Prevention of the development and rupture of abdominal aortic aneurysm

Keywords: aneurysm, abdominal aorta, prevention, smoking, screening

Introduction

Abdominal aortic aneurysm (AAA) is a pathology that has a significant impact on public health. In the USA, it is responsible for approximately 14,000 deaths per year, a figure that is probably underestimated given that 5% of the 200,000 sudden deaths per year may have an undiagnosed AAA as the cause of death [1]. Therefore, knowledge of the prevention of the development and rupture of AAA is essential in daily medical practice. The objective of this article is to analyse the evidence and recommendations about the prevention of AAA and its rupture through an updated literature review.

Prevention of AAA

Table 1 summarises the main recommendations regarding the prevention of the development of AAA and its rupture.

Table 1. Recommendations regarding the prevention of AAA.

AAA: abdominal aortic aneurysm

Prevention of the development of AAA

The main risk factors for the development of AAA include advanced age, male sex, smoking and a family history of AAA [2].

Smoking cessation

Smoking is the only modifiable variable in the aforementioned risk factors, in addition to being deemed the most important factor in the genesis and growth of AAA [2]. Statistically, more than 90% of AAA patients have smoked at some point in their life [3]. The pathophysiological mechanism that explains the association between smoking and AAA is based on the smoking of tobacco causing inflammation of the arterial wall by promoting the generation of free radicals. This in turn stimulates the proteolytic activity of the extracellular matrix, consequently degrading the elastin and collagen present in the aortic wall and thus contributing to the formation of AAA [2].

The prevalence of this disease is seven times higher in tobacco users than in those who do not smoke. There is a strong association between the risk of developing an AAA and the duration of smoking history, more so than the total number of cigarettes smoked [2]. The relative risk of the appearance of AAA increases by 4% for each year of smoking. For its part, smoking cessation and smoking-free duration have been shown to reduce the prevalence of AAA [2]. A recent meta-analysis that included 23 prospective studies established that the probability of developing an AAA in current and ex-smokers is 4.87 and 2.10 times higher, respectively, than in those who have never smoked. Likewise, the relative risk of those who have stopped smoking for 25 years was similar to that in those who have never smoked [4]. Therefore, smoking cessation advice during each medical consultation has the highest yield in preventing the development of AAA.

Other measures

Arterial blood pressure control

The prevalence of high blood pressure in patients with AAA is approximately 82% [1]. A meta-analysis that included 21 cohort studies with data on 28,162 AAA patients and 5,440,588 individuals showed that high blood pressure increases the risk of developing AAA by 66%. In addition, this study showed that, for every 20 mmHg of increase in systolic blood pressure and for every 10 mmHg of increase in diastolic blood pressure, there is a relative risk of AAA development of 14% and 28%, respectively [5]. Thus, it is reasonable to achieve an adequate control of blood pressure as a measure to prevent the development of AAA.

Control of other risk factors

A cohort study involving more than 3 million individuals published an association between the development of AAA and the presence of certain comorbidities such as dyslipidaemia, overweight, obesity and coronary, cerebrovascular or peripheral vascular disease. Although the impact of these diseases on the development of AAA is weak [1], they play a greater role in indicating the long-term prognosis of patients with AAA. A British study found a higher 5-year survival rate in those AAA patients treated with statins, antiplatelet therapy or antihypertensive drugs [6]. Therefore, adequate control and treatment of cardiovascular risk factors in patients with AAA is crucial.

Paradoxically, unlike what occurs in subjects with atherosclerotic pathology, the prevalence of AAA and the speed of their growth are lower in diabetic subjects [2,3].

Prevention of AAA rupture

The risk of rupture depends on multiple factors - the diameter of the aneurysm, the growth rate, its morphology (saccular aneurysms have a worse prognosis) and a positive family history [2,7]. 

