Comparison Study of the Effect of Aliskiren Versus Negative Controls on Aortic Stiffness in Patients With Marfan Syndrome Under Treatment With Atenolol

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 (i.e., angiotensin II receptor blockers or ACE inhibitors) for 90 days prior to screening. Exclusion criteria were previous medical history of aortic surgery and/or dissection, significant valve disease requiring surgery, aortic root dimension > 5.0 cm, renal dysfunction (creatinine > upper normal limit), pregnancy or planned pregnancy within 12 months of study entry or current breast feeding, known renal artery stenosis, hypersensitivity to aliskiren or any of the excipients, elevation of serum creatinine during follow-up (> 30% of baseline), diarrhea resulting in severe dehydration, development of gout or ureter stone, symptomatic hypotension (systolic blood pressure <90 mmHg with symptoms), hyperkalemia, and concomitant treatment with cyclosporin A.

Follow-up and outcomes All included patients were clinically followed to monitor adverse effects of angioedema, gastrointestinal symptoms, rash, gout, hypotension, and renal stone at initial examination, 1 week, 4 weeks, 8 weeks, 16 weeks, and 24 weeks. The following laboratory data were collected during the same period: potassium, electrocardiogram, creatinine, uric acid, and urine analysis. Echocardiographic evaluation, peripheral tonometric measurements of peripheral PWV, central aortic blood pressure and augmentation index, cardiac magnetic resonance imaging (cardiac MRI), and biomarkers were analyzed at baseline and after 24 weeks of treatment.

Safety information was collected, including all adverse events and all serious adverse events. Completion of a serious adverse event form was required for all serious adverse events that occurred during the study period. All serious adverse events were assessed by investigators and reported to the Novartis safety desk within 24 hours.

The primary end point was central aortic distensibility by cardiac MRI at 24 weeks, reported as the change over the 24-week period after randomization. The secondary end points were central aortic PWV by cardiac MRI, change in central aortic blood pressure (hereafter, aortic BP), augmentation index, peripheral PWV by tonometry, aortic root diameter by echocardiography, severity of aortic regurgitation by echocardiography, and dissection/rupture/operation of aneurysm.