A randomized, placebo-controlled trial of doxycycline after endoluminal aneurysm repair

Abstract

Background The late durability of endovascular aneurysm repair (EVAR) has been limited by progressive aortic degeneration believed to be mediated by matrix metalloproteases (MMP). The goal of this study was to evaluate the effect of a MMP inhibitor, doxycycline, on EVAR. Methods and Results Patients undergoing EVAR were randomized to doxycycline (100mg twice daily) or placebo for 6 months following the procedure. Clinical data, blood samples and CT scans were obtained pre-operatively, post-operatively (blood only), and at 1 and 6 month follow-up. Forty-four subjects were analyzed based on intention-to-treat. Plasma MMP-9 decreased significantly below baseline in the doxycycline (N=20) treated patients at 6 months (−16.4±20.7%, P<0.05) while there was a non-significant increase in the placebo (N=24) group (128.1±73.5%). This was primarily related to changes between one and six months. In patients with endoleaks at 6 months, plasma MMP-9 increased in 83% of the placebo treated patients, but in only 14% of the doxycycline treated group (P<.03). Among endoleak-free patients with AneuRx or Excluder endografts, doxycycline treatment resulted in greater decreases in maximum aortic diameter than placebo treatment (−13.3±3.3% vs. −3.8±3.0%, P<.05). Furthermore, doxycycline treatment significantly reduced the aortic neck dilatation at six months in Excluder treated patients. Conclusion There is evidence of persistent MMP release representing ongoing aortic degradation after endografting which can be inhibited by doxycycline therapy. In analyses based on the endograft used, treatment with doxycycline also demonstrated evidence of increased aortic dimensional stability, a surrogate marker for long-term success of EVAR. Although encouraging, these results require confirmation in larger patient populations. Doxycycline should undergo more thorough evaluation as a potential adjuvant treatment to improve the results of EVAR, particularly in certain subgroups.

Loss of Timp3 Gene Leads to Abdominal Aortic Aneurysm Formation in Response to Angiotensin II

“…In addition, inhibition of one specific MMP did not provide beneficial outcomes in limiting AAA progression, whereas inhibition of a number of ECM-targeting MMPs was a more effective approach. Consistent with our findings, doxycycline, a broad spectrum MMP inhibitor, has been a promising treatment in preventing AAA expansion and rupture (62)(63)(64)(65), whereas other treatments including ␤-blockers, angiotensin-converting enzyme inhibitors, and statins have been ineffective (1-4, 6). Overall, our study provides evidence that TIMP3 is critical in constructive vascular remodeling, and as such, targeted overexpression of TIMP3 could serve as a promising therapeutic approach in preventing aneurysm formation or controlling its expansion.…”

Doxycycline Ameliorates the Susceptibility to Aortic Lesions in a Mouse Model for the Vascular Type of Ehlers-Danlos Syndrome

“…Furthermore, doxycycline therapy with 100 mg twice daily up to 2 years decreased hemorrhagic risk in brain vascular malformations (Frenzel et al, 2008). Doxycyclin therapy with the same dosage reduced aortic neck dilatation 6 months after endovascular aneurysm repair (Hackmann et al, 2008). Clinical trials with other indications of doxycycline are on the way.…”

Azelnidipine Decreases Plasma Matrix Metalloproteinase-9 Levels after Endovascular Abdominal Aortic Aneurysm Repair

“…Hackmann et al [24] has showed that the use of doxycycline after EVAR produced a significantly greater decrease in plasma MMP-9 levels and accelerated aneurysmal shrinkage as compared with a placebo. Doxycycline treatment significantly improved the aneurysmal shrinkage rate compared with placebo treated patients at postoperative 6 months ( -13.3%±3.3% vs -3.8%±3.0%, P<0.05).…”