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Highlights from

European Society of Cardiology

Congress 2018

Munich 25-29 August 2018

AIMS: Irbesartan slows rate of aortic root dilatation in Marfan syndrome

Take-home messages
  • Irbesartan at standard doses is associated with significant 30% reduction in the rate of aortic root dilatation versus placebo
  • A trend for clinical benefit was observed in younger patients
  • Irbesartan was well tolerated in both children and adults
“In these patients with Marfan syndrome, irbesartan at standard doses is associated with significant reduction in the rate of aortic root dilatation.”

Dr Michael Mullen
St. Bartholomew’s Hospital, London, UK

Irbesartan, an angiotensin II receptor antagonist that lowers blood pressure, significantly reduces the rate of aortic root dilatation in children and young adults with Marfan syndrome, according to results of the Aortic Irbesartan Marfan Study (AIMS).

Results were presented at ESC Congress 2018 by Dr Michael Mullen, principal investigator from St Bartholomew’s Hospital, London, UK, where the AIMS study was conducted.

“In these patients with Marfan syndrome, irbesartan at standard doses is associated with significant reduction in the rate of aortic root dilatation. We saw a trend to benefit in younger patients and those who had already had aortic dilatation with Z-score at baseline of greater than three,” said Dr Mullen, reporting the study findings.

“Importantly, the medication was well tolerated in children and adults and, ultimately, if these findings are translated into clinical practice, long-term irbesartan treatment may impact favourably on clinical outcomes for these patients,” he added.

Although patients had normal blood pressure at baseline, the treatment resulted in a reduction in systolic blood pressure but was well tolerated in both children and adults.

Marfan syndrome is an inherited connective tissue disorder, which affects one in 5,000-10,000 people. It is caused by mutations in fibrillin 1 and is characterised by skeletal, cardiac and eye abnormalities, but also aortic aneurysm and dissection that may result in premature death. Surgery to replace the aortic root can be performed to slow dilatation when dilatation reaches 4.5-5.0 cm. Slowing the dilatation of the aorta is an important objective of Marfan syndrome treatment strategy.

Beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin II blockers have been used to slow progression of aortic dilatation but many individuals with Marfan syndrome cannot tolerate the side effects that accompany these drugs; thus, there is an unmet medical need for alternative therapies.

“Experimental evidence indicates a potential role for angiotensin receptor inhibition in retarding aortic dilatation mediated through reduced TGF-β (transforming growth factor beta) activity,” Dr Mullen remarked. “Previous studies with losartan have largely shown negative results in Marfan syndrome.”

Against this background, Dr Mullen instigated the first investigator-led prospective, randomised, placebo-controlled, double-blind, multicentre study to investigate the role of irbesartan in this patient population. A total of 192 patients with Marfan syndrome, aged 6 to 40 years of age, with no previous or planned cardiac surgery and an aortic root Z-score (an expression of aortic sinus diameter dilatation) of greater than 0 were included. “They couldn’t have a smaller than average aorta but they could have a larger aorta,” said Dr Mullen, describing the inclusion criteria.

Patients were randomised to irbesartan 150/300 mg once daily (depending on weight; n=104) in addition to standard medical therapy including a beta-blocker if tolerated (56% of patients) and placebo (n=88). One quarter of patients were aged 6-11 years and the median age was 18 years. Aortic dilatation was measured at a core laboratory by annual echocardiogram with follow-up to 5 years. The primary outcome was absolute change in aortic root diameter (mm/year).

“We found a significant 30% reduction in the absolute rate of aortic root dilatation in the irbesartan group compared to placebo (0.53 versus 0.74 mm/year), corresponding to a difference of -0.21 per year (95% CI, -0.41 to -0.02; p=0.03),” reported Dr Mullen.

“We also noticed a significant difference in the rate of change or aortic root Z-score and systolic blood pressure,” he added.

In terms of safety, irbesartan was well tolerated with no differences in serious adverse events between groups. “This trial was not powered to detect differences in clinical outcomes and there was no difference in the numbers of patients who underwent surgery during the trial with five on irbesartan and four on placebo. There were no deaths.”

Based on Mullen M. Aortic Irbesartan Marfan Study. Presented Tuesday, 28 August 2018.

Top image: © Mutlu Kurtbas

Article image: © janulla

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.

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