Beta-Blocker, ARB Similarly Protective of Aorta in Marfan's

November 26, 2014

CHICAGO, IL — In a rare randomized trial of drug therapy for kids and young adults with Marfan's syndrome, the rate of aortic-root dilatation, adjusted to body-surface area, was about the same over 3 years whether patients were on the angiotensin-receptor blocker (ARB) losartan or the more conventional treatment, beta blockade with atenolol[1].

That was the primary finding; importantly, however, there was a strong suggestion that both drugs benefited the patients. Both the ARB and beta-blocker appeared to slow the rate of disease progression as measured by changes in aortic-root diameter compared with baseline, reported investigators here at the American Heart Association (AHA) 2014 Scientific Sessions.

Although technically a negative trial for showing no advantage of losartan over atenolol, it could also be taken as "positive for both drugs," said Dr Ronald V Lacro (Boston Children's Hospital, MA) during a panel discussion following his presentation at the AHA. "There was no significant difference. So I think that there are two interpretations: they are equally effective or ineffective. And I think based on all data, the data from the trial and other studies, I would look at it as benefit with both drugs."

The study was published November 18 in the New England Journal of Medicine, with Lacro as first author, to coincide with his formal AHA presentation.

At a media briefing, Lacro addressed the prospect of perhaps having two effective drugs for Marfan's syndrome. Some patients will be intolerant of atenolol or losartan, so the choice of agent "I think it will depend on each patient and the severity of disease. There's also data from other trials that suggest that the combination of both drugs together might be better than beta-blockers alone. So I think that we have different options now."

And, he said, "I think it's going to be important in future studies to identify subgroups of patients that might respond better to one or the other."

At the panel discussion, Dr John A Elefteriades (Yale University School of Medicine, New Haven, CT), the assigned discussant, said ARBs wouldn't be his first choice in Marfan's. "We have found and published multiple times that most [aortic] dissections [in such patients] are triggered by extreme physical exertion or extreme emotional stress. And that's why I would favor beta-blockers. I think that they may blunt that response."

And he was less sanguine than Lacro about the trial's outcome. "In all respects this was a negative trial," he said at the media briefing. "Losartan simply did not live up to the promise [seen] in early animal and clinical testing."

But according to an editorial accompanying the published study[2], "The critical question is whether [the result] argues for the rejection of losartan as a therapeutic option, or whether the study design masked its true benefit. We believe the answer is, let's wait and see," write Dr Juan M Bowen and Dr Heidi M Connolly (Mayo Clinic, Rochester, MN).

For example, given that atenolol was the comparator in the study, not a placebo, "It is possible that the atenolol dose used in this trial was more effective than the investigators had anticipated. Therefore, both beta blockade and angiotensin-receptor blockade may be effective and equivalent treatments for aortic protection."

In all, according to Bowen and Connolly, "these findings indicate that clinicians should continue to consider beta-blockers to be the primary medical therapy for aortic protection in Marfan's syndrome. Losartan appears to be a reasonable treatment option, especially in patients who cannot take beta-blockers."

The trial randomized 608 patients with Marfan's between the ages of 6 months and 25 years to atenolol or losartan; 268 and 267 patients, respectively, completed the 3-year follow-up. Atenolol was titrated to at least a 20% decrease in mean heart rate, to a maximum of 4 mg/kg/day. Losartan was started at 0.4 mg/kg/day and escalated to a maximum of 1.4 mg/kg/day. Achieved dosages averaged 2.7 mg/kg/day for atenolol and 1.3 mg/kg/day for losartan.

The rate of aortic-root dilatation adjusted for body-surface area, as measured by annual change in the echocardiographic aortic-root "z score," did not significantly differ between the groups: –0.139 per year with atenolol vs –0.107 per year with losartan (P=0.08). As both values were significantly less than zero, according to the authors, both treatments were associated with a decrease in aortic-root dimensions relative to body-surface area.

The results didn't seem to be dose-dependent, and there were no differences in rates of overall or serious adverse events, the report says.

"The dose of atenolol used in this study was higher than in many other [Marfan's] studies," and probably higher than dosages used in clinical practice for aortic protection, Lacro observed. That's likely because it was titrated according to hemodynamics and could potentially explain why losartan didn't emerge as significantly better.

Therefore, he said, "If you're going to use a beta-blocker, it needs to be optimized for hemodynamic effect."

The study was funded primarily by the National Heart, Lung, and Blood Institute. Lacro had no disclosures. Disclosures for the other authors are listed in the report. Elefteriades discloses being a principal and having equity in CoolSpine, and being on the data safety monitoring board for Jarvik Heart. Neither Bowen nor Connolly had disclosures.

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