Sildenafil to Reduce Vascular Remodeling During Left Ventricular Assist Device Support

Overview

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.

Interventions

• Drug Sildenafil
  Orally administered phosphodiesterase-5 (PDE-5) inhibitor, which enhances nitric oxide signaling in platelets and blood vessels.
• Other Placebo
  Matched capsule not containing any medication

Primary outcome measures

• Change in Aortic Pulse Wave Velocity [Time frame: From Baseline to 180 days]
• Change in Gastrointestinal Angiodysplasia (GIAD) Foci [Time frame: From Baseline to 180 days]
• Change in Vascular Reactivity Index [Time frame: From Baseline to 180 days]

Secondary outcome measures (2)

• Change in Urinary Protein to Creatinine Ratio (PCR) [Time frame: From Baseline to 180 days and, as available, 12, 18, and 24 months]
• Platelet Gene Expression [Time frame: Baseline, 3 months, and 6 months]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Montefiore Medical Center — The Bronx

Publications

• 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. PMID 33983838
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT06510322 · 2024-16098 · 1R01HL172972

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