ACE Inhibitors/ARBs for Aortic Stenosis?

Abstract & Commentary

By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationship relevant to this field of study.

Source: Nadir MA, et al. Impact of renin-angiotensin system blockade therapy on outcome in aortic stenosis. J Am Coll Cardiol 2011;58:570-576.

In severe symptomatic aortic stenosis (AS), surgical AVR improves mortality, but there is no medical therapy proven to slow progression of the valvular stenosis. Because AS is accompanied by left ventricular (LV) hypertrophy and fibrosis, and because the risk factors for AS are similar to those for coronary artery disease (CAD), it makes sense that blockade of the renin-angiotensin system may benefit patients with AS. Nadir and colleagues performed a retrospective observational study to address this issue. They linked several databases in the Tayside region of Scotland and were able to ascertain patient level data, including echocardiographic data, mortality, hospital admissions, medications, and laboratory tests. The use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in patients with AS identified by echocardiography was then studied in terms of clinical outcomes.

A total of 2117 patients with AS were identified, 46% were male and the mean age was 73 ± 12 years. Aortic stenosis was mild or moderate in 75%, and severe in 25%. One-third of patients were on ACEI or ARB therapy. There were significant baseline differences between those who received ACEIs or ARBs and those who did not receive them. Those receiving ACEIs or ARBs were older, and had a higher prevalence of LV dysfunction, diabetes, and prior cardiovascular (CV) events. However, they had less severe AS and more of them were receiving aspirin, beta-blockers, digoxin, anti-coagulants, and statins.

After a mean follow-up of 4.2 years, patients taking ACEIs or ARBs had lower mortality and fewer cardiovascular (CV) events. Adjusted hazard ratio [HR] for death was 0.76 (P < 0.0001) and for CV events was 0.77 (P < 0.0001). When stratified by severity of AS, the use of ACEI or ARB therapy was associated with a greater reduction in CV events in patients with severe AS (HR 0.64, P = 0.04) than in mild or moderate AS (HR 0.78, P = 0.01). To confirm these findings, the authors performed a propensity score matched cohort analysis on 532 patients. In this analysis, they also found that the use of ACEI or ARB therapy was associated with a reduction in all-cause mortality (HR 0.67) and CV events (HR 0.71). They also performed a time-scale analysis (Kaplan Meier) that confirmed these results. Importantly, for those patients in whom on-treatment blood pressure recordings were available (330 patients), there was no difference in systolic or diastolic blood pressure between groups. The authors conclude that this large observational study suggests ACEI or ARB therapy is associated with an improved survival and a lower risk of CV events in patients with AS.

Commentary

Arterial vasodilators have long been relatively contraindicated in patients with severe LV outflow obstruction. Several medications, including ACEIs, have failed to prevent progression of AS severity in clinical trials. This dataset from Nadir and colleagues is intriguing because they did not study the severity of the valve disease, but instead chose to study clinical events in AS patients. They demonstrate a striking reduction in CV events and death in patients taking ACEIs or ARBs, and this reduction in CV events was greater in those with more severe AS. The mechanism of the benefit is not immediately clear. It may relate to protection against myocardial fibrosis and hypertrophy, which are arrhythmogenic substrates. Alternatively, it may reduce vascular events, such as myocardial infarction. It is important to recognize that there were significant differences in baseline characteristics between groups. The authors performed several different statistical analyses that all demonstrated similar findings, which increases the confidence in their results. Despite this rigorous statistical methodology, there are likely to be confounding factors for which their analyses could not account. Therefore, it is important to interpret the data cautiously. However, their data do suggest that ACEIs or ARBs are safe in AS.

In light of these data, should all patients with AS be treated with ACEIs or ARBs? I think it is too soon to make such recommendations. However, if another indication for such a therapy exists, such as concomitant hypertension, then ACEIs or ARBs would be a reasonable choice for an antihypertensive. Future studies into the mechanism of any potential benefit, as well as prospective, randomized, controlled clinical trials are needed before we can recommend ACEIs or ARBs in patients with AS.