Introduction
An abdominal aortic aneurysm (AAA) is a ballooning of the infrarenal aorta to either 1.5 times its normal anteroposterior (AP) diameter or to an absolute value of ≥ 3 cm.1 Small AAAs can be defined as those between 3.0 cm and 5.4 cm in diameter. These small AAAs have a low risk of rupture, whereas the operation to repair them is fatal in approximately 2–3% of patients.2 Small AAAs are generally managed by optimising cardiovascular health and placing the patient on a surveillance programme to measure the AAA diameter at regular intervals. Once AAAs reach 5.5 cm (or if initially detected at a larger size), they are often repaired as the risk of rupture rises exponentially above this size. If rupture does occur, the results of emergency aneurysm repair are not good, with only about 40% of patients surviving. Without repair few survive, so that overall the survival of AAA rupture is probably < 20%. Although recent reports have suggested that the incidence of aneurysms appears to be in decline,3,4 AAA remains a significant health risk in the older population, with around 4000 deaths each year in England and Wales attributed to AAA rupture.5
Except when they rupture, most AAAs are usually asymptomatic and so, until recently, they were detected as an incidental finding on clinical examination or ultrasonography, abdominal computerised tomography (CT) or magnetic resonance imaging performed for other purposes. However, in the UK, the NHS Abdominal Aortic Aneurysm Screening Programme (NAAASP) was introduced in 2009 and so many more small AAAs are now being detected early. The programme has been very successful and screened its millionth man in autumn 2015. There is an opportunity to reduce the number of patients needing AAA repair if AAA growth can be slowed or prevented in this growing cohort of patients.
Although data on the effects of angiotensin-converting enzyme inhibitors (ACE-Is) in this context are not consistent, ACE-Is have been associated with a reduced incidence of AAA rupture in analysis of administrative databases.6 Previous trials of some other drugs to slow AAA growth have been hindered by poor patient compliance.7 Therefore, this pilot trial was undertaken to assess whether or not ACE-Is could potentially slow AAA growth and are well tolerated in doing so. We are unaware of any other completed randomised controlled trials (RCTs) designed to examine the efficacy of ACE-Is or angiotensin receptor blockers (ARBs) in limiting or inhibiting AAA progression, although two trials of the impact of ARBs on the growth of AAAs are in progress.
Risk factors
A wide variety of risk factors have been attributed to the formation and progression of AAAs. The single most important risk factor for AAAs has consistently been found to be smoking,8–10 although other risk factors including male sex, age, high blood pressure (BP) [particularly raised diastolic BP (DBP)] and family history of AAA are frequently linked with the aetiology of AAA.11 Low prevalence rates have been observed among African12 and Asian13 men compared with Caucasian men. Several studies have also found a strong coexistence of localised and generalised atherosclerosis and AAA,14,15 an underlying disturbed connective tissue metabolism16 and an increased risk for AAA with increasing alcohol consumption.17
There are many genetic syndromes that are associated with aortic aneurysmal disease affecting patients often at a very early age, including Marfan syndrome, Ehlers–Danlos syndrome, Loeys–Dietz syndrome and familial thoracic aortic aneurysms and dissections.18
The NHS Abdominal Aortic Aneurysm Screening Programme
Phased implementation of the NAAASP began in July 2009. It was introduced after data from a number of studies and existing local screening programmes in England showed a reduction in aneurysm-related mortality when men aged ≥ 65 years were offered ultrasound screening.
The Multicentre Aneurysm Screening Study (MASS) was designed to assess whether or not AAA screening would be beneficial.19 This study enrolled men aged 65–74 years who were randomised to receive screening or not. Extended follow-up of patients confirmed that screening resulted in a reduction in all-cause mortality. Over 13 years there were 224 AAA-related deaths out of the 33,883 participants in the invited group and 381 AAA-related deaths out of the 33,887 participants in the control group, a 42% relative reduction.20
In 2005 this evidence was assessed by the UK National Screening Committee, which concluded that ultrasound screening should be offered to men in their 65th year, with men aged ≥ 65 years being able to self-refer within the NHS.5
The initial outcomes from the NAAASP in England identified a lower prevalence of AAA than reported in the MASS (1.4% vs. 4.7%). However, in the MASS, men aged 65–74 years were included, whereas the NAAASP invites men in their 65th year only for screening.
