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Controlling the expansion of abdominal aortic aneurysms

The prevalence of aneurysmal disease is increasing and in the UK it accounts for more than 8000 deaths annually. Most deaths are due to rupture of previously undetected asymptomatic aneurysms, an event that is associated with an overall mortality rate of approximately 80 per cent. The Multicentre Aneurysm Screening Study (MASS)1 recently reported the results of a trial that randomized 67 800 men aged 65–74 years to an invitation to aneurysm screening or to a non-invited control group. Eighty per cent of the invited group attended for screening and 4·9 per cent of those scanned had an abdominal aortic aneurysm (AAA); receipt of a screening invitation reduced the aneurysmrelated mortality rate by 42 per cent. Routine screening programmes for AAA therefore seem justified. The rationale for surgical management of a large AAA has been outlined previously2–4, and trials are under way to assess the place of endovascular treatment. However, data from the MASS suggest that the management of small (3·0–5·5 cm diameter) AAAs requires further evaluation, as 88 per cent of screen-detected lesions were below the threshold for elective surgical repair. Current management of patients with a small AAA depends on serial ultrasonographic surveillance to document aneurysm expansion until the threshold for operative repair is reached. Although some progress has been made in identifying patients at risk of rapid aneurysm expansion by correlating biological markers of aneurysm growth with expansion rates, these markers are still at the preliminary investigation stage. On average, aneurysms expand at 10 per cent of their diameter per year. Most patients with a small AAA progress to surgery (61 per cent in the UK Medical Research Council’s Small Aneurysm Trial3), and so a treatment strategy for small AAAs is clearly desirable. In recent years the concept of pharmacotherapy has evolved, with the aim of reducing the expansion and rupture rates of aortic aneurysms. Effective pharmacotherapy could be used to reduce the need for surgery in patients with small lesions, to reduce rupture rates in those with larger aneurysms denied surgery owing to medical co-morbidity, and to reduce aortic neck expansion following endovascular or conventional aneurysm repair. The medical treatment of aneurysm expansion has two facets, modifying known risk factors for aneurysm expansion and specific pharmacotherapy targeted towards the aneurysmal process itself. Established associations with aneurysm expansion and rupture include smoking and hypertension. Clearly, these factors should be targeted in every patient with an AAA. An effective pharmacological strategy to reduce expansion involves the biological processes driving aneurysm growth; in recent years these processes have become better understood5. Aneurysm formation is characterized by degradation of the extracellular matrix, a ubiquitous inflammatory infiltrate, and excessive proteolysis. Loss of elastin from the arterial media occurs early in aneurysm formation, with a consequent inability to resist the tensile stress of the circulation and subsequent compensatory collagen deposition. The loss of elastin is mediated by excessive secretion of proteases, particularly matrix metalloproteinases (MMPs), from the activated inflammatory infiltrate. The inflammatory and proteolytic processes appear to be the dominant mechanisms controlling aneurysm expansion, acting in conjunction with other less well characterized mechanisms, including haemodynamic stress, infection and autoimmunity. Most of these pathological systems have been suggested as targets for pharmacotherapy, and such intervention has been tested successfully in a variety of in vitro and in vivo models. Extrapolation from these models to the clinical situation is difficult as there is no spontaneous model of aneurysm formation, but several contemporary studies have reported the results from clinical trials. Early interest in the medical control of dilatation concentrated on β-blockers, which could potentially both reduce blood pressure and stabilize the cross-linkage of elastin in the aorta. Retrospective series suggested that this approach was associated with a reduced aneurysm growth rate, but a randomized trial showed no benefit from propranolol therapy and poor compliance (68 per cent) with treatment6. More promising results were obtained when the inflammatory process in the aortic wall was targeted. Experimental studies have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the secretion of inflammatory mediators from the aorta. A non-randomized analysis in patients with a small AAA taking NSAIDs revealed a reduction in median aneurysm growth from 3·2 to 1·5 mm per annum7. An alternative approach to