Sildenafil for Vascular Disease

Overseen By Lorenzo D'Angelo, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Montefiore Medical Center

Must not be taking: Nitric oxide donors

Disqualifiers: Aortic valve prosthesis, Aortic graft, Carotid occlusion, others

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 180 days

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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.

Do I need to stop my current medications for the trial?

If you are taking any nitric oxide (NO) donor medications, you will need to stop them to participate in this trial.

Is sildenafil safe for use in humans?

Sildenafil, known by various brand names like Viagra and Revatio, is generally considered safe for most people, but it should not be used with nitrates (medications for chest pain) as this can cause a dangerous drop in blood pressure. Some reports have noted heart-related issues, especially in those with existing heart conditions, so it's important to consult a doctor if you have heart disease. ^{1 2 3 4 5}

How is the drug sildenafil unique for treating vascular disease?

Sildenafil is unique for treating vascular disease because it not only helps with erectile dysfunction and pulmonary hypertension but also shows promise in protecting the heart from damage due to reduced blood flow and other cardiovascular issues. It works by inhibiting an enzyme called phosphodiesterase-5, which helps relax blood vessels and improve blood flow. ^{4 6 7 8 9}

What data supports the effectiveness of the drug sildenafil for vascular disease?

Sildenafil, known for treating erectile dysfunction, has shown promise in improving heart health by protecting against heart damage and lowering blood pressure in certain conditions. It is also effective in treating pulmonary arterial hypertension, a type of high blood pressure affecting the lungs. ^{4 6 10 11 12}

Who Is on the Research Team?

Omar Saeed, MD

Principal Investigator

Montefiore Medical Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 who are receiving durable left ventricular assist device (LVAD) support and can give informed consent. It's not suitable for those with a pre-existing aortic valve prosthesis or graft, allergy to sildenafil, complete carotid occlusion, or those taking nitric oxide donor medications.

Inclusion Criteria

Durable left ventricular assist device support

Be able to give informed consent

I am over 18 years old.

Exclusion Criteria

History of pre-existing aortic valve prosthesis or an aortic graft

Allergy to sildenafil

I have had a complete blockage in my carotid artery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sildenafil or placebo to assess vascular remodeling during LVAD support

180 days

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Sildenafil

Trial Overview The study is testing if sildenafil can slow down vascular aging in patients with LVADs. Vascular aging often leads to strokes and bleeding. Participants will either receive sildenafil or a placebo without knowing which one they're getting.

How Is the Trial Designed?

Group I: Sildeanfil Active Control 1 Intervention

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.

Group II: Placebo Placebo Group 1 Intervention

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

Sildenafil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in European Union as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in United States as Revatio for:

• Pulmonary arterial hypertension

Approved in Canada as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in Japan as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Who Is Running the Clinical Trial?

Montefiore Medical Center

Lead Sponsor

Trials

468

Recruited

599,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Sildenafil citrate (Viagra) has been prescribed to over 10 million patients and has shown significant improvements in erectile function across various conditions, including diabetes and cardiovascular disease, based on clinical trials.

The medication is generally well-tolerated, with most side effects being mild or moderate and rarely causing patients to stop treatment, indicating its safety in a wide range of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-year update of sildenafil citrate (Viagra) efficacy and safety. Sadovsky, R., Miller, T., Moskowitz, M., et al.[2022]

Phosphodiesterase 5 inhibitors, like sildenafil, vardenafil, and tadalafil, effectively treat erectile dysfunction by increasing cGMP levels, which relaxes smooth muscle and can slightly lower blood pressure, but caution is needed when used with nitric oxide donors due to the risk of significant hypotension.

These medications not only help with erectile dysfunction but also show potential in treating pulmonary hypertension and may have cardioprotective effects, making them valuable for patients with cardiovascular risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular effects of phosphodiesterase 5 inhibitors. Reffelmann, T., Kloner, RA.[2019]

Sildenafil citrate (Revatio) is an effective oral treatment for pulmonary arterial hypertension (PAH), significantly improving exercise capacity compared to placebo in patients with idiopathic PAH and other related conditions.

The treatment was well tolerated and also led to improvements in functional class and hemodynamic parameters, indicating its overall efficacy and safety in managing PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil: a review of its use in pulmonary arterial hypertension. Croom, KF., Curran, MP.[2021]

Revatio, a medication used to treat pulmonary hypertension, is actually the same drug as sildenafil, which is commonly known as Viagra, highlighting the need for healthcare practitioners to be aware of this dual branding.

There have been incidents where the contraindication of using nitroglycerin with sildenafil was overlooked, emphasizing the importance of educating healthcare providers about the risks associated with Revatio to prevent medication errors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALERT: Revatio is another brand name for sildenafil. Koczmara, C., Hyland, S., Greenall, J.[2017]

Sildenafil, originally developed for angina, has proven effective as an on-demand treatment for erectile dysfunction and is now being explored as a treatment for pulmonary hypertension, showcasing its versatility in cardiovascular health.

