Ranolazine for Heart Disease

Overseen By Barbra Streisand Women's Heart Center

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Cedars-Sinai Medical Center

Must be taking: Statins, ACE inhibitors

Disqualifiers: Obstructive CAD, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

634 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to better understand and treat Cardiac Syndrome X, a condition causing chest pain due to small heart vessel issues, primarily affecting women. The focus is on using noninvasive tests to improve diagnosis and management. Participants will undergo various tests, such as heart imaging and blood tests, to monitor heart health over time. The trial seeks women and men who experience chest pain from heart issues but lack major artery blockages, as shown by past tests. As an unphased trial, participants can contribute to groundbreaking research that may enhance the diagnosis and management of Cardiac Syndrome X.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the study involves testing for heart conditions, it's best to discuss your current medications with the trial coordinators.

What prior data suggests that these noninvasive tests are safe for diagnosing Cardiac Syndrome X?

Research has shown that ranolazine is generally safe for people with heart conditions. Studies have found that most patients tolerate it well, experiencing few problems. Some individuals reported only minor side effects, indicating the drug's safety. Ranolazine has successfully reduced chest pain and improved the quality of life for patients with certain heart issues. This offers reassurance about its safety for those considering participation in a clinical trial with ranolazine. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Ranolazine is unique because it offers a novel approach to managing heart disease by targeting the late sodium current in cardiac cells, which is different from traditional treatments like beta-blockers or calcium channel blockers. Researchers are excited about ranolazine because it has the potential to improve blood flow to the heart without significantly affecting heart rate or blood pressure, which is a common side effect of existing therapies. Additionally, ranolazine might benefit patients who have not responded well to standard treatments, providing a new option for those with difficult-to-treat conditions.

What evidence suggests that this trial's treatments could be effective for Cardiac Syndrome X?

Research has shown that ranolazine can improve symptoms in people with heart problems. Studies have found that it enhances heart function and reduces chest pain in individuals with ischemic heart disease, a condition where the heart lacks sufficient blood and oxygen. Additionally, it aids blood flow to the heart, which is particularly beneficial for women with Cardiac Syndrome X, where chest pain occurs without major artery blockage. Overall, ranolazine effectively manages symptoms and prevents heart conditions from worsening.

Note: This trial is a single-arm study, meaning all participants will receive the same treatment and undergo various noninvasive tests and follow-up assessments as part of the study protocol. ^{1 4 6 7 8}

Who Is on the Research Team?

C.Noel Bairey-Merz, MD

Principal Investigator

Cedars-Sinai Medical Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 who experience chest pain or signs of heart strain but don't have major blockages in their large heart arteries. It's open to both women and men with specific types of angina or related symptoms, provided they've had no severe coronary artery disease diagnosed in the last two years.

Inclusion Criteria

I am older than 18 years.

You have not had a heart condition where the arteries are partially blocked in the past 24 months.

I experience chest pain or discomfort due to heart issues without major artery blockages.

Exclusion Criteria

My heart's pumping ability is reduced.

I have been diagnosed with a heart condition that blocks blood flow.

I have had or am planning to have heart surgery or had a heart attack in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants fill out baseline demographic and health/medical history questionnaires, CV risk factors, reasons of diagnosis of ischemia, information of coronary artery, and medication use

1 week

1 visit (in-person)

Testing

Participants undergo clinically indicated coronary angiography with adenosine coronary flow reserve measurement and acetylcholine provocative testing, noninvasive Peripheral Artery Tonometry (PAT) testing, and Cardiac Magnetic Resonance (CMR) imaging if indicated

1-2 weeks

1 visit (in-person)

Follow-up

Participants are monitored for clinical status at 6 weeks, 6 months, and annually thereafter

6 weeks, 6 months, and annually

Phone questionnaires

What Are the Treatments Tested in This Trial?

Interventions

• Noninvasive Tests

Trial Overview

The study tests noninvasive methods to diagnose small vessel heart disease, which may cause chest pain without showing up on standard checks. The goal is to improve diagnosis and treatment, potentially reducing health risks and costs associated with misdiagnosis.

How Is the Trial Designed?

