Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome
- Registration Number
- NCT00429364
- Lead Sponsor
- Carelon Research
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 608
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Atenolol 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. Losartan Losartan Potassium 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).
- Primary Outcome Measures
Name Time Method Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Body-surface-area-adjusted Z-score Up to 3 years following randomization. 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
- Secondary Outcome Measures
Name Time Method Annual Rate of Change in the Absolute Diameter of the Ascending Aorta Up to 3 years following randomization. Event Rate of Aortic Dissection. Up to 3 years following randomization. Percentage of participants who had aortic dissection over a 3-year period following randomization.
Number of Death. Up to 3 years following randomization. Annual Rate of Change in Aortic Root (Sinuses of Valsalva) Absolute Dimension Up to 3 years following randomization. The rate of change in the absolute dimension of the aortic root over a 3-year period following randomization
Annual Rate of Change in Body Mass Index 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 Weight 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 Upper to Lower Segment Ratio Up to 3 years following randomization. Number of Participants With Aortic Dissection. 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. 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 Height Up to 3 years following randomization. Annual Rate of Change in Arm Span to Height Ratio Up to 3 years following randomization. Event Rate of Death Up to 3 years following randomization. Percentage of participants who died over a 3-year period following randomization.
Event Rate of the Composite Adverse Clinical Outcomes, Including Aortic Dissection, Aortic-root Surgery and Death. Up to 3 years following randomization. Percentage of participants who had aortic dissection, aortic-root surgery or death over a 3-year period following randomization
Adverse Drug Reactions Reported at the Baseline Visit At baseline 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-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-for-age Z-score Up to 3 years following randomization. Event Rate of Aortic-Root Surgery Up to 3 years following randomization. Percentage of participants who had aortic-root surgery over a 3-year period following randomization.
Number of Participants With Aortic-root Surgery. Up to 3 years following randomization. Adverse Drug Reactions Reported During Routine Follow-up Surveillance From 6 months to 3 years following randomization.
Trial Locations
- Locations (26)
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Lucile Packard Children's Hospital
🇺🇸Palo Alto, California, United States
Rady Children's Hospital / UCSD
🇺🇸San Diego, California, United States
Stanford University School of Medicine
🇺🇸Stanford, California, United States
Children's Memorial Hospital
🇺🇸Chicago, Illinois, United States
Johns Hopkins University School of Medicine
🇺🇸Baltimore, Maryland, United States
Children's Hospital Boston
🇺🇸Boston, Massachusetts, United States
Children's Hospital of Minnesota - St. Paul
🇺🇸Saint Paul, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Weill Medical College of Cornell University
🇺🇸New York, New York, United States
Mount Sinai Medical Center
🇺🇸New York, New York, United States
Columbia College of Physicians and Surgeons
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Brody School of Medicine at East Carolina University
🇺🇸Greenville, North Carolina, United States
Wake Forest University Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Hospital of the University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Primary Children's Medical Center
🇺🇸Salt Lake City, Utah, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Ghent University Hospital
🇧🇪Ghent, Gent, Belgium
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada