Clinical trial NCT03199612
Conditions: Thrombosis Hemolysis
Keywords: Thrombosis during Continuous Flow Pump Support
Sponsor: Montefiore Medical Center
Start date: 2019-06-03; Completion date: 2023-01-20
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: Negative control to understand the potential changes in platelet activation and aggregation in comparison to sildenafil.
Interventions: intervention 1: Sildenafil intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: 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. intervention 2: Negative control to understand the potential changes in platelet activation adn aggregation in comparison to sildenafil.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Hemolysis and Platelet Activation during Continuous Flow 
Mechanical Circulatory Support (CF MCS)
NCT03199612
Date: 2/10/2023






















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#UiH@i3j§■1 IRB NUMBER: 2016-7404
_,....,..,_ ....... IRB APPROVAL DATE: Cl211Glf.20l!9
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Journal of the American College of Cardiology, 2012. 59(13): p. 1123-1133. 
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Meyer, A.L., et al., Acquired von Willebrand syndrome in patients with a centrifugal or 
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11 



ICF_001.pdf: 
ALBERT EINSTEIN COLLEGE OF MEDICINE
MONTEFIORE MEDICAL CENTER
DOCUMENTATION OF INFORMED CONSENT AND HIPAA AUTHORIZATION
Introduction
You are being asked to participate in a research study called “Hemolysis and Platelet 
Activation during Continuous Flow Mechanical Circulatory Support (Aim 2)”
Your participation is voluntary -- it is up to you whether you would like to participate. It is 
fine to say “no” now or at any time after you have started the study. If you say “no,” your 
decision will not affect any of your rights or benefits or your access to care.
The researcher in charge of this project is
The Institutional Review Board (IRB) of
called the “Principal Investigator.” His name is
the Albert Einstein College of Medicine
Omar
Saeed, MD. You can reach Dr. Saeed at: and Montefiore Medical Center has
approved this research study. The IRB #
Office Address:
is in the stamp in the upper right hand
3400 Bainbridge Avenue, 7
 Floor
corner. If you have questions regarding
Bronx, NY 10467
your rights as a research subject you
718-920-2248
may contact the IRB office at 718-430-
For questions about the research study, or if
2253 or by mail:
you believe you have an injury, contact the
Principal Investigator or the IRB.
Einstein IRB
Albert Einstein College of Medicine
Support for this research study is provided by:
1300 Morris Park Ave., Belfer Bldg
Division of Cardiology, Department of
#1002
Medicine, Montefiore Medical Center
Bronx, New York 10461
Why is this study being done?
The overall goal of this study is to understand why in some cases clotting occurs during 
blood flow support provided by a device called a Continuous Flow Pump and whether 
the study drug may reduce the likelihood of clotting. Clotting can lead to severe side 
effects such as stroke and it is important to understand why it occurs to improve how we 
treat and prevent it.
In this research study, we will try to determine if a medication, called Sildenafil, may be 
effective in reducing activity of specific blood particles that may lower the chances of 
clot formation. We will test samples of your blood and urine to find out if sildenafil leads 
to reduced activity of such blood particles.
If you chose to enroll into this study, then you will receive treatment with either sildenafil 
or placebo. The placebo is a pill that looks like sildenafil but has no effect on the body 
after it is taken (no active medication). For the purposes of this study neither you nor the 
IRB NUMBER: 2016-7404
IRB APPROVAL DATE: 01/11/2023
IRB EXPIRATION DATE: 01/10/2024


