Children With Marfan Syndrome and Aortic Root Dilation
Children With Marfan Syndrome and Aortic Root Dilation
The design of this trial has been reported. In brief, individuals 6 months to 25 years of age who met the original Ghent criteria and had a body surface area–adjusted aortic root diameter z-score >3.0 were eligible for inclusion (Table I). The study was designed to include subjects with this degree of aortic dilation at the time of enrollment because these individuals may be more likely than those with less aortic root dilation to show a treatment effect within the 3-year time frame of this study. Similarly, we excluded subjects with severe aortic dilation (≥5 cm) because they would likely withdraw before 3 years because of the need for surgery. To evaluate the effect of growth on change in z-score, we compared younger children who were still growing to older teenagers and young adults who were expected to have achieved final height at the time of study entry (≥16 years for males and ≥15 years for females). The study protocol was approved by the institutional review board or institutional ethics board at each participating center, and informed consent was obtained from the patient or a parent or legal guardian before trial enrollment.
The study design included a multitiered screening, consent, and randomization process summarized in Figure 1. Revised diagnostic criteria for MFS were published after initiation of this trial. After completion of trial enrollment, we retrospectively compared the original and revised Ghent diagnostic criteria in the enrolled subjects and screened population. Nearly all the randomized subjects (603 of 608) and nonrandomized patients eligible for consent (42/43), all of whom had an aortic root diameter z-score >3.0, satisfied both the original and revised criteria.
(Enlarge Image)
Figure 1.
Flowchart of Pediatric Heart Network Marfan trial screened population. Abbreviations: LDS, Loeys-Dietz syndrome; SGS, Shprintzen-Goldberg syndrome. 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%). Twenty patients were ineligible following consent to participate in the trial because of ineligible baseline echocardiogram, 24-hour ambulatory electrocardiogram (Holter), or laboratory studies.
Echocardiograms were performed under a standardized protocol and interpreted centrally by investigators blinded to treatment arm. Aortic root diameter was measured at the sinuses of Valsalva at its maximum dimension in systole, from inner edge to inner edge, in the parasternal long-axis view, and body surface area–adjusted aortic root diameter z-score was calculated.
Weight, height, and body mass index (BMI) z-scores were derived from 2000 CDC Growth Charts. Descriptive statistics are shown as means ± SDs and number of subjects (percentage); medians and interquartile ranges (IQRs) are presented for highly skewed measures. Continuous variables were compared with analysis of variance or its nonparametric analogue (Kruskal-Wallis) between groups. Categorical variables were compared between groups with a Fisher exact test; ordinal variables were compared with a Fisher exact test and the Mantel-Haenszel test for trend. Because of the large number of comparisons, 2-sided P values < .01 were considered to be statistically significant.
This study was supported by U01 grants from the NHLBI (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057) and the FDA Office of Orphan Products Development. Additional support was provided by the National Marfan Foundation, Merck & Co, Inc, and Teva Canada Limited. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents. The contents do not necessarily represent the official views of NHLBI or National Institutes of Health.
Methods
Screening and Randomization Protocol
The design of this trial has been reported. In brief, individuals 6 months to 25 years of age who met the original Ghent criteria and had a body surface area–adjusted aortic root diameter z-score >3.0 were eligible for inclusion (Table I). The study was designed to include subjects with this degree of aortic dilation at the time of enrollment because these individuals may be more likely than those with less aortic root dilation to show a treatment effect within the 3-year time frame of this study. Similarly, we excluded subjects with severe aortic dilation (≥5 cm) because they would likely withdraw before 3 years because of the need for surgery. To evaluate the effect of growth on change in z-score, we compared younger children who were still growing to older teenagers and young adults who were expected to have achieved final height at the time of study entry (≥16 years for males and ≥15 years for females). The study protocol was approved by the institutional review board or institutional ethics board at each participating center, and informed consent was obtained from the patient or a parent or legal guardian before trial enrollment.
The study design included a multitiered screening, consent, and randomization process summarized in Figure 1. Revised diagnostic criteria for MFS were published after initiation of this trial. After completion of trial enrollment, we retrospectively compared the original and revised Ghent diagnostic criteria in the enrolled subjects and screened population. Nearly all the randomized subjects (603 of 608) and nonrandomized patients eligible for consent (42/43), all of whom had an aortic root diameter z-score >3.0, satisfied both the original and revised criteria.
(Enlarge Image)
Figure 1.
Flowchart of Pediatric Heart Network Marfan trial screened population. Abbreviations: LDS, Loeys-Dietz syndrome; SGS, Shprintzen-Goldberg syndrome. 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%). Twenty patients were ineligible following consent to participate in the trial because of ineligible baseline echocardiogram, 24-hour ambulatory electrocardiogram (Holter), or laboratory studies.
Echocardiograms were performed under a standardized protocol and interpreted centrally by investigators blinded to treatment arm. Aortic root diameter was measured at the sinuses of Valsalva at its maximum dimension in systole, from inner edge to inner edge, in the parasternal long-axis view, and body surface area–adjusted aortic root diameter z-score was calculated.
Statistical Methods
Weight, height, and body mass index (BMI) z-scores were derived from 2000 CDC Growth Charts. Descriptive statistics are shown as means ± SDs and number of subjects (percentage); medians and interquartile ranges (IQRs) are presented for highly skewed measures. Continuous variables were compared with analysis of variance or its nonparametric analogue (Kruskal-Wallis) between groups. Categorical variables were compared between groups with a Fisher exact test; ordinal variables were compared with a Fisher exact test and the Mantel-Haenszel test for trend. Because of the large number of comparisons, 2-sided P values < .01 were considered to be statistically significant.
This study was supported by U01 grants from the NHLBI (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057) and the FDA Office of Orphan Products Development. Additional support was provided by the National Marfan Foundation, Merck & Co, Inc, and Teva Canada Limited. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents. The contents do not necessarily represent the official views of NHLBI or National Institutes of Health.
