Sub-Q Nesiritide in Chronic HF Reverses Remodeling, Easy on Kidneys in Small Study

September 21, 2010

September 21, 2010 (San Diego, California) — Whether intravenous nesiritide (Natrecor, Scios) helps or hurts in acute decompensated heart failure (ADHF), one of the great controversies in cardiology of the past few years, remains an open question. But a number of small studies have seen no major toxic effects in various settings of chronic, advanced heart failure, whether or not there was also clinical benefit.

Now another small study finds that outpatients with NYHA 2–3 heart failure who gave themselves subcutaneous injections of nesiritide--a pharmaceutical form of human B-type natriuretic factor (BNP) that has multiple properties that might help in heart failure, showed significant improvements in cardiac structure and function but no evidence of renal toxicity over two months [1].

The latter finding from the "proof-of-concept" study, reported by Dr Horng H Chen (Mayo Clinic, Rochester, MN) last week at the Heart Failure Society of America 2010 Scientific Meeting, is noteworthy because nesiritide, once widely popular as an ADHF treatment, came under fire in two 2005 meta-analyses for allegedly increasing renal dysfunction and short-term mortality when given IV in that setting.

As covered in detail by heartwire over several years, clinicians were divided on whether the drug should be pulled from the market, and eventually nesiritide's manufacturer got behind a large randomized controlled trial aimed at resolving the issues. Called the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND HF), the trial is scheduled for presentation at this November's American Heart Association Scientific Sessions.

The current study of subcutaneous nesiritide, which began in 2003 before the controversy ignited and concluded in 2008 after the launch of ASCEND HF, showed benefit in some "very encouraging clinically relevant end points" and suggests potential for the drug in outpatient use but also raises some doubts, according to the presentation's discussant, Dr John R Teerlink (University of California and Veterans Affairs Medical Center, San Francisco). For example, nesiritide in the study showed a signal of possibly increased hypotension, a potentially dire development in patients with heart failure.

As Chen described, the study randomized in double-blind fashion 45 patients with LVEF <35% for at least two years who had NYHA class 2–3 heart failure on optimal medications to self-administer either 10 µg/kg nesiritide or placebo twice daily for eight weeks.

Five patients were omitted from the final analysis: three who developed hypotension by symptoms or blood-pressure readings (per protocol), one who withdrew for personal reasons, and one in whom heart failure worsened during the eight weeks, Chen said.

The 20 evaluable nesiritide recipients showed significant improvement in multiple structural and functional parameters by cardiac magnetic resonance (CMR) imaging compared with the 20 controls; the drug showed no adverse effect on renal function--and if anything, as Teerlink observed, may have improved renal function.

Absolute Changes in Structural, Functional, and Laboratory End Points, Eight Weeks Subcutaneous Nesiritide vs Placebo

Parameter Nesiritide, n=20 Placebo, n=20 p
LVSVI (mL/m2) -5 +6 <0.05
LVDVI (mL/m2) -10 +6 <0.05
LV mass index (mg/m2) -4 +6 <0.05
LVEF (% points) 0 -1 0.735
E/e' ratio -7 +7 <0.05
LA volume index (mL/m2) -5 +1 <0.05
GFR (mL/1.73 m2) +6 -2 0.14
Plasma renin activity (ng/mL/hr) -3 +2 <0.05

LVSVI=LV end-systolic volume index; LVDVI=left ventricular end-diastolic volume index; E/e'= ratio of mitral peak early-filling velocity to early diastolic mitral annular velocity; LA=left atrial; GFR=glomerular filtration rate

Nesiritide recipients also benefitted in Minnesota Living with Heart Failure quality-of-life scores (p<0.05) and showed no significant differences in heart rate or systolic blood pressure compared with the controls. Nor, Chen said, were there significant differences in adverse events such as lightheadedness, flushing, atrial fibrillation, hyperkalemia, or edema.

In his presentation, Teerlink pointed out that fully one-fourth of the patients originally randomized to nesiritide, three who dropped out (and so weren't in the final analysis) and three others, developed hypotension, prospectively defined as a systolic blood pressure <85 mm Hg or symptoms of lightheadedness or visual disturbance.

There's some kind of disconnect between what we think we know about the pharmacokinetics of the drug and the potential pharmacodynamics and what we saw in this trial.

"We have a drug that has been shown in acute settings to cause hypotension when given intravenously, and when you turn it off, the hypotension lasts two and half hours," he said, referring to the VMAC study.

"If you give this subcutaneously and cause hypotension, what kind of bad events will occur? What we've seen in multiple trial settings [is that] hypotension is anathema to heart failure and actually winds up hurting [patients] significantly."

Teerlink also highlighted the question of how the drug might work in chronic heart failure when given as it was in the current study, considering that plasma levels peaked at 60 minutes after subcutaneous injection and, along with blood pressure, urine sodium, and urine output, returned to baseline by 120 minutes.

"If you give this drug twice a day, how does that have long-term benefits? So there's some kind of disconnect between what we think we know about the pharmacokinetics of the drug and the potential pharmacodynamics and what we saw in this trial. That may be a limitation of the pharmacodynamics and pharmacokinetics, or it may be that these trial results aren't fully representative of what the long-term effects would be in the real population."

Chen discloses receiving research grants from Scios. Teerlink discloses receiving research support from or being a consultant to Abbott, Actelion, Amgen, Astellas, Bayer, Bristol-Myers Squibb, CardioDynamics, CHF Solutions, CoGenesys/Teva, Corthera, Cytokinetics, Forest Pharmaceuticals, Geron, GlaxoSmithKline, Indigo Pharma, Medtronic, Merck, Momentum Research, Myogen, NovaCardia, Novartis, Protein Design Labs, Sanofi-Aventis, Scios, Wyeth, and Zealand Pharma.

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