Between 2009 and 31 March 2014 the NAAASP had scanned > 700,000 men and referred > 1000 men with a large AAA for surgery. In the period 2013–14, 491 of the screened men had an elective AAA repair and four of these men died (an elective repair mortality rate of 0.8%). In addition, seven of the 10 screened men who suffered aneurysmal rupture died (a rupture mortality rate of 70%).21
Because of the NAAASP a greater number of patients with a small AAA are being detected and, if there were effective treatments to slow AAA growth, this could provide an opportunity to intervene before the AAAs expand significantly and rupture. Also, the NAAASP potentially provides a useful pool of patients for research purposes, not only for logistical reasons but also because this group of patients (who were previously unaware of their AAA) may be receiving less clinical/medical intervention than patients who are already receiving monitoring for their AAA. They are therefore of particular interest for interventional studies.
Current guidelines for the management of small abdominal aortic aneurysms
Given the variability in aneurysm expansion rates,22 the optimal interval between surveillance scans remains uncertain. Meta-analysis of small AAA growth rates has demonstrated that the screening interval should be dependent on diameter and that long intervals between screening may be safe for the majority of patients.23 However, guidelines must balance the need to reduce the cost of surveillance programmes and the need to ensure safety, as well as increasing the face-to-face time for direct cardiovascular risk factor education.
The UK guidelines recommend that rescreening intervals should shorten as the aneurysm enlarges and these guidelines are expected to be updated in 2017.24 Usual clinical practice in the UK, and for those patients in the NAAASP, involves follow-up surveillance imaging at 12-monthly intervals for patients with an AAA of 3.0–4.4 cm in diameter and at 3-monthly intervals for those patients with an AAA diameter between 4.5 cm and 5.4 cm.
Abdominal aortic aneurysm treatment
In both the USA and the UK, elective surgery by either open or endovascular repair is undertaken to prevent AAA rupture and this is generally recommended for patients with an AAA of ≥ 5.5 cm in diameter, for symptomatic aneurysms or for aneurysms that have increased by > 0.5 cm in the past 6 months. The UK Small Aneurysm Trial (UKSAT) demonstrated that the overall mortality of patients with an aneurysm of < 5.5 cm in diameter who received surveillance was similar to that in patients who received early open surgery.22 Furthermore, surveillance was the more cost-effective option. Subsequent studies that have randomised patients to surveillance or endovascular treatment of AAAs have corroborated this finding.25,26 There has been an increasing trend in the proportion of repairs performed as endovascular aneurysm repair (EVAR) procedures, increasing from 54% in 2009 to 66% in 2013.27
Studies indicate that without surgery the 5-year survival rate for patients with an aneurysm of diameter > 5 cm is about 20%.28 Surgery to replace the aneurysmal segment or endovascular placement of a covered stent graft excluding the aneurysm is recommended if the risk of aneurysm rupture is high enough to justify the risk of surgery. The rate of rupture of an aneurysm rises exponentially after it reaches 5.5 cm in size, justifying the need for repair in most patients as aneurysm rupture is associated with a high mortality rate. Approximately half of the patients with a ruptured AAA fail to reach hospital and, of those patients who undergo emergency surgery, there is a 35–40% mortality rate at 30 days.29
Open surgical repair carries a significant risk of perioperative morbidity and mortality. The 2014 National Vascular Registry report stated that, over the 5 years between 2009 and 2013, in-hospital mortality for open repairs was 3.6%.27 The less-invasive EVAR technique has significantly lowered perioperative morbidity and mortality rates27 but not all patients are anatomically suitable for EVAR and there is still debate regarding the long-term benefits of EVAR. Several trials, including the EVAR,30 DREAM (Dutch Randomized Endovascular Aneurysm Repair)31 and OVER (Open Versus Endovascular Repair)32 trials, have found that the advantage of EVAR over open repair is lost during mid-term follow-up, with survival rates beyond 2 years being similar in both groups.