Group I: Single Arm Experimental Treatment 1 Intervention

1. fill out baseline demographic and health/medical history questionnaires, CV risk factors, reasons of diagnosis of ischemia, information of coronary artery, and medication use 2. undergo clinically indicated coronary angiography with adenosine coronary flow reserve measurement and acetylcholine provocative testing in the cardiac catheterization laboratory (Appendix); 3. undergo noninvasive Peripheral Artery Tonometry (PAT) testing (Appendix); 4. undergo clinically indicated Cardiac Magnetic Resonance (CMR) imaging (Appendix) to detect subendocardial ischemia (if indicated and referred by the treating physician). The three tests (heart catheterization with adenosine coronary flow reserve testing, acetylcholine provocative vasomotor testing during heart catheterization, cardiac MRI) are performed for standard care. 5. have blood and urine testing. 6. fill out health questionnaires 7. be followed prospectively 6-week, 6-month, and annually for clinical status

Noninvasive Tests is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Statins for:

• High cholesterol
• Cardiovascular disease prevention
• Coronary microvascular disease

Approved in United States as Statins for:

• High cholesterol
• Cardiovascular disease prevention
• Coronary microvascular disease

Approved in Canada as Statins for:

• High cholesterol
• Cardiovascular disease prevention
• Coronary microvascular disease

Who Is Running the Clinical Trial?

Cedars-Sinai Medical Center

Lead Sponsor

Trials

523

Recruited

165,000+

Published Research Related to This Trial

Ranolazine's pharmacokinetics are significantly affected by CYP3A4 inhibitors like ketoconazole, which increases its plasma concentrations, confirming that CYP3A4 is the main pathway for its metabolism.

The combination of ranolazine with diltiazem or simvastatin is safe and well tolerated, with diltiazem reducing ranolazine clearance, while ranolazine slightly increases the levels of simvastatin and its metabolites without major safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. Jerling, M., Huan, BL., Leung, K., et al.[2015]

Statins may not be safe for primary prevention in patients with low absolute risk of coronary heart disease (CHD), as they could potentially increase mortality by 1% over 10 years in these individuals.

The study suggests that statin treatment should be carefully considered for patients with a CHD event risk of less than 13% over 10 years, emphasizing the need for risk assessment before starting statin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statins for primary prevention: at what coronary risk is safety assured? Jackson, PR., Wallis, EJ., Haq, IU., et al.[2019]

In a study involving 1,049 patients with moderate hypercholesterolemia, atorvastatin demonstrated a significantly greater reduction in LDL cholesterol and other lipid markers compared to lovastatin after 52 weeks, indicating its superior efficacy.

Atorvastatin was well tolerated, with a similar safety profile to lovastatin, and more patients on atorvastatin reached LDL cholesterol target levels, especially those with coronary heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Atorvastatin Study Group I. Davidson, M., McKenney, J., Stein, E., et al.[2019]

In a study of 35 patients with acute coronary syndrome (ACS), rosuvastatin (20 mg/day) was shown to significantly reduce levels of pro-inflammatory cytokines TNF-alpha and IFN-gamma within 72 hours, indicating its rapid anti-inflammatory effects.

The treatment with rosuvastatin also inhibited the Th-1 immune response, suggesting that its benefits in ACS may extend beyond just lowering cholesterol levels to include important immunomodulatory actions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. Link, A., Ayadhi, T., Böhm, M., et al.[2015]

In a study of 19 patients with high cholesterol, 12 weeks of treatment with 20mg simvastatin daily significantly reduced levels of malonaldehyde, a marker of lipid peroxidation, indicating a decrease in oxidative stress.

Simvastatin also lowered stable metabolites of nitric oxide (NOx), suggesting an anti-inflammatory effect, while levels of interleukin 6, another inflammation marker, remained unchanged, highlighting the specific mechanisms through which statins may exert their cardiovascular benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of short-term treatment with simvastatin on the inflammatory profile of patients with hypercholesterolaemia. Deskur-Smielecka, E., Wykr towicz, A., Kempa, M., et al.[2019]

Lipid-lowering drugs, specifically HMG-CoA reductase inhibitors, have significantly reduced cardiovascular events in patients with coronary artery disease, as shown in multiple secondary prevention trials involving various lipid fraction improvements.

