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Completed

NCT Number: NCT03199612

Sildenafil To Prevent Clot

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.

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Key information

Conditions

Thrombosis Cardiovascular Diseases Embolism and Thrombosis Hemolysis Pathologic Processes Pathological Conditions, Signs and Symptoms Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Early Phase 1

Primary location

Montefiore Medical Center

The Bronx, New York, 10467, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Sildenafil

Drug

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.

Other names: Viagra, Revatio

Placebo oral tablet

Drug

Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil.

Other names: Sildenafil matching placebo

Primary outcomes

  1. Area Under the Curve for Adenosine Diphosphate (ADP)

    Time frame: Baseline, day 8 and day 15

    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. Platelet activation and aggregation is measured as an area under the curve (AUC) derived as the resistance (ohms) x time (s). There is no reference range for ADP induced AUC. Higher values of AUC indicate greater platelet aggregation.

Secondary outcomes

  1. Pro-thrombotic Inflammation as Measured by High-sensitivity C-reactive Protein (hs CRP)

    Time frame: Baseline, day 8 and day 15

    During the study period pro-thrombotic inflammatory markers, including hs CRP (mg/L) in serum will be measured by ELISA. The upper limit of normal reference for hs CRP is 0.5 mg/dL. Higher values of hs CRP indicate greater pro-thrombotic inflammation.

  2. Pro-thrombotic Inflammation as Measured by Fibrinogen

    Time frame: Baseline, day 8 and day 15

    During the study period pro-thrombotic inflammatory markers including fibrinogen (mg/dL) will be measured by ELISA. The upper limit of normal reference for fibrinogen is 187-502 mg/dl. Higher values of fibrinogen indicate greater thrombo-inflammation.

Other outcomes

  1. Serum Angiopoietin-2 to Angiopoietin-1 Ratio

    Time frame: Baseline, day 8 and day 15

    Mediator of vascular remodeling. This is a relative unit and there is no reference range in the context of magnetically levitated left ventricular assist device support. A higher Angiopoietin-2 to Angiopoietin-1 ratio indicates greater microvascular remodeling and inflammation.

  2. Concentration of Serum Endothelin-1

    Time frame: Baseline, day 8 and day 15

    Mediator of vascular fibrosis. The normal reference is 1-2 pg/ml. Higher values indicate greater deviation from normal.

Sponsors and collaborators

Lead sponsor

Montefiore Medical Center

Other

Collaborators

  • National Heart, Lung, and Blood Institute (NHLBI)

Registry information

Official study title

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

Acronym: SToPClot

Important dates

Study start
2019
Primary completion
2023
Study completion
2023
First posted
Jun 27, 2017
Registry last updated
Jul 10, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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