Abstract Aims Observational studies provide a signal that phosphodiesterase-5 inhibitors such as sildenafil are associated with lower mortality and ischemic stroke during durable left ventricular assist device (LVAD) support. This study aims to determine causal effects of sildenafil on platelet activation and circulating mediators of vascular remodeling during LVAD support. Methods and Results We conducted a double-blind, randomized, placebo-controlled study to determine the effect of sildenafil on platelet activation and circulating mediators of vascular remodeling. Stable participants on LVAD support were assigned to sildenafil or placebo every 8 hours for a 15-day period. Three primary endpoints were percent change in platelet activation by collagen, thromboxane (Tx) A2 and adenosine diphosphate (ADP). Secondary endpoints included changes in circulating mediators of vascular remodeling. Twenty participants were randomized. On day 15, those on sildenafil had lower collagen (-41%, -60 to -24, vs. -7%, -18 to 79, p=0.038) but not TxA2 (-24%, -45 to -14 vs. 3%, -15 to 87, p=0.112) and ADP (-5%, -70 to 25 vs. 31%, -29 to 242, p=0.122) induced platelet activation compared to placebo. Endothelin-1 changed by -30% (-53 to 4) in the sildenafil group vs. -3% (-18 to 22) with placebo (p=0.041). Angiopoietin (ang)-2 changed by -5% (-11 to -4) with sildenafil compared to 3% (-5 to 15) with placebo (p=0.039), while ang-1 increased by 24% (17-54) with sildenafil and was -4% (-19 to -2) with placebo (p=0.001), leading to a change in the ang-2/ang-1 ratio by -23% (-45 to -15) with sildenafil compared to 8% (-3 to 24) with placebo (p=0.001). Hs-CRP and fibrinogen were unchanged between groups. Conclusions Fifteen days of sildenafil exposure modifies platelet activation and lowers mediators of vascular remodeling on LVAD support.
Saeed et al. (Thu,) studied this question.