Given the risks involved with AAA repair, strategies to reduce the need for surgery are needed. Currently, there are no clear recommendations on pharmacological treatment approaches to prevent aneurysm progression or reduce the risk of rupture.33
Growth rates of small abdominal aortic aneurysms
The growth rate of AAAs is highly variable both between patients and in the same patient over time. Average growth rates increase as the aneurysm enlarges. The average growth rate for a 3.5-cm aneurysm is estimated at 1.90 mm per year, whereas that for a 4.5-cm aneurysm is 3.52 mm/year. Therefore, given an exponentially increasing aneurysm diameter, it would take an average of 6.2 years for a 3.5-cm aneurysm to grow to 5.5 cm, whereas a 4.5-cm aneurysm would grow to 5.5 cm in 2.3 years.34 These growth rates highlight the need for very accurate measurements of AAA to be obtained in a trial setting.
In the UKSAT, AAA growth was most strongly associated with diameter at baseline22 and smoking was associated with an incrementally increased growth rate of 0.4 mm per year. Multivariate analysis of other potential risk factors demonstrated that the presence of peripheral arterial disease (adversely) or diabetes (beneficially) influenced AAA growth.
The risk factor profile for aneurysm growth has been reproduced in other studies, with AAA growth being increased in smokers8,35 and decreased in patients with diabetes.36
Average baseline diameters and growth rates reported in the Western Australia screening study,37 MASS,19 Propranolol Aneurysm Trial,7 UKSAT22 and Second Manifestation of ARTerial disease study38 are shown in .
Average baseline diameters and growth rates from the Western Australia Screening study, MASS, Propranolol Aneurysm Trial, UKSAT and SMART study
Rupture rates of small abdominal aortic aneurysms
Aneurysm size is one of the strongest predictors of the risk of rupture, with risk increasing considerably for aneurysm diameters of > 5.5 cm. The UKSAT reported the risk of rupture for AAAs up to 5.5 cm in diameter to be < 1 per 100 person-years in men and 3 per 100 person-years in women.39
Similarly, the 5-year overall cumulative rupture rate of incidentally diagnosed AAAs in population-based samples is 25–40% for aneurysms of > 5.0 cm diameter and 1–7% for aneurysms of 4.0–5.0 cm in diameter.40,41
Rupture rates have been found to be doubled in current smokers compared with ex-smokers or non-smokers (p = 0.001) and to increase with mean arterial pressure (per 10 mmHg) (p = 0.001).42
Blood pressure and abdominal aortic aneurysms
Raised BP was the leading risk factor contributing to the overall global burden of disease in 2010.43 The recent decrease in case fatality rates associated with acute cardiovascular events in high-income countries has been associated with a rise in the numbers of patients living with cardiovascular disease and the wider use of preventative drugs in the context of primary and secondary prevention.
An association between hypertension and the incidence of AAA is frequently cited.12,44 The CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) study used linked electronic health records to assemble a cohort of > 1 million patients aged ≥ 30 years and initially free from cardiovascular disease, one-fifth of whom received BP-lowering treatments.36
Of all cardiovascular diseases, AAA had the strongest association with DBP [hazard ratio (HR) per 10 mmHg 1.45, 95% confidence interval (CI) 1.34 to 1.56] and mean arterial pressure (HR 1.61, 95% CI 1.48 to 1.75) and the weakest association with systolic BP (SBP) (HR 1.08, 95% CI 1.00 to 1.17). Furthermore, it was the only cardiovascular outcome for which the association with higher pulse pressure was reversed (HR 0.91, 95% CI 0.86 to 0.98).36
However, mean baseline BP levels reported in several large AAA surveillance studies7,19,22,37 () are all above what is currently considered as controlled (< 140/90 mmHg45) and the AAA growth rates observed in these studies (see ) may at least in part be related to these higher BPs.
Mean baseline BPs reported in the Western Australia Screening study, MASS, Propranolol Aneurysm Trial and UKSAT
Despite the relatively strong association between hypertension and the prevalence of AAA, the association between increased BP and the rate of AAA growth or incidence of rupture is not clear and the evidence supporting increased growth as a result of hypertension is lacking.
