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Sildenafil To Prevent Clot (SToPClot)

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ClinicalTrials.gov Identifier: NCT03199612
Recruitment Status : Recruiting
First Posted : June 27, 2017
Last Update Posted : November 7, 2019
Sponsor:
Information provided by (Responsible Party):
Omar Saeed, Montefiore Medical Center

Brief 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.

Condition or disease Intervention/treatment Phase
Thrombosis Hemolysis Drug: Sildenafil Drug: Placebo Oral Tablet Early Phase 1

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 during ongoing low level hemolysis in outpatients on chronic CF pump support can be reduced by sildenafil.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Placebo controlled randomized trial with 1:1 enrollment in each study arm.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Role of Hemolysis in Promoting Thrombosis During Mechanical Circulatory Support With Continuous Flow Pumps (Aim 2)
Actual Study Start Date : June 3, 2019
Estimated Primary Completion Date : August 30, 2023
Estimated Study Completion Date : August 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Clots

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 Name: Sildenafil matching placebo




Primary Outcome Measures :
  1. Change in platelet activation and aggregation (aggregometry) [ 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.


Secondary Outcome Measures :
  1. Changes in Endothelial Function as measured by the vascular reactivity index (VRI) [ Time Frame: Baseline, day 8 and day 15 ]
    During the study period endothelial function will be measured by the VRI as calculated by the Endothelix device, after a 5 minute blood pressure cuff occlusion of the brachial artery.

  2. Changes in Endothelial Function as measured by Endothelin 1 [ Time Frame: Baseline, day 8 and day 15 ]
    During the study period changes in endothelial function, will be measured by blood endothelin-1 (pg/mL) levels trough ELISA

  3. Change in pro-thrombotic inflammatory markers as measured by 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.

  4. Change in pro-thrombotic inflammatory markers 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03199612


Contacts
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Contact: Thiru Chinnadurai, MD 718-920-2626 tchinnad@montefiore.org
Contact: Omar Saeed, MD 718-920-2626 osaeed@montefiore.org

Locations
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United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10467
Contact: Omar Saeed, MD    718-920-2626    osaeed@montefiore.org   
Sponsors and Collaborators
Montefiore Medical Center
Investigators
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Principal Investigator: Omar Saeed, MD Montefiore Medical Center

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Responsible Party: Omar Saeed, MD, Montefiore Medical Center
ClinicalTrials.gov Identifier: NCT03199612     History of Changes
Other Study ID Numbers: 2016-7404
First Posted: June 27, 2017    Key Record Dates
Last Update Posted: November 7, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Omar Saeed, Montefiore Medical Center:
Thrombosis during Continuous Flow Pump Support
Additional relevant MeSH terms:
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Thrombosis
Hemolysis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents