When French pediatrician Antoine-Bernard Marfan first described the syndrome that would bear his name in 1896, doctors knew little about the management and prognosis of the connective tissue disorder.
In the century since that first description, what was once a fatal syndrome due to the risk of aortic dissection is now a condition that can be managed with proper care and follow-up. Two decades ago, a trial demonstrated that patients who were given beta blockade with propranolol had a lower rate of aortic enlargement than those given placebo, ushering in the beta blocker as a key component of therapy for those with Marfan’s.
More recently, basic science research into the pathogenesis of the disease has led to a new management strategy using angiotensin receptor blockade in lieu of beta blockade. Now, a study in this week’s issue of NEJM adds to this body of research, suggesting that one treatment modality might be no better than the other.
The science behind this trial dates back to the early 1990s, when researchers discovered that mutations in the gene encoding a protein called fibrillin-1 were responsible for Marfan’s syndrome. Fibrillin-1 is a structural component of elastic fibers in connective tissue, and also influences cell signaling activity through binding the protein TGF beta. Animal studies have provided evidence that excessive TGF beta signaling results in the clinical findings of Marfan’s, including aortic dilatation. This finding led to the question – could angiotensin receptor blockers (ARBs), which inhibit TGF beta signaling, reduce aortic dilatation in Marfan’s?
This hypothesis first led to mouse studies, which did in fact show a reduced rate of aortic enlargement in Marfan’s mice who received losartan, an ARB, compared to those who were given beta blockers or placebo. A small series of patients and then two clinical studies comparing a beta blocker-ARB combination to beta blockade alone came to similar conclusions.
With this background, R.V. Lacro and colleagues set out to determine whether losartan is more effective than beta-blockers in slowing aortic-root enlargement in Marfan’s syndrome. The investigators enrolled just over 600 patients with Marfan’s whose ages ranged from 6 months to 25 years old. The study participants were randomly assigned to receive either atenolol or losartan. They were followed over a 3-year period for the primary outcome, which was the rate of aortic-root enlargement. Investigators also monitored rates of aortic-root surgery, aortic dissection and adverse events.
Their findings were surprising, given the strong rationale for treatment with an ARB in this population. In all of the endpoints studied, the investigators found that losartan performed no better than atenolol. There was no significant difference between groups in the rate of aortic-root enlargement, nor in rates of surgery, dissection or death.
What to take from this study? In an accompanying editorial, Juan Bowen and Heidi Connelly discuss certain limitations of the study design that might have masked the true benefit of losartan for Marfan’s syndrome and urge physicians, instead of casting aside losartan as a therapeutic option, to “wait and see.” First, the editorialists note, the study did not have a placebo group and thus, cannot address the question of whether both beta-blockade and angiotensin-receptor blockade might be equally effective. The study also did not assign patients to a combined beta and angiotensin receptor blockade group, which could have demonstrated synergistic effects. Additionally, the losartan dose might not have been sufficient to meet its goal – suppressing TGF beta signaling. Finally, the enrolled patients had “advanced aortic disease” as gauged by their aortic root dilation scores at young ages. Perhaps, they note, blocking TGF beta could work more effectively at earlier disease stage.
Despite the study’s limitations, Bowen and Connelly write that they expect these results to stimulate debate and further research into how best to treat patients with Marfan’s. They conclude, “Each step forward gives hope to those living with Marfan’s syndrome as they strive to live healthier, longer, and more productive lives.”