Recent studies indicate that sildenafil has cardioprotective effects against various heart conditions, suggesting its potential for treating issues like hypertension, ischemia/reperfusion injury, and heart failure, paving the way for broader cardiovascular applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase. Kukreja, RC.[2018]

Sildenafil, approved for erectile dysfunction since 1998, has been associated with serious cardiovascular risks, including three reported deaths in Dutch patients, raising concerns about its safety in individuals with heart disease.

The concurrent use of sildenafil and nitrates is contraindicated due to the risk of severe blood pressure drops, and patients with a history of heart disease should undergo a treadmill test to assess their physical stress tolerance before using the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Side effects of sildenafil: findings from two years practical experience]. van Grootheest, AC., Straus, SM., Heeringa, M.[2015]

In a study involving anesthetized rabbits, sildenafil did not significantly affect infarct size or the area of no-reflow during ischemic heart conditions, suggesting it does not worsen heart damage in patients with ischemic heart disease.

Sildenafil lowered arterial blood pressure and reduced left ventricular contractility, but it did not lead to major arrhythmias or significant changes in heart function during ischemia, indicating a safety profile for its use in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation. Reffelmann, T., Kloner, RA.[2019]

Sildenafil has a good safety profile for men with erectile dysfunction and cardiovascular disease, showing no significant increase in the risk of ischemic events during therapy.

Discontinuation rates due to adverse events are similar to those seen with placebo, and sildenafil does not interact dangerously with most cardiovascular medications, except for nitrates, which should not be taken within 24 hours of sildenafil use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular safety of sildenafil. Tran, D., Howes, LG.[2018]

A large observational study involving 22,471 patients found that sildenafil, used primarily for erectile dysfunction, has a safety profile consistent with expectations, with no unexpected adverse drug reactions reported.

The study showed that the standardized mortality ratio for deaths due to ischemic heart disease in patients taking sildenafil was not higher than that of the general male population in England, indicating no increased risk associated with the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the safety of sildenafil for male erectile dysfunction: experience gained in general practice use in England in 1999. Boshier, A., Wilton, LV., Shakir, SA.[2015]

Vardenafil, a PDE-5 inhibitor, has been shown to significantly improve erectile function in men with erectile dysfunction, with effects observed in various aspects of sexual performance, including confidence and satisfaction, across different age groups and conditions such as diabetes and post-prostatectomy.

The medication has a rapid onset of action, allowing for successful sexual intercourse as soon as 16 minutes after administration, and is well tolerated with mild to moderate side effects, making it a safe option for long-term use in up to 92% of patients over more than 2 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vardenafil: a new approach to the treatment of erectile dysfunction. Hellstrom, WJ.[2019]

In a study involving 8 healthy male volunteers, the combination of 20 mg tadalafil (a phosphodiesterase-5 inhibitor) and 5 mg nitrendipine (a calcium channel blocker) did not lead to significant hypotension, indicating that this combination may be safe for patients with erectile dysfunction and stable coronary artery disease.

The study found that while nitrendipine lowered systolic blood pressure, the combination with tadalafil did not result in critical hypotension (systolic blood pressure <85 mmHg), suggesting that nitrendipine can be safely used for angina treatment after taking tadalafil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sublingual application of liquid nitrendipine does not result in critical hypotension in healthy volunteers under phosphodiesterase-5 inhibition. Park, JW., Leithäuser, B., Jung, F.[2015]

Phosphodiesterase 5 inhibitors (PDE5-Is) like sildenafil, tadalafil, and others are not only effective for treating erectile dysfunction but also show promise in treating other conditions such as heart failure, cystic fibrosis, and certain cancers, based on recent research.

While PDE5-Is have demonstrated positive results in various diseases, discrepancies between pre-clinical and clinical data highlight the need for further research to fully understand their mechanisms and therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Therapeutic Applications of Phosphodiesterase 5 Inhibitors (PDE5-Is). Ribaudo, G., Pagano, MA., Bova, S., et al.[2022]

Citations

1. India pubmed.ncbi.nlm.nih.gov

Three-year update of sildenafil citrate (Viagra) efficacy and safety. [2022]

2. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Cardiovascular effects of phosphodiesterase 5 inhibitors. [2019]

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

Sildenafil: a review of its use in pulmonary arterial hypertension. [2021]

4. Canada pubmed.ncbi.nlm.nih.gov

ALERT: Revatio is another brand name for sildenafil. [2017]

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

Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

[Side effects of sildenafil: findings from two years practical experience]. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation. [2019]

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

Cardiovascular safety of sildenafil. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Evaluation of the safety of sildenafil for male erectile dysfunction: experience gained in general practice use in England in 1999. [2015]

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

Vardenafil: a new approach to the treatment of erectile dysfunction. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Sublingual application of liquid nitrendipine does not result in critical hypotension in healthy volunteers under phosphodiesterase-5 inhibition. [2015]

12. United Arab Emirates pubmed.ncbi.nlm.nih.gov

New Therapeutic Applications of Phosphodiesterase 5 Inhibitors (PDE5-Is). [2022]