ASCEND-HF: Nesiritide Safe But of Limited Dyspnea Benefit in Acute HF

November 14, 2010

November 14, 2010 (Chicago, Illinois) — Designed to settle a debate that loomed over cardiology about five years ago, a randomized trial with >7000 patients has concluded that the IV vasodilator nesiritide (Natrecor, Scios/Johnson & Johnson) doesn't compromise renal function or increase mortality within a month of its use in acute decompensated heart failure (ADHF) [1].

Nor, of note, does it seem to have much more of an effect against acute dyspnea than can be currently achieved in ADHF with conventional diuretics and vasodilators, both of which are less expensive than nesiritide, a mass-production version of a native natriuretic peptide.

Dr Robert Califf

In the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure(ASCEND HF), there was "no evidence for a major benefit" from nesiritide vs placebo on top of standard care, said Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) at a presentation of the trial for the media. The trial was scheduled for formal presentation later in the day here at the American Heart Association 2010 Scientific Sessions by Dr Adrian F Hernandez (Duke Clinical Research Institute).

Califf chairs the ASCEND-HF executive committee, which he said collectively concluded that physicians, based on the data, "can make their [own] decisions about the value of the effect of this drug on dyspnea."

He addressed the past controversy about whether nesiritide--once widely popular for what seemed to be a consistent, rapid benefit against dyspnea in ADHF--might worsen renal function and actually increase 30-day mortality, as suggested by two meta-analyses [2,3]. "We constantly put drugs on the market without doing the right outcome trials. If this outcome trial had been done earlier, clinicians and patients would have had a much better idea of the potentially very limited role of this treatment, but they also would have known that it was not harmful."

Nesiritide rode to widespread use on the basis of studies with designs that made them inconclusive, Califf observed for heartwire . "The effect of nesiritide on dyspnea was overestimated, partly because the original trial withheld other therapies for the first three hours," he said.

Dr Clyde W Yancy

Also at the press conference, Dr Clyde W Yancy (Baylor University Medical Center, Dallas, TX), a longtime nesiritide investigator but not part of ASCEND-HF, agreed with Califf on the trial's essential message to clinicians. "The practitioner will need to interpret the dyspnea information in ASCEND-HF to understand whether or not the very modest benefit is of value to the patient who is presenting with decompensation. It is clear that it is not a significant effect, and one could achieve similar results with appropriately administered diuretic therapy on top of already-available and appropriate evidence-based medical care," he said.

"So those will be highly individualized decisions. But one would not refrain from using it because of concern over risk."

Elaborating for heartwire , Yancy said another main message from the trial is that "the guidelines are correct. The guidelines suggest as an adjunctive approach you can use vasodilator therapy," and that includes nesiritide along with, conventionally, nitroglycerin and nitroprusside.

"Oddly enough," Yancy said, "the database supporting the use of those [latter] two vasodilators is very small compared with what we now have on nesiritide. So if the prompt is to use a vasodilator because your patient is ill, then [nesiritide] is the best-studied vasodilator." It's important to consider, however, that based on ASCEND-HF, it improves dyspnea but not clinical outcomes.

Still, he said, "If you go to a patient who is short of breath and say, 'Do you want me to help your breathing improve?' the answer is, 'Hell, yeah! Give me whatever it takes.' And I believe that what's going to continue to be the role for the vasodilators."

Dr Keith D Aaronson

Dr Keith D Aaronson (University of Michigan, Ann Arbor), a coauthor on the two 2005 meta-analyses that sparked more than a year of loud debate--in the literature and at meetings--by suggesting nesiritide may promote renal dysfunction and increase short-term mortality when given IV in that setting, commented for heartwire that it "seems clear" ASCEND-HF was a neutral study.

"It puts to rest concerns [we] had about mortality and development of renal dysfunction," he said. "But it also seems to put to rest hopes that others had for its clinical effectiveness." First, do no harm, and then the physician wants to do some good, Aaronson said in a take-off of the familiar adage. With nesiritide in ADHF, "there's very little evidence that we're doing something good."

On the other hand, he said, "these data are very substantial in terms of providing a signal of safety, and one could argue that that signal is firmer than it is for the other vasodilators, which have not been well studied."

ASCEND-HF randomized 7141 patients in 30 countries (including 45% from North America) in double-blind fashion and within 24 hours of hospitalization and institution of acute IV therapy for ADHF to receive IV nesiritide or placebo on top of standard therapy.

The drug was infused at 0.01 µg/kg/min for up to seven days (duration at physician's discretion based on clinical signs), sometimes preceded (at physician's discretion) by a nesiritide bolus of 2 µg/kg.

For the clinical end points in the analysis, Califf explained, any differences had to exceed a p value of 0.045 to be significant. For the dyspnea end points, a difference was significant if the p was <0.005 at both six and 24 hours or <0.0025 at either six or 24 hours. The differences between the two groups didn't meet these tests for significance.

Primary Results and Renal-Function Safety End Point in ASCEND-HF, IV Nesiritide in ADHF

End points

Placebo (%), n=3511

Nesiritide (%), n=3496

p

30-d death/HF hospitalization*

10.1

9.4

0.31

30-d death

4.0

3.6

 

30-d HF rehospitalization

6.1

6.0

 

Dyspnea at 6 h*

42.1 44.5

0.030

Moderately better

28.7

29.5

 

Markedly better

13.4

15.0

 

Dyspnea at 24 h*

66.1 68.2

0.007

Moderately better

38.6

37.8

 

Markedly better

27.5

30.4

 

>25% decrease eGFR

29.5

31.4

0.11

*Co–primary end points.

eGFR=estimated glomerular filtration rate

Dr Mariell Jessup

Program chair for the scientific sessions, Dr Mariell Jessup (University of Pennsylvania School of Medicine, Philadelphia), said for heartwire that ASCEND-HF underscores that "we have a crying need for new therapies [for ADHF]."

Jessup, who is an ASCEND-HF investigator, said clinicians will probably continue to use nesiritide as one option, though not a first-tier one. "But we run out of options fast in acute decompensated heart failure. There are some patients who respond to it despite not responding to other therapies."

Yancy speculated for heartwire that the "standard care" that all patients received in ASCEND-HF, to which nesiritide was added, must have been very good compared with what is generally the case in clinical practice.

"If you look at the event rates with placebo, presented as about 10% today, when the expected rate was 14%--that has to happen for some good reason," he said. "But even more than that, at 30 days the mortality rate in ASCEND-HF was dramatically less than what it is in clinical practice."

Based on Centers for Medicare & Medicaid Services data, according to Yancy, "About 10% of patients admitted with heart failure are dead at 30 days. In ASCEND-HF, that number was less than 5%. That's huge, and it reflects not a drug, but a process of care, adhering to evidence-based therapies. So I think whatever it is that we do in a clinical trial that promotes more adherence, we need to replicate that in clinical practice."

Califf reports receiving research grants from Johnson & Johnson. Aaronson reports receiving research grants from HeartWare and Terumo and being a consultant or on an advisory board for HeartWare. Jessup reports receiving research grants from Thoratec and HeartWare. Yancy reports having been a consultant and receiving research grants from Scios prior to three years ago but has no relevant disclosures for the period since then.

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