SGC Stimulation, Perioperative Vascular Reactivity, and Organ Injury in Cardiac Surgery

Phase 4

Recruiting

• Conditions: Vascular Diseases; Brain Disease; Vascular Inflammation; Endothelial Dysfunction; Kidney Injury
• Interventions: Drug: Placebo; Drug: Vericiguat

• Registration Number: NCT05812755
• Lead Sponsor: Vanderbilt University Medical Center

Brief Summary

The goal of this mechanistic clinical trial is to learn about the effects of medications called soluble guanylyl cyclase stimulators on vascular function and markers of kidney and brain injury in patients having heart surgery. The main questions it aims to answer are:

1. Does soluble guanylyl cyclase stimulation improve blood vessel function compared to placebo?

2. Does soluble guanylyl cyclase stimulation decrease markers of kidney injury and brain injury compared to placebo?

Participants will be randomized to a soluble guanylyl cyclase stimulator called vericiguat or placebo, and researchers will compare vascular function and markers of brain and kidney injury to see if vericiguat improves vascular function and reduces markers of injury.

This will provide important information to determine the underlying reasons that patients have some kidney and brain function problems after having heart surgery.

Detailed Description

Patients undergoing elective cardiac surgery will be randomized to the soluble guanylyl cyclase stimulator vericiguat versus placebo before surgery through the day of surgery and vascular function will be quantified using ultrasound and direct assessment of arterial relaxation ex-vivo. Markers of brain and kidney injury will be measured in plasma and urine.

Study Timeline

• Study First Submitted: 2023-03-28
• Study First Submitted QC: 2023-04-11
• Study First Posted: 2023-04-14
• Study Start: 2023-05-19
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-26
• Last Update Posted: 2024-06-27
• Primary Completion: 2026-10
• Study Completion: 2027-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 170

Inclusion Criteria

1. Age ≥18 years
2. Elective open-heart surgery, defined as surgery on the heart or aorta that requires sternotomy or thoracotomy

Exclusion Criteria

1. Intolerance to vericiguat
2. Use of other soluble guanylyl cyclase stimulators or current use of phosphodiesterase-5 inhibitors
3. Pregnancy or breast feeding. Pregnancy will be excluded in women of child-bearing potential by a urine or serum beta hcg test
4. Renal replacement therapy within 30 days prior to screening
5. Estimated glomerular filtration rate <15 ml/min per 1.73 m2 per Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation at time of screening
6. Systolic blood pressure less than 120 mmHg at the time of screening
7. Prior kidney transplantation
8. History of significant liver dysfunction (defined as Child-Pugh class C)
9. Surgery scheduled to be performed with circulatory arrest
10. Surgery scheduled to correct a major congenital heart defect
11. Extracorporeal membrane oxygenation (ECMO) prior to surgery
12. Active systemic infection or surgery for infectious endocarditis
13. Ventricular assist device or intraaortic balloon pump support prior to surgery
14. Prisoners

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	placebo administered orally once daily for three days (through day of surgery)
Vericiguat	Vericiguat	10 mg vericiguat administered orally once daily for three days (through day of surgery)

Primary Outcome Measures

Name	Time	Method
Neutrophil gelatinase associated lipocalin (NGAL) urine concentration	Enrollment through postoperative day 2	NGAL will be measured in urine to quantify effects of vericiguat vs. placebo on markers of renal injury (Aim 2 primary renal outcome)
Ex vivo vascular relaxation	Day of surgery	Ex vivo arterial relaxation (percent) in participants with available vascular tissue (Aim 1 primary outcome)
Ubiquitin C-terminal hydrolase L1 (UCHL1) plasma concentration	Enrollment through postoperative day 2	UCHL1 will be measured in plasma to quantify effects of vericiguat vs. placebo on neuronal injury (Aim 2 primary neuronal outcome)
Brachial artery flow-mediated dilation	Day of surgery	Percent change in brachial artery diameter from baseline to maximum post-forearm ischemia adjusted for shear-rate (Aim 1 primary outcome).

Secondary Outcome Measures

Name	Time	Method
Endothelial Activation - intercellular adhesion molecule 1 (ICAM1)	Enrollment through postoperative day 2	Endothelial activation will be quantified as plasma concentrations of ICAM1 (Aim 1 secondary outcome)
Endothelial barrier breakdown - claudin-5	Enrollment through postoperative day 2	Endothelial barrier breakdown will be quantified as plasma concentration of claudin-5 (Aim 1 secondary outcome)
Endothelium mediated inflammation and coagulation - plasminogen activator inhibitor-1 (PAI-1)	Enrollment through postoperative day 2	Endothelium mediated inflammation and coagulation will be quantified as plasma concentration of PAI-1 (Aim 1 secondary outcome)
Phosphorylated vasodilator stimulated phosphoprotein (phospho-VASP)	Enrollment through postoperative day 2	Soluble guanylyl cyclase stimulation will be further quantified as arterial phospho-VASP/VASP ratio(Aim 1 secondary outcome)

Trial Locations

Locations (1)

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States