Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome

Trial of Beta Blocker Therapy (Atenolol) Versus Angiotensin II Receptor Blocker Therapy (Losartan) in Individuals With Marfan Syndrome (A Trial Conducted by the Pediatric Heart Network)

Marfan syndrome is a hereditary connective tissue disorder. Many individuals with this condition die because of the associated heart and blood vessel abnormalities. This study will compare the effectiveness of two medications, losartan and atenolol, at slowing aortic root enlargement in individuals with Marfan syndrome.

Study Overview

• Status: Completed
• Conditions: Marfan Syndrome
• Intervention / Treatment: Drug: Atenolol; Drug: Losartan Potassium

Detailed Description

Marfan syndrome is an inheritable disorder that affects the body's connective tissue. An abnormal protein results in connective tissue that is weaker than normal. Because connective tissue is found throughout the body, Marfan syndrome can affect many body systems, including the skeleton, eyes, nervous system, skin, lungs, heart, and blood vessels. Overall, heart and blood vessel abnormalities are the leading cause of death in individuals with Marfan syndrome. A common blood vessel abnormality associated with this disease involves the aorta, which is the large artery that carries blood away from the heart to the rest of the body. The aortic root, the portion of the aorta that is attached to the heart, may enlarge and tear or even rupture. A tear or rupture is considered a life-threatening emergency. Recent studies have shown that the medication losartan may reduce aortic root growth and improve heart function. The purpose of this study is to compare the effectiveness of losartan versus atenolol at slowing aortic root growth in individuals with Marfan syndrome.

This 3-year study will enroll individuals with Marfan syndrome. Participants will be randomly assigned to receive either losartan or atenolol on a daily basis. All participants will initially receive a low dose of their assigned medication. This dose will be gradually increased every 3 to 4 weeks until the maximum tolerated dose is reached. A continuous electrocardiogram (ECG) that monitors heart rate and activity in 24-hour intervals will be used to determine the proper dose increase for each participant. Participants will then receive the maximum tolerated dose for the remainder of the study. Study visits will occur at baseline and Months 6, 12, 24, and 36. Each study visit will include a physical examination, a medical history review, an ECG, an echocardiogram, and questionnaires. Additionally, at the baseline study visit blood will be collected for laboratory testing.

• Study Type: Interventional
• Enrollment (Actual): 608
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Gent
    • Ghent, Gent, Belgium, 185 9000
      • Ghent University Hospital
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital
    • San Diego, California, United States, 92123
      • Rady Children's Hospital / UCSD
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University School Of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Children's Hospital of Minnesota - St. Paul
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia College of Physicians and Surgeons
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10021
      • Weill Medical College of Cornell University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27834
      • Brody School of Medicine at East Carolina University
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of Marfan syndrome, according to Ghent criteria (more information can be found in Appendix D of the protocol)
• Aortic root Z-score greater than 3.0

Exclusion Criteria:

