Marfan Sartan: A Randomized, Double-Blind, Placebo-Controlled Trial

Olivier Milleron; Florence Arnoult; Jacques Ropers; Philippe Aegerter; Delphine Detaint; Gabriel Delorme; David Attias; Florence Tubach; Sophie Dupuis-Girod; Henry Plauchu; Martine Barthelet; Francois Sassolas; Nicolas Pangaud; Sophie Naudion; Julie Thomas-Chabaneix; Yves Dulac; Thomas Edouard; Jean-Eric Wolf; Laurence Faivre; Sylvie Odent; Adeline Basquin; Gilbert Habib; Patrick Collignon; Catherine Boileau; Guillaume Jondeau

Disclosures

Eur Heart J. 2015;36(32):2160-2166. 

In This Article

Abstract and Introduction

Abstract

Aims To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS).

Methods and results A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving β-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (−0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (−0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)].

Conclusion Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. β-Blocker therapy alone should therefore remain the standard first line therapy in these patients.

Introduction

Marfan syndrome (MFS) is a rare disease (with a usually reported incidence of one case per 5000) carrying a vital risk related to progressive aortic dilatation leading to dissection and rupture.[1] This genetic disease, usually associated with mutations in the FBN1 gene, has benefited from standardised care including limitation in sports, β-blocker therapy and regular echocardiographic follow-up allowing timely preventive aortic root surgery, when aortic diameter increases >50 mm.[2–4] Although standardized care delays the progression of aorta diameter, the aorta still dilates, and preventive aortic surgery is required in the majority of patients during the course of the disease.[5] Therefore, the identification of further preventive pharmacological therapy is actively sought.

In an FBN1 mutation knockin (KI) mouse model (Fbn1C1039G/+), oral Losartan treatment completely prevented dilatation.[6] It was suggested that excessive TGF-β signalling contributed to the aortic aneurysm formation of, and that TGF-β antagonism with Losartan represented a productive treatment strategy. In addition to this potential signalling effect, Losartan could also act through its vasodilator properties. Therefore, a new therapy combining β-blocker and Losartan was viewed as potentially beneficial in Marfan patients, as well as in other forms of thoracic aortic aneurysm (TAA). This elicited great expectations in Marfan patients and their national support groups.

To test this hypothesis, clinical trials were launched worldwide. Recently, the PHN trial failed to demonstrate the expected superiority of Losartan over Atenolol in young patients with MFS and dilated aorta.[7] We report the results of the first large-scale, double-blind, placebo-controlled trial which aimed at evaluating the safety and benefit of Losartan on aortic root growth in MFS when added to standard preventive therapy.

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