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: Patients undergoing EVAR were randomized to doxycycline (100 mg twice daily) or placebo for 6 months following the procedure. Clinical data, blood samples, and computed tomography (CT) scans were obtained preoperatively, postoperatively (blood only), and at 1- and 6-month follow-up. Forty-four subjects were analyzed based on intention-to-treat.

Results: Plasma MMP-9 decreased significantly below baseline in the doxycycline (N = 20) treated patients at 6 months (-16.4% +/- 20.7%, P < .05) while there was a nonsignificant increase in the placebo (N = 24) group (128.1% +/- 73.5%). This was primarily related to changes between 1 and 6 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 6 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.

Figures

Figure 1. Study enrollment data

Inclusion and exclusion criteria for enrollment are as listed at the conclusion of the study. During the first year of enrollment, the maximal aortic diameter necessary for enrollment was 5.0 cm; this resulted in most of the anatomic exclusions. After randomization, but before dispensing the study medications we had 4 withdrawals: 1 developed a postoperative ileus and was unable to take the medication. 1 patient had an open AAA repair, and 1 patient from each group decided not to accept the study medications after surgery and withdrew. After the medications were dispensed we had an additional 8 withdrawals before 6 months of follow-up, 1 Doxy and 1 Placebo patients withdrew claiming medication GI side effects, 4 developed other illnesses and declined further participation, and 2 withdrew without stating a reason, 1 person withdrew due to a change in insurance coverage and did not return to our facility, 1 patient in the placebo group died from complications of COPD and there was 1 patient whom we could not contact and was lost to subsequent follow-up.

Figure 2. Correlation between pre-operative MMP-9 and MMP-2 and maximum aortic diameter

Although the adjusted correlation coefficient (adj. R2) for MMP-9 is considerably greater than that for MMP-2, circulating levels of both enzymes significantly correlate with the magnitude of aneurysmal dilatation.

Figure 3. Effect of doxycycline treatment on maximal aneurysm diameter change after endoluminal exclusion of an abdominal aortic aneurysm

Change in maximal diameter was calculated as a percentage change in the maximum infrarenal aortic diameter between the 1 and 6 month CT scans. Patients with evidence of a Type II endoleak on the 6 month CT follow-up were excluded from this analysis. Doxycycline treatment resulted in a significantly greater decrease in maximal aneurysm size among the combined group of AneuRx and Excluder treated patients (P<.05>

Figure 4. Effect of doxycycline treatment on aortic neck diameter among patients with Excluder endograft

In the placebo treated group all aortic necks significantly increased in diameter between the pre-operative and 6 month CT scan measures. Among the patients treated with an Excluder endograft, doxycycline prevented this increase in aortic neck diameter. The treated patients demonstrated a significantly smaller increase in aortic diameter than the untreated patients for this sub-group (P<.05 data is expressed as a percentage of the aortic neck diameter measured on cross-sectional imaging relative to nominal endograft oversized>

Figure 5. Effect of doxycycline therapy on the circulating levels of MMP-9

The mean levels of plasma MMP-9 are plotted before and at all follow-up intervals after placement of an aortic endograft. While the surgical procedure caused an initial increase in plasma MMP-9, these levels decreased over the first post-operative month in both groups. While plasma MMP-9 subsequently increased by 6 months in the placebo treated patients, doxycycline treatment resulted in a continued decrease of circulating MMP-9 in this interval. At 6 months plasma MMP-9 decreased significantly below pre-operative levels in the doxycycline treated group (P<.03 but not in the placebo treated patients. overall change mmp-9 during study was significantly different between treatment groups>