If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Management of abdominal aortic aneurysms (AAAs) relies on surgical repair of larger AAAs. Consequently medical interventions inhibiting AAA progression could greatly reduce the need for surgical repair. A spectrum of pharmaceutical strategies has been reported, albeit conclusions often appear contradictory. Given the longstanding interest in pharmaceutical AAA stabilization, a systematic review of the available literature is relevant.
Objectives
The aim is to provide an up to date systematic review of the available data on pharmaceutical therapies for stabilizing or impeding AAA growth.
Methods
A search using Pubmed, Embase, Web of science, Cochrane, CINAHL, Academic Search Premier, and Science Direct identified 27 eligible papers that studied the clinical effect of the pharmaceutical therapy on AAA diameter growth.
Results
This review shows that there is currently no pharmaceutical strategy that reduces AAA growth. Most studies are of poor methodological quality. Initial promising reports are often not confirmed in subsequent larger studies, raising the possibility of selective reporting.
Conclusion
There is currently no pharmaceutical means that halts AAA growth.
Pharmaceutical abdominal aortic aneurysm stabilization is an unmet medical need. To date, over numerous clinical and hundreds, of pre-clinical papers show the potential of numerous interventions. Yet conclusions from clinical reports are not fully consistent. As such, a systematic review of the available clinical data is relevant.
Introduction
The risk of rupture of an abdominal aortic aneurysm (AAA) progressively increases in larger AAAs > 55 mm. Four large clinical trials have not shown a benefit of earlier repair
(i.e. for aneurysms <55 mm). Therefore, the therapeutic approach to AAAs is surveillance of small aneurysms and prophylactic surgical open or endovascular aneurysm repair (EVAR) in AAAs over 55 mm.
Yet while open repair has excellent long-term outcomes, it has a significant peri-operative morbidity and mortality. Although EVAR comes with a significantly lower peri-operative morbidity and mortality, its cost effectiveness is being questioned. Consequently, a pharmaceutical means of slowing down or stabilizing the progression of small AAAs, and thus postponing or obviating the need for surgery could provide a major advance.
In fact, pharmaceutical stabilization of AAA is now considered an unmet medical need.
A large body of preclinical evidence has shown that interference with aspects of vascular inflammation and/or proteolytic activity alleviates AAA formation in rodent models of the disease.
The clinical evidence has been reviewed in 78 papers (from a systematic literature search), yet a comprehensive systematic review is missing. Given the renewed interest in pharmaceutical AAA stabilization, a systematic review of the available evidence on pharmaceutical interventions for stabilizing or impeding AAA growth in humans is relevant.
Methods
Search strategy
The studies included in this review were identified from PubMed, Embase, Web of science, Cochrane, CINAHL, Academic Search Premier, and Science Direct. The search was not limited, and thus all languages and publication types (e.g. reviews or conference abstracts) were included. The search was most recently updated on April 17, 2015.
Two search themes were created, which were combined in the search by AND. The first theme was created for AAAs by using all terms for abdominal aortic aneurysm, such as abdominal aneurysm or abdominal aorta aneurysm. The second term consisted of all terms for pharmacology, including specific drug group names, such as medical treatment or drugs or hydroxymethylglutaryl-coA reductase inhibitors. Details of the search strategy are available in the supplementary data.
Inclusion criteria
Only studies providing original clinical data on an effect of pharmaceutical therapy on AAA growth were included. Hence, all animal studies and studies that exclusively described an effect of pharmaceutical intervention on molecular processes in the aneurysm wall; all reviews (n = 79) and commentaries were excluded.
Two authors (V.K. and J.L.) independently reviewed the results of the search strategy. A first selection was made on title; all articles potentially reporting an effect of a pharmaceutical intervention on AAA disease were included. A second selection was made by reading the abstract of articles that were selected on the basis of the title. The final selection was made on basis of the full text.
The quality of the identified studies was scored using the STROBE scoring system.
Statistical analysis was not performed because of the marked heterogeneity of the included studies.
