Sildenafil To Prevent Clot

Thrombosis Clinical Trial

— SToPClot  

Official title:

The Role of Hemolysis in Promoting Thrombosis During Mechanical Circulatory Support With Continuous Flow Pumps (Aim 2)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03199612
• Other study ID #: 2016-7404
• Status: Completed
• Phase: Early Phase 1
• 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
• 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: January 20, 2023
• Est. primary completion date: January 20, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion:

-Adult outpatients (=18 years old) with ongoing durable CF pump support.

Exclusion:

• Taking sildenafil or nitrates for clinical indications

• Ongoing infection

• Unwilling or unable to give written, informed consent

Related Conditions & MeSH terms

• Hemolysis
• Thrombosis

Intervention

Drug:
• Sildenafil
To conduct a randomized placebo controlled study to test the hypothesis that platelet activation and aggregation during ongoing low level hemolysis in outpatients on chronic CF pump support can be reduced by sildenafil.
• Placebo Oral Tablet
Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil.

Locations

Country	Name	City	State
United States	Montefiore Medical Center	Bronx	New York

Sponsors (1)

Lead Sponsor	Collaborator
Montefiore Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in serum Angiopoietin-2 to Angiopoietin-1 ratio	Mediator of vascular remodeling	Baseline, day 8 and day 15
Other	Change in concentration of serum Endothelin-1	Mediator of vascular fibrosis	Baseline, day 8 and day 15
Primary	Change in platelet activation and aggregation (aggregometry)	During the study period platelet activation and aggregation will be measured from drawn blood samples. Platelet rich plasma will be isolated from these samples and platelet aggregometry will be used to measure platelet activation and aggregation.	Baseline, day 8 and day 15
Secondary	Change in pro-thrombotic inflammatory markers as measured by hs CRP	During the study period pro-thrombotic inflammatory markers, including hs CRP (mg/L) in serum will be measured by ELISA.	Baseline, day 8 and day 15
Secondary	Change in pro-thrombotic inflammatory markers as measured by fibrinogen	During the study period pro-thrombotic inflammatory markers including fibrinogen (mg/dL) will be measured by ELISA.	Baseline, day 8 and day 15