One of the earliest agents to demonstrate decreased aneurysmal growth in pre-clinical models was propranolol, an effect believed to be related to reduced cardiac contractility and an effect on aortic tensile strength [5–7]. Further nonrandomized human trials suggested a beneficial effect of beta-blockade on aneurysmal growth rates [8, 9]. Based on this background, the Propanolol Aneurysm Trial Investigators conducted a multicenter, double-blind randomized placebo-controlled trial to study the effect of propranolol on the growth rate of AAAs measuring 3.0–5.0 cm. Having recruited 276 patients into the experimental arm and 272 patients into the placebo arm, the study ultimately demonstrated no significant reduction of growth due to the beta-blocker by intention to treat analysis (2.2 mm/year on propranolol vs 2.6 mm/year on placebo, p = 0.11) over a mean follow up period of 2.5 years. Furthermore, the propranolol treatment was poorly tolerated by these elderly patients – 39 % of the patients permanently withdrew from the trial due to adverse effects of the drug, namely fatigue, shortness of breath, and bradycardia [10].

Based on studies that demonstrated the presence Chlamydophilia pneumoniae in atherosclerotic arterial lesions and AAAs [11–13], as well as an association between IgA positivity against C. pneumoniae and expanding small AAA [14], Vammen et al. investigated the role of antibiotic therapy on AAA growth rate. The macrolide antibiotic roxithromycin was compared to placebo in a double-blind randomized controlled trial; pre-recruitment power calculations estimated a need for 100 subjects to detect a 33 % reduction in expansion rate. Ultimately, 92 eligible men were randomized into the trial with a mean follow up of 1.5 years. The trial resulted in a 43 % reduction in overall mean expansion rate in the roxithromycin group (1.56 mm/year vs. 2.75 mm/year, p = 0.02). On post-hoc analysis, this was found to be most effective during the first year of treatment; the change in rate during the second year was not significantly different between the two treatment arms [15].

More recently, the effect of azithromycin on small AAA growth rate was tested by Karlsson et al. in a larger double-blind randomized controlled trial; the aims of this study also included assessing the association between titers of C. pneumoniae antigen and AAA growth. 247 patients were randomized into the experimental azithromycin regimen (600 mg daily for 3 days, then once weekly for 15 weeks) or placebo and followed for at least 18 months; 34 patients were excluded due to loss to follow up. Between the two treatment arms, no significant difference was found in median AAA expansion rate (2.2 mm/year in the azithromycin group vs. 2.2 mm/year in the placebo group, p = 0.85). Likewise, no correlation was identified between the rate of aneurysm expansion and the level of serological markers for C. pneumoniae infection [16].

The most readily apparent histologic change associated with AAA is the fragmentation and loss of medial elastin. Unlike the rationale for the macrolide antibiotic use, the use of doxycycline is primarily predicated on its capacity to broadly inhibit the activity of elastolytic matrix metalloproteases, which are thought to be responsible for the loss of the elastic fibers [17–19]. Mosorin et al., conducted a pilot double-blind, randomized placebo-controlled trial to elucidate the effect of doxycycline on small aneurysm growth rates. A small study population of 34 patients were randomized into a group of 17 patients receiving 150 mg doxycycline daily for 3 months or a control placebo group of 15 patients (2 patients excluded due to emergent surgery unrelated to AAA and death) and observed with ultrasound scanning for a mean follow up of 18 months. While the overall aneurysm expansion rate was higher in the placebo group than the experimental arm over the course of the trial, this difference did not reach statistical significance (1.5 mm/year vs 3.0 mm/year, p > 0.05). Only on post-hoc analysis of timeframes in this small study does there appeared to be a significant difference: in the 6–12 month follow up period (0.0 mm/year vs. 2.0 mm/year, p = 0.01), as well as the 12–18 month period (0.0 mm/year vs 5.0 mm/year, p = 0.01) [20].

These study results are remarkable in three ways. First, this was the first randomized trial to show a significant effect on AAA growth. Second, the effect on AAA growth appeared to be durable long after the cessation of the doxycycline therapy. Third, the effect of doxycycline on AAA growth did not become evident until after the first 6 months.

Subsequent to this pilot investigation, the PHarmacologic Aneurysm Stabilization Trial (PHAST) study – a double blind, randomized placebo controlled trial – was conducted in 14 Dutch hospitals between 2008 and 2011, as eported by Meijer et al. Two groups of patients were randomized for the trial, one with AAA diameters between 3.0 and 5.0 cm and a second group where the maximal AAA diameter was >5.0 cm, but the patient was either a poor candidate for surgical intervention or refused surgical repair. A total of 286 patients were recruited and randomized to a daily dose of 100 mg of doxycycline or placebo over 18 months; growth rate was measured by ultrasound in the AP plane only using a single ultrasonographer. This study was closed prematurely at an interim safety review due to apparent futility. There was also a larger than expected loss to follow-up. A revised post-hoc data analysis, conducted under a linear mixed model, indicated that doxycycline treatment was associated with an increase in aneurysm growth (difference in diameter of growth 0.8 mm, 95 % CI 0.1–1.4 mm, p = 0.016) [21].

Careful examination of the PHAST data shows that the majority of the apparent accelerated growth effect of doxycycline occurred in the first 6 months of therapy. Subsequently, the growth curves did not appear to further diverge. Combined with the interval results of the Mosorin study, this finding suggests that the effect of doxycycline may be delayed. It should also me noted that the journal’s editorial staff included a boxed note indicating that this study’s results, while provocative, could not be considered definitive.

The class of hydroxymethylglutaryl-CoA reductase inhibitors (“statins”) are among the most studied in medical literature. With strong evidence of efficacy in other realms of cardiovascular disease including claudication [22], cardiac risk reduction [23], and stroke prevention [24], much attention has been paid to the potential for these drugs in the treatment of aortic aneurysmal disease. All published literature to date consists of cohort studies, most frequently based on re-analysis of the results of longitudinal studies of patients with AAA. Twine and Williams published a meta-analysis of 12 of these cohort studies in 2011, aiming to validate claims of a beneficial effect of statin therapy on AAA growth rates. In their subgroup analysis of high-quality cohort studies examining the growth rate in small AAA, they found no significant difference in AAA expansion rates associated with the drug (SMD -0.14 mm/year, p = 0.16) [25].

More recently, Takagi et al. conducted a separate meta-analysis of 7 “high quality” observational studies, including studies in the Twine analysis, addressing the effect of HMG-CoA reductase inhibitors on AAA growth. Their study demonstrated a statistically significant result favoring statin therapy (SMD −0.367, 95 % CI −0.566 to −0.168, p < 0.001). Because management of patients with small AAA should include statin therapy as part of a program to reduce cardiovascular events in these patients, it is unlikely that the effect of statins on AAA growth will ever be analyzed in a randomized placebo controlled trial. Based on these cohort analyses, these agents can reasonably be administered to patients with small AAA without concern for adverse effects on AAA growth [26].

Compared to the other pharmacological interventions discussed, the data supporting aspirin (ASA) use in AAA disease tends to be of lower quality. Lindholt et al. published an observational cohort study in 2008 that examined the role of low-dose aspirin. Over a mean follow up of 6.6 years, 148 patients with small AAA were followed annually after a positive screening exam until they were referred to surgery when the aneurysm reached 5.0 cm in diameter. Among those patients with an aortic diameter of 4.0–4.9 cm on initial screening, those on low-dose ASA were found to have a statistically significant 43 % reduction in aneurysmal growth rate compared to non-users (2.92 mm/year vs. 5.18 mm/year; difference 2.27 mm/year, 95 % confidence interval 0.42–4.11) [27].