Oral Milrinone for the Treatment of Right Ventricular Failure in LVAD Patients

Purpose Early and late right ventricular failure (RVF) are major complications during left ventricular assist device (LVAD) support. Therapies to treat RVF are limited, leading to significant morbidity and increased mortality. Intravenous inotropes are a therapy for severe, persistent cases of RVF, but long-term use carries significant risks of infection and thrombosis associated with venous access. CRD-102 is a novel, extended-release form of oral milrinone. The aim of this study is to evaluate the safety of CRD-102 in LVAD patients with chronic RVF. Methods This is a Phase IIa, non-randomized, open-label study of CRD-102. Patients were eligible if they had a durable LVAD for more than 30 days, evidence of right ventricular dysfunction on echocardiogram, an implantable cardioverter defibrillator (ICD) and a right atrial pressure ≥ 12 mmHg. Patients with ongoing ventricular arrhythmias or uncontrolled atrial fibrillation were excluded. Hemodynamics, echocardiographic measures, ICD interrogation and biomarkers were measured before and during a 2-week period of treatment with CRD-102. Results Six patients were enrolled with mean age 64 ± 10 years, 4 male. The average duration of LVAD support was 5.0 ± 2.3 years. At baseline, mean tricuspid annular plane systolic excursion was 9.9 ± 1.3 mm, right atrial pressure was 16 ± 4 mmHg and pulmonary artery pulsatility index was 1.0 ± 0.4. Five patients completed the study and had no ventricular arrhythmias or increased incidence of atrial arrhythmias during the study period (ICD interrogation). One patient stopped study medication after an ICD shock due to ventricular fibrillation while potassium level was 2.8 mmol/L. There were no other adverse events related to therapy. During treatment, cardiac output significantly improved (5.0 ± 1.3 to 6.4 ± 1.7 L/min, p=0.008) while other hemodynamic parameters were unchanged. NT-proBNP numerically improved during the therapy, but did not reach statistical significance (1570 ± 902 to 1068 ± 390 pg/mL, p=0.3). Patient-reported quality of life improved during support. Conclusion Extended-release oral milrinone has an acceptable safety profile. Further studies are warranted to investigate the efficacy of this therapy for chronic RVF in LVAD patients.