Angiotensin Receptor Blockers for Aortic Stenosis

(ARBAS Trial)

Recruiting at1 trial location

Overseen by Marie-Annick Clavel, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Institut universitaire de cardiologie et de pneumologie de Québec, University Laval

Must not be taking: Renin-angiotensin meds, Aliskiren

Disqualifiers: Renal dysfunction, Diabetes, Coronary artery disease, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing whether medications that help relax blood vessels can slow down the worsening of aortic stenosis and heart muscle problems. The study focuses on patients with mild-to-moderate aortic stenosis. These medications work by blocking chemicals that can make these heart conditions worse. They are a new class of drugs with broad therapeutic potential in cardiovascular disease.

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 currently using or need medications that affect the renin-angiotensin system, like Aliskiren.

What data supports the effectiveness of the drug Angiotensin Receptor Blockers for Aortic Stenosis?

Research suggests that Angiotensin Receptor Blockers (ARBs) may help in slowing the progression of aortic valve calcification and reducing heart muscle thickening in patients with aortic stenosis, potentially leading to better survival rates, especially before and after valve replacement surgery. ^{1 2 3 4 5}

Are angiotensin receptor blockers (ARBs) safe for humans?

Angiotensin receptor blockers (ARBs) are generally considered safe for humans, with side effects similar to a placebo. Serious side effects are rare but can include cough, swelling, anemia, liver damage, and kidney issues. They are not recommended during pregnancy or for people with certain kidney or liver problems. ^{1 6 7 8 9}

How do angiotensin receptor blockers (ARBs) differ from other drugs for aortic stenosis?

Angiotensin receptor blockers (ARBs) are unique for aortic stenosis because they may help slow the progression of the disease and improve heart function by reducing heart muscle thickening and fibrosis (scarring). Unlike other treatments, ARBs target the renin-angiotensin system, which plays a role in the condition's development, potentially offering benefits before and after valve replacement surgery. ^{1 3 4 10 11}

Research Team

Marie-Annick Clavel, PhD

Principal Investigator

Institut universitaire de cardiologie et de pneumologie de Québec, University Laval

Eligibility Criteria

This trial is for adults with mild to moderate aortic stenosis, normal heart pump function, and stable blood pressure. It's not for those with certain heart valve issues, on specific heart medications, allergic to ARBs, cognitive impairments like Alzheimer's or dementia, severe kidney problems, chronic high potassium levels, serious liver conditions, recent diabetes diagnosis or uncontrolled diabetes, advanced coronary artery disease or recent heart attack.

Inclusion Criteria

Your systolic blood pressure is higher than 110 mmHg.

Your heart is pumping normally, at 50% or higher.

My heart valve narrowing is mild to moderate.

Exclusion Criteria

I have moderate to severe heart valve issues.

I am allergic to or cannot tolerate ARBs.

I have long-term high potassium levels.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either angiotensin receptor blockers or placebo orally once a day

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Angiotensin Receptor Blockers (Angiotensin Receptor Blockers)
• Placebo (Other)

Trial Overview The study examines the effects of angiotensin receptor blockers (ARBs) compared to a placebo in patients with mild-to-moderate aortic stenosis. Participants will be randomly assigned to receive either the ARB medication or an inactive substance without any active drug (placebo).

Participant Groups

Group I: Angiotensin Receptor Blockers Experimental Treatment 1 Intervention

Angiotensin Receptor Blockers will be given orally once a day for 2 years.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive a matched placebo orally once a day for 2 years.

Angiotensin Receptor Blockers is already approved in Canada, Japan for the following indications:

Approved in Canada as ARBs for:

• Hypertension
• Heart Failure
• Diabetic Nephropathy
• Chronic Kidney Disease

Approved in Japan as ARBs for:

• Hypertension
• Heart Failure
• Diabetic Nephropathy
• Chronic Kidney Disease

Who Is Running the Clinical Trial?

Institut universitaire de cardiologie et de pneumologie de Québec, University Laval

Lead Sponsor

Trials

26

Recruited

6,300+

Odense University Hospital

Collaborator

Trials

808

Recruited

1,272,000+

Kim Brixen

Odense University Hospital

Chief Medical Officer since 2023

MD

Bjarne Dahler-Eriksen

Odense University Hospital

Chief Executive Officer since 2023

MD

Findings from Research

In a study of 1873 asymptomatic patients with mild to moderate aortic stenosis, the use of renin-angiotensin system inhibitors (RASI) did not increase the risk of sudden cardiac death, cardiovascular death, or all-cause mortality over a median follow-up of 4.3 years.

RASI treatment was associated with significant benefits, including a greater reduction in systolic blood pressure and less progression of left ventricular mass, suggesting potential advantages for heart health in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renin-angiotensin system inhibition is not associated with increased sudden cardiac death, cardiovascular mortality or all-cause mortality in patients with aortic stenosis. Bang, CN., Greve, AM., Køber, L., et al.[2014]

In a study involving 5,139 heart failure patients, those treated with candesartan had a significantly higher one-year survival rate of 90% compared to 83% for those on losartan.

