Sildenafil to Reduce Vascular Remodeling During Left Ventricular Assist Device Support

NCT06510322 | Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: 2024-160981R01HL172972
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Contemporary left ventricular assist device (LVAD) therapy improves survival during advanced heart failure but vascular aging develops rapidly leading to major adverse events including stroke and bleeding in nearly half of patients. In this study, the study team aims to investigate whether sildenafil pharmacotherapy, which has anti-fibrotic effects, can reduce vascular aging during LVAD support. An aim of this study is to compare changes in small blood vessels in the gastrointestinal tract between participants receiving sildenafil or placebo. Video capsule endoscopy (VCE) will be used to assess these changes in small blood vessels.

Conditions

Vascular Diseases

Outcome Measures

Primary Outcomes (3)

• Change in Aortic Pulse Wave Velocity

  Pulse wave velocity (PWV) will be measured by vascular ultrasound. PWV will be calculated by dividing the distance between the carotid and femoral artery waveform acquisition sites (in meters) by the carotid-femoral transit time (change in time, in seconds). Change in group mean PWV from baseline will be summarized. Increases in PWV can be an indicator of vascular fibrosis and are associated with increased risk of cardiovascular comorbidities.

  From Baseline to 180 days

• Change in Gastrointestinal Angiodysplasia (GIAD) Foci

  Microvascular angiodysplasia will be assessed by video capsule endoscopy (VCE). VCE is a minimally invasive technique used to identify gastrointestinal lesions and diagnose GIAD. Change in the group mean number of GIAD foci/lesions per patient from baseline to 180 days will be determined. GIAD formation will only be assessed at baseline and at 180 days unless the patient(s) experiences an episode of gastrointestinal bleeding prior to 180 days.

  From Baseline to 180 days

• Change in Vascular Reactivity Index

  Endothelial function will be determined by the finger vascular reactivity index (VRI) during LVAD support. VRI will be assessed by a non-invasive method using the Endothelix device. VRI is determined by measuring fingertip temperature change before and after cuff deflation. Change in group median VRI values from baseline will be summarized. Positive changes from baseline are associated with improved endothelial function.

  From Baseline to 180 days

Secondary Outcomes (2)

• Change in Urinary Protein to Creatinine Ratio (PCR)

  From Baseline to 180 days and, as available, 12, 18, and 24 months

• Platelet Gene Expression

  Baseline, 3 months, and 6 months

Study Arms (2)

Sildenafil

ACTIVE COMPARATOR

Participants in this arm will receive sildenafil 20mg every 8 hours for 1 week and then dose will be up titrated to 40mg every 8 hours for the duration of the study period.

Drug: Sildenafil

Placebo

PLACEBO COMPARATOR

Participants in this arm will receive matching placebo, which serves as a negative control to understand changes in small and large blood vessels.

Other: Placebo

Interventions

Sildenafil DRUG

Orally administered phosphodiesterase-5 (PDE-5) inhibitor, which enhances nitric oxide signaling in platelets and blood vessels.

Sildenafil

Placebo OTHER

Matched capsule not containing any medication

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Over 18 years of age
• Supported by a durable LVAD or planned to undergo placement of a durable LVAD
• Be able to give informed consent

You may not qualify if:

• History of pre-existing aortic valve prosthesis or an aortic graft
• Allergy to sildenafil
• Taking any nitric oxide (NO) donor medications
• History of complete carotid occlusion

Sponsors & Collaborators

• Montefiore Medical Center: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Montefiore Medical Center

The Bronx, New York, 10461, United States

RECRUITING

Related Publications (20)

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  PMID: 33983838 BACKGROUND

• Molina EJ, Shah P, Kiernan MS, Cornwell WK 3rd, Copeland H, Takeda K, Fernandez FG, Badhwar V, Habib RH, Jacobs JP, Koehl D, Kirklin JK, Pagani FD, Cowger JA. The Society of Thoracic Surgeons Intermacs 2020 Annual Report. Ann Thorac Surg. 2021 Mar;111(3):778-792. doi: 10.1016/j.athoracsur.2020.12.038. Epub 2021 Jan 16.

