SOLSTICE: SGC Stimulation, Perioperative Vascular Reactivity, and Organ Injury in Cardiac Surgery
Study Details
Study Description
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:
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Does soluble guanylyl cyclase stimulation improve blood vessel function compared to placebo?
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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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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 Design
Arms and Interventions
| 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
|
Outcome Measures
Primary Outcome Measures
- 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).
- 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)
- 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)
Secondary Outcome Measures
- 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)
- 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)
- 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)
Other Outcome Measures
- Exploratory clinical outcome: serum creatinine [Postoperative day 0 up to 1 year postoperatively (e.g., approximately 1 year after the day of surgery)]
Serum creatinine
- Exploratory clinical outcome: Kidney Disease Improving Global Outcomes (KDIGO) Acute Kidney Injury (AKI) [Postoperative day 0 up to 1 year postoperatively (e.g., approximately 1 year after the day of surgery)]
Incidence of KDIGO creatinine criteria AKI
- Exploratory clinical outcome: delirium [Postoperative day 0 to 10 days postoperatively]
Incidence (percent of participants) with a positive delirium exam measured using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).
- Exploratory clinical outcome: delirium severity [Postoperative day 0 to 10 days postoperatively]
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
- Exploratory clinical outcome: Infection [Postoperative day 0 to 10 days postoperatively]
Infection defined as initiation of antibiotics postoperatively not part of perioperative antibiotic prophylaxis.
- Exploratory clinical outcome: Respiratory failure [Postoperative day 0 to hospital discharge (e.g., up to approximately 30 days following surgery)]
Respiratory failure defined as the need for mechanical ventilation
- Exploratory clinical outcome: Thrombocytopenia [Postoperative day 0 to hospital discharge(e.g., up to approximately 30 days following surgery)]
Thrombocytopenia defined at platelet count less than 50,000
- Exploratory clinical outcome: Arrythmia [Postoperative day 0 to hospital discharge (e.g., up to approximately 30 days following surgery)]
Arrhythmia defined the onset of new atrial or ventricular dysrhythmia
- Exploratory clinical outcome: Intensive care unit (ICU) length of stay [Postoperative day 0 to until discharge from the ICU (e.g. up to approximately 10 days following surgery)]
ICU length of stay in days
- Exploratory clinical outcome: Hospital length of stay [Postoperative day 0 to hospital discharge (e.g., up to approximately 30 days following surgery)]
Hospital length of stay in days
- Exploratory clinical outcome: Death [Postoperative day 0 to one year postoperatively]
Mortality measured up to one year
- Exploratory cognitive status outcome: Telephone interview for cognitive status [6 months postoperatively]
Six-month follow-up (Telephone Interview for Cognitive Status) obtained by phone interview. Maximum score is 41 and lower score indicates worse cognitive function.
- Exploratory functional status outcome: Katz Activities of Daily Living (ADL) assessment [6 months postoperatively]
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.
- Exploratory functional status outcome: Pfeffer functional activities questionnaire [6 months postoperatively]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age ≥18 years
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Elective open-heart surgery, defined as surgery on the heart or aorta that requires sternotomy or thoracotomy
Exclusion Criteria:
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Intolerance to vericiguat
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Use of other soluble guanylyl cyclase stimulators or current use of phosphodiesterase-5 inhibitors
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Pregnancy or breast feeding. Pregnancy will be excluded in women of child-bearing potential by a urine or serum beta hcg test
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Renal replacement therapy within 30 days prior to screening
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Estimated glomerular filtration rate <15 ml/min per 1.73 m2 per Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation at time of screening
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Systolic blood pressure less than 120 mmHg at the time of screening
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Prior kidney transplantation
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History of significant liver dysfunction (defined as Child-Pugh class C)
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Surgery scheduled to be performed with circulatory arrest
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Surgery scheduled to correct a major congenital heart defect
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Extracorporeal membrane oxygenation (ECMO) prior to surgery
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Active systemic infection or surgery for infectious endocarditis
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Ventricular assist device or intraaortic balloon pump support prior to surgery
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Prisoners
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Vanderbilt University Medical Center | Nashville | Tennessee | United States | 37204 |
Sponsors and Collaborators
- Vanderbilt University Medical Center
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Marcos Lopez, MD, Vanderbilt University Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 222089
- R01HL164909