Non-pharmacological treatments to reduce the growth and rupture rate of abdominal aortic aneurysms
There is clear observational evidence that smoking increases the likelihood of developing an AAA.11,12,46 For example, in the large (n = 114,567) Aneurysm Detection and Management (ADAM) screening study, a history of ever smoking was associated with an odds ratio of 2.97 (95% CI 2.65 to 3.32) for 3.0- to 3.9-cm AAAs and 5.07 (95% CI 4.13 to 6.21) for ≥ 4-cm AAAs.46 In addition, a recent prospective population-based study of 92,728 men in Oxfordshire found that men aged 65–74 years who were current smokers had a 3% 10-year risk of acute AAA, highlighting the need for screening campaigns to reach this high-risk group.47
Furthermore, several studies8,15,17 and meta-analyses48 have found higher growth rates in current smokers than in past smokers.
Consequently, the standard non-pharmacological treatment for AAA is smoking cessation. However, it has been suggested that smoking cessation may lose some of its importance once significant aortic dilatation has occurred.35
Pharmacological treatments to reduce the growth and rupture rate of abdominal aortic aneurysms
There remains a significant need to find medical therapies that could reduce the growth and rupture rates of small and medium-sized AAAs.
As well as interest in the development of new AAA-specific treatments, there has also been interest in assessing the impact of treatments already in use for other indications. Early evidence often arises from animal studies but a small number of RCTs in humans have been carried out to assess the efficacy of some of the currently available drugs.
Beta-blockers
Evidence that the use of beta-blockers might reduce the growth of AAAs first arose from animal studies.49,50 However, a placebo-controlled RCT including 548 patients failed to find an association between beta-blocker use and a significant reduction in AAA expansion.7 Compliance with the medication was a problem, with 117 of 276 (42%) randomised to propranolol and 73 of 272 (27%) allocated to placebo stopping the drugs because of side effects. Furthermore, the increase in AAA diameter was similar in both the propranolol group and the placebo group (2.2 and 2.6 mm per year, respectively; p = 0.11) based on an intention-to-treat (ITT) analysis. Patients receiving propranolol also reported a significantly worse quality of life, leading the authors to conclude that the drug did not affect the growth rate of small AAAs and patients with AAAs do not tolerate propranolol well. Similarly, no protective association was observed for beta-blockers in a large observational study of patients with an AAA.6
Statins
The evidence supporting the use of statins for the reduction of growth and rupture rates in AAA is inconsistent. The UK Heart Protection Study (UKHPS) compared simvastatin with placebo for the reduction of cardiovascular events over a mean of 5 years in 20,536 patients with vascular disease or at high risk of vascular disease at baseline.51 This included 6748 patients with peripheral artery disease. The study reported that the requirement for AAA repair was unaffected (1.2% in both groups). The Tromsø study related statin prescription to the development of AAAs in 4345 subjects who were scanned over 7 years.44 The use of statins was associated with an increased risk of developing an AAA.
Contrary to the UKHPS51 and Tromsø study,44 a systematic review in 2008 found that statin use was associated with reduced growth rates of AAAs.52 This included two cohort studies that both showed reduced growth rates in patients taking statins.53,54 Evidence suggesting that statins may be of benefit was also presented in a population-based combined case–control and follow-up study, which found that statin use was associated with a reduced risk of ruptured AAA and lower case fatality following ruptured AAA.55
Despite inconsistent evidence, current guidelines recommend statin therapy in patients diagnosed with an AAA because of their high cardiovascular risk.1
Doxycycline
Doxycycline was investigated as a treatment for AAA as a result of the theory that chlamydia or related infections might be involved in AAA formation and growth.56 However, clear evidence for the role of infection in the progression of AAAs is limited with small antibiotic trials showing no difference in expansion rate.57
More recent studies have investigated the effects of doxycycline as an inhibitor of matrix metalloproteinases. Matrix metalloproteinases are thought to play a role in the destruction of elastin and collagen in the aortic wall, leading to degeneration, and several matrix metalloproteinases have been detected in AAAs, importantly in greater proportions at the site of rupture.58–60 Doxycycline has been found to inhibit aneurysm development and progression in numerous animal models.61–63 A small randomised pilot trial (n = 32) in patients with small AAAs found that the AAA expansion rate in the doxycycline group was significantly lower than that in the placebo group during both the 6- to 12-month period and the 12- to 18-month period.64 However, a recent larger randomised trial (n = 286) found that 18 months of doxycycline therapy did not reduce aneurysm growth or influence the need for AAA repair or time to repair.55 Nevertheless, the results of this trial are being challenged in a new American trial, the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (NTA3CT), using transverse aorta CT measurements of AAA growth (NCT01756833). Trials incorporating other protease inhibitors are also expected in the near future.
