Sildenafil To Prevent Clot (SToPClot)

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

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.

Study Overview

• Status: Completed
• Conditions: Thrombosis; Hemolysis
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo Oral Tablet

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sildenafil; Baseline blood samples and study measurements will be acquired. Then 20 mg of the study drug will be administered. Then BP will be recorded every 30 minutes for two hours. If BP is stable (drop is < 5 mmHg after 2 hours and patient is asymptomatic), patient will proceed to take 20 mg of the study drug every 8 hours. The patient will return to clinic on day 8 and 20 mg of the study drug will be administered. After 2 hours blood samples and study measurements will be collected and the patient will resume 20 mg of the study for the next two doses. The patient will return for a third clinic visit on the next day and if BP is in the acceptable range, 40 mg of the study drug will be administered. If BP remains stable for 2 hours, then the patient will continue taking 40 mg every 8 hours. The patient will return to clinic on day 15 for a final study visit and will be given the last 40 mg dose of the study drug and after 2 hours blood samples and study measurements will be taken.	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.; Other Names: Viagra; Revatio
Placebo Comparator: Placebo Oral Tablet; Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil.	Drug: Placebo Oral Tablet; Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil.; Other Names: Sildenafil matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in serum Angiopoietin-2 to Angiopoietin-1 ratio	Mediator of vascular remodeling	Baseline, day 8 and day 15
Change in concentration of serum Endothelin-1	Mediator of vascular fibrosis	Baseline, day 8 and day 15

Collaborators and Investigators

• Sponsor: Montefiore Medical Center
• Investigators: Principal Investigator: Omar Saeed, MD, Montefiore Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2019
• Primary Completion (Actual): January 20, 2023
• Study Completion (Actual): January 20, 2023

Study Registration Dates

• First Submitted: June 22, 2017
• First Submitted That Met QC Criteria: June 23, 2017
• First Posted (Actual): June 27, 2017

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Thrombosis during Continuous Flow Pump Support
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Hemolysis; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 2016-7404

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes