(Atenolol vs Losartan Trial)

Study Summary

Marfan Syndrome (MFS) is a disorder that can affect the heart and large blood vessels as well as eyes, muscles, bones and lungs. The most serious problems can happen when the body’s largest blood vessel, the aorta, becomes enlarged in individuals with MFS.

This study was done to compare two drugs (Atenolol and Losartan) to see if one is better than the other at slowing the speed of aortic enlargement. The study also compared the kinds of side effects that can occur when taking either of these medicines. The study enrolled 608 individuals, ages 6 months to 25 years.

608 Participants

This study enrolled 608 participants.

6 Months to 25 Years

Participants ages ranged from 6 months to 25 years of age.

No Significant Differences

We found both medications worked equally to control the rate of aortic-root dilatation over a 3-year period.

Who was in the study?

Individuals enrolled in the study had:
  • A diagnosis of MFS according to Ghent criteria
  • Age 6 months to 25 years
  • Aortic root Z-score >3.0

What happened in the study?

This is what was done in the study:
  • We reviewed the individuals’ medical records from time to time to get data about heart problems, treatment history, and the results of previous echocardiograms.
  • Each study participant was randomized to either Atenolol or Losartan and took the study medication for 3 years.
  • There were 5 study visits over three years, including the first visit and then at 6, 12, 24 and 36 months after the first visit. Each study visit included an echocardiogram; some visits also included Holter monitoring and blood tests.

What were the results of the study?

Among children and young adults with Marfan’s syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. Both drugs were tolerated well and no differences were seen in side effects between the two groups.

Study Publications

  • Atenolol versus Losartan in Children and Young Adults with Marfan’s Syndrome

    R. Lacro, N Engl J Med 2014; 371:2061-2071.

    Among 608 children and young adults with Marfan’s syndrome (ages 6 months to 26 years) who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. Aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups.

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  • Rationale and Design of a Randomized Clinical Trial of B-Blocker Therapy (Atenolol) Versus Angiotensin II Receptor Blocker Therapy (Losartan) in Individuals with Marfan Syndrome

    R. Lacro, Am Heart J 2007; 154:624-631.

    The leading cause of death in people with Marfan syndrome is dilation, tearing and rupture of the aorta, the large artery that delivers blood from the heart to the body. Recent studies in mice with Marfan syndrome showed that treatment with Losartan, a medication used to treat high blood pressure, prevented dilation and improved the structure of the wall of the aorta. This article describes the design of a trial to compare Losartan to the standard medication (Atenolol) for patients with Marfan syndrome. The goal of the trial is to follow over 600 children and young adults for 3 years to determine which drug does a better job slowing the rate of growth of the aorta.

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  • Echocardiographic Methods, Quality Review, and Measurement Accuracy in a Randomized Multicenter Clinical Trial of Marfan Syndrome

    E. Selamet Tierney, J Am Soc Echocardiogr 2013; 26(6):657-666.

    This study describes the characteristics of the echocardiograms for subjects enrolled in the clinical trial. Even when different doctors reviewed and measured the aortas and heart structures of the trial participants, there was excellent agreement in the measurements. Having good agreement is important for accurately reporting the results of the clinical trial.

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  • Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy

    R. Lacro, Am Heart J 2013; 165:828-835.e3.

    This paper describes the population that was screened and then enrolled in the clinical trial. The average age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. Aortic root diameter z-score was 4.0 and wasn’t different by age. Mitral valve prolapse and mitral regurgitation were more common in females. 56% had a family member with aortic surgery and 32% had a family member with a history of aortic dissection.

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  • Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome

    ES. Selamet Tierney, Am J Cardiol 2018 May 1;121(9):1094-1101.

    The PHN randomized trial of atenolol versus losartan in Marfan Syndrome showed no treatment differences in the rates of aortic-root growth or clinical outcomes. This analysis examined treatment effects on aortic stiffness and determined whether baseline aortic stiffness predicts aortic-root growth and clinical outcomes. There was no treatment effect on the rate of change for ascending-aorta stiffness index, aortic-root elastic modulus, or ascending-aorta elastic modulus. We found that atenolol therapy was associated with a fall in aortic-root stiffness index, while losartan therapy was not. Higher baseline aortic-root stiffness index and elastic modulus were associated with a smaller decrease in aortic root z-score and increased risk for clinical outcomes. These data suggest that non-invasive aortic stiffness measures may identify patients at higher risk for progressive aortic enlargement and adverse clinical outcomes, potentially allowing for closer monitoring and more aggressive therapy for such patients.