Smoking cessation

Strong epidemiological evidence points to smoking as the main risk factor in the enlargement of AAA. In current tobacco users, the rate of growth of an AAA is 0.35 mm per year, a figure that is double the rate of expansion relative to non-smokers or those who have quit smoking [3]. In recent decades, the decline in smoking among American adults has followed a similar trend with a reduction in deaths from a ruptured AAA. In contrast, in those countries where the prevalence of smoking remains high, mortality associated with AAA continues to increase [3]. Therefore, stopping smoking is the most important intervention to prevent AAA growth [3]. Thus, it is recommended to use all available resources, both pharmacological and non-pharmacological, to achieve smoking cessation [7].

Arterial blood pressure control

High blood pressure increases the risk of AAA rupture, mainly due to elevated aortic wall stress. In a study by Bhak et al, an increase in the AAA expansion rate of 0.02 cm per year was evidenced for every 10 mmHg of increase in diastolic blood pressure [8]. Therefore, it is advisable to achieve adequate control of blood pressure in patients with AAA to prevent rupture.

Management of other risk factors

A retrospective cohort study showed that a cardiac rehabilitation programme reduces the growth rate of small AAAs [9]. In keeping with this, an improvement in cardiopulmonary capacity has been demonstrated in patients with AAA less than 55 mm who perform regular physical activity. Therefore, regular aerobic physical activity should be encouraged in these patients for its beneficial effect on general cardiovascular risk and for improvement of cardiopulmonary capacity. On the other hand, the practice of intense isometric exercises is not recommended in these patients [7].

Pharmacotherapy

• Statins: apart from their lipid-lowering effects, statins also have anti-inflammatory properties that could explain their beneficial effects in patients with AAA. Information published in a meta-analysis concluded that the use of statins is effective in slowing down the growth of AAA. What is more, the use of statins was associated with a reduced risk of aneurysmal rupture and improved survival in the event of rupture. Therefore, the use of statins is recommended in patients with AAA [2,7,10,11].
• Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs): the results of observational studies around the benefit of these drugs are contradictory. The only randomised study published to date that evaluated the effects of ACEIs in AAA patients was the AARDVARK trial. Two hundred and twenty-four (224) patients were randomised to 3 treatment groups - 10 mg of perindopril, 5 mg of amlodipine or placebo. Treatment with perindopril did not prevent AAA dilation, despite the fact that patients treated with this drug achieved better control of blood pressure [12]. With regard to ARBs, the TEDY trial is currently underway, which is evaluating the effects of telmisartan [10]. Despite this, the use of these drugs is reasonable in order to reduce cardiovascular risk, taking into account the frequent association between AAA and atherosclerotic disease [7].
• Beta-blockers: although studies in animal models have suggested a beneficial effect of beta-blockers on the growth rate of aneurysms and their rupture based on the hypothesis of a reduction in aortic wall stress, the information from meta-analyses within human subjects has not confirmed this effect. A Cochrane review that included three randomised clinical trials evaluating the effects of propanolol did not show a significant decrease in the AAA growth rate. In these studies, however, the rate of medication abandonment was high and, in one of the randomised trials, propanolol was associated with deterioration in quality of life. To date, there are no clinical studies that have evaluated the effect of other better tolerated beta-blockers. Therefore, there is insufficient evidence to support the recommendation of systematic use of beta-blockers in patients with AAA [7,13].
• Treatment of arterial hypertension: as previously mentioned, adequate control of blood pressure should be achieved to prevent both the development and the rupture of AAA. Given the high prevalence of atherosclerotic disease among patients with AAA and the benefit of the use of ACEIs and ARBs in these patients, it would be reasonable to suggest their use as the first option in patients for the treatment of arterial hypertension [5,8].
• Antiplatelet therapy: it has been found that the growth of AAA is associated with the development of mural thrombosis, which increases the risk of complications, which is why antiplatelet therapy has been proposed as a possible option in the treatment of these patients [7]. However, information from observational studies is controversial regarding the benefit of antiplatelet therapy in patients with AAA [10,11]. The only randomised study published to date is the TicAAA trial, which showed no reduction in the growth rate of small AAAs in patients treated with ticagrelor [14]. Therefore, currently there is no evidence to support the use of antiplatelet therapy in patients with AAA.
• Other treatments: the use of antibiotics (macrolides and tetracyclines) and mast cell inhibitors (pemirolast) has been evaluated in different studies; however, to date there is no solid evidence to justify the indication of any of these therapies in patients with AAA [10,11].

