Abstract 18132: A Phase 1 Study of Ranolazine in Pulmonary Arterial Hypertension
Introduction: Pulmonary arterial hypertension (PAH) causes right ventricular (RV) ischemia and failure. Agents that treat left ventricular ischemia may share elements of pathophysiology making cross development of anti-anginal agents an important opportunity for improving PAH care. Adapting new drugs across these disease populations warrants a structured approach.
Hypothesis: Ranolazine improves RV ischemia, acutely improving pulmonary vascular resistance, and with daily dosing, improves RV function.
Methods: A single center randomized placebo-controlled trial to assess the acute vasoreactivity (up to 360 minutes) and safety of ranolazine in PAH. This was followed by a 12-week phase Ib. Patients underwent monthly clinical evaluations and 12-week study of objective clinical assessments.
Results: 12 PAH patients enrolled: 5 idiopathic, 1 hereditary, 1 anorexigen, 2 connective tissue disease and 1 congenital heart disease. Patients were on monotherapy with oral or continuous infusion, or on a combination of oral and infusion therapy. All patients completed the acute phase; 10 completed the 12-week study. There were no acute hemodynamic changes in pulmonary vascular resistance with ranolazine treatment. Among 10 patients ranolazine was well tolerated at 1000 mg daily. Two serious adverse events required early withdrawal; worsening PAH and an acute asymptomatic rise in serum creatinine. The most common adverse events were diarrhea and nausea. Efficacy measures did not demonstrate any differences between treatment groups.
Conclusion: Ranolazine appears safe in combination with PAH therapies in Group 1 PAH. Ranolazine did not have acute hemodynamic effects or changes in objective measures of RV function or hemodynamics after 12 weeks. Longer administration may improve clinical parameters and outcomes but will require a larger detailed prospective study.
Author Disclosures: M. Gomberg-Maitland: Research Grant; Significant; Actelion, Gilead, Novartis, Medtronic, Lung Biotechnology, Ventripoint. Honoraria; Modest; Medscape. Consultant/Advisory Board; Modest; Gilead, Merck, Medtronic, United Therapeutics, Actelion, Bayer. Other; Modest; Ikaria- adjudication committee. R. Schilz: Research Grant; Significant; Actelion, Bayer, GeNO, Gilead, Ikaria, Novartis, Reata, United Therapeutics. Speakers Bureau; Significant; Actelion, Bayer, Gilead, United Therapeutics. Consultant/Advisory Board; Modest; Actelion, Bayer, GeNO, Gilead. A. Mediratta: None. K. Addetia: None. S. Coslet: Speakers Bureau; Modest; United Therapeutics. Consultant/Advisory Board; Modest; Gilead, United Therapeutics, Bayer. H. Gilles: Employment; Significant; Gilead. R. Oudiz: Research Grant; Significant; Actelion,Bayer, Gilead, Ikaria, Lung Biotechnology, Reata, United Therapeutics. Speakers Bureau; Significant; Actelion, Bayer, Gilead, Lung Biotechnology, United Therapeutics. Consultant/Advisory Board; Significant; Actelion, Bayer, Gilead, Lung Biotechnology, Medtronic, Pfizer, Reata, United THerapeutics.
- © 2014 by American Heart Association, Inc.