Losartan for Coarctation of the Aorta

(VALUE Trial)

Overseen By Alexander Egbe, MBBS, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Mayo Clinic

Must not be taking: Beta blockers, Antihypertensives

Disqualifiers: Pregnancy, Hyperkalemia, Severe valve issues, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how well Losartan works for people with coarctation of the aorta, a condition where part of the main artery narrows, leading to high blood pressure. Researchers aim to determine if Losartan, a medication for high blood pressure, can effectively manage this condition compared to a placebo or another medication, Amlodipine. Individuals who have undergone previous repair for coarctation and are experiencing high blood pressure might be suitable candidates. The trial includes separate groups for each treatment to compare their effects. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

If you are currently taking beta blockers or have received any antihypertensive medications in the past year, you cannot participate in this trial. The protocol does not specify about other medications, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Losartan, a medication often used for high blood pressure, is generally well-tolerated. Studies have safely used Losartan in various doses, particularly in individuals weighing less than 50 kg, with 25 and 40 mg doses yielding good results. Side effects are usually mild, though some individuals might experience dizziness or a stuffy nose.

Amlodipine, another medication tested, is also commonly used for high blood pressure. Known for its safety, it is widely prescribed. Most individuals handle it well, though a few might experience swelling or headaches.

Both Losartan and Amlodipine have FDA approval for treating high blood pressure and other conditions, which supports their safety. While side effects can occur, these medications are generally considered safe based on their extensive use in treating high blood pressure. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Losartan is unique because it targets the renin-angiotensin system to lower blood pressure, which is different from the usual surgical interventions or beta-blockers typically used for coarctation of the aorta. Researchers are excited about Losartan because it offers a non-surgical approach with a potential for fewer side effects compared to traditional methods. Additionally, Losartan's ability to specifically block the angiotensin II receptor might provide a more targeted effect on blood pressure control, which could improve outcomes for patients with this condition.

What evidence suggests that this trial's treatments could be effective for coarctation of the aorta?

In this trial, participants with coarctation of the aorta and high blood pressure will join one of three groups. Research has shown that losartan, which participants in the Losartan Group will receive, can effectively lower blood pressure in people with this condition. One study found that losartan significantly reduced both systolic and diastolic blood pressure compared to a placebo in patients with high blood pressure due to this condition. This is encouraging because managing blood pressure is crucial for treating coarctation of the aorta.

Similarly, participants in the Amlodipine Group will receive amlodipine, another medication used to lower high blood pressure. It works as well as other drugs in its class, called calcium channel blockers, which help relax blood vessels and lower pressure. Both medications aim to control high blood pressure, a common issue for those with coarctation of the aorta, even after surgery. ^{1 3 6 7 8}

Who Is on the Research Team?

Alexander Egbe, MBBS, MPH

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults with a history of early childhood repair of coarctation of the aorta and slightly elevated blood pressure. They must not be on beta blockers, pregnant, or have severe kidney issues, high potassium levels, significant heart valve problems, coronary artery disease, or taken blood pressure meds in the last year.

Inclusion Criteria

My average blood pressure is between 120-139.

COA Repair prior to age 10

No residual COA; Based on mean doppler COA gradient <20mmHg within past 12 months

Exclusion Criteria

I have taken medication for high blood pressure in the last year.

eGFR<30

Hyperkalemia (serum potassium >5.5mmol/L)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Losartan, Amlodipine, or Placebo for the treatment of coarctation of aorta

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Amlodipine
• Losartan
• Placebo

Trial Overview The study is testing Losartan's effectiveness against cardiovascular remodeling in patients who've had an aortic coarctation repair. It compares Losartan to Amlodipine and placebo to see which better improves heart structure and function.

How Is the Trial Designed?

Group I: Losartan Group Experimental Treatment 1 Intervention

Subjects with Coarctation of Aorta (COA) and high blood pressure will receive Losartan.

Group II: Amlodipine Group Active Control 1 Intervention

Subjects with Coarctation of Aorta (COA) and high blood pressure will receive Amlodipine.

Group III: Placebo Group Placebo Group 1 Intervention

Subjects with Coarctation of Aorta (COA) and high blood pressure will receive Placebo.

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

Approved in United States as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Stroke prevention in hypertension and left ventricular hypertrophy

Approved in European Union as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Approved in Canada as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In both canine models and human patients with aortic coarctation, the study found that the renin-angiotensin system is not the primary cause of hypertension, as there was no significant elevation in plasma renin activity in dogs and only a moderate response in humans after coarctation correction.

However, in humans, there was a notable increase in plasma renin activity in response to postural changes and exercise, suggesting that while the renin-angiotensin system is not the main driver of hypertension in coarctation, it may still play a role that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Studies of plasma renin activity in coarctation of the aorta. Van Way, CW., Michelakis, AM., Anderson, WJ., et al.[2019]

In a study of eight children with aortic coarctation, plasma renin activity (PRA) significantly decreased from a mean of 21.4 ng/ml/hour before surgery to 5.5 ng/ml/hour after surgical correction, indicating a reduction in renin-angiotensin activity post-operation.

The results highlight the importance of managing increased renin-angiotensin activity in patients with aortic coarctation, suggesting that surgical correction can effectively normalize this activity over a follow-up period of 32 to 51 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative and postoperative renin levels in coarctation of the aorta. Parker, FB., Streeten, DH., Farrell, B., et al.[2019]

In rats with suprarenal aortic coarctation, stimulation of angiotensin type 2 receptors (AT2R) by CGP42112 was found to significantly reduce carotid pulse pressure, indicating a potential mechanism for managing blood pressure under pressure overload conditions.

