Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial

Abstract

Background: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome.

Methods: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794.

Findings: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events.

Interpretation: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications.

Funding: British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Figure 1

Study profile *These adverse events were not serious. †Four did not attend, four withdrew consent, three non-compliance to medication, and two investigator decisions. ‡Nine did not attend, five withdrew consent, five non-compliance to medication, three investigator decisions, and three were ineligible.

Figure 2

Aortic diameter measurements over time (A) Mean aortic root diameter over time. (B) Mean aortic Z score over time. Means were estimated by use of a linear mixed effects model for repeated measures. At the final follow up visit the majority of patients had not reached 5 years of study participation, which accounts for the sharp decrease in numbers available for follow-up between year 4 and 5.

Figure 3

Differences in rate of aortic root diameter change