Atenolol versus losartan in children and young adults with Marfan's syndrome

Abstract

Background: Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers.

Methods: We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events.

Results: From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups.

Conclusions: 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. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

Figure 1. Screening, Randomization, and Follow-up

The most common exclusion criterion during the medical-record review (71% of records reviewed) was an aortic-root-diameter z score of less than 3.0. Among the 543 participants who remained in the trial, data for the primary end point at 3 years were available for all but 11, who had unacceptable or missing echocardiograms (5 participants in the atenolol group and 6 in the losartan group). In addition, 3 participants withdrew late from the study (2 participants in the atenolol group because of aortic-root surgery and 1 in the losartan group because of unplanned pregnancy); the echocardiograms obtained at the time of withdrawal for these 3 participants served as the 3 year measurements, yielding a total of 535 participants with data for the primary end point at 3 years (268 participants in the atenolol group and 267 in the losartan group). ARB denotes angiotensin II–receptor blocker.

Figure 2. Change in Aortic-Root z Score and Aortic-Root Diameter, According to Treatment Group

The aortic-root z score is the z score for the maximum diameter of the aortic root, indexed to body-surface area. Panel A shows the baseline-adjusted rate of change in the aortic-root z score over the 3-year period (solid lines), with 95% confidence intervals (dashed lines) for the pointwise comparison. Panel B shows the baseline-adjusted rate of change in the maximum diameter of the aortic root over the 3-year period (solid lines), with 95% confidence intervals (dashed lines) for the point-wise comparison.

Figure 3. Freedom from Adverse Clinical Outcomes, According to Treatment Group

The graph shows the estimated probability of freedom from aortic dissection, aortic-root surgery, and death (solid lines), according to treatment assignment, with 95% confidence intervals (dashed lines) for the pointwise comparison. A total of 543 participants completed the 3-year follow-up visit (mean follow-up, 3.0±0.1 years). The inset shows the same data on an enlarged y axis.