Screening

Diseases are suitable for screening when they meet certain criteria: 1) the pathology is a common cause of morbidity and mortality; 2) it is both detectable and treatable during the pre-symptomatic stage; 3) the tests used to diagnose the presence or absence of the condition must be effective, efficient and safe; 4) early diagnosis and treatment should provide better outcomes than those achieved in subjects treated during the symptomatic phase; and 5) the potential damage or side effects of the intervention during the asymptomatic phase should be less than those of the intervention in the symptomatic phase. Applying these principles to screening for AAA, it is a frequent pathology occurring in men over 65 years of age; subjects are asymptomatic for many years; detection of the disease using a test such as ultrasound is cheap, safe and readily available; and the use of screening and early intervention demonstrates an observable reduction in morbidity and mortality [15]. As a result, AAA constitutes a disease that could be screened for.

Screening methods

Palpation of a pulsating abdominal mass is the classic clinical sign; however, the sensitivity of physical examination to diagnose AAA is very low due to the retroperitoneal location of the abdominal aorta. Furthermore, it is extremely difficult to detect small or saccular aneurysms via physical examination, especially in patients who are obese or have a large body surface area [3].

Almost three quarters of AAAs are asymptomatic at the time of diagnosis and are incidental findings on routine physical examination or are a supplemental finding in studies requested for other medical reasons [7]. 

The test of choice to diagnose, track and monitor AAA is ultrasound, due to its high sensitivity (95%) and specificity (close to 100%), in addition to the fact that it is a safe, low-cost technique with high availability in the different medical centres [7]. Factors limiting the diagnostic performance of ultrasound include the presence of suprarenal or juxtarenal aneurysms, compromised iliac arteries, obesity and the presence of abdominal distention. These limiting factors are exacerbated when the ultrasound is performed by practitioners with limited experience [2].

In subjects whose ultrasound shows a finding of an AAA, the iliac, femoral and popliteal arteries should also be assessed to rule out any concomitant aneurysms, due to their frequent association with AAAs [2,7]. 

In subjects in whom AAAs are found to be expanding rapidly, or in those subjects with borderline diameters for surgical intervention, a second imaging method is recommended, preferably computed tomography (CT) [7].

The use of other imaging techniques such as CT and magnetic resonance imaging (MRI) for screening purposes is discouraged due to its high cost compared to ultrasound, and radiation exposure and the use of iodinated contrast (in the CT case). However, these imaging modalities can detect the presence of an AAA when requested for other reasons [7].

Effectiveness of screening

It is important to assess the impact of screening programmes on reducing the occurrence of events linked to AAAs. To answer this question, multiple randomised clinical studies have been performed. Here we provide a literature review of their findings.

Ultrasound screening in males: there are four randomised clinical trials that included more than 125,000 participants older than 65 years of age, who were randomised to ultrasound scan or regular follow-up. Two of these trials were carried out in the United Kingdom (MASS and Chichester), one in Denmark (Viborg) and the other in Australia (Western). The mean prevalence of AAA across these studies was approximately 5.5%. The results of these four randomised clinical trials were recently analysed in a systematic review by Ali et al, which showed a 42% reduction in mortality associated with AAA and a 38% decrease in the rupture rate in the population tracked at a 15-year follow-up. Based on this analysis, approximately 200 people had to be screened to avoid one death from AAA. After 15 years of follow-up, the implementation of a screening programme resulted in a 2% reduction in total mortality. Elective treatment procedures for an AAA doubled among patients enrolled in active and systematic screening programmes, while halving the need for emergency procedures. This translated into a 54% decrease in 30-day surgical mortality [16]. 

