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Heart failure
Improved renal function and modest hemodynamic changes with adenosine-receptor antagonist
September 25, 2008 | Michael O'Riordan
Toronto, ON - An investigational adenosine A1-receptor antagonist modestly improved hemodynamics and renal function in stable heart-failure patients, a small dose-response study has shown. The agent reduced pulmonary capillary wedge pressures at the highest doses, although not significantly, had a weak diuretic effect, and improved renal-function measures, including cystatin C, urine volume, and sodium and potassium excretion.
Presenting the findings during the late-breaking clinical-trials session here at the Heart Failure Society of America 2008 Scientific Meeting, lead investigator Dr Veselin Mitrovic (Kerckhoff-Klinik, Bad Nauheim, Germany) said the drug was safe and well tolerated and the findings are consistent with other investigational agents in this class.
The drug, known as SLV320 (Solvay Pharmaceuticals), "may offer a new therapeutic strategy for the treatment of patients with heart failure," said Mitrovic. Discussing the findings, Dr Barrie Massie (San Francisco VA Medical Center, CA) agreed with the investigators, saying he sees a role for the agent in hospitalized heart-failure patients and used in association with diuretics to increase salt and water excretion and maintain renal blood flow.
Effects of the kidney important
SLV320 is one of several adenosine A1-receptor antagonists currently being studied. In this phase 2 dose-ranging investigation, 111 NYHA class 2 and 3 heart failure patients with an ejection fraction <35% were randomized to placebo; to 5 mg, 10 mg, or 15 mg of SLV320 given intravenously over 60 minutes; or to furosemide.
There were nonsignificant improvements from baseline in pulmonary capillary wedge pressure with SLV320 at the 10-mg and 15-mg doses, the study's primary end point. There were trends in improvements in right atrial pressure and systemic vascular resistance, but these were also nonsignificant. Renal effects, including urine volume, sodium excretion, and potassium chloride excretion, were significantly improved from baseline with the 10-mg and 15-mg doses. Cystatin C was significantly reduced from baseline with SLV320.
Massie said the modest hemodynamic effects are not surprising, and the goal of the drug is to increase excretion and preserve kidney function. The diuretic effect with SLV320 is modest, but the class is not intended to replace furosemide. Combining the two agents could potentially improve diuresis and glomerular filtration rate.
Adenosine plays an important role in stabilizing the electrical activity in the brain, noted Massie, and some of the antagonists have been associated with seizures. This was observed with other drugs and is likely to be a possible complication, he said, although no deaths or serious adverse events were noted in this study. More research into the effects of A1-receptor antagonists on morbidity and mortality are still needed, said Mitrovic and Massie.
Solvay Pharmaceuticals sponsored the study. Massie has done investigational work with other A1-receptor antagonists, including rolofylline, an agent licensed to NovaCardia. |