  PMID: 33465365 BACKGROUND

• Colombo PC, Mehra MR, Goldstein DJ, Estep JD, Salerno C, Jorde UP, Cowger JA, Cleveland JC Jr, Uriel N, Sayer G, Skipper ER, Downey FX, Ono M, Hooker R Jr, Anyanwu AC, Givertz MM, Mahr C, Topuria I, Somo SI, Crandall DL, Horstmanshof DA. Comprehensive Analysis of Stroke in the Long-Term Cohort of the MOMENTUM 3 Study. Circulation. 2019 Jan 8;139(2):155-168. doi: 10.1161/CIRCULATIONAHA.118.037231.

  PMID: 30586698 BACKGROUND

• Yuzefpolskaya M, Schroeder SE, Houston BA, Robinson MR, Gosev I, Reyentovich A, Koehl D, Cantor R, Jorde UP, Kirklin JK, Pagani FD, D'Alessandro DA. The Society of Thoracic Surgeons Intermacs 2022 Annual Report: Focus on the 2018 Heart Transplant Allocation System. Ann Thorac Surg. 2023 Feb;115(2):311-327. doi: 10.1016/j.athoracsur.2022.11.023. Epub 2022 Dec 1.

  PMID: 36462544 BACKGROUND

• Jorde UP, Saeed O, Koehl D, Morris AA, Wood KL, Meyer DM, Cantor R, Jacobs JP, Kirklin JK, Pagani FD, Vega JD. The Society of Thoracic Surgeons Intermacs 2023 Annual Report: Focus on Magnetically Levitated Devices. Ann Thorac Surg. 2024 Jan;117(1):33-44. doi: 10.1016/j.athoracsur.2023.11.004. Epub 2023 Nov 8.

  PMID: 37944655 BACKGROUND

• Schmitto JD, Shaw S, Garbade J, Gustafsson F, Morshuis M, Zimpfer D, Lavee J, Pya Y, Berchtold-Herz M, Wang A, Gazzola C, Potapov E, Saeed D. Fully magnetically centrifugal left ventricular assist device and long-term outcomes: the ELEVATE registry. Eur Heart J. 2024 Feb 21;45(8):613-625. doi: 10.1093/eurheartj/ehad658.

  PMID: 38036414 BACKGROUND

• Demirozu ZT, Radovancevic R, Hochman LF, Gregoric ID, Letsou GV, Kar B, Bogaev RC, Frazier OH. Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant. 2011 Aug;30(8):849-53. doi: 10.1016/j.healun.2011.03.008. Epub 2011 Apr 29.

  PMID: 21530318 BACKGROUND

• Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, Asmar R, Reneman RS, Hoeks AP, Breteler MM, Witteman JC. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation. 2006 Feb 7;113(5):657-63. doi: 10.1161/CIRCULATIONAHA.105.555235.

  PMID: 16461838 BACKGROUND

• Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005 May;25(5):932-43. doi: 10.1161/01.ATV.0000160548.78317.29. Epub 2005 Feb 24.

  PMID: 15731494 BACKGROUND

• Ambardekar AV, Hunter KS, Babu AN, Tuder RM, Dodson RB, Lindenfeld J. Changes in Aortic Wall Structure, Composition, and Stiffness With Continuous-Flow Left Ventricular Assist Devices: A Pilot Study. Circ Heart Fail. 2015 Sep;8(5):944-52. doi: 10.1161/CIRCHEARTFAILURE.114.001955. Epub 2015 Jul 1.

  PMID: 26136459 BACKGROUND

• Ambardekar AV, Stratton MS, Dobrinskikh E, Hunter KS, Tatman PD, Lemieux ME, Cleveland JC, Tuder RM, Weiser-Evans MCM, Moulton KS, McKinsey TA. Matrix-Degrading Enzyme Expression and Aortic Fibrosis During Continuous-Flow Left Ventricular Mechanical Support. J Am Coll Cardiol. 2021 Nov 2;78(18):1782-1795. doi: 10.1016/j.jacc.2021.08.047.