study doctor will know if you received sildenafil or a placebo until the study is 
completed.
Sildenafil is approved by the U.S. Food and Drug Administration (FDA) for patients with 
pulmonary hypertension (i.e. high blood pressure in the blood vessels of the lungs). This 
medication is routinely given to patients with high blood pressure in the blood vessels of 
their lungs and is generally well tolerated. However, the FDA has not approved 
sildenafil to prevent blood clots in heart assist devices. This is the question that is 
being tested by this study.
Why am I being asked to participate?
You are being asked to participate in this study because you are being supported by a 
device called a Continuous Flow Pump that assists your heart in creating adequate 
blood flow as part of your standard clinical care.
How many people will take part in the research study?
You will be one of about 62 people who will be participating in this study.
How long will I take part in this research?
You will participate in the study for 15 days.
What will happen if I participate in the study?
You will continue to be treated with whatever routine aspirin and coumadin 
therapy you have been prescribed while you are enrolled in this research study.
You will be asked to sign this consent form before participating in the study. After 
enrollment into the study, we will collect 2 teaspoons of blood from you.  Then we will 
inflate a blood pressure cuff on your arm for 5 minutes.  After deflating it, we will 
measure the blood flow to understand the health of your blood vessels. Blood flow will 
be measured by using an ultrasound to see the change in the size of the artery in your 
arm and as well as the change in temperature of your finger.  
Then you will be randomly assigned (like by flipping a coin) to either one of two study 
groups, sildenafil group or placebo group. Your chance of getting either sildenafil or 
placebo in this study is 50/50.
After study group assignment on day 1, your blood pressure will be checked to make 
sure it is safe to take the study drug. If safe, you will receive 20 mg of the study drug. 
Then your blood pressure will be monitored for 2 hours and if it is stable you will be 
asked to take 20 mg of the study drug every 8 hours starting the next day for a total of 6 
days and return to the clinic on day 8. In clinic, we will give you a 20 mg dose of the 
study drug and after two hours we will collect 2 teaspoons of blood and check the blood 
flow in your arm after inflating a blood pressure cuff. Then you will return to clinic on the 
IRB NUMBER: 2016-7404
IRB APPROVAL DATE: 01/11/2023
IRB EXPIRATION DATE: 01/10/2024


next weekday and if your blood pressure is in the safe range, you will receive 40 mg of 
the study drug. Then your blood pressure will be monitored for 2 hours and if it is stable 
you will be asked to take 40 mg of the study drug every 8 hours starting the next day. 
You will be asked to return to the clinic on day 15 and we will give you a 40 mg dose of 
the study drug and after two hours we will collect 2 teaspoons of blood and we check 
the blood flow in your arm after inflating a blood pressure cuff. This will end your 
participation in the study.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time.
Genetic Testing
This study will not involve genetic research or genetic testing.
Specimen Banking (Future Use and Storage)
We will destroy the specimens ( blood) when the study is complete.
Will I be paid for being in this research study?
You will not receive any payment or other compensation for taking part in this study. We
will reimburse you for transportation cost.
Will it cost me anything to participate in this study?
Taking part in this study will not involve added costs to you. All study drugs will be given 
to you free of charge. You and/or your insurance company will have to pay for any costs 
that are part of your regular medical care.
What will happen if I am injured because I took part in this study?
If you are injured as a result of this research, only immediate, essential, short-term 
medical treatment as determined by the participating hospital, will be available for the 
injury without charge to you personally.

No monetary compensation will be offered.

You are not waiving any of your legal rights by signing this informed consent
document. If additional treatment is required as a result of a physical injury 
related to the research, necessary medical treatment will be provided to you and 
billed to your insurance company or to you as part of your medical expenses.
Immediately report any discomforts, problems or injuries you experience during the 
course of your participation in the study to [Omar Saeed, MD and 718-920-2626].
IRB NUMBER: 2016-7404
IRB APPROVAL DATE: 01/11/2023
IRB EXPIRATION DATE: 01/10/2024


What else do I have to do?
You must tell the research study doctor about any past and present diseases or 
allergies you are aware of and about all medications you are taking including “over-the-
counter” remedies and nutritional supplements or herbs.
Confidentiality
We will keep your information confidential, however, a risk of taking part in this study is 
that your confidential information might be shared accidentally with someone who is not 
on the study team and is not supposed to see or know about your information. This is 
very unlikely, because the study team takes confidentiality of your information seriously. 
Your research records will be kept confidential and your name will not be used in any 
written or verbal reports. Your information will be given a code number and separated 
from your name or any other information that could identify you. The form that links your 
name to the code number will be kept in a locked file cabinet and only the investigator 
and study staff will have access to the file. All information will be kept in a secure 
manner and computer records will be password protected. Your study information will 
be kept as long as they are useful for this research.
The only people who can see your research records are:

