Tall Order: Losartan Looks Promising in Marfan Syndrome

Shelley Wood

September 02, 2013

AMSTERDAM — Hopes that angiotensin-receptor blockers (ARBs) could help reduce aortic dissections in Marfan syndrome got another boost today in the form of a small randomized trial from the Netherlands. Dr Maarteen Groenink (Academic Medical Center, Amsterdam, the Netherlands) presented the COMPARE trial results here at the European Society of Cardiology (ESC) 2013 Congress this morning.

According to Groenink, losartan added to standard of care, including beta-blockers in many patients, reduced aortic-root dilatation in both native aortas and in the aortas of patients who had already undergone aortic-root replacement.

On the basis of these results, and because blood-pressure lowering is already recommended in Marfan, losartan "can be recommended" to patients with this syndrome, both to those already taking beta-blockers and those who are not, he said.

A Constellation of Signs, Symptoms

Marfan is a genetic tissue disorder characterized by tall height, long limbs and fingers as well as some potentially lethal cardiovascular effects, including arrhythmia, valve disease, and aortic dilatation and dissection. The affected gene, FBN1, encodes the connective protein fibrillin-1, which regulates the bioavailability of TGF-beta. Losartan was first investigated in a mouse model of Marfan because the drug appears to block TGF-beta activity, potentially slowing or halting the aortic effects.

As reported by heartwire , losartan has previously been shown to slow the rate of aortic-root dilatation in a small series of pediatric patients. Another study has looked at the effect of ACE inhibitors in Marfan patients.

In the current study, Groenink and colleagues enrolled adults (mean age 41) at four Marfan screening centers in the Netherlands, ultimately randomizing 113 patients to losartan and 105 to a placebo. More than one-quarter of the participants had already undergone aortic-root replacement, and 73% were already taking beta-blockers. All subjects underwent MRI screening at baseline and after three years.

On their follow-up MRI, losartan-treated patients had significantly less aortic-root enlargement than placebo-treated patients. Moreover, half of losartan-treated patients had no aortic-root growth, compared with less than one-third of controls.

COMPARE End Points

End point Losartan Control p
Aortic-root enlargement from baseline (mm) 0.77 1.35 0.014
No aortic-root growth (%) 50 31 0.022

 

Low Blood Pressure Important

Discussing the study results with the press, Groenink acknowledged that investigators have not collected enough patients or years of follow-up to have insights on hard clinical events. During follow-up, nine patients in both groups required aortic-root replacement, at the treating physician's discretion. Two dissections occurred in the control group, and one patient died from noncardiovascular causes.

Whether the effects on the aortic root are specifically related to the ARB or whether it is simply the effects on blood pressure remain to be clarified. "I think both mechanisms will contribute to the effects," Groenink told reporters.

And while his study was conducted in adults over age 20, there are good reasons to study losartan in younger patients, as a previous study has done. "In my belief, the effects on the aortic wall are caused by the fibrillin-1, but also wear and tear. So from that perspective, the earlier you start the better." There are other trials still ongoing in children, he added.

Asked just how many Marfan patients a typical cardiologist would see, Groenink noted that most Marfan patients would be followed up at specialized clinics, but this wouldn't include the many undiagnosed patients, many of whom, tragically, are not identified until they suffer an aortic dissection.

While the estimated prevalence of Marfan syndrome is somewhere in the arena of one in 5000, Groenink believes the true number may be higher.

"There are probably a lot of them just walking around, we just can't see their aortas."

Groenink had no conflicts of interest.

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