The role of the renin–angiotensin system
The renin–angiotensin system (RAS) is a peptidergic hormone system that has been recognised to be highly involved in disturbances of the cardiovascular system. RAS blockade by ACE-Is and ARBs has been found to not only decrease arterial pressure but also prevent or reverse endothelial dysfunction and aspects of the atherosclerotic process, which results in a reduction in cardiovascular mortality and morbidity.65,66
In experimental studies both angiotensinogen and angiotensin type 1 receptors have been found to be upregulated by approximately twofold in the walls of AAAs compared with the walls of atherosclerotic aortas, although the expression of angiotensin type 2 receptors was similar.67 In hypercholesterolaemic mice, angiotensin II infusion induces medial dissection of the aorta proximal to aortic branch points, with subsequent formation of suprarenal aortic aneurysms, which can be prevented with the use of ACE-Is.68
Furthermore, in a recent study, perindopril (Coversyl arginine, Servier) inhibited aortic degeneration and AAA formation in the experimental AAA model induced by elastase and calcium chloride.69
Angiotensin-converting enzyme inhibition
In line with the animal studies that have suggested a potential role of the RAS system in AAA formation and growth, an observational case–control study on a group of > 15,000 patients with AAAs found that patients who received an ACE-I before admission were 20% less likely to present with a ruptured aneurysm.6 These results remained after adjustments were made for demographic characteristics, comorbidities, contraindications to ACE-Is, measures of health-care use and aneurysm screening. The group noted that the reduction in risk of aortic rupture was distinct from antihypertensive and other medications, suggesting that the mechanism may not be related to a BP-lowering effect. Calcium channel blockers (CCBs) and beta-blockers, for example, were not associated with any reduction in risk.6 This large-scale study demonstrated an impressive reduction in AAA rupture but there were several potential confounders in this study, not least the compliance with ACE-Is in smokers.
In addition, a recent cohort study of 21,791 patients with AAA identified from Danish registries suggested that treatment with ACE-Is or ARBs was associated with a decreased risk of all-cause death and death from AAA in patients who had not yet undergone surgery for AAA.70 However, there was no reduction in the need for surgery for AAA.
When considering growth rate modulation by agents acting on the RAS, the evidence is certainly conflicting. The Chichester small AAA surveillance study suggested an association between ARB prescription and reduced AAA progression.71 However, in contrast, a report from the UK Small Aneurysm Study group reported a small but significant association between ACE-I prescription and increased AAA expansion.72 This significant difference remained after adjustment for known confounders such as smoking, diabetes, BP and peripheral atherosclerosis.
In summary, currently there is no clear or consistent evidence that medication designed to inhibit the RAS limits AAA progression or leads to a decrease in the risk of rupture.
Designing the trial
To date we are unaware (based on a recent literature review) of any other completed RCTs designed to examine the efficacy of ACE-I or ARBs in limiting or inhibiting AAA progression. This report describes the AARDVARK (Aortic Aneurysmal Regression of Dilation: Value of ACE-Inhibition on RisK) trial, which was commissioned by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme to address this need.
Objectives
Secondary
To evaluate any BP-independent effects of perindopril on the growth rate of small AAAs.
To determine differences in AAA rupture rate and/or time taken to reach an AAA diameter of 5.5 cm and/or referral for surgical intervention among the three randomised groups.
To evaluate how well perindopril is tolerated as measured by compliance, adverse events (AEs) and quality of life.
To compare the repeatability of ultrasound measurements of internal and external small AAA diameters.
Later, pending the results of this pilot trial, our objective was to work with local and national aneurysm screening programmes to conduct a larger, more definitive RCT to investigate the hypothesis that the use of an ACE-I reduces the rate of AAA-related mortality, rupture or elective surgery.