The study showed that while losartan and PD123319 did not affect pulse pressure, the increase in AT2R protein levels in the thoracic aorta of these rats suggests that AT2R plays a crucial role in the cardiovascular response to aortic coarctation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of upregulated angiotensin II type 2 receptors decreases carotid pulse pressure in rats with suprarenal abdominal aortic coarctation. López, RM., Castillo, MC., López, JS., et al.[2018]

Coarctation or hypoplasia of the abdominal aorta can lead to severe hypertension primarily due to increased renin levels from renal artery stenosis, making medical management challenging.

Surgical interventions, such as renal artery revascularization and aortic bypass or replacement, are often necessary early in life, with a focus on using autogenous methods for reconstruction to optimize outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coarctation of the abdominal aorta: current options in surgical management. Hallett, JW., Brewster, DC., Darling, RC., et al.[2022]

In a 12-week study involving 366 hypertensive patients, losartan significantly reduced both systolic and diastolic blood pressure compared to placebo, demonstrating its efficacy as an antihypertensive medication.

Losartan was well tolerated with a safety profile similar to placebo, and there was no evidence of rebound hypertension after stopping the medication, indicating it is a safe option for managing mild-to-moderate hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative antihypertensive effects of losartan 50 mg and losartan 50 mg titrated to 100 mg in patients with essential hypertension. Ikeda, LS., Harm, SC., Arcuri, KE., et al.[2019]

Losartan potassium, an angiotensin II receptor antagonist, shows significant haemodynamic benefits in patients with heart failure, based on extensive clinical trials.

The drug is well tolerated with a low incidence of adverse effects related to kidney function, making it a safe option for treating hypertension and heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan in heart failure: preclinical experiences and initial clinical outcomes. Sweet, CS., Rucinska, EJ.[2019]

In a study of Marfan syndrome patients, losartan significantly reduced the rate of aortic root dilatation over 3 years, with an average reduction from 1.3 mm to 0.8 mm in those treated with losartan compared to those who did not receive the medication.

The effectiveness of losartan varied by genetic mutation type: it was particularly effective in patients with haploinsufficient FBN1 mutations, reducing dilatation from 1.8 mm to 0.5 mm, while it showed no significant effect in patients with dominant negative mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome. Franken, R., den Hartog, AW., Radonic, T., et al.[2016]

In a study involving 140 patients with Marfan syndrome, losartan and atenolol were found to have similar effects on the progression of aortic dilation over 3 years, with no significant differences in aortic root or ascending aorta diameters.

Both medications were well-tolerated, with no serious drug-related adverse effects reported, indicating that they are safe options for managing aortic dilation in Marfan syndrome patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. Forteza, A., Evangelista, A., Sánchez, V., et al.[2017]

A 64-year-old woman developed severe pustular vasculitis likely caused by losartan, an antihypertensive medication, indicating a rare but serious side effect of this drug.

Withdrawal of losartan and treatment with corticosteroids led to the resolution of the skin lesions, highlighting the importance of monitoring for adverse reactions in patients taking this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Severe pustular and polymorphous vasculitis caused by losartan]. Piérard Franchimont, C., Henry, F., Piérard, GE.[2022]

In a study of 7 hypertensive patients with aortic coarctation, the angiotensin II antagonist saralasine significantly reduced diastolic blood pressure, indicating its effectiveness in managing hypertension related to the renin-angiotensin system (RAS).

The beta-blocker acebutolol also inhibited renin secretion but showed only a moderate antihypertensive effect, suggesting that the RAS plays a crucial role in this condition, similar to the Goldblatt model of kidney-related hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Role of the renin-angiotensin system in arterial hypertension with aortic coarctation in young adults]. Lardoux, H., Corvol, P., Kreft, C., et al.[2009]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12009809/

Hypertension in aortic coarctation - PMC - PubMed Central - NIH Despite advances in surgical and percutaneous interventions, hypertension remains a significant complication in AoC patients, even after successful repair.

2. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.123.19454

Coarctation of the Aorta: Modern Paradigms Across ... CoA is a lifelong disease strongly associated with long-term hypertension, regardless of age at diagnosis or quality of repair.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8522551/

Delayed Therapy of Descending Aortic Coarctation Results in ... We present a 13-year-old boy with an anterior cerebral rupture following a delayed diagnosis for descending CoA.

4. med.virginia.edu med.virginia.edu/pediatrics/wp-content/uploads/sites/237/2015/12/200307.pdf

7 Amlodipine Use in Pediatric Hypertension The authors concluded that amlodipine was as effective as standard calcium channel blockers in their pediatric population and offered the advantage of once- ...

5. researchgate.net researchgate.net/publication/358666083_Hypertension_after_coarctation_repair-a_systematic_review

Hypertension after coarctation repair—a systematic review Results: In this systematic review on HT after CoA Repair the mean prevalence of HT was 47.3% (20-70%). A progressive character was of the HT ...

6. ahajournals.org ahajournals.org/doi/10.1161/JAHA.119.012056

Coronary Artery Disease in Adults With Coarctation of Aorta Baseline Clinical and Echocardiographic Data ; Beta blockers, 238 (37%), 186 (21%) ; Calcium channel blockers, 62 (10%), 91 (10%) ; RAAS antagonist ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2666668523000186

Systemic hypertension in adults with congenital heart ... Coarctation of the aorta (COA) is the most well-known CHD at risk for HTN. Indeed, approximately 30% of children develop HTN after early repair of COA [6], and ...

8. cureus.com cureus.com/articles/371034-hypertension-secondary-to-severe-aortic-coarctation-in-an-adult-patient.pdf?email=

Hypertension Secondary to Severe Aortic Coarctation in an ... A 42-year-old man with a 24-year history of poorly controlled hypertension was admitted following a traumatic femoral fracture.