Effects of Losartan Versus Atenolol on Aortic and Cardiac Muscle Stiffness in Adults With Marfan Syndrome

• ClinicalTrials.gov Identifier: NCT00723801
• Recruitment Status: Completed
• First Posted: July 29, 2008
• Results First Posted: September 1, 2014
• Last Update Posted: September 9, 2014
• Sponsor: Brigham and Women's Hospital
• Collaborator: Boston Children's Hospital
• Information provided by (Responsible Party): Mark Alan Creager, MD, Brigham and Women's Hospital

Study Description

Brief Summary:

Marfan syndrome is an inherited connective tissue disorder with morbidity and mortality from aortic dilation and dissection. The degree of aortic dilation and response to beta-blockade (standard of care) vary in adults with Marfan syndrome. However, aortic stiffness is often present, and can be a predictor of aortic dilation and cardiovascular complications. In addition, adults with Marfan syndrome develop left ventricular diastolic dysfunction, which can progress to heart failure. Aortic stiffness and diastolic dysfunction are important and logical therapeutic targets in adults with Marfan syndrome.

TGF-beta mediates disease pathogenesis in Marfan syndrome and contributes to aortic stiffness. The angiotensin receptor blocker, losartan, inhibits TGF-beta activity and reverses aortic wall pathology in a Marfan mouse model. Losartan also decreases aortic stiffness and improves diastolic function in hypertension, renal disease and hypertrophic cardiomyopathy.

This trial is a randomized, double-blind trial of 50 adults with Marfan syndrome, treated with 6 months of atenolol vs. losartan. Arterial tonometry for aortic stiffness and echocardiography for diastolic function will be performed at the beginning and end of treatment. A blood draw for serum markers of extracellular matrix turnover and inflammation will also be performed at 0 and 6 months. We plan to determine whether losartan decreases aortic stiffness and left ventricular diastolic dysfunction significantly more than atenolol.

Condition or disease	Intervention/treatment	Phase
Marfan Syndrome	Drug: Atenolol; Drug: Losartan	Phase 3

Detailed Description:

Please See Summary.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Losartan vs Atenolol on Aortic Stiffness and Diastolic Function in Adults With Marfan Syndrome
• Study Start Date: October 2007
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: December 2012

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Subjects Randomized to Losartan; Losartan: 100 mg PO QD	Drug: Losartan; Losartan 100mg PO QD; Other Name: Cozaar
Active Comparator: Subjects Randomized to Atenolol; Atenolol: 50 mg PO QD	Drug: Atenolol; Atenolol 50mg PO QD; Other Name: Tenormin

Outcome Measures

Primary Outcome Measures :

1. Aortic Biophysical Properties - Pulse Wave Velocity [ Time Frame: Baseline and 6 months ]
   Aortic stiffness was assessed using applanation tonometry (SphygmoCor®, AtCor Medical, West Ryde, NSW, Sydney, Australia) to measure carotid to femoral artery pulse wave velocity (PWV). With the patient lying supine in a quiet environment, a handheld micromanometer-tipped probe was applied to the skin surface over the carotid and femoral arteries, compressing the vessel wall so that transmural forces within the vessel wall were perpendicular to the arterial surface. The distance from the sternal notch to the sites of carotid and femoral pulse acquisition were measured and inputted into the device to represent the relative distance from the carotid to femoral artery. The calculation of distance divided by time of pulse upstroke relative to the upstroke of the QRS on a 3 lead surface EKG was used by the device to calculate velocity. All recorded measurements met the manufacturer's quality control standards integrated into the software package.

Secondary Outcome Measures :

1. Diastolic Function - Ejection Fraction [ Time Frame: Baseline and 6 months ]
   Two-dimensional echocardiography was performed using a 3.0 MHz transducer (General Electric VIVID 7). Left ventricular and left atrial dimensions were determined in parasternal long axis views. Left ventricular ejection fraction was calculated using the modified Simpsons calculation in the apical two and four chamber views.

Eligibility Criteria

• Ages Eligible for Study: 25 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age greater than 25 years
• Clinical Marfan Syndrome

Exclusion Criteria:

• Previous aortic or cardiac surgery
• Pregnancy
• Renal Insufficiency
• Medication intolerance

Contacts and Locations

Locations

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Brigham and Women's Hospital

Boston Children's Hospital

Investigators

• Principal Investigator: Mark A Creager, MD; Brigham and Women;s Hospital

More Information

• Responsible Party: Mark Alan Creager, MD, Principal Investigator, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT00723801
• Other Study ID Numbers: 2007p-001762
• First Posted: July 29, 2008
• Results First Posted: September 1, 2014
• Last Update Posted: September 9, 2014
• Last Verified: September 2014

Keywords provided by Mark Alan Creager, MD, Brigham and Women's Hospital:

Marfan syndrome; Losartan; Atenolol; Diastolic Function; Aortic Stiffness

Additional relevant MeSH terms:

Marfan Syndrome; Arachnodactyly; Syndrome; Disease; Pathologic Processes; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Limb Deformities, Congenital; Musculoskeletal Abnormalities; Losartan; Atenolol; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Adrenergic beta-1 Receptor Antagonists