STOCKHOLM – Daily subcutaneous injections of nesiritide led to significant improvements in left ventricular volume in a placebo-controlled pilot study with 40 heart failure patients treated for 8 weeks.
Nesiritide, a B-type natriuretic peptide, has a U.S.-approved indication for intravenous treatment of patients with acutely decompensated heart failure. The treatment is usually maintained for no more than a couple of days. The new findings came from a novel regimen of chronic, daily therapy over 8 weeks, a “very different” approach, Dr. Horng H. Chen said at the annual congress of the European Society of Cardiology.
“This proof of concept pilot study supports the hypothesis that 8 weeks of therapy with subcutaneous BNP [B-type natriuretic peptide] improves left ventricular remodeling, diastolic function, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) score in patients with symptomatic, systolic heart failure on optimal treatment,” said Dr. Chen, a cardiologist at the Mayo Clinic in Rochester, Minn. The next step should be a large phase II study, with about 500 patients and clinical end points, he said in an interview. He and his associates also want to eventually test daily nesiritide treatment on patients with less-advanced heart failure.
The new findings also advance a novel understanding of heart failure as a protein deficiency disease in which the missing hormone is nesiritide (BNP). ”In severe heart failure, the heart makes abnormal forms of BNP that lack full biologic activity,” said Dr. John C. Burnett Jr., professor of medicine at Mayo and senior investigator for the study. A severely failing heart “does not make enough [BNP] to prevent progression.”
This reasoning led to Dr. Chen’s study using BNP to relieve the protein deficiency in the same way that insulin treats insulin deficiency in patients with type 1 diabetes. Dr. Burnett and his associates are also developing new analogues of BNP with extended plasma half-life and bioavailability, and with enhanced biologic activity that may make oral treatment possible.
The NICE BNP (Novel Protein Therapeutics for Chronic Systolic Heart Failure: Chronic Subcutaneous BNP Administration) study enrolled 45 patients aged 18 or older with New York Heart Association class II or III heart failure and a left ventricular ejection fraction of 35% or less. The researchers randomized 24 patients to receive subcutaneous injection with 10 mcg/kg nesiritide twice daily and 21 patients to placebo in addition to optimal medical therapy. At baseline, three patients in the nesiritide group had hypotension (defined as a systolic blood pressure less than 85 mm Hg), or had symptoms of light-headedness or visual disturbances and left the study, and another two patients withdrew for personal reasons, leaving 20 patients in each treatment arm.
The patients’ average age was about 65 years, and about two-thirds were women. Their average left ventricular ejection fraction was about 32%.
After 8 weeks of treatment, patients in the nesiritide arm showed significant declines in the study’s primary end points: their left ventricular systolic volume index (which fell by an average of about 5 mL/m2, compared with baseline) and their left ventricular diastolic volume index (which fell by an average of about 9 mL/m2, compared with baseline). In contrast, patients in the placebo arm averaged 5 mL/m2 increases in both measures, Dr. Chen reported.
Nesiritide treatment also produced significant improvement in several other measures, including left ventricular mass and measures of cardiac diastolic function. The average score on the MLHFQ improved by 8 points in the nesiritide patients, whereas the average worsened by about 1 point in the placebo patients. Patients in the nesiritide arm also showed preserved renal function, with their average glomerular filtration rate rising but not significantly, whereas heart rate and blood pressure showed no significant changes. The nesiritide patients also showed a significant drop in plasma renin activity: an average reduction of about 3 ng/mL per hour, compared with a small, average rise in the placebo patients.
No patient had drug-related serious adverse events. The adverse event profile in the nesiritide arm generally matched the profile in the placebo arm. The most notable difference was that three patients on nesiritide reported light-headedness, with none withdrawing from the study, compared with no episodes of light-headedness in the placebo arm, a between-group difference that did not reach statistical significance.
The study received partial funding from Scios, which markets nesiritide (Natrecor). Dr. Chen said that he had no other disclosures. Dr. Burnett is chairman of the scientific advisory board of Nile Therapeutics, a company started by the Mayo Clinic to develop novel, therapeutic forms of BNP.