Boca Raton, FL - The drug nesiritide (Natrecor, Scios), beset by controversy about whether it helps or harms patients with acute decompensated heart failure, and in particular whether it promotes renal dysfunction, was found to be neither renotoxic nor renoprotective when given at recommended dosages in a prospective, randomized study [1].

Dr Margaret M Redfield (Source: Mayo Clinic)

An early analysis from the ongoing trial "provides reassurance that standard-dose nesiritide does not adversely affect renal function in acute decompensated heart failure. However, it does not demonstrate hoped-for improvements in renal function, diuretic responsiveness, or neurohormonal profile," according to the report from Dr Margaret M Redfield (Mayo Clinic, Rochester, MN) and colleagues that was presented here at the Heart Failure Society of America (HFSA) 2005 Annual Scientific Meeting. The authors speculate that concurrent diuretic therapy and blood-pressure reduction may attenuate the renoprotective effects they are sure nesiritide can provide.

Nesiritide, a bioengineered version of brain-type natriuretic peptide (BNP), was approved as a vasodilator for patients with acute decompensated HF, and studies suggest that it may also modulate neurohormones. But it gained a reputation for being diuresis enhancing and possibly renoprotective when added to conventional therapy. It had become widely used by the time two meta-analyses appeared in the literature, one suggesting that the drug may promote renal dysfunction and another pointing to a possible increased risk of death at 30 days [2,3].

But the prospective study presented at the HFSA enters the controversy somewhere in the middle. "Clearly our data do not suggest a potent renoprotective effect at the standard dose, but they don't show any trend toward an adverse effect," Redfield told heartwire. "And we certainly don't see any enhancement of natriuresis with diuretics."

Her group randomized 65 patients with acute decompensated HF and "mild-to-moderate" renal dysfunction, defined as a creatinine clearance of 20-60 mL/min, to receive standard management with or without a nesiritide infusion. In the unblinded trial, the drug was given at the recommended dosage of a 2-µg/kg bolus followed by 0.01 µg/kg per minute over 48 hours.

Compared with standard care, nesiritide infusions were associated with significantly reduced blood pressure, serum creatinine, and blood-urea nitrogen over the first day but showed no such differences by 48 hours. Nor did it alter patients' responses to furosemide (Lasix, Sanofi Aventis), neurohormonal profile, or risk of developing cardiorenal syndrome.

Total diuretic dosage at 48 hours and mean effects of diuresis

Parameter	Nesiritide standard therapy, n=34	Standard therapy alone, n=31	p
Mean total 48-h furosemide dose (mg)	272	255	NS
Change in fluid balance at 48 h (L)	-2.7	-3.8	0.05
Change in weight at 48 h (kg)	-2.2	-3.3	0.07

Dr Clyde Yancy

Commenting on the study for heartwire, Dr Clyde Yancy (University of Texas Southwestern Medical Center, Dallas) said he interprets the patients as having "at least moderate renal insufficiency" based on their maximum creatinine clearance of 60 mL/min, and so they are a subtype of nesiritide recipients who haven't been well studied. Therefore, the study's findings don't necessarily apply to every kind of patient who has received the drug. Moreover, he noted, none of the diverse natriuretic-peptide physiological effects will necessarily show up all the time in every patient. "Not everybody's going to have natriuresis and not everybody will have diuresis or any of the other effects we feel are important. But in certain subsets of patients, a given property will predominate, maybe as a function of renal insufficiency or disease severity."

Yancy affirmed his confidence in the therapeutic potential of natriuretic peptides and said that some of the major questions are about their clinical application: "Which patient, what dose, what concomitant medical treatments?"

Redfield said her group has laboratory and retrospective clinical data supporting a possible renoprotective effect from lower-than-standard doses of nesiritide, minus the bolus, in patients with low blood pressure and very poor creatinine clearance. "Maybe a dose that doesn't drop the blood pressure so much is beneficial," she said.

"In our practice we have a small percentage of patients who, despite oxygen and one dose of Lasix, are very symptomatic. I feel comfortable using nesiritide in those patients for its primary indication as a vasodilator," Redfield said. "Should we be giving it to everyone to try to enhance renal function? Based on this [study], we would say no. But because there are so many indications that it might have beneficial renal effects, we think it's important to go on and look at lower doses."