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

NCT00723801 | Completed Phase 3 Results DMC

• 1 other identifier: 2007p-001762
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Marfan Syndrome

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Aortic Biophysical Properties - Pulse Wave Velocity

  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.

  Baseline and 6 months

Secondary Outcomes (1)

• Diastolic Function - Ejection Fraction

  Baseline and 6 months

Study Arms (2)

Subjects Randomized to Losartan

ACTIVE COMPARATOR

Losartan: 100 mg PO QD

Drug: Losartan

Subjects Randomized to Atenolol

ACTIVE COMPARATOR

Atenolol: 50 mg PO QD

Drug: Atenolol

Interventions

Atenolol DRUG

Atenolol 50mg PO QD

Also known as: Tenormin

Subjects Randomized to Atenolol

Losartan DRUG

Losartan 100mg PO QD

Also known as: Cozaar

Subjects Randomized to Losartan

Eligibility Criteria

• Age: 25 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than 25 years
• Clinical Marfan Syndrome

You may not qualify if:

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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Boston Children's Hospital: collaborator

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Marfan Syndrome

Interventions

Atenolol; Losartan

Condition Hierarchy (Ancestors)

Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Results Point of Contact

• Title: Mark Creager
• Organization: Brigham and Women's Hospital

mcreager@partners.org

617-732-5267

Study Officials

• Mark A Creager, MD

  Brigham and Women;s Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 25, 2008
• First Posted: July 29, 2008
• Study Start: October 1, 2007
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: September 9, 2014
• Results First Posted: September 1, 2014

Record last verified: 2014-09

Locations

US (1)