Invited commentary

Article Outline

• Copyright

Despite progressive improvement in endovascular device design and deployment techniques, a small but significant fraction of post-endovascular aneurysm repair (EVAR) patients continue to experience late aneurysm-related complications. In light of the recent US Food and Drug Administration Public Health Notice regarding increasing late aneurysm-related mortality following EVAR (http://www.fda.gov/cdrh/safety/031808-medtronic.html), this prospective, randomized trial of adjuvant doxycycline therapy to improve procedural durability seems particularly timely. While providing tantalizing insights into potential mechanisms of interest, this study does not clarify the potential value of doxycycline as either adjuvant or primary therapy for abdominal aortic aneurysm (AAA) disease.

Primary study endpoints included (1) a reduction in plasma matrix metalloproteinases (MMP)-9 levels with doxycycline therapy and (2) a reduction in aneurysm sac size at 6 months. Secondary endpoints included plasma MMP-2, serum IL-6, IL-8, and highly-sensitive C-reactive protein (hs-CRP) levels at 6 months. Of these, only plasma MMP-9 levels were noted to decrease in doxycycline-treated patients between 1 and 6 months following EVAR. Doxycycline-induced reductions in plasma MMP-9 levels did not translate into reduced AAA sac size. While endograft-specific outcome analyses suggested evidence of enhanced aneurysm sac and neck stability with doxycycline, these were post-hoc analyses to be interpreted with caution. These types of analyses are best used to generate additional hypotheses for further study.

Prior studies (including reference 16 of the article above) have suggested that post-procedural plasma MMP levels are reduced following either open surgical repair or EVAR, particularly in the absence of endoleaks. In placebo treated patients in the current series, interestingly, plasma MMP-9 levels actually rose slightly following endografting. Why these plasma responses to EVAR should differ between these series is unclear. This also highlights the uncertain clinical relevance of reduced plasma MMP-9 levels in the absence of significant structural effects: in reference 5, plasma MMP-9 levels were reduced following oral doxycycline therapy in small AAA patients even though no influence was noted on ultrasound-determined diameter enlargement. Clearly more conclusive data is needed, requiring much larger treatment groups appropriately stratified by size, endoleak status, device type and exclusion methodology (eg, uni-iliac vs bifurcated device, etc), thrombus size and location and all other variables known or suspected to influence late aneurysm remodeling and regression following EVAR.

Most importantly this intriguing study underscores the need for rigorous and fully-powered trials to test the ability of doxycycline to suppress mural proteolysis in AAA, either following EVAR or as primary therapy to limit progression of early disease. More than 10 years after the original studies suggesting potential efficacy, fully-funded clinical trials are long overdue and clearly justified. Patients deserve to know whether or not doxycycline therapy will reduce their risks of death and disability from AAA disease.