Toronto, ON - New observational data have shown that the use of ACE inhibitors is associated with a reduced risk of ruptured abdominal aortic aneurysm [1]. The relationship between ACE-inhibitor use and aortic rupture was not apparent for other antihypertensive medications or for other drugs, such as lipid-lowering agents or drugs for osteoporosis, used in preventive health care.

Dr Daniel Hackam

"There are about four or five direct studies in animals that suggested ACE inhibitors, but not other antihypertensive agents, prevent aortic aneurysm rupture," lead investigator Dr Daniel Hackam (University of Toronto, ON) told heartwire. "The mechanism seems to be that angiotensin II has a direct toxic effect on the wall of large arteries, causing dilatation and fragmentation of elastin and underlying connective tissue. By blocking angiotensin II production, it is possible that the ACE inhibitors are turning off that process. This is preliminary human confirmation of that animal data."

In addition to the animal studies, Hackam pointed out that in several genetic studies, polymorphisms at the ACE gene are associated with aortic, coronary, and cerebral aneurysm. He added that for abdominal aortic aneurysms the main treatment option available is surgical repair, which carries an approximate 5% mortality rate and 32% complication rate. Less-invasive treatment with endovascular repair also carries similar mortality risks. "There is a real need to be able to stabilize aortic aneurysms medically, because a lot of these patients are too sick for surgery," said Hackam.

In an accompanying editorial published with the study, Drs Nicolas Diehm and Iris Baumgartner (University Hospital Bern, Switzerland) echo the need for medical therapy to treat aortic aneurysms [2]. "It seems that patients and doctors are still waiting for aneurysms to rupture or to become large enough to justify surgical or endovascular repair," they write.

The results of the study and the editorial are published in the August 19, 2006 issue of the Lancet.

To investigate the association between ACE inhibitors and aortic rupture, investigators in this retrospective, population-based, case-control study examined several linked administrative databases over 10 years in Ontario, Canada. The sample included 15 326 consecutive patients >65 years old admitted to the hospital with a primary diagnosis of ruptured or intact abdominal aortic aneurysm between 1992 and 2002.

Of the patients with abdominal aortic aneurysm admitted to the hospital during the study period, 22% had ruptured aneurysms and 78% had intact aneurysms. Overall, 3426 patients, including 665 patients with ruptured aneurysms and 2761 of those with intact aortas, were treated with an ACE inhibitor. Patients treated with an ACE inhibitor had a significant 18% lower risk of aortic rupture compared with patients not treated with an ACE inhibitor. After adjustment for demographic characteristics, risk factors for rupture, other comorbidities, contraindications, measures of healthcare use, and screening, the results were similar.

Hackam noted that the reduction in risk of aortic rupture was distinct from antihypertensive and other medications, suggesting the mechanism is not related to a blood-pressure-lowering effect. Calcium-channel blockers and beta blockers, for example, said Hackam, were not associated with any reduction in risk. The study also showed that patients who were prescribed ACE inhibitors but discontinued the drugs before admission were not protected from aortic rupture. ACE-inhibitor therapy also showed a protective association across various prespecified subgroups, as well as similar protection for the three most commonly prescribed ACE inhibitors (enalapril, lisinopril, and ramipril).

Although investigators did not measure smoking status, they note that it was unlikely smoking influenced the results. Among those with ruptured or intact aortic aneurysm, there were similar rates of emphysema and respiratory disease, likely indicating similar baseline smoking status between the two groups. As noted in the editorial and related to heartwire by Hackam, many of the patients in the case-control series were undertreated. Only 16% were taking lipid-lowering medications, and only 22% were taking ACE inhibitors, despite the existence of underlying coronary artery disease in approximately one third of patients.

"As this is an observational study, it does not prove that ACE inhibitors prevent aortic aneurysm rupture," said Hackam. "We need a randomized, controlled study to say that. But we think that this paper really paves the way, on the shoulders of the animal studies, toward a randomized, controlled trial. We also think the data really support the guidelines released in the past year by the AHA [American Heart Association] and by the Canadian Journal of Cardiology suggesting that patients with aortic aneurysm should have very aggressive management of cardiovascular risk. ACE inhibitors are probably a cornerstone of that management."