Pharmaceutical Aneurysm Stabilisation Trial

An abdominal aortic aneurysm (AAA) affects 5-7% of people over 60, and is responsible for more than 15.000
deaths annually in the US alone. For unknown reasons, the incidence has been steadily increasing over the last
two decades, and a further increase is anticipated. Current approaches towards AAA are surveillance, and
preventive surgical elimination ('repair') of AAA over 5.5 cm. Unfortunately, traditional (open) elective AAA repair is
associated with a relatively high morbidity and mortality. Although short-term results of endovascular repair appear
more favourable, mid- and long-term mortality is similar to that of conventional repair. Moreover, the high incidence
of endograft failure repair requires life-long follow-up. According to the available studies, including a Dutch
randomized trial, endovascular repair is currently not cost-effective. Hence availability of medical therapy, inhibiting
aneurysmal growth and reducing the need for invasive treatment, could have major advances both from patients'
as well as from socio-economical perspective.

Increased activities of the matrix metalloproteinases, in particular MMP-9, are considered a key-factor in AAA
development and growth. The tetracycline analogue doxycycline attenuates both MMP expression and activity. It
was thus hypothesised that doxycycline may prevent AAA growth. Indeed, doxycycline has been shown to prevent
aneurysm formation in animal models of the disease. Results from two small clinical studies suggest that
doxycycline treatment may also arrest AAA growth in patients with medium sized aneurysm.

We evaluated the effect of pre-operative doxycycline treatment in patients undergoing conventional AAA repair
(NHS 2000B165), and confirmed the effects of doxycycline on expression of the gelatinase MMP-9. Our results
also revealed remarkable suppression of MMP-8 (neutrophil collagenase) protein expression. These findings are
new and remarkable. MMP-8 is a stored secondary granule protein that is only expressed during the late myeloid
maturation pathway of neutrophils, but not in mature, infiltrating neutrophils. This suggests that the effect of
doxycycline on aneurysm growth may extend beyond the effect on MMP expression and involves attenuation of
neutrophil influx. We confirmed the effect on neutrophil influx by immunohistochemical analysis and explored the
mechanism underlying reduced neutrophil influx. This analysis showed that that doxycycline, via its effects on the
transcription factors AP-1 and C/EBP, profoundly reduces IL-6 and IL-8 hyperexpression in AAA. This not only
results in reduced neutrophil influx, but also in attenuation of cytotoxic T-cell activation.

Doxycycline has a well-established safety record, is generally well tolerated and is inexpensive. Doxycycline
should thus be considered a promising lead-candidate for the pharmaceutical stabilization of AAA. Yet, its
efficiency remains to be established in a prospective, sufficiently powered clinical trial. We therefore propose to
evaluate the effects of doxycycline (standard dose, 100 mg/day) on AAA growth in a double blind placebo
controlled multi-centre study in patients under surveillance for a small (3,5-5,0 cm) or patients with larger (over 5,5
cm) AAA who are unfit for or refuse intervention.

AAA is a common disease and a major cause of death due to rupture. Preventive surgical aneurysm repair is
costly and associated with considerable morbidity and mortality. Doxycycline has been shown to attenuate the
expansion of aneurysm in animal models of AAA and results from two small clinical trials show that 12 months
doxycycline treatment is well tolerated and may arrested AAA growth.

We hypothesize that standard dose doxycycline treatment is a cost effective and well-tolerated means of stabilizing
AAA. Thus providing a pharmaceutical means of stabilizing AAA, and reducing the need for AAA repair.

Baseline measurements, follow up at 6 months (6, 12 and 18 mo)

Doxycycline 100mg or placebo daily, 18 mo