By John Curci
The small abdominal aortic aneurysm poses little immediate health risk to a patient. While these small aneurysms are easily identified, we currently lack any safe and effective means to prevent the inevitable growth, and subsequent rupture risk, of these aneurysms.
Capitalising on an opportunity to alter the natural history of small abdominal aortic aneurysms has been the goal of the last two decades of scientific research into the biological basis of aneurysm development. These investigations have produced unique insights into the pathologic changes of the aneurysm. We now know that the development of an aneurysm depends on the progressive degeneration of the normal medial structure of the aorta.
Particularly remarkable is the loss of the typically durable layers of elastic tissue. These changes of the aortic media are associated with altered cellular function and infiltration of inflammatory cells which produce enzymes, including many of the matrix metalloproteinase (MMP) class, capable of degrading the elastic fibres.
Based on this research, several pharmacologic treatments have emerged as having potential to alter the natural history of the small abdominal aortic aneurysm. To be effective, any aneurysm treatment must have one or more of the following effects: 1) prevent the development of an aneurysm, 2) cause the damaged wall to regenerate and heal with regression of the dilatation, or 3) slow or stop the progressive degeneration and dilatation of the aortic wall.
The most achievable initial goal of therapy will be to slow the growth of a small abdominal aortic aneurysm. However, the inhibition must be sufficient to delay the need for surgical intervention to beyond the natural life of the patient with the small aneurysm. Recent studies show that 78% of patients with a small and growing abdominal aortic aneurysm will eventually progress to a size that requires aneurysm repair. Based on sophisticated statistical modeling by Dr Michael Terrin and associates at the University of Maryland, a reduction in small aneurysm growth by 40% would be necessary to reduce the chance of surgical intervention by more than 10% – the minimal difference likely to be acceptable for clinical adoption.
The Non-invasive Treatment for Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT) is one upcoming NIH National Institute for Aging-sponsored study which will evaluate the clinical effectiveness of protease inhibition to alter the growth of small abdominal aortic aneurysms. This is a double-blind, placebo-controlled trial using the well-known and well-tolerated antibiotic, doxycycline (200mg/day), which is also a very effective inhibitor of MMP activity.
The N-TA3CT will evaluate diameter of the aneurysm on CT scans every six months for a minimum of two years on each patient enrolled. The study will also evaluate well-being during the study and collect peripheral blood samples for current and future biomarker analyses. Sixteen centres across the country will soon be ready to begin enrolment of 248 patients with small aneurysms (3.5–5cm maximal diameter in men and 3.5–4.5cm in women).
Other mechanisms underlying aneurysm development and growth may also present good targets for novel therapy. Several other clinical trials of non-surgical interventions for aneurysm stabilisation are underway, about to start or recently completed but unpublished.
These include the AARDVARK trial evaluating the ACE-inhibitor, perindopril, with abdominal ultrasound; the AAA:STOP trial evaluating the effect of exercise therapy with ultrasound and CT scans; the PISA trial evaluating the renin inhibitor, aliskiren, with CT scans; and the PHAST trial evaluating doxycycline (100mg/day) with ultrasound. Other agents and interventions are in various stages of preclinical trial development.
State-of-the-art clinical care for aneurysm disease is soon likely to evolve beyond endovascular interventions as decades of basic science breakthroughs are translated to the bedside management of small aneurysms.
John Curci, vascular surgeon, Department of Surgery, Washington University School of Medicine, St Louis, USA.