The Pivotal Role of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertension Management and Cardiovascular and Renal Protection: A Critical Appraisal and Comparison of International Guidelines

Abstract

Arterial hypertension is the main preventable cause of premature mortality worldwide. Across Latin America, hypertension has an estimated prevalence of 25.5-52.5%, although many hypertensive patients remain untreated. Appropriate treatment, started early and continued for the remaining lifespan, significantly reduces the risk of complications and mortality. All international and most regional guidelines emphasize a central role for renin-angiotensin-aldosterone system inhibitors (RAASis) in antihypertensive treatment. The two main RAASi options are angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Although equivalent in terms of blood pressure reduction, ACEis are preferably recommended by some guidelines to manage other cardiovascular comorbidities, with ARBs considered as an alternative when ACEis are not tolerated. This review summarizes the differences between ACEis and ARBs and their place in the international guidelines. It provides a critical appraisal of the guidelines based on available evidence from randomized controlled trials (RCTs) and meta-analyses, especially considering that hypertensive patients in daily practice often have other comorbidities. The observed differences in cardiovascular and renal outcomes in RCTs may be attributed to the different mechanisms of action of ACEis and ARBs, including increased bradykinin levels, potentiated bradykinin response, and stimulated nitric oxide production with ACEis. It may therefore be appropriate to consider ACEis and ARBs as different antihypertensive drugs classes within the same RAASi group. Although guideline recommendations only differentiate between ACEis and ARBs in patients with cardiovascular comorbidities, clinical evidence suggests that ACEis provide benefits in many hypertensive patients, as well as those with other cardiovascular conditions.

Fig. 1

Mechanism of action for angiotensin-converting enzyme inhibitors (ACEis). ACEis block the conversion of angiotensin I to angiotensin II, thereby blocking its action on multiple different receptors (AT1, AT2, and AT4) involved in vasodilation, vasoconstriction, apoptosis, inflammation, and angiogenesis. ACEi therapy is also associated with an increase in bradykinin levels and bradykinin-mediated stimulation of angiogenesis, which can lead to improved hypoxia-induced neovascularization. ACEi angiotensin-converting enzyme inhibitor, Ang angiotensin, Cox-2 cyclo-oxygenase-2, eNOS endothelial nitric oxide synthase, VEGFR vascular endothelial growth factor receptor

Fig. 2

Mechanism of action for angiotensin receptor blockers (ARBs). ARBs inhibit the binding of angiotensin II to the AT1 receptor, thereby preventing vasoconstriction. However, the increased angiotensin II levels can lead to stimulation of AT2 and AT4 receptors, which can cause inappropriate endothelial apoptosis and release of proinflammatory cytokines. Long-term ARB therapy may also play a role in microvascular rarefaction, cardiac remodeling (including left ventricular hypertrophy), and fibrosis. Ang, angiotensin, ARB angiotensin receptor blocker, Cox-2 cyclo-oxygenase-2, eNOS endothelial nitric oxide synthase, VEGFR vascular endothelial growth factor receptor