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

Abstract

SummaryBackgroundIrbesartan, 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.MethodsWe 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.FindingsBetween 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.InterpretationIrbesartan 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.FundingBritish Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

Characterization of doxycycline-mediated inhibition of Marfan syndrome-associated aortic dilation by multiphoton microscopy

“…Unfortunately, clinical data available on β-blockers and ARBs in MFS are scarce and inconsistent, with recent systematic and meta-analyses deeming no benefit of these medications in MFS patients 19,20 . However very recently, the AIMS trial has shown an association with a reduction in the rate of aortic dilation in MFS following treatment with the ARB irbesartan 21 . Despite a reduction in aortic root diameter rates, there is still an apparent overall increase in aortic root diameter over time.…”

Inhibition of Angiotensin II Dependent AT1a Receptor Stimulation Attenuates Thoracic Aortic Pathology in Fibrillin-1C1041G/+Mice

“…Indeed, it has been demonstrated recently that irbesartan significantly attenuated aortic root expansion in individuals with Marfan syndrome. 37 Conversely, ASO affords chronic and persistent inhibition of AGT synthesis to effect long-term depletion of angiotensin ligands. These durable effects of ASO enables inhibition of AGT synthesis to be tested as a possible approach to reduce TAA in Marfan syndrome.…”

Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment

“…In a retrospective study, they demonstrated that ARB usage was associated with reduced aortic root growth in severely affected pediatric MFS patients. Multiple randomized controlled trials followed [129,130,[166][167][168][169][170][171] (Table 3). In 2013, the randomized open-label controlled COMPARE trial was published, which investigated the potential benefit of adding losartan to standard care, including a β-blocker in > 70% of the patients [129].…”

“…Also, this metaanalysis did not include the long-term follow-up study from the COMPARE trial [179]. Thus, when taking the results from the COMPARE, AIMS, and the long-term follow-up study of the COMPARE trial together, it seems that combining ARBs and β-blockers in MFS patients is not only preferential to prevent aneurysm growth but also to prevent long-term adverse outcomes [129,130,179].…”