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Inhibition of the renin–angiotensin system (RAS) is currently considered as an established strategy for cardiovascular prevention, and indeed, RAS inhibitors are widely used in patients with cardiovascular disease or those at high risk of cardiovascular events. ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are two major classes of RAS inhibitors. There remain two important controversies regarding the effects of RAS inhibitors; one question is whether RAS inhibitors have anti-atherosclerotic effects beyond lowering blood pressure. Accumulated evidence demonstrates that the benefit of RAS inhibition is most prominent in patients with heart failure or those who have suffered from myocardial infarction (MI), suggesting that RAS inhibitors prevent cardiovascular events and improve outcomes in patients with cardiac injury and/or dysfunction. However, less evidence is available about cardiovascular risk reduction by RAS inhibitors independent of their blood pressure lowering effects in patients with arteriosclerotic diseases or those at a high risk but without cardiac dysfunction. For instance, despite the success of ACEIs and ARBs in inhibiting the progression of accelerated arteriosclerosis in animal models, randomised clinical trials (RCTs) testing ACEIs’ effectiveness in preventing restenosis after percutaneous coronary intervention have mostly failed.1–3 There are also RCTs, such as the ALLHAT and VALUE trials, comparing the occurrence of cardiovascular events between patients on either ACEI or ARB with those on other classes of antihypertensive drugs that have failed to demonstrate a blood pressure-lowering-independent cardiovascular preventive effect of RAS inhibitors. Thus, it is often difficult to predict the clinical significance of molecular and cellular mechanisms and the clinical benefits of theoretically effective treatments.
The other important question is whether ACEIs and ARBs have equivalent effectiveness in preventing cardiovascular events. Data from basic research have shown the complexity of the RAS and the effects of RAS inhibition, which aroused our interest in the difference between ACEIs …
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