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

Abstract

Background: The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects.

Methods and results: Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area-adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection.

Conclusions: Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome.

Trial registration: ClinicalTrials.gov NCT00429364.

Figure 1

Flowchart of Pediatric Heart Network Marfan trial screened population. Abbreviations: LDS, Loeys-Dietz syndrome; SGS, Shprintzen-Goldberg syndrome. ^a, The most common exclusion criterion at this stage of the screening process (not mutually exclusive) was having an aortic root diameter z-score ≤3 (71%), followed by indication of a prior aortic surgery or dissection or aortic surgery planned within 6 months (10%) and intolerance to angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, or β-blocker (10%). A relatively small proportion of ineligible patients indicated therapeutic usage of angiotensin-converting enzyme inhibitor, β-blocker, or calcium-channel blockers (6%), inability to complete study procedures (6%), current or planned pregnancy (3%), aortic root dimension >5 cm (2%), and diabetes or renal dysfunction (1%). ^b, Twenty patients were ineligible following consent to participate in the trial because of ineligible baseline echocardiogram, 24-hour ambulatory electrocardiogram (Holter), or laboratory studies.

Figure 2

Prevalence of Ghent criteria in aggregate and by treatment arm. The prevalence of Ghent criteria, both major and involvement of organ systems, is shown. Prevalence of organ system involvement is calculated in subjects who do not meet major criteria in the respective organ system, with the exception of cardiovascular involvement. Because all subjects had aortic root dilation and, therefore, met the major criterion for the cardiovascular system, cardiovascular involvement indicates the prevalence of additional minor cardiovascular criteria of MVP and dilated main pulmonary artery in all randomized subjects.

Figure 3

Gender differences. Gender differences in family history of aortic surgery, neurodevelopmental history, measurable (mild or more) mitral valve regurgitation, and MVP. Family history of aortic surgery was restricted to subjects who indicated a family history of MFS. **P < .01, ***P < .001.

Figure 4

Differences by age at randomization. Prevalence of major Ghent criteria in the skeletal, dura, and ocular organ systems; number of major Ghent criteria met; and involvement of pulmonary and skin organ systems by age at randomization quartiles. **P < .01, ***P < .001.