These medications not only lower total and LDL cholesterol but also stabilize plaque surfaces, leading to a 25% to 92% decrease in cardiovascular events and a significant reduction in mortality, indicating their efficacy in modifying the progression of coronary artery disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monotherapy with HMG-CoA reductase inhibitors and secondary prevention in coronary artery disease. Rackley, CE.[2019]

In a two-year safety study involving 45 patients taking Simvastatin and 35 patients taking Pravastatin for primary hypercholesterolemia, no drug-induced changes in eye health were observed, indicating a lack of cataractogenic effects.

Regular ophthalmological examinations and advanced imaging techniques showed no evidence of lens opacifications, supporting the safety of these cholesterol-lowering medications in terms of eye health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The HMG-CoA reductase inhibitors simvastatin and pravastatin. No indication for side effects in use on humans]. Schmidt, J., Schmitt, C., Hockwin, O.[2013]

In a study of 534 hypercholesterolemic patients over 8 weeks, atorvastatin at doses of 10, 20, and 40 mg significantly reduced LDL cholesterol levels more effectively than equivalent doses of simvastatin, pravastatin, lovastatin, and fluvastatin.

All statin medications, including atorvastatin, showed similar safety profiles with no serious side effects like persistent liver enzyme elevation or muscle inflammation, indicating they are well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) Jones, P., Kafonek, S., Laurora, I., et al.[2022]

In an 8-week study involving 37 patients with coronary artery disease, HMG CoA reductase inhibitors (pravastatin and simvastatin) significantly reduced total and LDL cholesterol levels by 20.3% and 31.4%, respectively, compared to placebo.

The therapy also decreased platelet thrombus formation by 8.0%, suggesting that these lipid-lowering effects may help reduce the risk of cardiovascular events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of hydroxy-methyl-glutaryl co-enzyme A reductase inhibitors on platelet thrombus formation. Thompson, PD., Moyna, NM., White, CM., et al.[2022]

In the Asymptomatic Carotid Artery Progression Study involving 919 participants aged 40-79, lovastatin significantly reduced the progression of early-stage carotid atherosclerosis, as indicated by a decrease in mean maximum intimal-medial thickness (IMT) over 3 years (p < 0.001).

Lovastatin treatment led to a 28% reduction in LDL cholesterol levels within 6 months, which remained stable throughout the study, and was associated with a lower incidence of major cardiovascular events compared to the placebo group (5 vs 14 events, p < 0.05).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of the primary outcome measure and clinical events from the Asymptomatic Carotid Artery Progression Study. Probstfield, JL., Margitic, SE., Byington, RP., et al.[2019]

In this study, various statins were tested for their ability to inhibit HMG-CoA reductase in human liver microsomes, revealing that cerivastatin was the most potent with an IC50 of 6 nM.

Statins were categorized into three classes based on their inhibitory strength, with atorvastatin and fluvastatin showing moderate potency (IC50 between 40-100 nM), while pravastatin, simvastatin, and lovastatin were less potent (IC50 between 100-300 nM).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HMG-CoA reductase activity in human liver microsomes: comparative inhibition by statins. Dansette, PM., Jaoen, M., Pons, C.[2018]

Simvastatin is found to be twice as potent as lovastatin and pravastatin on a milligram-per-milligram basis, making it a strong option for lowering cholesterol levels.

Pravastatin is recommended as the preferred choice for patients requiring higher doses due to its lower incidence of myopathy, especially in posttransplant patients receiving cyclosporine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Hsu, I., Spinler, SA., Johnson, NE.[2018]

HMG-CoA reductase inhibitors, commonly known as statins, effectively lower total and LDL cholesterol levels more than any previous medications, significantly reducing cardiovascular events and slowing atherosclerosis progression across various age groups.

The Scandinavian Simvastatin Survival Study highlighted that statins not only lower cholesterol but also significantly reduce all-cause mortality by decreasing cardiovascular-related deaths, making them a recommended first-line treatment for patients with established atherosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in treatment of cholesterol abnormalities. The role of HMG-CoA reductase inhibitors. Rackley, CE.[2016]

Statins, such as atorvastatin and simvastatin, generally have low systemic bioavailability due to extensive first-pass metabolism, which is beneficial since their primary action occurs in the liver.

Different statins vary in their metabolism and the presence of active metabolites, with atorvastatin having the longest half-life (11-14 hours) and pravastatin showing the lowest protein binding, which may influence their efficacy and safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of statins. García, MJ., Reinoso, RF., Sánchez Navarro, A., et al.[2007]

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