Results
The search strategies identified 3,557 articles. Selecting title and abstract narrowed the number of articles to 30 original studies. Two of the 30 original studies were excluded because of missing data on the AAA growth rate.
As a result, 27 original articles were available for this review (Fig. 1). Identified studies are summarized in Table 1 and their quality assessed (STROBE scoring system,
Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms.
The effect of azithromycin and Chlamydophilia pneumonia infection on expansion of small abdominal aortic aneurysms – a prospective randomized double blind trial.
Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study.
Beta blockers and other antihypertensive drugs were the first agents to be evaluated for their potential to reduce the AAA expansion rate. Beta blockers were evaluated in two randomized controlled trials (RCTs),
Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms.
Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms.
There are several reports on other classes of hypertensives. A retrospective study suggesting an effect of angiotensin converting enzyme (ACE) inhibition on AAA stability
was followed by five studies investigating an effect of ACE inhibitors on AAA growth. Four of these studies, two small retrospective analyses within a prospective case control study
In contrast, a recent prospective cohort study of 1701 patients participating in the UK small aneurysm trial, unexpectedly indicated a significant increase in aneurysm growth rate in patients taking ACE inhibitors, implying that ACE inhibitors may adversely affect AAA growth.
Both studies found no association between these antihypertensive agents and AAA growth rate.
Statins
A potential effect of statins on AAA progression was evaluated in 12 studies. Six studies reported a beneficial effect of statin use on the AAA growth.
Most studies did not specify the type of statin investigated. Simvastatin and Atorvastatin were the dominant statins in the four studies that specified the statin type.
There is an apparent paradox in conclusions for an effect of statins, with the earlier small studies reporting an association between the statin use and reduced AAA expansion,
Moreover, none of the larger studies (including more than 250 patients) found a difference in AAA expansion rate between statin users and non-statin users.
A presumed role for chlamydia in AAA growth led to studies testing an effect of macrolide treatment on the growth rate of small AAAs. Two RCTs evaluated the effect of roxithromycin on the expansion rate. The first, conducted in 2001, reported a significantly lower expansion rate in the roxithromycin treated patients (p = .02).
The effect of azithromycin and Chlamydophilia pneumonia infection on expansion of small abdominal aortic aneurysms – a prospective randomized double blind trial.
in 2009 (n = 247). This study did not observe a significant difference between the AAA expansion rate in the azithromycin treated patients and controls.
Tetracyclines
In 2001, a small RCT showed a pronounced effect of 3 months of doxycycline treatment on AAA expansion for the 6–12 and 12–18 month follow up periods.
Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study.
revealed significant reduction in MMP9 levels after 6 months of doxycycline treatment. Nevertheless, no significant change was seen for the overall AAA expansion rate. Results from an adequately powered multicenter RCT failed to show a beneficial effect of 18 months of doxycycline therapy on AAA progression. On the contrary, acceleration in AAA growth rate was reported during the 18 month follow up period.
investigated whether the mast cell inhibitor CRD007 (pemirolast) halted growth of small AAA. However, no difference in AAA growth rate was found between placebo and the mast cell inhibitor treated patients.
Anti-platelet therapy
Five studies investigated the potential of anti-platelet therapy in stabilizing human AAA growth.
The effect of azithromycin and Chlamydophilia pneumonia infection on expansion of small abdominal aortic aneurysms – a prospective randomized double blind trial.
A first case control study including 167 patients reported a decrease in AAA progression in those patients with a diameter between 40 and 49 mm. Patients with an AAA diameter smaller than 4.0 cm had a similar expansion rate with or without using aspirin.
Significantly reduced AAA progression in patients using aspirin was reported in a sub-analysis of case control data of a small RCT investigating the effect of azithromycin. The average growth rate of the 101 patients using aspirin was 1.8 mm/year compared with 2.6 mm/year in those not on antiplatelet therapy (p < .01).
The effect of azithromycin and Chlamydophilia pneumonia infection on expansion of small abdominal aortic aneurysms – a prospective randomized double blind trial.
