Sildenafil to Reduce Vascular Remodeling During Left Ventricular Assist Device Support

Montefiore Medicine Academic Health System

Status and phase: Enrolling; Early Phase 1

Conditions: Vascular Diseases

Treatments: Other: Placebo; Drug: Sildenafil

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT06510322

1R01HL172972 (U.S. NIH Grant/Contract)

2024-16098

Details and patient eligibility

About

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.

Full 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.

Enrollment: 50 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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50 participants in 2 patient groups, including a placebo group

Sildenafil

Active Comparator group

Description:

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.

Treatment:

Drug: Sildenafil

Placebo

Placebo Comparator group

Description:

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

Treatment:

Other: Placebo