Ranolazine for Heart Disease

Recruiting in Palo Alto (17 mi)

Overseen by C.Noel Bairey-Merz, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Cedars-Sinai Medical Center

Must be taking: Statins, ACE inhibitors

Disqualifiers: Obstructive CAD, Heart failure, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Women suffer disproportionately than men from Cardiac Syndrome X ( chest pain in the absence of flow limiting coronary artery stenosis). Coronary microvascular disease is hypothesized to mediate chest pain in this syndrome. This disorder of the small heart vessels (arterioles) compared to the large vessels (arteries) is not diagnosed during routine heart catheterization. This results in delays in diagnosis, missed opportunities for treatment, and likely contributes to the increased death rate from coronary heart disease in women compared to men. Current testing for small vessel disease is performed in the cardiac catheterization laboratory using specialized testing and is not performed routinely. Accordingly, women with this condition are either falsely reassured, or misdiagnosed as another non-cardiac condition. Unnecessary healthcare costs related to re-hospitalization and repeat angiography are incurred, while women are often not initiated on appropriate lifesaving treatment. We and others have demonstrated in randomized controlled trials that therapies that target the endothelium, e.g. statins, ACE inhibitors, and exercise are effective in this condition. Majority of women with Cardiac Syndorme X go undiagnosed. Recent studies have shown significant increased health care costs, morbidity and mortality related to this disease. It is becoming more important to further characterize this group of patients and we hope to do that with our study.

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 evidence supports the effectiveness of the drug Ranolazine for heart disease?

Research shows that HMG-CoA reductase inhibitors, which are part of the treatment, significantly reduce cholesterol levels and cardiovascular events in patients with heart disease. These drugs not only lower cholesterol but also stabilize plaque in arteries, reducing the risk of heart attacks and other heart-related issues. ^{1 2 3 4 5}

Is ranolazine safe for human use?

Ranolazine has been studied for safety in healthy adults, showing that it is generally well-tolerated, but it can interact with other medications like ketoconazole and diltiazem, which may increase its concentration in the body. These interactions suggest that while ranolazine is safe, it should be used cautiously with certain other drugs. ^{6 7 8 9 10}

How does the drug Ranolazine differ from other treatments for heart disease?

Ranolazine is unique because it works by affecting the electrical activity of the heart to help it use oxygen more efficiently, unlike statins (HMG-CoA reductase inhibitors) which primarily lower cholesterol levels. This makes Ranolazine particularly useful for patients who need an alternative approach to managing heart disease beyond cholesterol reduction. ^{7 11 12 13 14}

Research Team

C.Noel Bairey-Merz, MD

Principal Investigator

Cedars-Sinai Medical Center

Eligibility Criteria

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 been diagnosed with a type of heart attack or chest pain.

Trial Timeline

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

Treatment Details

Interventions

• Noninvasive Tests (Procedure)

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.

Participant Groups

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 Canada for the following indications:

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+

David E. Cohen

Cedars-Sinai Medical Center

Chief Medical Officer

MD and PhD in Physiology and Biophysics from Harvard University

Peter L. Slavin

Cedars-Sinai Medical Center

Chief Executive Officer

MD from Harvard Medical School, MBA from Harvard Business School

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. [2015]

2. England pubmed.ncbi.nlm.nih.gov

The influence of short-term treatment with simvastatin on the inflammatory profile of patients with hypercholesterolaemia. [2019]

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

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

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

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

5. Ireland pubmed.ncbi.nlm.nih.gov

The effects of hydroxy-methyl-glutaryl co-enzyme A reductase inhibitors on platelet thrombus formation. [2022]

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

Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. [2015]

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

[The HMG-CoA reductase inhibitors simvastatin and pravastatin. No indication for side effects in use on humans]. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Statins for primary prevention: at what coronary risk is safety assured? [2019]

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

Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) [2022]

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

Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Atorvastatin Study Group I. [2019]

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

Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. [2018]

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

Results of the primary outcome measure and clinical events from the Asymptomatic Carotid Artery Progression Study. [2019]

13. Spain pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of statins. [2007]

14. Germany pubmed.ncbi.nlm.nih.gov

HMG-CoA reductase activity in human liver microsomes: comparative inhibition by statins. [2018]