The median growth rate of the AAA diameter of 1.8 mm/year compares favorably to the 3.2 mm/year in patients not taking NSAIDs, p < .01.
Discussion
This systematic review shows that the number of studies evaluating a potential effect of pharmaceutical strategies to halt AAA growth in humans is limited. The majority of identified studies were of moderate quality, and initial promising reports were not confirmed by later larger studies. At this point, no pharmaceutical therapy can be recommended for the stabilization of AAA.
The search strategies identified 27 original papers that evaluated the potential of pharmaceutical intervention for AAA stabilization. Identified interventions can be subdivided into strategies that are part of general cardiovascular risk management (antihypertensive agents, statins, anti-platelet therapy), and into “anti-inflammatory” strategies: macrolides, tetracyclines, and mast cell inhibition.
The majority of studies were of moderate quality, as illustrated by a low to moderate score in the STROBE scoring system.
Interpretation is hampered by poor matching, lack of standardized diameter measurements, and inappropriate statistical analyses. Studies on longitudinal data such as aneurysm progression are prone to non-random drop out.
For example, older patients are more likely to drop out because of death, but are less likely to undergo repair due to different risk estimates. By the same token, patients with larger or fast growing AAA are more likely to drop out prematurely because of repair. As such follow up studies in AAA patients require specific statistical approaches,
a prerequisite that was not met in most studies. Moreover, it was observed that initial promising studies from small cohorts were not confirmed by later larger studies, an observation hinting at the phenomenon of selective reporting.
Most data are available for cardiovascular risk management (beta blockers, ACE inhibitors and statins). Trials with the beta blocker propranolol experienced high drop out rates because of poor tolerance.
Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms.
Statins and ACE inhibitors are well tolerated, yet a recent meta-analysis on the available data concluded that these drug classes did not influence AAA progression.
Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.
The second of the tested interventions was the anti-inflammatory group, with anti-inflammatory referring to an anti-microbial action, in the case of AAA because of a suspected causative role for chlamydia infection in the disease, or alternatively anti-inflammatory in the context of chronic tissue inflammation that is thought to drive AAA progression (doxycycline, mast cell inhibition).
Although aspirin has anti-inflammatory properties, it is unclear whether the dose used for anti-platelet therapy is sufficient to exert an anti-inflammatory effect on the aneurysm wall. Again, there was no evidence for a beneficial effect of anti-inflammatory strategies on AAA progression. On the contrary, evidence was found for growth acceleration in patients taking doxycycline.
The above conclusions contrast sharply with the available preclinical evidence that shows that pharmaceutical interference with aspects of the RAS system, cholesterol metabolism, vascular inflammation or protease activity alleviates aneurysm formation in rodent models of the disease
In conclusion, there is currently no established medical therapy for the stabilization of growing AAA. Interpretation of the available data is hampered by its moderate quality. A role for beta blockers, doxycycline, and the mast cell inhibitor pemirolast has been ruled out in RCTs. Available observational data for ACE inhibitors and statins is not consistent with a beneficial effect on aneurysm progression. A number of interventions are currently being evaluated in clinical trials (Table 2). At this moment, no therapy can be recommended although it cannot be excluded that AAA growth and rupture are disparate processes. Consequently although some interventions do not influence AAA progression, they may influence the AAA rupture rate,
a notion that requires independent confirmation. Moreover, although cardiovascular risk management does not influence AAA progression, it is important to point out that risk management is indicated in AAA patients as this group is at an extremely high cardiovascular risk.
Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms.
The effect of azithromycin and Chlamydophilia pneumonia infection on expansion of small abdominal aortic aneurysms – a prospective randomized double blind trial.
Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study.
Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.
To submit a comment for a journal article, please use the space above and note the following:
We will review submitted comments as soon as possible, striving for within two business days.
This forum is intended for constructive dialogue. Comments that are commercial or promotional in nature, pertain to specific medical cases, are not relevant to the article for which they have been submitted, or are otherwise inappropriate will not be posted.
We require that commenters identify themselves with names and affiliations.
00621-8&id=gr1.jpg){kind=link}