Effect of Doxycycline on Aneurysm Growth Among Patients With Small Infrarenal Abdominal Aortic Aneurysms: A Randomized Clinical Trial

Abstract

Importance: Abdominal aortic aneurysms affect more than 3% of US older adults.

Objective: To test whether doxycycline reduces the growth of abdominal aortic aneurysm over 2 years as measured by maximum transverse diameter.

Design, setting, and participants: Parallel, 2-group, randomized clinical trial that was conducted at 22 US clinical centers between May 2013 and January 2017, and enrolled patients 50 years or older with small (3.5-5.0 cm for men, 3.5-4.5 cm for women) infrarenal aneurysms. The final date of follow-up was July 31, 2018.

Interventions: Patients were randomized to receive twice daily for 2 years doxycycline 100 mg orally (as capsules) (n = 133) or placebo (n = 128).

Main outcomes and measures: The primary outcome was change in abdominal aortic aneurysm maximum transverse diameter measured from CT images at baseline and follow-up at 2 years. Patients were assigned ranks based on the maximum transverse diameter (measured or imputed) of the aorta and also if they underwent aneurysm repair or died. The ranks were converted to scores having a normal distribution to facilitate the primary analysis ("normal scores").

Results: Of 261 patients randomized, no follow-up CT scans were obtained on 7 (3%), leaving a final analysis set of 129 patients assigned to doxycycline and 125 to placebo (mean [SD] age, 71.0 years [7.4 years], 35 women [14%]). The outcome normal scores used in the primary analysis were based on maximum transverse diameter (measured or imputed) in 113 patients (88%) in the doxycycline group and 112 patients (90%) in the placebo group; aneurysm repair in 13 (10%) and 9 (7%), and death in 3 (2%) and 4 (3%), respectively. The primary outcome, normal scores reflecting change in aortic diameter, did not differ significantly between the 2 groups, mean change in normal scores, 0.0262 vs -0.0258 (1-sided P = .71). Mean (SD) baseline maximum transverse diameter was 4.3 cm (0.4 cm) for doxycycline and 4.3 cm (0.4 cm) for placebo. At the 2-year follow-up, the change in measured maximum transverse diameter was 0.36 cm (95% CI, 0.31 to 0.40 cm) for 96 patients in the doxycycline group vs 0.36 cm (95% CI, 0.30 to 0.41 cm) for 101 patients in the placebo group (difference, 0.0; 95% CI, -0.07 to 0.07 cm; 2-sided P = .93). No patients were withdrawn from the study because of adverse effects. Joint pain occurred in 84 of 129 patients (65%) with doxycycline and 79 of 125 (63%) with placebo.

Conclusions and relevance: Among patients with small infrarenal abdominal aortic aneurysms, doxycycline compared with placebo did not significantly reduce aneurysm growth at 2 years. These findings do not support the use of doxycycline for reducing the growth of small abdominal aortic aneurysms.

Trial registration: ClinicalTrials.gov Identifier: NCT01756833.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Baxter reported receiving grants from the National Institute on Aging, National Institutes of Health (NIA-NIH). Dr Matsumura reported receiving grants from the NIH, Abbott, Cook, Medtronic, Gore, and Endologix. Dr Curci reported receiving grants from the NIH. Dr McBride reported receiving grants from the University of Maryland. Dr Larson reported receiving grants from the National Institute of Allergy and Infection Diseases. Dr Blackwelder reported receiving grants from the NIH. Dr Lam reported that she is employed by Genentech, although the majority of the work was completed before employment began, and that she owns stock in Genentech and Merck. Dr Terrin reported receiving grants from NIH. No other disclosures were reported.

Figures

Figure 1.. Recruitment, Randomization, and Patient Flow Through the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial

aPatients may have had more than 1 reason for exclusion, less frequently were allergy or intolerance of tetracycline (n = 12), use of tetracycline in last 6 months (n = 19), long-term infection and antibiotic use (n = 20), enrollment in another clinical trial (n = 15), known genetic syndrome (n = 2). bPatients did not take treatment or did not return for follow-up. CT indicates computed tomography.

Figure 2.. Estimates of Matrix Metalloproteinase 9 Levels on a Log Scale From Generalized Estimating Equations Analysis by Treatment Assignment

The difference between doxycycline and placebo in slope per year is −0.001 (95% CI, −0.051 to 0.049; P = .86) for log(matrix metalloproteinase 9), ng/mL. Open circles represent mean values; lines in the boxes, medians; the box ends, interquartile ranges; and lines spanning boxes, slope.

Figure 3.. Estimates of C-Reactive Protein on a Log Scale From Generalized Estimating Equations Analysis by Treatment Assignment

The difference between doxycycline and placebo in slope per year is −0.089 (95% CI, −0.161 to −0.016; P = .002) for log(C-reactive protein), mg/L. Open circles represent mean values; lines in the boxes, medians; the box ends, interquartile ranges; and lines spanning boxes, slope.