How to treat Marfan syndrome: an update

This editorial refers to ‘Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial’^†, by A. Forteza et al., on page 978.

The only validated therapy for Marfan patients with aortic aneurysms has always been invasive surgery of the dilated aorta and awaiting progression of the disease to affect the remainder.^1,2 For >20 years, pharmacological treatment consisted of beta-blockade as a supportive therapy in order to slow down the rate of aortic dilatation, supposedly by lowering blood pressure and dP/dt in the aorta. Although recommended in North American and European guidelines, beta-blockade has been prescribed based on studies with conflicting results, and only one small, prospective, randomized study of 70 patients.³ Recently, after evidence of the effectiveness of losartan in a Marfan mouse model, expectations were sky high, as it was speculated that this drug might become a more causative treatment, by reducing transforming growth factor-β (TGF-β) signalling in the diseased aortic wall, proposed to be at the origin of the disease.⁴ The first results in humans were very encouraging. Losartan seemed effective in slowing down the aortic root dilatation rate in a small group of severely affected Marfan children (n = 18, median age 6.5 years), serving as their own controls,⁵ which was confirmed by another small randomized study in Taiwan (n = 28, mean age 13 years).⁶ Eight large randomized clinical trials were initiated worldwide, all with a slightly different design and study population. The randomized COMPARE trial (n = 145, mean age 37 years) was the first of these randomized trials to show a small, but significant difference in aortic root aneurysm expansion rate in favour of losartan treatment compared with standard clinical care in adult patients (including beta-blocker therapy in the vast majority of patients).⁷ However, the double-blinded randomized Marfan Sartan trial (n = 292, mean age 30 years, 38% aged <18 years) failed to demonstrate a beneficial effect of losartan in addition to high dose beta-blockers using echocardiography at 6-month intervals.⁸ In this issue of the journal, the fourth large randomized human trial to assess the effect of losartan failed to validate the beneficial effects of losartan as observed in the Marfan mouse model. In a double-blinded randomized way (n = 116), Forteza et al. were not able to detect a significant difference in aortic root dilatation rate between Marfan patients treated with atenolol and patients treated with losartan.⁹ These results confirm echocardiographic findings in a larger cohort of Marfan patients conducted by the Pediatric Heart Network in the USA (n = 608) using high dosages of beta-blockers in the control group.¹⁰ Forteza et al. used a more sophisticated imaging modality, namely magnetic resonance imaging (MRI), and extended results to older patients (mean age 25 years vs. 11 years in the Pediatric Heart Network study). None of the four mentioned randomized studies could demonstrate differences in hard clinical endpoints (death, aortic dissection, aortic surgery) during the 3-year follow-up duration of their studies. Differences in study design could have contributed to the controversial results regarding the aortic dilatation rate in the various studies, including study population, medication dosages, adherence to therapy, and imaging methods used. With the results so far, we may conclude that losartan does not seem to be more effective in reducing the rate of aortic dilatation than a high dosage of beta-blockers in patients with Marfan syndrome. Losartan in addition to low dose beta-blockers seems to be more effective than low dose beta-blockers alone.