Abdominal aortic aneurysms (AAA) are a common (2-5% of the population e 65 years: 4-9% men;0.5- 1.5% women) and lethal problem causing 15,000 deaths annually from rupture in the U.S. The only accepted treatment is repair of the AAA which is performed for 40,000 large AAA annually in the U.S. With recent, widespread screening, many more small (<5.0 cm in men, <4.5 cm in women) AAA will be detected. The natural history of AAA is expansion to a size at which the risk of rupture greatly increases. There is no proven medical intervention that will prevent or delay this progression, and surgical options are expensive and unnecessarily risky for small aneurysms. There is experimental and clinical evidence that a family of matrix degrading proteins called matrix metalloproteinases (MMPs) are involved in initiation and progression of AAA. Recent evidence from laboratory, animal models and observational studies demonstrate that doxycycline, working as an MMP inhibitor, can prevent progression of AAA. In recent studies, doxycycline has been shown to: (1) inhibit the growth of experimental abdominal aortic aneurysms;(2) inhibit MMP production in aortic smooth muscle cells and in explanted aneurysm tissue;(3) reduce MMP expression in aneurysm tissue when patients are treated prior to operation for aneurysm repair;(4) reduce circulating MMP levels in AAA patients;(5) decrease the growth rate of small AAA in a limited clinical trial. We have demonstrated that doxycycline is well-tolerated in patients with small AAA. We will bring together investigators with expertise in vascular surgery, clinical trial design, data analysis and management, image analysis of AAA and analysis of circulating biomarkers that reflect aneurysm growth. We will test primary and secondary hypotheses and mechanisms of action related to whether or not doxycycline will inhibit (>40%) the growth of small (3.5 - 5.0 cm in men, 3.5 - 4.5 cm in women) infrarenal AAA. We will determine the effects of doxycycline on the expansion rate of small AAA over a 24-month period for all patients with allowance made for outcomes missing for cause (death or aneurysm repair) or undetermined reasons. This will be done through a prospective, double blind, placebo controlled clinical trial of 248 patients. Patients will be randomly assigned to receive placebo or doxycycline (100 mg bid). The primary end point will be aneurysm growth rate determined by semiannual CT scan. The public health impact of testing the safety and efficacy of doxycycline in the treatment of abdominal aortic aneurysms derives from the absence of any medical therapy to avoid open surgery or endograft repair. Without medical therapy, ultrasound screening is considered cost-effective in selected patients only. Effective medical therapy would make early detection even more acceptable by providing an alternative to invasive repair of AAA.

Public Health Relevance

impact of testing the safety and efficacy of doxycycline in the treatment of abdominal aortic aneurysms derives from the large number of patients (hundreds of thousands) who could avoid open surgery or endograft repair (saving in excess of $500,000,000 per year) or, if we do not find doxycycline to be beneficial, who could avoid having an inefficacious therapy recommended. This clinical trial will be definitive for the management of small abdominal aortic aneurysm patients because progression to aneurysm repair is the state-of-the-art management for a known aneurysm that reaches a diameter threshold associated with increased risk of rupture.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037120-02
Application #
8316138
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Radziszewska, Barbara
Project Start
2011-08-15
Project End
2016-07-31
Budget Start
2012-08-15
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$2,658,963
Indirect Cost
$171,618
Name
University of Maryland Baltimore
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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