  PMID: 34711337 BACKGROUND

• Templeton DL, John R, Painter P, Kelly AS, Dengel DR. Effects of the left ventricular assist device on the compliance and distensibility of the carotid artery. Heart Vessels. 2013 May;28(3):377-84. doi: 10.1007/s00380-012-0271-4. Epub 2012 Aug 9.

  PMID: 22875409 BACKGROUND

• Kiyatkin M, Stöhr E, Zuver A, Gaudig A, Yuzefpolskaya M, Colombo P and Willey J. Carotid artery flow and its assciation with stroke during left ventricular assist device support. Critical Care Medicine. 2019;47:53.

  BACKGROUND

• Hackam DG, Spence JD. Antiplatelet Therapy in Ischemic Stroke and Transient Ischemic Attack. Stroke. 2019 Mar;50(3):773-778. doi: 10.1161/STROKEAHA.118.023954. No abstract available.

  PMID: 30626286 BACKGROUND

• Lebas H, Yahiaoui K, Martos R, Boulaftali Y. Platelets Are at the Nexus of Vascular Diseases. Front Cardiovasc Med. 2019 Sep 11;6:132. doi: 10.3389/fcvm.2019.00132. eCollection 2019.

  PMID: 31572732 BACKGROUND

• de Biasi AR, Manning KB, Salemi A. Science for surgeons: understanding pump thrombogenesis in continuous-flow left ventricular assist devices. J Thorac Cardiovasc Surg. 2015 Mar;149(3):667-73. doi: 10.1016/j.jtcvs.2014.11.041. Epub 2014 Nov 21. No abstract available.

  PMID: 25534307 BACKGROUND

• Diehl P, Aleker M, Helbing T, Sossong V, Beyersdorf F, Olschewski M, Bode C, Moser M. Enhanced microparticles in ventricular assist device patients predict platelet, leukocyte and endothelial cell activation. Interact Cardiovasc Thorac Surg. 2010 Aug;11(2):133-7. doi: 10.1510/icvts.2010.232603. Epub 2010 May 14.

  PMID: 20472650 BACKGROUND

• Liesdek OCD, Schutgens REG, de Heer LM, Ramjankhan FZ, Sebastian SAE, Rohof JJ, Suyker WJL, Urbanus RT. Acquired blood platelet disorder in patients with end-stage heart failure after implantation of a continuous centrifugal-flow left ventricular assist device: A prospective cohort study. Res Pract Thromb Haemost. 2023 Mar 6;7(2):100101. doi: 10.1016/j.rpth.2023.100101. eCollection 2023 Feb.

  PMID: 37063754 BACKGROUND

• Radovancevic R, Matijevic N, Bracey AW, Radovancevic B, Elayda M, Gregoric ID, Frazier OH. Increased leukocyte-platelet interactions during circulatory support with left ventricular assist devices. ASAIO J. 2009 Sep-Oct;55(5):459-64. doi: 10.1097/MAT.0b013e3181b235af.

  PMID: 19730003 BACKGROUND

• Griesshammer M, Beneke H, Nussbaumer B, Grunewald M, Bangerter M, Bergmann L. Increased platelet surface expression of P-selectin and thrombospondin as markers of platelet activation in essential thrombocythaemia. Thromb Res. 1999 Nov 1;96(3):191-6. doi: 10.1016/s0049-3848(99)00095-x.

  PMID: 10588461 BACKGROUND

MeSH Terms

Conditions

Vascular Diseases

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Omar Saeed, MD

  Montefiore Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Omar Saeed, MD

CONTACT

718-920-2626; osaeed@montefiore.org

Lorenzo D'Angelo, MD

CONTACT

718-920-2626

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2024
• First Posted: July 19, 2024
• Study Start: March 12, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029
• Last Updated: January 23, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)