Elsevier

The Lancet

Volume 368, Issue 9536, 19–25 August 2006, Pages 659-665
The Lancet

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Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study

https://doi.org/10.1016/S0140-6736(06)69250-7Get rights and content

Summary

Background

Angiotensin-converting enzyme (ACE) inhibitors prevent the expansion and rupture of aortic aneurysms in animals. We investigated the association between ACE inhibitors and rupture in patients with abdominal aortic aneurysms.

Methods

We did a population-based case-control study of linked administrative databases in Ontario, Canada. The sample included consecutive patients older than 65 (n=15 326) admitted to hospital with a primary diagnosis of ruptured or intact abdominal aortic aneurysm between April 1, 1992, and April 1, 2002.

Findings

Patients who received ACE inhibitors before admission were significantly less likely to present with ruptured aneurysm (odds ratio [OR] 0·82, 95% CI 0·74–0·90) than those who did not receive ACE inhibitors. Adjustment for demographic characteristics, risk factors for rupture, comorbidities, contraindications to ACE inhibitors, measures of health-care use, and aneurysm screening yielded similar results (0·83, 0·73–0·95). Consistent findings were noted in subgroups at high risk of rupture, including patients older than 75 years and those with a history of hypertension. Conversely, such protective associations were not observed for β blockers (1·02, 0·89–1·17), calcium channel blockers (1·01, 0·89–1·14), α blockers (1·15, 0·86–1·54), angiotensin receptor blockers (1·24, 0·71–2·18), or thiazide diuretics (0·91, 0·78–1·07).

Interpretation

ACE inhibitors are associated with a reduced risk of ruptured abdominal aortic aneurysm, unlike other antihypertensive agents. Randomised trials of ACE inhibitors for prevention of aortic rupture might be warranted.

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

References (59)

  • M Mamdani et al.

    Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study

    Lancet

    (2004)
  • PC Austin et al.

    A multicenter study of the coding accuracy of hospital discharge administrative data for patients admitted to cardiac care units in Ontario

    Am Heart J

    (2002)
  • AB Wilmink et al.

    Effectiveness and cost of screening for abdominal aortic aneurysm: results of a population screening program

    J Vasc Surg

    (2003)
  • MW Claridge et al.

    ACE inhibitors increase type III collagen synthesis: a potential explanation for reduction in acute vascular events by ACE inhibitors

    Eur J Vasc Endovasc Surg

    (2004)
  • ST MacSweeney et al.

    Smoking and growth rate of small abdominal aortic aneurysms

    Lancet

    (1994)
  • FA Lederle et al.

    The Aneurysm Detection and Management Study Screening Program: validation cohort and final results

    Arch Intern Med

    (2000)
  • RC Darling et al.

    Autopsy study of unoperated abdominal aortic aneurysms. The case for early resection

    Circulation

    (1977)
  • MJ Bown et al.

    A meta-analysis of 50 years of ruptured abdominal aortic aneurysm repair

    Br J Surg

    (2002)
  • EF Steinmetz et al.

    Prospects for the medical management of abdominal aortic aneurysms

    Vasc Endovascular Surg

    (2003)
  • DS Jacoby et al.

    Renin-angiotensin system and atherothrombotic disease: from genes to treatment

    Arch Intern Med

    (2003)
  • A Daugherty et al.

    Angiotensin II and abdominal aortic aneurysms

    Curr Hypertens Rep

    (2004)
  • M Ihara et al.

    Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta

    Hypertension

    (1999)
  • K Tsunemi et al.

    Possible roles of angiotensin II-forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta

    Hypertens Res

    (2002)
  • A Slowik et al.

    II genotype of the angiotensinconverting enzyme gene increases the risk for subarachnoid hemorrhage from ruptured aneurysm

    Stroke

    (2004)
  • M Keramatipour et al.

    The ACE I allele is associated with increased risk for ruptured intracranial aneurysms

    J Med Genet

    (2000)
  • K Takenaka et al.

    Angiotensin I-converting enzyme gene polymorphism in intracranial saccular aneurysm individuals

    Neurol Res

    (1998)
  • K Takeuchi et al.

    High incidence of angiotensin I converting enzyme genotype II in Kawasaki disease patients with coronary aneurysm

    Eur J Pediatr

    (1997)
  • MJ Osborne-Pellegrin et al.

    Induction of aneurysms in the rat by a stenosing cotton ligature around the inter-renal aorta

    Int J Exp Pathol

    (1994)
  • W Huang et al.

    Protection of the arterial internal elastic lamina by inhibition of the renin-angiotensin system in the rat

    Circulation Res

    (1998)
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