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  • Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome

    A. Hoskoppal, Pediatr Cardiol 2018 Jun 11. doi: 10.1007/s00246-018-1916-6.

    This was a secondary analysis of the PHN randomized clinical trial of atenolol vs. losartan in patients with Marfan syndrome that attempted to identify factors that predict rapid aortic root dilation and referral for aortic surgery. We found some statistically significant but only weakly predictive associations between more rapid aortic root dilation and older age, non-white race, and one aortic measurement: higher sinotubular junction z-score. We found similarly statistically significant but only weakly predictive associations between referral for aortic root surgery and some aortic measurements (larger aortic root diameter, higher ascending aorta z-score, and higher ratio between the diameters of the sinotubular junction and ascending aorta). Future studies may clarify whether monitoring generalized proximal aortic dilation and effacement of the sinotubular junction will help to risk-stratify young patients with Marfan syndrome and inform medical and surgical management.

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  • Frequency of Ventricular Arrhythmias and Other Rhythm Abnormalities in Children and Young Adults With the Marfan Syndrome

    D. Y. Mah, Am J Cardiol. 2018 Jul 17. pii: S0002-9149(18)31424-3. doi: 10.1016/j.amjcard.2018.07.006.

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  • Health-Related Quality of Life in Children and Young Adults with Marfan Syndrome

    J. C. Handisides, J Pediatr. 2019 Jan;204:250-255.e1. doi: 10.1016/j.jpeds.2018.08.061.

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  • Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

    S. Driest, J Pediatr. 2020 Jul;222:213-220.e5. doi: 10.1016/j.jpeds.2020.03.064.

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  • Recruitment, retention, and adherence in a clinical trial: The Pediatric Heart Network’s Marfan Trial experience

    M. S. Hamstra, Clin Trials 2020 Aug 21;1740774520945988. doi: 10.1177/1740774520945988.

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  • Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort

    J. A. N.  Meester, Genetics in Medicine 2022 Jan. doi: 10.1016/j.gim.2021.12.015.

    The purpose of our study was first to identify how many people with Marfan syndrome in the study have a mutation in the FBN1 gene. Afterwards, we investigated if the type of FBN1 mutation is associated with specific symptoms and whether the type of mutation made the treatment work any better or worse. In total, 373 young patients with Marfan syndrome participated in our study. We identified an FBN1 mutation in 91% of participants in our study. A dislocated eye lens happened more often in participants with dominant-negative gene mutations (which are mutations that lead to an abnormal protein) than in those with haplo-insufficient mutations (which are mutations that lead to  lower levels of normal protein). In participants with a dominant negative mutation, a dislocation of the eye lens happened more often if the mutation was located at the beginning of the protein (84%) than if the mutation was found towards the end of the protein (17%). If a dominant negative mutation was present in the middle of the protein, the participants had more severe cardiovascular symptoms. We could not prove whether the type of mutation made treatment work any better. In conclusion, we described new links between the type of gene mutation and symptoms in Marfan syndrome. Our findings will provide more information for families with Marfan syndrome about their condition.

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  • Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials

    A. Pitcher, Lancet 2022 Aug. doi: 10.1016/S0140-6736(22)01534-3.

    People with Marfan syndrome may have enlargement of the aortic root, and medications are often used to try to slow the rate of enlargement. This study combined data from 7 trials and 1442 patients with Marfan syndrome to see whether two types of medications (angiotensin receptor blockers and β blockers) could slow the rate of enlargement of the aortic root. The study found that, in people with Marfan syndrome and no previous aortic surgery, angiotensin receptor blockers reduced the rate of increase of the aortic root by about one half, even among those who were already taking a β blocker. The effects of β blockers were similar to those of angiotensin receptor blockers. They concluded that a combination of a β blocker and an angiotensin receptor blocker could reduce the rate of enlargement of the aortic root by at least one half, and potentially by much more than this, which may delay the need for aortic surgery.

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