 that it would be explored in an independently conducted, prospective randomized trial [4]. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), still in its early stages, has a high-profile leadership team and a planned enrolment of about 7000 patients.

But clinicians, as they became more familiar with the nesiritide safety debate, had already been pulling back on using the drug for ADHF. A study published in October 2006 suggested its use in ADHF had fallen by about two thirds since its peak [5].

Dr Barry M Massie

Meanwhile, Scios has been in hot water over allegations that its sales force actively encouraged physicians to add the potentially lucrative but off-label practice of administering intermittent outpatient nesiritide infusions to their care of patients with chronic HF, including those with much less severe disease than those in FUSION 2. The strategy has had some tenuous support in the literature and a lot of proponents but no basis in randomized, double-blind, placebo-controlled trials.

"FUSION-2 suggests that there's nothing dangerous about nesiritide when used in that manner with those doses, but it really didn't show any efficacy, so I don't think it's a practice physicians should use," Dr Barry M Massie (University of California and Veterans Affairs Medical Center, San Francisco) told heartwire. Massie is on the FUSION-2 steering committee.

In their public discussion after the trial was formally presented at the ACC meeting, Yancy and panelist Dr Douglas L Mann (Baylor Heart Clinic, Houston, TX) agreed that the outpatient practice should stop.

Safety outcomes, FUSION-2

Parameter	Nesiritide, n=605 (%)	Placebo, n=306 (%)	p
All adverse events	88.7	86.9	0.45
All drug-related adverse events	42.0	27.5	<0.01
All serious adverse events*	60.4	56.5	0.29
All adverse events leading to permanent withdrawal of randomized therapy	27.0	25.5	0.63

In addition, some observers contend that the trial is unable to enlighten the debate over nesiritide's safety in ADHF. After Yancy's presentation, Mann said, "It's really hard to say anything about safety one way or the other in a trial that is so underpowered as this one was."

Dr Jonathan Sackner-Bernstein

Dr Jonathan Sackner-Bernstein (CliniLabs, New York, NY), who coauthored two meta-analyses that implicated nesiritide in causing renal dysfunction and increased mortality when given for ADHF [2,3], said, "While I'm relieved that FUSION-2 did not show harm, I agree with Johnson & Johnson's commitment to prove the drug is safe in the ASCEND-HF trial." That FUSION-2 is underpowered and the outcomes data had wide confidence intervals, he told heartwire, "prevent the conclusion that the study proved it was safe."

The underpowered results, Yancy explained in his presentation, derived from fewer-than-anticipated observed clinical events—48% fewer events, in fact, than occurred in the FUSION-1 pilot study that was the basis for FUSION-2. Fewer events meant that the trial needed more patients for adequate statistical strength. The reduction likely came not only from very good background medical therapy but also from drug-therapy improvements during the trial, according to Yancy. For example, 75% of patients were on diuretics at baseline and 94% were using the agents during the study. The corresponding increase for ACE inhibitors or angiotensin receptor blockers was from 59% to 82%. Similar patterns were observed for beta blockers, aldosterone antagonists, and nitrates. Device therapy increased dramatically from the first trial to the second, Yancy said—from 25% use to 39% use of ICD-only devices and from 9% use to 24% use of biventricular pacing devices.

"Clearly," Yancy said, "an unmeasured, but we think very substantial, benefit of intensive heart-failure disease management—based on the once- or twice-weekly clinic visits, four to six hours at a time, with a concomitant observed improvement in medical therapy during the initial 12-week assessment period—mattered. We believe that the patients in FUSION-2 received not standard care but extraordinary care."

He also emphasized the trial's lack of any signal that nesiritide, as given, is harmful with respect to either adverse clinical events or effects on renal function. Although the overall event rate in the trial was high, he said, there was no observable important difference between the groups. Nesiritide-treated patients, he noted, experienced more drug-related adverse events, but these consisted "mainly of hypotension."

Changes in serum creatinine measured at outpatient clinic visits, FUSION-2

Degree of change	Nesiritide, n=605 (%)	Placebo, n=306 (%)	p
>0.5 mg/dL	32	39	0.05
>100%	4	5	0.45

Dr Mariell Jessup

Dr Mariell Jessup (University of Pennsylvania, Philadelphia), another panelist for Yancy's presentation, questioned any claims that the FUSION-2 nesiritide regimen is safe when there was a significant increase in the drug-related adverse-event rate.

"The safety issue has to be held in context," Yancy replied. "In this population with advanced disease, receiving bolus drug therapy for four to six hours, not 48 hours," he said, referring to the recommended infusion time in ADHF, "and following very carefully the particulars of renal function, we didn't see any evidence of renal harm. I don't think these data are sufficient to declare that the drug is safe in all circumstances, but in the context of the way we studied it, we didn't see a signal of risk."

The hypotension driving the increased drug-related adverse-event rate, Yancy continued, "did not result in renal insufficiency or evidence of excess mortality."

Massie said that the renal-function outcomes of FUSION-2 "should make people more comfortable" using nesiritide. But any increase in the risk of hypotension with the drug, he told heartwire, would be more of a concern in the setting of ADHF when the patients are receiving diuretics and other drugs.

Yancy and his coauthors for the FUSION-2 presentation, including Massie, report having received research grants from, having served as a consultant to, or having both relationships with Scios.