Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT03199612 |
Other study ID # |
2016-7404 |
Secondary ID |
|
Status |
Completed |
Phase |
Early Phase 1
|
First received |
|
Last updated |
|
Start date |
June 3, 2019 |
Est. completion date |
January 20, 2023 |
Study information
Verified date |
February 2024 |
Source |
Montefiore Medical Center |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The advent of continuous flow (CF) pumps for patients with severe heart failure has led to
marked improvements in survival; however, pump operation remains fraught with adverse
thrombotic events. This climbing rate of thrombosis and stroke during CF pump support has led
to a recent warning by the US Food and Drug Administration. Despite a rising incidence of
pump thrombosis and its downstream complications of stroke, the hematologic mechanisms behind
these devastating adverse events remain uncertain. Recently, it has been recognized that CF
pump induced hemolysis precedes and is associated with thrombosis. In-vitro studies show
increased platelet function with exposure to products of hemolysis, which is also known to
occur in diseases of intravascular hemolysis such as sickle cell anemia. This proposal will
investigate if hemolysis associated increased platelet function can be reduced by a
potentiation of nitric oxide signaling by an oral phosphodiesterase-5 inhibitor, sildenafil.
Elucidating mechanisms of hemolysis induced thrombosis may inform best strategies for
prevention of end organ damage and maintaining optimal CF pump operation.
Description:
Despite the remarkable improvements in survival with durable continuous flow (CF) pumps and
the clear lifesaving effects of Impella and veno-arterial extracorporeal membrane oxygenation
(VA ECMO), serious adverse hematological events such as bleeding and thrombosis create
substantial morbidity and mortality and remain major barriers for further expansion of this
technology. In particular, thrombosis is a devastating adverse event during CF pump support
as it can lead to stroke, device stoppage, and hemodynamic collapse. Although the annual
incidence of pump thrombosis has been reported to range from 8 to nearly 30%, the
pathobiological mechanisms of thrombus formation during CF pump support with ongoing
anticoagulation remain elusive. Our preliminary data associates hemolysis, which is inherent
to such devices due to high shear stress, with subsequent formation of thrombosis and stroke,
possibly through increasing platelet activation and aggregation. Our prelim data and drawing
from a body of literature from diseases of intravascular hemolysis such as sickle cell anemia
suggest that free hemoglobin released during hemolysis, which reduces NO levels, may be
activating platelets. In retrospective analysis, we have noted a significant reduction in
mean platelet volume (potential in-vivo marker of platelet activation), thrombosis and stroke
with concurrent sildenafil administration. However, this mechanism and efficacy of NO
signaling enhancers such as sildenafil remains to be proven during CF pump support.
Aim: To conduct a randomized placebo controlled study to test the hypothesis that platelet
activation and aggregation, endothelial dysfunction and pro-thrombotic inflammation in
outpatients on chronic CF pump support can be reduced by sildenafil.