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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the effectiveness and mechanism of action of Losartan in the treatment of coarctation of aorta.

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 losartan safe for humans?

Losartan is generally well tolerated in humans, with a low chance of causing kidney problems, but there have been rare cases of severe skin reactions linked to its use. ^{1 2 3 4 5}

How does the drug Losartan differ from other treatments for coarctation of the aorta?

Losartan is unique because it targets the renin-angiotensin system, which is involved in blood pressure regulation, and may help manage hypertension (high blood pressure) associated with coarctation of the aorta. Unlike surgical options that directly address the physical narrowing of the aorta, Losartan offers a non-surgical approach by potentially reducing blood pressure through its action on angiotensin receptors. ^{6 7 8 9 10}

Research Team

Alexander Egbe, MBBS, MPH

Principal Investigator

Mayo Clinic

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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 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]

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]

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 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]

References

1. England 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. [2019]

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

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome. [2016]

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

Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. [2017]

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

Losartan in heart failure: preclinical experiences and initial clinical outcomes. [2019]

5. France pubmed.ncbi.nlm.nih.gov

[Severe pustular and polymorphous vasculitis caused by losartan]. [2022]

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

Studies of plasma renin activity in coarctation of the aorta. [2019]

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

Activation of upregulated angiotensin II type 2 receptors decreases carotid pulse pressure in rats with suprarenal abdominal aortic coarctation. [2018]

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

Preoperative and postoperative renin levels in coarctation of the aorta. [2019]

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

Coarctation of the abdominal aorta: current options in surgical management. [2022]

10. France pubmed.ncbi.nlm.nih.gov

[Role of the renin-angiotensin system in arterial hypertension with aortic coarctation in young adults]. [2009]