Sildenafil To Prevent Clot

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

Status

Completed

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03199612

Acronym

SToPClot

Enrollment

Registered

2017-06-27

Start date

2019-06-03

Completion date

2023-01-20

Last updated

2024-07-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hemolysis, Thrombosis

Keywords

Thrombosis during Continuous Flow Pump Support

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.

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.

Interventions

DRUGSildenafil

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.

DRUGPlacebo Oral Tablet

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Intervention model description

Placebo controlled randomized trial with 1:1 enrollment in each study arm.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion 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

Design outcomes

Primary

Measure	Time frame	Description
Area Under the Curve for Adenosine Diphosphate (ADP)	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

Measure	Time frame	Description
Pro-thrombotic Inflammation as Measured by High-sensitivity C-reactive Protein (hs CRP)	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.
Pro-thrombotic Inflammation as Measured by Fibrinogen	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

Measure	Time frame	Description
Serum Angiopoietin-2 to Angiopoietin-1 Ratio	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.
Concentration of Serum Endothelin-1	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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. 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.	10
Placebo Oral Tablet Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil. Placebo Oral Tablet: Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil.	10
Total	20

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0

Baseline characteristics

Characteristic	Sildenafil	Placebo Oral Tablet	Total
Age, Continuous	55 years	56 years	55 years
Race/Ethnicity, Customized Hispanic	4 Participants	3 Participants	7 Participants
Race/Ethnicity, Customized Non Hispanic Black	5 Participants	4 Participants	9 Participants
Race/Ethnicity, Customized Non Hispanic White	1 Participants	3 Participants	4 Participants
Region of Enrollment United States	10 participants	10 participants	20 participants
Sex: Female, Male Female	2 Participants	2 Participants	4 Participants
Sex: Female, Male Male	8 Participants	8 Participants	16 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 10
other Total, other adverse events	1 / 10	0 / 10
serious Total, serious adverse events	0 / 10	0 / 10

Outcome results

Primary

Area Under the Curve for Adenosine Diphosphate (ADP)

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.

Time frame: Baseline, day 8 and day 15