Vericiguat for Vascular Function and Organ Injury in Heart Surgery Patients

(SOLSTICE Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Vanderbilt University Medical Center

Must not be taking: Phosphodiesterase-5 inhibitors

Disqualifiers: Pregnancy, Renal therapy, Low blood pressure, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 3 days

170 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using other soluble guanylyl cyclase stimulators or phosphodiesterase-5 inhibitors.

Is vericiguat safe for use in humans?

Vericiguat has been shown to be safe and well-tolerated in patients with heart failure, with no significant differences in rates of fainting or low blood pressure compared to placebo in clinical trials. ^{1 2 3 4 5}

How does the drug Vericiguat differ from other treatments for heart surgery patients?

Vericiguat is unique because it works by stimulating an enzyme called soluble guanylate cyclase, which helps relax blood vessels and improve blood flow, potentially reducing organ injury during heart surgery. This mechanism is different from other treatments that may not target this specific pathway. ^{6 7 8 9 10}

Research Team

Marcos G Lopez, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for adults over 18 who are scheduled for elective open-heart surgery. It's not suitable for those with severe kidney issues, low blood pressure, liver dysfunction, or on certain medications like phosphodiesterase-5 inhibitors. Pregnant or breastfeeding individuals and prisoners are also excluded.

Inclusion Criteria

I am scheduled for open-heart surgery that involves opening my chest.

Exclusion Criteria

Pregnancy or breast feeding. Pregnancy will be excluded in women of child-bearing potential by a urine or serum beta hcg test

Prisoners

I am not taking any medication that affects blood vessel dilation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either vericiguat or placebo orally once daily for three days through the day of surgery

3 days

Daily visits (in-person)

Postoperative Monitoring

Participants are monitored for vascular function and markers of brain and kidney injury using various assessments

10 days

Daily monitoring (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cognitive and functional status assessments

6 months

Phone interviews and assessments

Treatment Details

Interventions

• Placebo
• Vericiguat

Trial Overview The study tests if vericiguat, a drug that stimulates soluble guanylyl cyclase (SGC), can improve blood vessel function and reduce brain and kidney injury markers after heart surgery compared to a placebo. Participants will be randomly assigned to either the drug or placebo group.

Participant Groups

Group I: Vericiguat Active Control 1 Intervention

10 mg vericiguat administered orally once daily for three days (through day of surgery)

Group II: Placebo Placebo Group 1 Intervention

placebo administered orally once daily for three days (through day of surgery)

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study involving 30 healthy juvenile pigs, the sGC stimulator riociguat showed a significant vasodilatory effect in systemic circulation, working in an additive manner with nitric oxide (NO), which could be beneficial in various cardiovascular disease states.

In contrast, the sGC activator cinaciguat completely blocks the endogenous NO effect, making it less favorable for clinical application due to its complex interaction with NO-tone and limited vascular control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic Effects of a Soluble Guanylate Cyclase Stimulator, Riociguat, and an Activator, Cinaciguat, During NO-Modulation in Healthy Pigs. Næsheim, T., How, OJ., Myrmel, T.[2021]

In the VICTORIA trial, patients with lower left ventricular ejection fraction (LVEF) had higher levels of certain biomarkers and experienced worse clinical outcomes, indicating a more severe heart failure condition.

Vericiguat showed consistent efficacy across different LVEF levels, with the most significant benefit observed in patients with the lowest LVEF (≤24%), suggesting it is a valuable treatment option for patients with varying degrees of heart failure severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ejection Fraction, Biomarkers, and Outcomes and Impact of Vericiguat on Outcomes Across EF in VICTORIA. Butler, J., Zheng, Y., Khan, MS., et al.[2023]

Vericiguat is a new medication that stimulates soluble guanylate cyclase (sGC) to increase cGMP production, which helps treat chronic heart failure without relying on nitric oxide.

It was recently approved in the USA for patients with heart failure and an ejection fraction of less than 45%, based on positive results from the phase III VICTORIA trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vericiguat: First Approval. Markham, A., Duggan, S.[2021]

In the VICTORIA trial involving 5050 patients with chronic heart failure, vericiguat demonstrated a 10% reduction in the risk of cardiovascular death or heart failure hospitalization compared to placebo, indicating its efficacy in managing severe heart failure.