• Prior aortic surgery
• Aortic root dimension at the sinuses of Valsalva greater than 5 cm
• Planned aortic surgery within 6 months of study entry
• Aortic dissection
• Shprintzen-Goldberg syndrome
• Loeys-Dietz syndrome
• Therapeutic (i.e., for arrhythmia, ventricular dysfunction, or valve regurgitation) rather than prophylactic use of angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, or calcium channel blocker
• History of angioedema while taking an ACE inhibitor or beta-blocker
• Intolerance to losartan or other angiotensin II receptor blocker (ARB) that resulted in termination of therapy
• Intolerance to atenolol or other beta-blocker that resulted in termination of therapy
• Kidney dysfunction (i.e., creatinine greater than the upper limit of age-related normal values)
• Asthma of sufficient severity to prohibit the use of a beta-blocker
• Chronic use of steroids and/or beta-adrenergic agents with exacerbations of asthma that are frequent (averaging three or more per year) or severe (requiring hospitalization)
• Diabetes mellitus
• Pregnant or planning to become pregnant within 36 months of study entry
• Inability to complete study procedures, including history of poor acoustic windows (i.e., inability to obtain accurate measurement of aortic root)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atenolol; Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.5 - 4.0 mg/kg/day Atenolol (not to exceed a total dose of 250 mg), with a goal of a 20% or greater decrease in the mean heart rate.	Drug: Atenolol; Atenolol .5 - 4 mg/kg; Other Names: Tenormin
Active Comparator: Losartan; Participants with Marfan's syndrome and ≥3 maximum aortic root z-score received 0.4 - 1.4 mg/kg/day Losartan (not to exceed a total dose of 100 mg).	Drug: Losartan Potassium; Losartan .3 - 1.4 mg/kg; Other Names: Cozaar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score	The rate of aortic root enlargement, expressed as the annual change in the maximum aortic-root-diameter z score indexed to body-surface area over a 3-year period following randomization	Up to 3 years following randomization.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension	The rate of change in the absolute dimension of the aortic root over a 3-year period following randomization	Up to 3 years following randomization.
Annual Rate of Change in Ascending-aorta-diameter Z Score, Adjusted by Body-surface-area.		Up to 3 years following randomization.
Annual Rate of Change in the Absolute Diameter of the Ascending Aorta		Up to 3 years following randomization.
Annual Rate of Change in Aortic-annulus-diameter Z Score, Adjusted by Body-surface Area		Up to 3 years following randomization.
Annual Rate of Change in the Absolute Diameter of the Aortic Annulus		Up to 3 years following randomization.
Annual Rate of Change in Total Aortic Proximal Regurgitant Jet Area Indexed to Body-surface-area		Up to 3 years following randomization.
Annual Rate of Change in Weight		Up to 3 years following randomization.
Annual Rate of Change in Weight-for-age Z-score		Up to 3 years following randomization.
Annual Rate of Change in Weight-for-height Z-score		Up to 3 years following randomization.
Annual Rate of Change in Height		Up to 3 years following randomization.
Annual Rate of Change in Height-for-age Z-score		Up to 3 years following randomization.
Annual Rate of Change in Body Mass Index		Up to 3 years following randomization.
Annual Rate of Change in Body Mass Index for Age Z-score		Up to 3 years following randomization.
Annual Rate of Change in Arm Span to Height Ratio		Up to 3 years following randomization.
Annual Rate of Change in Upper to Lower Segment Ratio		Up to 3 years following randomization.
Number of Participants With Aortic Dissection.		Up to 3 years following randomization.
Event Rate of Aortic Dissection.	Percentage of participants who had aortic dissection over a 3-year period following randomization.	Up to 3 years following randomization.
Number of Participants With Aortic-root Surgery.		Up to 3 years following randomization.
Event Rate of Aortic-Root Surgery	Percentage of participants who had aortic-root surgery over a 3-year period following randomization.	Up to 3 years following randomization.
Number of Death.		Up to 3 years following randomization.
Event Rate of Death	Percentage of participants who died over a 3-year period following randomization.	Up to 3 years following randomization.
Number of Participants With the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.		Up to 3 years following randomization.
Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death.	Percentage of participants who had aortic dissection, aortic-root surgery or death over a 3-year period following randomization	Up to 3 years following randomization.
Adverse Drug Reactions Reported at the Baseline Visit		At baseline
Adverse Drug Reactions Reported During Routine Follow-up Surveillance		From 6 months to 3 years following randomization.

Collaborators and Investigators

• Sponsor: Carelon Research
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); FDA Office of Orphan Products Development; National Marfan Foundation
• Investigators: Principal Investigator: Ron Lacro, MD, Boston Children's Hospital

Publications and helpful links

General Publications

• Hoskoppal A, Menon S, Trachtenberg F, Burns KM, De Backer J, Gelb BD, Gleason M, James J, Lai WW, Liou A, Mahony L, Olson AK, Pyeritz RE, Sharkey AM, Stylianou M, Wechsler SB, Young L, Levine JC, Tierney ESS, Lacro RV, Bradley TJ; Pediatric Heart Network Investigators. Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome. Pediatr Cardiol. 2018 Oct;39(7):1453-1461. doi: 10.1007/s00246-018-1916-6. Epub 2018 Jun 11.
• Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, Pearson GD, Selamet Tierney ES, Levine JC, Atz AM, Benson DW, Braverman AC, Chen S, De Backer J, Gelb BD, Grossfeld PD, Klein GL, Lai WW, Liou A, Loeys BL, Markham LW, Olson AK, Paridon SM, Pemberton VL, Pierpont ME, Pyeritz RE, Radojewski E, Roman MJ, Sharkey AM, Stylianou MP, Wechsler SB, Young LT, Mahony L; Pediatric Heart Network Investigators. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014 Nov 27;371(22):2061-71. doi: 10.1056/NEJMoa1404731. Epub 2014 Nov 18.
• Lacro RV, Guey LT, Dietz HC, Pearson GD, Yetman AT, Gelb BD, Loeys BL, Benson DW, Bradley TJ, De Backer J, Forbus GA, Klein GL, Lai WW, Levine JC, Lewin MB, Markham LW, Paridon SM, Pierpont ME, Radojewski E, Selamet Tierney ES, Sharkey AM, Wechsler SB, Mahony L; Pediatric Heart Network Investigators. Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy. Am Heart J. 2013 May;165(5):828-835.e3. doi: 10.1016/j.ahj.2013.02.019. Epub 2013 Mar 26.

Helpful Links

• Click here for the Pediatric Heart Network Web site
• Click here for the National Marfan Foundation Web site

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: January 29, 2007
• First Submitted That Met QC Criteria: January 29, 2007
• First Posted (Estimated): January 31, 2007

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 18, 2025
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Aortic Root Dilation; Aortic Root Dissection; Pediatric Heart Network
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Disease; Musculoskeletal Abnormalities; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Abnormalities, Multiple; Bone Diseases, Developmental; Limb Deformities, Congenital; Syndrome; Marfan Syndrome; Arachnodactyly; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Anti-Arrhythmia Agents; Adrenergic Agents; Antihypertensive Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Atenolol; Losartan
• Other Study ID Numbers: 461; U01HL068270 (U.S. NIH Grant/Contract)