BACKGROUND: Despite improvements in hemocompatibility-related adverse events (HRAEs) with the HeartMate 3 left ventricular assist device (LVAD), hemodynamic related events (HDREs) such as right ventricular failure (RVF) and aortic insufficiency still result in considerable morbidity and mortality. We investigated a comprehensive upfront RV protection strategy combining hemodynamic, ventilatory, and pharmaceutical optimization to mitigate the risk of RVF. METHODS/RESULTS: Participants were prospectively randomized in a 1:1 fashion to either the RV protection strategy or usual care for post-operative LVAD management. The RV protection strategy targeted RV afterload (inhaled NO ≥48hrs, PCWP <
18), RV preload (CVP 8-14), RV perfusion (MAP 70-90, Hgb >
8), RV contractility (IV inotropes), rate/rhythm control (HR >
100, normal sinus), ventilatory management (SpO2 >
95, PaCO2 <
50, plateau pressure <
30, PEEP ≤5), and RV geometry (echo-guided septal position). Primary outcome was survival free from any HDREs or HRAEs at 24-weeks. Secondary outcomes included severe RVF by INTERMACS and ARC definitions. 20 participants were randomized: 10 to RV protection strategy and 10 to usual care. Median age was 60 years (IQR 54-69), 50% Black, and 50% ischemic. At 24-weeks, the RV protection strategy had significantly greater survival free from HDREs or HRAEs compared to usual care (80% vs. 40%, p=0.04). Event-free survival for HRAEs resulted in similar findings. No HDREs occurred with the RV protection strategy vs. 3 (30%) with usual care (p=0.067). Similarly, severe RVF by INTERMACS or ARC did not occur in the RV protection strategy vs. 3 (30%) with usual care (p=0.20). CONCLUSIONS: Participants receiving a novel, comprehensive upfront RV protection strategy post-LVAD implantation had significantly greater survival free from HDRE or HRAE at 24-weeks.