Fast track — ArticlesAngiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study
Introduction
Abdominal aortic aneurysms develop in 4–8% of men and 0·5–1·5% of women older than 50 years.1, 2 The most catastrophic complication of this condition is rupture, which in the past occurred in up to a third of patients left untreated.3 After rupture, 50% of patients die before reaching hospital.4 Of the remainder, 24% die before surgery and 42% die after surgery, with a total mortality of 80–90%.5, 6 Elective surgical repair of unruptured abdominal aortic aneurysm carries a lower mortality rate (about 5%) but the overall rate of complications is 32%.7 To date, no medical treatment has been shown to prevent aortic rupture or forestall the need for surgical repair.8
Activation of the renin-angiotensin system has been implicated in the genesis of several important cardiovascular pathologies, including heart failure, hypertension, and atherosclerosis.9 Emerging evidence also links the renin-angiotensin system to the development of aortic aneurysms.10 Angiotensin II is strongly upregulated in human aortic aneurysms, with increases mediated through pathways dependent on angiotensin-converting-enzyme (ACE) and chymase.11, 12, 13 In genetic studies, polymorphisms at the ACE locus are associated with aortic, coronary, and cerebral aneurysms.14, 15, 16, 17, 18, 19 Data from studies in animals also suggest that ACE inhibitors might slow the progressive course of aortic aneurysms. In several animal models, ACE inhibitors prevented aortic expansion and rupture.20, 21, 22, 23, 24, 25 Such protective effects were not apparent for angiotensin receptor blockers, hydralazine, calcium channel blockers, or spironolactone, suggesting that the mechanism involved might not be related to reduction of blood pressure.21, 22, 23, 24, 25, 26, 27
We postulated that treatment with ACE inhibitors alters the risk of aortic aneurysm rupture in a population-based setting. We compared patients with ruptured and unruptured aortic aneurysm according to antecedent use of ACE inhibitors, taking into account important confounding factors. We tested for specificity by analysing the use of other antihypertensive and non-antihypertensive medications to ascertain whether the findings with ACE inhibitors were unique or were shared with other medications. We tested for selection bias by using a parallel cohort analysis and comparing the incidence of several important health-related outcomes in patients receiving and not receiving an ACE inhibitor.
Section snippets
Setting and data sources
We designed a retrospective, population-based, case-control study by linking several administrative health-care databases over 10 years in the province of Ontario. Throughout the study, Ontario was Canada's most populous province, with about 12 million people, of whom 1·6 million were aged 65 years or older. Elderly patients in Ontario had universal access to hospital care, doctors' services, and prescription drug coverage. Additionally, health-care records could be analysed using encrypted
Results
15 326 patients with abdominal aortic aneurysm were admitted to 231 hospitals during the 10-year accrual period. Of the sample, 22% had ruptured aneurysms and 78% had intact aneurysms (table 1). Overall, the mean age was 75 years (SD 6), and 78% of the patients were men. Contraindications to ACE inhibitor treament were rare (all ≤2%). Indications for ACE inhibitors were balanced between the two groups but, as expected, controls were more likely to have undergone abdominal imaging or surgical
Discussion
We showed that ACE inhibitors were associated with a reduced risk of rupture in patients who have abdominal aortic aneurysms. This association was maintained after adjustment for measured confounders, was robust in sensitivity analyses of different agents and doses, and was consistent across predefined patient subgroups. Moreover, the relation between ACE inhibitors and aortic rupture was distinct and was not apparent for other antihypertensive medications or for drugs linked to preventive
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