Clinical trial NCT06510322: Sildenafil to Reduce Vascular Remodeling During Left Ventricular Assist Device Support
Official title: Sildenafil to Reduce Vascular Remodeling During Left Ventricular Assist Device Support
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Vascular Diseases
Lead sponsor: Montefiore Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2024-07-19
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Over 6.5 million individuals in the United States suffer from heart failure (HF), with the burden of this disease expected to grow over the next decade. Approximately 300,000 of these patients have advanced HF and may benefit from durable left ventricular assist device (LVAD) therapy, which can improve outcomes during advanced HF. However, despite advancements in device design that have increased survival rates, large registries of real- world cases reveal that nearly half of patients experience severe vascular adverse events, including stroke and bleeding, during prolonged contemporary LVAD support. This elevated adverse-event rate remains a major barrier to safely expanding the use and durability of LVAD therapy. Vascular remodeling or aging of the large and small blood vessels is known to promote stroke and bleeding within the general population. Critically, such remodeling is rapidly accelerated under conditions of reduced pulsatility produced by LVADs, evidenced by large vessel stiffening and fibrosis, small vessel angiodysplasia, and endothelial dysfunction. Phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are prescribed to select LVAD patients with pulmonary hypertension and right heart failure. However, given that these agents enhance nitric oxide-cGMP signaling in platelets and vascular smooth muscle cells, leading to anti-thrombotic and anti-fibrotic effects, they may also reduce vascular remodeling and related adverse events. Here, based on preliminary findings, a double-blind, randomized, placebo-controlled trial will be conducted to determine the effects of chronic sildenafil administration on vascular remodeling during LVAD support.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Change in Aortic Pulse Wave Velocity
timeFrame: From Baseline to 180 days
measure: Change in Gastrointestinal Angiodysplasia (GIAD) Foci
timeFrame: From Baseline to 180 days
measure: Change in Vascular Reactivity Index
timeFrame: From Baseline to 180 days
Secondary outcomes:
measure: Change in Urinary Protein to Creatinine Ratio (ACR)
timeFrame: From Baseline to 180 days
Other outcomes:
Locations:
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
Study officials:
affiliation: Montefiore Medical Center
name: Omar Saeed, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Roger VL. Epidemiology of Heart Failure: A Contemporary Perspective. Circ Res. 2021 May 14;128(10):1421-1434. doi: 10.1161/CIRCRESAHA.121.318172. Epub 2021 May 13.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.