The research team and staff who work with them clinicians and staff at
Montefiore who review your records for your care groups that review research
(the Einstein IRB, and the Office for Human Research Protections)
These people, who receive your health information, may not be required by privacy laws 
to protect it and may share your information with others without your permission, if 
IRB NUMBER: 2016-7404
IRB APPROVAL DATE: 01/11/2023
IRB EXPIRATION DATE: 01/10/2024
permitted by laws governing them. All of these groups have been asked to keep your 
information confidential.
Certificate of Confidentiality
As a way to protect your privacy, we have obtained a Certificate of Confidentiality from 
the National Institutes of Health, which is funding this study. If information from this 
study were requested or subpoenaed by government agencies or the courts, we would 
use the Certificate to attempt to legally refuse to provide that information. These 
requests are rare – in only a few cases did researchers have to use the Certificate, and 
it was honored most of the time, but not every time. There are several kinds of 
situations to which the Certificate does not apply. For example, we are still required to 
report child abuse and some diseases, and we must make data available to the 
government for review or evaluation of our research. The Certificate does not prevent 
you or a member of your family from voluntarily sharing information. Similarly, if an 
insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers may not use the Certificate to withhold that 
information.


Are there any risks to me?
The main risk of taking sildenafil is a mild drop in blood pressure which will be closely 
monitored during the study period and promptly addressed as necessary. Since you are 
being supported by a heart assist device your chances of experiencing a drop in blood 
pressure are minimal – (may occur in less than 1 out of every 100 patients). Other risks 
or complications that are most common (occurring in more than or equal to 3 out of 100 
people taking sildenafil) are nose bleeding, headache, heart burn, flushing, insomnia, 
skin redness, shortness of breath, and runny nose.  Although uncommon at the low 
doses being used in this study, there is a possibility of having more erections, as well as 
a prolonged erection that could be considered a medical emergency.  During and after 
blood pressure cuff inflation you may feel temporary soreness in the arm but this 
technique is known to be very safe and without any known long term side effects.
Blood Draw
Rarely, the vein where we inserted the needle will become sore or red. Sometimes, a 
temporary harmless “black and blue” may develop. Very rarely, fainting may occur.
Are there possible benefits to me?
If you are randomized to the group that receives the placebo as a study drug, you will 
get no benefit from participating in the Study. Since the expected effect of sildenafil is to 
prevent clotting, if you are randomized to receive sildenafil, you may be at a lower risk 
of forming a blood clot or having a stroke during the study period. In either case, your 
participation in the study will generate important information that may help others who 
will get heart assist devices in the future.
What choices do I have other than participating in this study?
You can decline to participate in the study. If you decide not to participate, the medical 
care providers at this facility will still give you all of the standard care and treatment that 
is appropriate for you.
Your other choices are:
-
To continue on support with a Continuous Flow pump or other heart assist
device(s) without participating in this research study.
-
Sildenafil is available outside this study, and even after the study is completed.
Are there any consequences to me if I decide to stop participating in this study?
No. If you decide to take part, you are free to stop participating at any time without 
giving a reason. This will not affect your care and you will continue to be treated at this 
facility. However, the blood and urine samples you have already given may not be 
removed from the study and will still be used for analysis.
IRB NUMBER: 2016-7404
IRB APPROVAL DATE: 01/11/2023
IRB EXPIRATION DATE: 01/10/2024


Can the study end my participation early?
Your participation will end if the investigator stops the study earlier than expected.
CONSENT TO PARTICIPATE
I have read the consent form and I understand that it is up to me whether or not I 
participate. I know enough about the purpose, methods, risks and benefits of the 
research study to decide that I want to take part in it. I understand that I am not waiving 
any of my legal rights by signing this informed consent document. I will be given a 
signed copy of this consent form.
_________________________ ________________________________________ _________
Printed name of participant
Signature of participant
Date
_________________________ ________________________________________ _________
Printed name of person obtaining
Signature of person obtaining consent
Date
consent
IRB NUMBER: 2016-7404
IRB APPROVAL DATE: 01/11/2023
IRB EXPIRATION DATE: 01/10/2024