Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial.
BACKGROUND
Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent studies have found transforming growth factor beta (TGF beta) to be involved in the aortic aneurysm formation. Losartan, an angiotensin II type 1 receptor blocker inhibits TGFbeta in a mouse model of Marfan syndrome leading to inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome.


METHODS
COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label, randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and ventricular function. We will also investigate gene and protein expression change in the skin under losartan therapy and create prediction models for losartan-treatment response and aortic dilatation.


CONCLUSIONS
The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation. This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide further insight in the pathogenesis and treatment of Marfan syndrome.


BACKGROUND
Netherlands Trial Register NTR1423.
Radonic
Teodora
T
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center Amsterdam, the Netherlands. t.radonic@amc.nl
de Witte
Piet
P
Baars
Marieke J H
MJ
Zwinderman
Aeilko H
AH
Mulder
Barbara J M
BJ
Groenink
Maarten
M
D000328:Adult; D000784:Aortic Dissection / Q000209:etiology / Q000517:prevention & control; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D001014:Aortic Aneurysm / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000517:prevention & control*; D001706:Biopsy; D004452:Echocardiography; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019808:Losartan / Q000627:therapeutic use*; D018810:Magnetic Resonance Angiography; D008382:Marfan Syndrome / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D009426:Netherlands; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D014656:Vascular Surgical Procedures; D016276:Ventricular Function / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan