AIMS: Irbesartan Slows Aortic Dilatation in Marfan Syndrome, Is Lower BP the Key?

September 05, 2018

MUNICH — Long-term treatment with the angiotensin receptor blocker (ARB) irbesartan apparently slowed the process of aortic-root dilatation, a measure of disease progression, in a small population of children, adolescents, and young adults with Marfan syndrome.

Study participants also achieved small but sustained reductions in systolic blood pressure (BP) when taking irbesartan compared with placebo, on top of standard management.

Although the BP reduction wasn't surprising — the ARB is commonly used in hypertension — all patients in the Aortic Irbesartan Marfan Study (AIMS) were normotensive at baseline.

The trial's researchers and observers speculate that the slowing of aortic-root dilatation may have been mediated by BP lowering, despite statistical independence of the two findings in the small study. Still, they say, a contribution from ARB-specific biologic effects can't be ruled out.

Slowing of disease progression in the ARB group was also independent of patient age or whether standard care included a β-blocker, used in more than half of the patients in both groups.

Four patients dropped out from each group because of intolerance of their assigned therapy, suggesting that the ARB was well tolerated, even by the children and adolescents, Michael Mullen, MB, St Bartholomew's Hospital, London, United Kingdom, told | Medscape Cardiology.

On the other hand, younger patients tend not to tolerate β-blockers well, so unsurprisingly, only 59% of controls and 56% in of those assigned the ARB took the drugs during the study, Mullen said. And even then, he added, dosages ranged widely and were often small.

The AIMS study, which Mullen presented here at the European Society of Cardiology (ESC) 2018 Congress, follows a 2014 randomized trial with 608 similar patients with Marfan syndrome in the United States that found no significant difference in effects on aortic-root dilatation between another ARB, losartan, and standard therapy with the β-blocker atenolol.

Evidence supporting β-blockers in Marfan syndrome is weak, Mullen noted, so AIMS took a different approach by exploring ARB therapy as an add-on to standard care that could include β-blockers. "Our study more closely represents how these medications are used in the real world."

Because the two drug classes have different mechanisms of action, he said, "It's arguable there may be synergy between the two, that maybe you need both. But we didn't see any sign of that."

The AIMS findings are clinically important for younger patients in particular, who may be still growing while their genetic disease is progressing.

A new treatment that improves on standard therapy at slowing disease progression in children could postpone the day when major corrective surgery is needed, observed Susanna Price, MBBS, BSc, Royal Brompton Hospital, London, in an interview.

"What will kill these patients young is the progressive dilatation of the aorta associated with rupture or dissection. We know that when it gets to a certain threshold, it will be life-limiting," said Price, who was not involved in AIMS.

"If we're able to stop that process, one could potentially take a young patient and prevent them from having major surgery. Even delaying it by some years could be beneficial."

Mullen agreed that the ARB regimen could potentially achieve that important goal, but there was no sign of it in the current study. Five patients taking irbesartan and four in the control group went on to corrective aortic surgery during the trial.

Although it had a planned enrollment of 490 patients with the rare disease, AIMS entered 192 patients aged 6 to 40 years at 22 centers in the United Kingdom. They were required to have an aortic-root diameter that was in the highest 5% of normal range and less than 4.5 cm.

The patients were assigned to irbesartan at 75 mg/day, with escalation to as high as 300 mg/day after 2 months, or to placebo, and were followed with transthoracic echocardiography for 5 years.

The 104 patients receiving the ARB showed a 30% reduction in rate of change in aortic-root diameter compared with the 88 controls. There was no statistical interaction between that outcome and use of β-blockers (P = .62), age (P = .43), or aortic-root Z score at baseline (P = .24).

Table. Average Annual Rate of Change in Aortic Dimensions and Systolic Blood Pressure in AIMS

Endpoints Placebo (n = 88) Irbesartan (n = 104) P Value
Aortic root diameter (mm) 0.74 0.53 .03
Aortic root Z scorea 0.15 0.05 .04
Systolic BP (mm Hg) 1.27 –0.42 <.001
aZ score reflects aortic-root diameter by echocardiography adjusted for body surface area.


In mouse studies suggesting a possible ARB role in Marfan syndrome, the drugs were given at essentially 10 times the dosage used in humans, a level at which ARBs might show a unique biologic effect on the disease process, speculated Artur Evangelista, MD, University Hospital Vall d'Hebron, Barcelona, Spain.

"But in the usual doses that we can prescribe, I think it is not a biologic effect. It's reduction in blood pressure. A reduction of 1 to 2 mm Hg over several years may reduce dilatation of the aorta," said Evangelista to | Medscape Cardiology.

"If it was a biologic effect, I think we would have obtained better benefits over the long term" compared with what was seen in AIMS, said Evangelista, a Marfan imaging expert who was the invited discussant after Mullen's presentation of AIMS. "I think it is sustained reduction in blood pressure that is the key to the treatment."

In an interview, Mullen said it's currently unknown whether BP reduction by means other than ARB treatment would have the same effects.

"It's possible that lowering blood pressure is what you need to do, and that reduces the stress. That might be a mechanism. Our study can't answer that, but what it can say is that using irbesartan this way does have an effect."

It's also possible that, regardless of mechanism of benefit, one drug or drug class isn't going to help all patients with Marfan syndrome, with their "wide range of phenotypic expression," said Price. Development of genetic tests that predict likely responders, she proposed, might help in selecting patients for drug therapy and spare others from exposure to it.

"To start taking drugs when you're 5 or 6 years old, and expect to take them for 20 to 30 years, that's a big burden."

AIMS received funding from the British Heart Foundation and the UK Marfan Trust and Marfan Association. Sanofi and Brecon Pharmaceuticals supplied irbesartan and its placebo. Mullen discloses receiving research funding and payment for teaching from Edwards Lifesciences.

European Society of Cardiology (ESC) Congress 2018. Hot Line Session 5. August 28, 2018.

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