Vericiguat was found to be safe and well-tolerated, with no significant differences in rates of syncope or hypotension, and it did not require laboratory testing, making it a convenient option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging concepts in heart failure management and treatment: focus on vericiguat. Kaplinsky, E., Perrone, S., Barbagelata, A.[2023]

Vericiguat was found to be ineffective in reducing cardiovascular deaths or hospitalizations related to heart failure, based on a meta-analysis of four studies involving 6705 patients.

The study showed no significant difference in adverse effects between patients taking vericiguat and those on placebo, suggesting that it may be safe but not effective for heart failure treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of vericiguat in heart failure: a meta-analysis. Ma, J., Guo, S., Jiang, H., et al.[2023]

Both bupivacaine and levobupivacaine cause a rapid increase in skin blood flow that is dose-dependent, indicating their potential for effective local anesthetic use.

At higher concentrations, bupivacaine shows a sustained vasodilation effect, while at lower doses, both drugs can lead to vasoconstriction, suggesting a complex interaction that may influence their therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin blood flow changes in response to intradermal injection of bupivacaine and levobupivacaine, assessed by laser Doppler imaging. Newton, DJ., Burke, D., Khan, F., et al.[2019]

In a study involving nine anesthetized pigs, ventriculocisternal perfusion of bupivacaine led to significant increases in heart rate and blood pressure, indicating an indirect cardiovascular stimulating effect via the central nervous system.

The cardiovascular changes induced by bupivacaine were reversible upon wash-out with mock cerebrospinal fluid, suggesting that the drug's effects on the cardiovascular system may be linked to its action on the CNS rather than direct cardiac toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hemodynamic effects of a ventriculo-cisternal perfusion of bupivacaine]. Schäfer, MK., Eberle, B., Otto, S., et al.[2013]

Clinical trials comparing venotropic drugs to placebo are crucial for assessing their effectiveness, focusing on three key areas: increasing venous tone, reducing capillary permeability, and improving microcirculation.

Calf plethysmography is a reliable method for measuring venous tone, while fluorescein angioscopy is the most sensitive for assessing capillary permeability, although not widely available; laser-Doppler is effective for evaluating microcirculation impairment and correlates well with chronic venous insufficiency severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Drug treatments of chronic venous insufficiency: pharmaco-clinical evaluation]. Chauveau, M.[2016]

Lidocaine and bupivacaine significantly increase capillary blood flow in a dose-dependent manner, with bupivacaine showing the highest increase, indicating a strong vasodilatory effect.

Mepivacaine, on the other hand, does not enhance blood flow beyond saline levels and may even reduce blood flow at lower concentrations, suggesting a mild vasoconstrictor effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of local anesthetic concentration on capillary blood flow in human skin. Guinard, JP., Carpenter, RL., Morell, RC.[2013]

In a study involving seven anesthetized rabbits, both levobupivacaine and bupivacaine significantly impaired heart contractility at doses above 1.32 mg/kg, indicating a risk of cardiac depression with these drugs.

Ropivacaine, however, did not show a significant impact on contractility at a clinical dose of 4.25 mg/kg, suggesting it may be a safer alternative in terms of cardiac effects compared to bupivacaine and levobupivacaine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The myocardial and vascular effects of bupivacaine, levobupivacaine, and ropivacaine using pressure volume loops. Royse, CF., Royse, AG.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Hemodynamic Effects of a Soluble Guanylate Cyclase Stimulator, Riociguat, and an Activator, Cinaciguat, During NO-Modulation in Healthy Pigs. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Ejection Fraction, Biomarkers, and Outcomes and Impact of Vericiguat on Outcomes Across EF in VICTORIA. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Vericiguat: First Approval. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Emerging concepts in heart failure management and treatment: focus on vericiguat. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of vericiguat in heart failure: a meta-analysis. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Skin blood flow changes in response to intradermal injection of bupivacaine and levobupivacaine, assessed by laser Doppler imaging. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

[Hemodynamic effects of a ventriculo-cisternal perfusion of bupivacaine]. [2013]

8. France pubmed.ncbi.nlm.nih.gov

[Drug treatments of chronic venous insufficiency: pharmaco-clinical evaluation]. [2016]

9. United States pubmed.ncbi.nlm.nih.gov

Effect of local anesthetic concentration on capillary blood flow in human skin. [2013]

10. United States pubmed.ncbi.nlm.nih.gov

The myocardial and vascular effects of bupivacaine, levobupivacaine, and ropivacaine using pressure volume loops. [2021]