Candesartan was associated with a 43% lower risk of mortality compared to losartan, indicating it may be a more effective treatment option for reducing mortality in heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of candesartan vs losartan with all-cause mortality in patients with heart failure. Eklind-Cervenka, M., Benson, L., Dahlström, U., et al.[2021]

Renin-angiotensin system (RAS) blockade therapy shows promise in improving outcomes for patients with aortic stenosis (AS), potentially slowing the progression of the disease and enhancing survival rates both before and after aortic valve replacement (AVR).

Current evidence suggests that RAS inhibition is associated with significant survival advantages in patients undergoing surgical or transcatheter AVR, highlighting the need for further randomized trials to confirm these benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renin-Angiotensin System Blockade in Aortic Stenosis: Implications Before and After Aortic Valve Replacement. Goel, SS., Kleiman, NS., Zoghbi, WA., et al.[2021]

In a study of 2,117 patients with aortic stenosis (AS), those treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) showed a significant reduction in all-cause mortality, with a hazard ratio of 0.76, indicating a 24% lower risk of death compared to those not on these medications.

Patients on ACEIs or ARBs also experienced fewer cardiovascular events, with a hazard ratio of 0.77, suggesting a 23% lower risk of cardiovascular death or hospitalizations, highlighting the potential benefits of these medications in managing AS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis. Nadir, MA., Wei, L., Elder, DH., et al.[2021]

Angiotensin-receptor blockers have been shown to significantly improve outcomes in patients at high cardiovascular risk, beyond just lowering blood pressure.

Clinical trials have led to expanded uses for these medications, indicating their potential benefits in various cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-receptor blockers: benefits beyond lowering blood pressure. Silverstein, RL., Ram, CV.[2019]

Angiotensin II receptor blockers (ARBs) have been shown to effectively reduce cardiovascular events and mortality across various patient populations, from those at risk to post-myocardial infarction patients, based on a review of large, well-designed studies.

ARBs have demonstrated comparable efficacy to ACE inhibitors in certain groups, indicating their potential as a reliable treatment option for cardiovascular disease prevention, with ongoing studies expected to further clarify their benefits in additional populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for the efficacy of ARBs across the cardiovascular continuum. Gupta, M., Honos, GN., Velazquez, EJ., et al.[2010]

A systematic review of 46 randomized controlled trials involving 13,451 participants found that angiotensin receptor blockers (ARBs) lower blood pressure modestly, with an average reduction of -8 mm Hg for systolic and -5 mm Hg for diastolic blood pressure at maximum recommended doses.

The study indicates that there are no significant differences in blood pressure-lowering efficacy among different ARBs, and that starting doses achieve 60-70% of the maximum effect, suggesting that higher doses may not provide additional benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Heran, BS., Wong, MM., Heran, IK., et al.[2022]

Angiotensin II type 1 receptor blockers are well-tolerated cardiovascular agents with side effects occurring at rates similar to placebo, making them a safer option compared to traditional angiotensin converting enzyme inhibitors, particularly regarding cough.

Serious side effects are rare but can include cough, angioneurotic edema, and renal issues; these blockers are not recommended for use in pregnancy or in patients with severe renal or hepatic impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse effects of angiotensin II type 1 receptor blockers ]. Preobrazhenskiĭ, DV., Sidorenko, BA.[2018]

Angiotensin receptor blockers (ARBs) are effective and safe antihypertensive medications that work by blocking the angiotensin II type 1 receptor, and they may also stimulate the type 2 receptor, contributing to their therapeutic effects.

In addition to lowering blood pressure, ARBs have shown benefits in treating heart failure, diabetic nephropathy, and preventing strokes, making them a versatile class of drugs with multiple protective actions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pleiotropic effects of angiotensin receptor blockers. Chrysant, SG., Chrysant, GS.[2023]

In a study of 20 hypertensive patients with aortic valve stenosis, ACE inhibitors significantly lowered systolic blood pressure and improved stroke volume during peak stress, indicating a positive effect on stress haemodynamics.

Despite these benefits, ACE inhibitors also led to an increased mean pressure gradient, suggesting that their afterload relief effect is countered in patients with aortic stenosis, but they should still be continued due to their overall favorable impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study. Jiménez-Candil, J., Bermejo, J., Yotti, R., et al.[2018]

Hypertension significantly accelerates the progression of aortic stenosis (AS) and increases the risk of mortality, as shown in a study of 338 patients over an average follow-up of 6.2 years.

Angiotensin-receptor blockers (ARBs) were associated with slower AS progression and did not increase mortality risk, while angiotensin-converting enzyme inhibitors (ACEIs) did not provide the same protective effect against mortality in hypertensive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis. Capoulade, R., Clavel, MA., Mathieu, P., et al.[2013]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Renin-angiotensin system inhibition is not associated with increased sudden cardiac death, cardiovascular mortality or all-cause mortality in patients with aortic stenosis. [2014]

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

Association of candesartan vs losartan with all-cause mortality in patients with heart failure. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Renin-Angiotensin System Blockade in Aortic Stenosis: Implications Before and After Aortic Valve Replacement. [2021]

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

Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis. [2021]

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

Angiotensin-receptor blockers: benefits beyond lowering blood pressure. [2019]

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

Evidence for the efficacy of ARBs across the cardiovascular continuum. [2010]

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

Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. [2022]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Adverse effects of angiotensin II type 1 receptor blockers ]. [2018]

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

The pleiotropic effects of angiotensin receptor blockers. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis. [2013]