Ultrasound screening in females: the Chichester trial is the only randomised trial to have examined aneurysm screening in women. This included approximately 9,300 women. A much lower prevalence of AAA was found compared to men (1.3% versus 7.6%). The conclusion was that, in the female population, systematic screening showed no effect on AAA-related mortality or on the aneurysmal rupture rate at 10 years of follow-up [16]. Due to the low prevalence of AAA in women, there is a lack of data regarding the benefit of systematic screening in females [2]. On the other hand, aneurysmal ruptures in women occur with aortic diameters 5-10 mm smaller than in males, and the risk of death due to rupture of an AAA is 4 times greater in relation to men with similar aneurysmal diameters [2]. In this sense, there is a high-risk subgroup (those older than 65 years with a current or past smoking history, or those with first-degree relatives with a history of AAA), where screening can be considered [3].

Since the conduct of randomised studies evaluating the efficacy of systematic screening at the end of the last century and the beginning of this century, a change in the epidemiology of AAA appears to have occurred. This is evidenced in data derived from the Swedish and British screening programmes, which showed an AAA prevalence of 1.5% and 1.34%, respectively [17,18]. This may be due to a decrease in smoking today [3], as well as the fact that both programmes are applied when men turn 65 and are not carried out in the age range of 65 to 74 years as in randomised studies. However, both the British and Swedish reports conclude that screening programmes continue to be effective in reducing mortality associated with AAA in men [17,18]. 

In a cost-effectiveness analysis performed with data from the MASS study and the Swedish screening programme, it was concluded that the programmes will continue to be cost-effective until an AAA prevalence of 0.5% is reached [19]. Cost-effectiveness has also been demonstrated in relation to other commonly used screening programmes such as cervical and prostate cancer screening [20].

Ultrasound screening in patients with a family history of AAA: a positive family history of AAA, particularly among first-degree relatives, is associated with a twofold to fivefold increased risk of developing this disease [2]. Therefore, screening is recommended in first-degree relatives (older than 65 years) of patients with an AAA [3].

Surveillance of small and borderline AAAs

Patients with an abdominal aortic diameter less than 25 mm are considered to be at a very low risk of experiencing significant growth in the next 10 years. In those patients with borderline enlargement of their abdominal aorta (25-29 mm), follow-up imaging should be repeated after 4 years [7]. According to data from a meta-analysis that evaluated repeated abdominal aortic diameter measurements, it is feasible to propose an ultrasound monitoring scheme every 3, 2 and 1 years for AAA of 30-39 mm, 40-44 mm and 45 -54 mm, respectively. Using these follow-up intervals, the risk of a spontaneous rupture of an AAA would be less than 1% [7] (Table 2).

As stated earlier, an association exists between the velocity of growth of an AAA and its risk of rupture. An AAA is deemed to be growing rapidly when its rate of expansion exceeds more than 10 mm per year [7].

Table 2. Recommended follow-up of small and borderline AAAs.

AAA: abdominal aortic aneurysm; CT: computed tomography

Conclusions

AAA is a pathology with a significant impact on public health. It is therefore essential to recognise patients at high risk of having this condition in order to implement appropriate prevention measures. Strong evidence exists justifying smoking cessation, adequate blood pressure control, and statin use with the aim of slowing the rate of expansion of known aneurysms as well as the establishment of screening programmes in at-risk population groups. Also, ultrasound surveillance in subjects with small AAAs is recommended to guide timely elective repair to improve clinical outcomes. Given the frequent association of atherosclerotic disease in patients with AAA, adequate control of cardiovascular risk factors has demonstrated improvements in the long-term survival in this patient group.