Clinical Trial: Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS
Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
Official Title: Comparison Study of the Effect of Aliskiren Versus Negative Controls on Aortic Stiffness in Patients With Marfan Syndrome Under Treatment With Atenolol
Brief Summary:
Marfan syndrome (MFS) is an inherited disorder of connective tissue with morbidity and mortality from aortic dilatation and dissection. The current standard of care is beta-blocker (BB) treatment and therapeutic target is heart rate. The degree of aortic dilatation and response to BB vary in adults with MFS. However, aortic stiffness is often present, and can be a predictor of aortic dilatation and cardiovascular complications. Aortic stiffness is a logical therapeutic target in adults with MFS.
Transforming growth factor beta(TGF-beta) mediates disease pathogenesis in MFS and contributes to aortic stiffness. Cross-talk between TGF-beta system and renin-angiotensin system (RAS) has been demonstrated. The angiotensin receptor blocker (ARB), losartan, inhibits TGF-beta activity and reverses aortic wall pathology in a Marfan mouse model. In a small cohort study, the use of ARB therapy (losartan or irbesartan) significantly slowed the rate of progressive aortic dilatation in patients with MFS, after BB therapy had failed to prevent aortic root dilatation. In another study, angiotensin converting enzyme inhibitor, perindopril, reduced both aortic stiffness and aortic root diameter in patients with MFS taking standard BB therapy. Renin inhibitor, aliskiren, has not been studied to reduce aortic stiffness and attenuate aortic dilatation in patients with MFS.
This trial is a randomized, open-label trial of 32 patients with Marfan syndrome, treated with 6 months of aliskiren vs. negative controls in patients with MFS under atenolol treatment. MRI for aortic pulsed wave velocity (PWV) and distensibility, measurements of central BP (CBP) and augmentation index (AIx) will be performed at the beginning and end of treatment. A blood drawn for serum markers of TGF-beta, extracellular matrix turnover and inflammation will also be performe
Detailed Summary:
Study design and study population The study design was a prospective randomized intervention study in a single center. A randomization process was performed to assign participants to either the aliskiren-treatment group or the negative control group in an open-label design. The duration of the study period was 24 weeks as the time frame for treatment. Duration of treatment was decided based on previous studies using RAS inhibitor 13,25. Aliskiren was administered to patients in the treatment group at an oral dose of 150-300 mg per day. Medication administration started after a baseline study with a dose of 150 mg of aliskiren, which was escalated to 300 mg of aliskiren at 4 weeks after evaluation of tolerability and the presence of adverse effects as angioedema, gastrointestinal symptoms, rash, gout, hypotension, and renal stones. The patients stopped taking aliskiren if serious adverse events such as angioedema or allergic reactions definitely related to the medication developed. Dose reduction was considered in cases with development of hyperkalemia, elevation of serum creatinine to twice baseline, symptomatic hypotension, gout, or renal stones. Dose reduction to 150 mg after escalation was performed on the decision of the investigators if the patient complained of discomfort and side effects that were probably related to the medication.
MFS patients were recruited at Samsung Medical Center from November 2009 to October 2014. All patients were receiving atenolol as standard β-blocker therapy. All patients gave written informed consent to participate in the study, which was approved by the Samsung Medical Center Ethics Committee. This trial is registered at ClinicalTrial.gov. (Identifier: NCT01715207) Inclusion criteria were age 14 to 55 years, a diagnosis of MFS by Ghent criteria, β-blocker treatment for at least 3 months, and no chronic RAS inhibitor therapy
Sponsor: Samsung Medical Center
Current Primary Outcome: Central Aortic Distensibility by MRI [ Time Frame: 6 months ]
Original Primary Outcome: Central aortic distensibility by MRI at week 24 [ Time Frame: 6 months ]
Current Secondary Outcome: Central Aortic PWV(Pulsed Wave Velocity) [ Time Frame: 6 months ]
Original Secondary Outcome: Central aortic PWV(pulsed wave velocity) [ Time Frame: 6 months ]
Information By: Samsung Medical Center
Dates:
Date Received: October 24, 2012
Date Started: June 2010
Date Completion:
Last Updated: March 23, 2017
Last Verified: March 2017