Effect of sildenafil on platelet activation and mediators of vascular remodelling during LVAD support.

INTRODUCTION

Observational studies provide a signal that phosphodiesterase-5 inhibitors such as sildenafil are associated with lower mortality and ischaemic stroke during durable left ventricular assist device (LVAD) support. This study aims to determine the causal effects of sildenafil on platelet activation and circulating mediators of vascular remodelling during LVAD support.

METHODS

We conducted a double-blind, randomized, placebo-controlled study to determine the effect of sildenafil on platelet activation and circulating mediators of vascular remodelling. Stable participants on LVAD support were assigned to sildenafil or placebo every 8 h 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 remodelling.

RESULTS

Twenty participants were randomized. On day 15, those on sildenafil had lower collagen (-41%, -60 to -24, vs. -7%, -18 to 79, P = .038), but not TxA2 (-24%, -45 to -14 vs. 3%, -15 to 87, P = .112), and ADP (-5%, -70 to 25 vs. 31%, -29 to 242, P = .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 = .041). Angiopoietin (ang)-2 changed by -5% (-11 to -4) with sildenafil compared to 3% (-5 to 15) with placebo (P = .039), while ang-1 increased by 24% (17-54) with sildenafil and was -4% (-19 to -2) with placebo (P = .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 = .001). Hs-CRP and fibrinogen were unchanged between the groups.

CONCLUSION

Fifteen days of sildenafil exposure modifies platelet activation and lowers mediators of vascular remodelling on LVAD support.