BY BRUCE JANCIN
AT THE HFSA ANNUAL SCIENTIFIC MEETING
LAS VEGAS (FRONTLINE MEDICAL NEWS) – Patients with pulmonary hypertension due to systolic left ventricular dysfunction show marked hemodynamic and quality of life improvements in response to oral riociguat if they have low baseline pulmonary vascular resistance, but not if their baseline pulmonary vascular resistance exceeds 240 dyn s/cm5, Dr. Marc J. Semigran reported at the annual meeting of the Heart Failure Society of America.
This was the key finding of a prespecified secondary analysis of the Left Ventricular Systolic Dysfunction Association with Pulmonary Hypertension Riociguat Trial (LEPHT).
LEPHT was a phase-IIb, double-blind, placebo-controlled study in which 201 affected patients were randomized to 16 weeks of oral riociguat or placebo. This previously reported study ( Circulation 2013;128:502-11 ) did not meet its primary endpoint because patients on riociguat at 2 mg t.i.d. did not experience a significantly greater decrease in mean pulmonary artery pressure than with placebo. However, the investigators hypothesized that the response to riociguat would differ based upon baseline pulmonary vasomotor tone, and this hypothesis was testable in the secondary analysis, explained Dr. Semigran, medical director of the heart failure and transplantation program at Massachusetts General Hospital, Boston.
Riociguat (Adempas) is a first-in-class oral stimulator of soluble guanylate cyclase. It is approved for two indications: chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension, both of which are uncommon conditions. The LEPHT study was part of an ongoing program to win an additional indication for a much more common condition: pulmonary hypertension caused by systolic left ventricular dysfunction.
For the new secondary analysis, Dr. Semigran and coworkers divided the LEPHT population into two subgroups: the 92 patients with a low baseline pulmonary vascular resistance (PVR) of 240 dyn s/cm5, and 109 others with a PVR above that threshold. The two groups were well balanced in terms of baseline characteristics with two exceptions: ischemic etiology of heart failure and diabetes mellitus were both more common in the high PVR group.
While both groups showed a significant reduction in systemic vascular resistance over 16 weeks in response to riociguat at 2 mg t.i.d., only patients in the low baseline PVR group experienced significant reductions in pulmonary capillary wedge pressure (–6.55 mm Hg) and mean arterial pressure (–8.8 mm Hg). Moreover, improvements in stroke volume (+17 mL) and cardiac index (+0.6 L/min/m2) in response to riociguat were confined to the low-baseline-PVR group.
“The increase in cardiac index and decrease in pulmonary capillary wedge pressure seen in the low PVR group may reflect balanced pulmonary and systemic vasodilation, although a direct myocardial effect can’t be excluded based on the data at hand,” the cardiologist said.
Also, riociguat-treated patients in the low PVR group showed a mean 12-point improvement on the Minnesota Living With Heart Failure Questionnaire, while those with high baseline PVR didn’t show a significant change.
“I think a question for future consideration is, do the patients in the lower baseline PVR group have less advanced disease, making them better candidates for soluble guanylate cyclase stimulator therapy?” Dr. Semigran concluded.
The LEPHT study was sponsored by Bayer. As principal investigator in the trial, Dr. Semigran received a research grant from the company.