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.
Highlights
Marfan syndrome is a dominantly inherited disorder of connective tissue caused by mutations in the gene that encodes fibrillin-1.1 Cardiovascular complications, including aortic root dilatation, dissection, and rupture, are the leading cause of morbidity and mortality.[2] β blockers have been advocated to reduce the rate of aortic root dilatation in people with Marfan syndrome.[3,4]
Experimental models of Marfan syndrome suggest that angiotensin-II type 1 receptor blockers (ARBs) can alter biological pathways, including excessive TGF-β signalling, that might contribute to the pathogenesis of aortic complications,[5,6,7,8] a finding that is supported by obser vational data in clinical studies.[9]
Randomised trials in Marfan syndrome have compared the effects of the angiotensin-II type receptor blockers (ARBs) losartan with either β blockers or control on aortic dilatation[10,11,12,13,14,15] without clear evidence of benefit
Summary
Marfan syndrome is a dominantly inherited disorder of connective tissue caused by mutations in the gene that encodes fibrillin-1.1 Cardiovascular complications, including aortic root dilatation, dissection, and rupture, are the leading cause of morbidity and mortality.[2] β blockers have been advocated to reduce the rate of aortic root dilatation in people with Marfan syndrome.[3,4] Experimental models of Marfan syndrome suggest that angiotensin-II type 1 receptor blockers (ARBs) can alter biological pathways, including excessive TGF-β signalling, that might contribute to the pathogenesis of aortic complications,[5,6,7,8] a finding that is supported by obser vational data in clinical studies.[9] Randomised trials in Marfan syndrome have compared the effects of the ARB losartan with either β blockers or control (where standard medical therapy could include β blockers) on aortic dilatation[10,11,12,13,14,15] without clear evidence of benefit. Other ARBs, such as irbesartan, might have greater bioavailability and a longer half-life than losartan with more potent antihypertensive effects. We aimed to determine the effects of the ARB irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
