Effect of Doxycycline on Aneurysm Growth Among Patients With Small Infrarenal Abdominal Aortic Aneurysms

Abstract

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 MEASURESThe 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 No patients were withdrawn from the study because of adverse effects.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.

Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm

“…There have been a few drug classes that have gone into clinical trials such as doxycycline, angiotensin-converting enzyme (ACE) inhibitors, and a few studies evaluating statins. However, conclusive evidence suggesting effective reduction in size or growth rate has yet to be reported, though some trials are still ongoing [ 10 , 11 , 12 ]. Moreover, therapeutic advancement would positively affect surgery and stenting application [ 13 ].…”

Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights

“…However, in contrast to the successes in preclinical studies, the Pharmaceutical Aneurysm Stabilization Trial (PHAST) trial found no effect after 18 months of doxycycline treatment (100 mg/day) [ 66 ]. This was confirmed by a recently published randomized clinical trial by Baxter et al (Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA 3 CT)), reporting that doxycycline (200 mg/day) did not reduce AAA growth at 2 years as compared to placebo in patients with small infrarenal AAA [ 67 ]. While it was previously argued that the doxycycline dose used in the PHAST trial was too low to have an effect on AAA, the dose in the N-TA 3 CT trial corresponded to circulating levels of doxycycline that were required to reduce AAA growth in preclinical studies with mice [ 67 ].…”

“…This was confirmed by a recently published randomized clinical trial by Baxter et al (Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA 3 CT)), reporting that doxycycline (200 mg/day) did not reduce AAA growth at 2 years as compared to placebo in patients with small infrarenal AAA [ 67 ]. While it was previously argued that the doxycycline dose used in the PHAST trial was too low to have an effect on AAA, the dose in the N-TA 3 CT trial corresponded to circulating levels of doxycycline that were required to reduce AAA growth in preclinical studies with mice [ 67 ]. The promising results of the preclinical studies could therefore not be confirmed in human clinical trials.…”

Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks?

“…Favourable clinical outcomes have also been observed with tetracyclines in indications like rheumatoid arthritis, osteoarthritis, Fragile X syndrome, etc. [129,131,[297][298][299][300][301][302][303][304]. A comprehensive summary of pleiotropic non-antibacterial actions and on-going clinical trials was published in 2010 [11] listing 54 and 88 clinical trials for minocycline and doxycycline, respectively, in indications like e.g.…”