Vol. 14 •Issue 4 • Page 22
Drug Data
Advance in Pulmonary Hypertension Treatment Revealed
A new approach to treating pulmonary hypertension, both respiratory-associated and cardiovascular-associated, was among the highlights of the American Heart Association’s Scientific Sessions 2004 held in New Orleans.
Intravenous nesiritide (Natrecor®, Scios), a well-known vasodilatory agent indicated for treatment of decompensated congestive heart failure, improves hemodynamics and symptoms in patients with pulmonary hypertension and decompensated right ventricular failure. It increases right ventricular filling pressure and decreases left ventricular diastolic dysfunction as shown by magnetic resonance imaging, according to Roxana Sulica, MD, instructor in medicine/cardiology, Mount Sinai Medical Center, New York City.
Nesiritide is a recombinant form of human B-type natriuretic peptide (hBNP), a pulmonary vasodilator that relaxes blood vessels, increases the excretion of sodium and fluid, and decreases neurohormones that can have injurious consequences over a sustained period of time. In pulmonary hypertension, levels of endogenous hBNP correlate with right ventricular function and exercise capacity.
While it’s known that nesiritide has favorable short-term hemodynamic effects in pulmonary arterial hypertension, the effects of IV nesiritide in overall pulmonary hypertension and isolated right heart failure are unknown.
Nesiritide isn’t approved by the Food and Drug Administration for the indication of pulmonary hypertension. This is, however, being looked into for future consideration because of the results of recent and ongoing studies, according to the drug’s manufacturer.
TWO-PHASE STUDY
Researchers carried out a two-phase study to determine the vasodilator’s short-term effects over six hours and long-term effects over seven days. The first phase was double-blind, and the latter phase was an open-label trial. The primary endpoint at six hours was changes in mean hemodynamic values, while the primary endpoints for the open-label trial were symptoms and hemodynamic parameters.
Seven patients with pulmonary hypertension and decompensated right heart failure requiring hospitalization were enrolled in the study. Baseline hemodynamics were mean pulmonary artery pressure (MPAP) 55 mm Hg, mean right atrial pressure (RAP) 19.8 mm Hg, cardiac index (CI) 1.8 L/min/m2, and pulmonary capillary wedge pressure (PCWP) 12 mm Hg. Five of these patients had pulmonary arterial hypertension, and two patients had respiratory disease-associated pulmonary hypertension.
The patients underwent pulmonary artery catheterization for assessment of pulmonary vascular resistance index (PVRI), MPAP, RAP, PCWP, arterial oxygen saturation, heart rate and mean blood pressure at baseline. The study was initiated after two hours of clinical and hemodynamic stability, with patients being randomly assigned to receive IV nesiritide 2 mcg/kg bolus and 0.01 mcg/kg/min infusion or placebo for six hours, with Swan-Ganz monitoring.
In an attempt to decrease the number of observations required and to increase reproducibility of results, MRI was performed. MRI determined right atrial dimension in four-chamber view as the product of the largest orthogonal diameters (DI X D2) and as the ex-circumferential area at the beginning of ventricular systole after tricuspid valve closure.
At the end of the six-hour study periods, PVRI, MPAP, RAP and PCWP all improved significantly, as did central venous pressure. There were no significant changes in blood pressure, heart rate or oxygen saturation, as well as no increases in supplemental oxygen requirements.
In the open-label phase of the study, dyspnea and fatigue improved in 60 percent of the patients. In addition, left ventricular function rose from 55 percent to 59 percent. Lastly, right atrial dimensions improved significantly on MRI, particularly with regard to DI X D2 and area.
MECHANISM OF ACTION
Results from a recent study demonstrate that IV nesiritide exerts its effects through significantly increased production of nitric oxide (NO) and smooth muscle cyclic guanosine monophosphate (cGMP) in the systemic and pulmonary vascular beds in patients with pulmonary hypertension, said Andrew D. Michaels, MD, assistant professor of medicine, University of San Francisco Medical Center, Calif.
Pulmonary hypertension patients have a decreased pulmonary vascular expression of NO, a compound that acts as a vasodilator by increasing production of cGMP through the stimulation of soluble guanylate cyclase (GC). Natriuretic peptides increase cGMP by stimulating particulate GC.
Twenty patients with pulmonary hypertension, 10 with pre-capillary pulmonary hypertension (PCWP 15 mm Hg), and 10 with post-capillary pulmonary hypertension (PCWP greater than 15 mm Hg) were enrolled into the study to define the mechanisms by which nesiritide exerts its effects in pulmonary hypertension.
Patients underwent right heart catheterization before and 30 minutes after treatment with nesiritide as an IV bolus 2 mcg/kg and an IV infusion 0.01 mcg/kg/min. Levels of NO and cGMP from the pulmonary and systemic arteries were obtained at baseline and 30 minutes after nesiritide therapy.
At baseline, NO levels were 32 percent higher in the pulmonary arteries compared to the systemic arteries. There was no baseline difference in a cGMP between the pulmonary arteries and the systemic arteries.
After nesiritide treatment, NO increased 29 percent in the systemic arteries and 36 percent in the pulmonary arteries, while cGMP increased 331 percent in the systemic arteries and 344 percent in the pulmonary arteries. The post-capillary pulmonary hypertension patients had a significant decrease in PVRI, while the pre-capillary patients showed no change.
Pulmonary hypertension often is closely related to heart failure. The treatment of this disorder, therefore, might be carried out by the cardiologist or the pulmonologist, whichever of the two uncovers the problem first, or treatment could turn out to be a joint effort.
Lawrence M. Prescott, PhD, a frequent ADVANCE contributor, is a medical and science writer in San Diego, and former World Health Organization microbiologist and pathologist.
