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

The Effects of Soluble Guanylyl Cyclase Stimulation on Perioperative Vascular Reactivity and Organ Injury in Cardiac Surgery

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.

Study Overview

• Status: Recruiting
• Conditions: Vascular Diseases; Endothelial Dysfunction; Kidney Injury; Brain Disease; Vascular Inflammation
• Intervention / Treatment: Drug: Vericiguat; Drug: Placebo

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 Type: Interventional
• Enrollment (Estimated): 170
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Marcos G Lopez, MD; Phone Number: 615-936-5894; Email: marcos.g.lopez@vumc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vericiguat; 10 mg vericiguat administered orally once daily for three days (through day of surgery)	Drug: Vericiguat; Vericiguat 10 mg administered orally starting 2 days prior to heart surgery through the day of surgery
Placebo Comparator: Placebo; placebo administered orally once daily for three days (through day of surgery)	Drug: Placebo; Matched placebo administered orally starting 2 days prior to heart surgery through the day of surgery

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory clinical outcome: serum creatinine	Serum creatinine	Postoperative day 0 up to 1 year postoperatively (e.g., approximately 1 year after the day of surgery)
Exploratory clinical outcome: Kidney Disease Improving Global Outcomes (KDIGO) Acute Kidney Injury (AKI)	Incidence of KDIGO creatinine criteria AKI	Postoperative day 0 up to 1 year postoperatively (e.g., approximately 1 year after the day of surgery)
Exploratory clinical outcome: delirium	Incidence (percent of participants) with a positive delirium exam measured using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).	Postoperative day 0 to 10 days postoperatively
Exploratory clinical outcome: delirium severity	Severity of delirium measured using the CAM-ICU-7 score for at least 3 days postoperatively up to 10 days postoperatively for participants who remain in ICU. This is a 7 point scale score with higher scores indicating higher severity of delirium	Postoperative day 0 to 10 days postoperatively
Exploratory clinical outcome: Infection	Infection defined as initiation of antibiotics postoperatively not part of perioperative antibiotic prophylaxis.	Postoperative day 0 to 10 days postoperatively
Exploratory clinical outcome: Respiratory failure	Respiratory failure defined as the need for mechanical ventilation	Postoperative day 0 to hospital discharge (e.g., up to approximately 30 days following surgery)
Exploratory clinical outcome: Thrombocytopenia	Thrombocytopenia defined at platelet count less than 50,000	Postoperative day 0 to hospital discharge(e.g., up to approximately 30 days following surgery)
Exploratory clinical outcome: Arrythmia	Arrhythmia defined the onset of new atrial or ventricular dysrhythmia	Postoperative day 0 to hospital discharge (e.g., up to approximately 30 days following surgery)
Exploratory clinical outcome: Intensive care unit (ICU) length of stay	ICU length of stay in days	Postoperative day 0 to until discharge from the ICU (e.g. up to approximately 10 days following surgery)
Exploratory clinical outcome: Hospital length of stay	Hospital length of stay in days	Postoperative day 0 to hospital discharge (e.g., up to approximately 30 days following surgery)
Exploratory clinical outcome: Death	Mortality measured up to one year	Postoperative day 0 to one year postoperatively
Exploratory cognitive status outcome: Telephone interview for cognitive status	Six-month follow-up (Telephone Interview for Cognitive Status) obtained by phone interview. Maximum score is 41 and lower score indicates worse cognitive function.	6 months postoperatively
Exploratory functional status outcome: Katz Activities of Daily Living (ADL) assessment	Activities of daily living will be assessed with the Katz ADL assessment via phone interview. This survey assesses independence in 6 activities, and will be summarized as the average number of independent activities.	6 months postoperatively
Exploratory functional status outcome: Pfeffer functional activities questionnaire	Activities of daily living will be assessed with the Pfeffer functional activities questionnaire via phone interview. Maximum score is 30. A score of greater than 9 indicates impaired function and possible cognitive impairment.	6 months postoperatively

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Marcos Lopez, MD, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: March 28, 2023
• First Submitted That Met QC Criteria: April 11, 2023
• First Posted (Actual): April 14, 2023

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Inflammation; Wounds and Injuries; Brain Diseases
• Other Study ID Numbers: 222089; R01HL164909 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No