ACE Inhibitors and Angiotensin Receptor Blockers for the Primary and Secondary Prevention of Cardiovascular Outcomes: Recommendations from the 2024 Egyptian Cardiology Expert Consensus in Collaboration with the CVREP Foundation

Abstract

Introduction

The renin–angiotensin–aldosterone system (RAAS) plays a pivotal role in regulating blood pressure (BP), with dysregulation of RAAS resulting in hypertension and potentially heart failure (HF), myocardial infarction (MI), cardio-renal syndrome, and stroke. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), have advantages beyond BP control. However, differences between these two drug classes need to be considered when choosing a therapy for preventing cardiovascular events.

Methods

A panel of 36 Egyptian cardiologists developed consensus statements on RAAS inhibitors for primary and secondary prevention of cardiovascular outcomes and stroke, using a modified three-step Delphi process.

Results

The consensus statements highlight the importance of effective BP control and the role of RAAS blockade for prevention and management of various cardiovascular diseases. ACEis and ARBs differ in their mode of action and, thus, clinical effects. On the basis of available evidence, the consensus group recommended the following: ACEis should be considered as first choice (in preference to ARBs) to reduce the risk of MI, for primary prevention of HF, and for secondary prevention of stroke. ACEis and ARBs show equivalent efficacy for the primary prevention of stroke. Evidence also favors the preferential use of ACEis in patients with type 2 diabetes, for BP control, for the primary prevention of diabetic kidney disease, and to reduce the risk of major cardiovascular and renal outcomes. Treatment with an ACEi should be started within 24 h of ST segment elevation MI (and continued long term) in patients with HF, left ventricular systolic dysfunction, and/or diabetes. Angiotensin receptor/neprilysin inhibitors (ARNIs) are the first choice for patients with HF and reduced ejection fraction, with ACEis being the second choice in this group. ARBs are indicated as alternatives in patients who cannot tolerate ACEis. ACEis may be associated with cough development, but the incidence tends to be overestimated, and the risk can be reduced by use of a lipophilic ACEi or combining the ACEi with a calcium channel blocker.

Conclusion

RAAS blockade is an essential component of hypertension therapy; however, the protective effects provided by ACEis are superior to those of ARBs. Therefore, an ACEi is indicated in almost all cases, unless not tolerated.

Plain Language Summary

Overstimulation of the renin–angiotensin–aldosterone system—a key regulator of blood pressure, and fluid and electrolyte balance—is known to cause an increase in blood pressure (also known as “hypertension”) and other diseases of the heart and blood vessels (the cardiovascular system). As such, treatments to block (or inhibit) this overstimulation are an essential part of medical strategies designed for the prevention of cardiovascular disease, especially in patients with hypertension (in whom the risk of death due to cardiovascular causes is high). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are two types of medication that block overstimulation of the renin–angiotensin–aldosterone system, but they work in different ways. Angiotensin-converting enzyme inhibitors are superior to angiotensin receptor blockers after heart attacks (acute myocardial infarction), in patients with heart failure, for the prevention of stroke in individuals who have already had a stroke, and in patients with diabetes. Both types of medication have beneficial effects on the kidneys and associated outcomes, but only angiotensin-converting enzyme inhibitors have been shown to significantly reduce death due to cardiovascular causes, as well as death due to any cause. Overall, the protective effects of angiotensin-converting enzyme inhibitors on the heart are substantially greater than those of angiotensin receptor blockers, meaning that treatment with an angiotensin-converting enzyme inhibitor is preferred in all patients, except those who cannot tolerate the side effects of this drug class.

Key Summary Points

Why carry out this study?

The aim of the consensus meeting was to develop statements from a group of Egyptian cardiology experts (in collaboration with the CVREP Foundation) on renin–angiotensin–aldosterone system (RAAS) inhibition for the primary and secondary prevention of cardiovascular outcomes and stroke.

Both angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are potential options for RAAS inhibition, but these agents have different mechanisms of action and, therefore, differ in their cardioprotective effects.

What was learned from the study?

ACEis are superior to ARBs after acute myocardial infarction, in patients with heart failure with reduced ejection fraction, for the secondary prevention of stroke, and in patients with diabetes mellitus.

Both classes of agent have beneficial effects on renal outcomes, but an ACEi is preferred over an ARB due to the additional cardiovascular risk reduction.

Only ACEis have been shown to significantly reduce both cardiovascular and all-cause mortality.

Introduction

Hypertension is a leading cardiovascular risk factor, with more than 10 million deaths worldwide attributed to hypertension [1]. Hypertension is also responsible for a substantial number of disability-adjusted life years, and therefore has a huge economic burden on healthcare systems [1, 2]. Renin–angiotensin–aldosterone system (RAAS) blockade has long been a cornerstone of antihypertensive drug therapy, both for reducing blood pressure (BP) and protecting against hypertension-mediated target organ damage. Agents that block the RAAS include angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), direct renin inhibitors, aldosterone antagonists, and angiotensin receptor/neprilysin inhibitors (ARNis; valsartan/sacubitril). Of these, ACEis and ARBs are the mainstay of hypertension management, and valsartan/sacubitril seems to be reserved for treating heart failure (HF) [3]. However, these two drug classes achieve RAAS inhibition via different mechanisms of action. Therefore, it is important to understand the comparative efficacy, cardiovascular protection, and side effects of these two classes of molecules. A choice needs to be made about which to use because the combination of an ACEi and an ARB is not recommended by clinical guidelines [4].

International Society of Hypertension (ISH) guidelines now recommend initiating antihypertensive therapy with combination therapy with a dihydropyridine calcium channel blocker (CCB) plus an ACEi or ARB [5]. However, the choice between an ACEi or ARB is left to the physician according to treatment availability, cost, patient characteristics, and tolerability. ISH guidelines note that comparative randomized controlled trials (RCTs) with ACEis and ARBs differ in their patient populations [5]. Most RCTs make pairwise comparisons between one single agent and another, which limits the ability of meta-analyses to compare multiple interventions simultaneously [6], and makes it difficult for physicians to determine which class of agent to use in patients with hypertension.

Therefore, to assist physicians with the selection of the most appropriate treatment, a group of Egyptian experts was convened to first review published data on the use of ACEis and ARBs in patients with hypertension (to understand the evidence base supporting each drug class) and then to develop recommendations on the use of ACEis and ARBs for the primary and secondary prevention of cardiovascular events. The aim of the project was to provide physicians with guidance on the choice of ACEi or ARB treatment for individual patients seen in clinical practice.

Methods

Panel Recruitment

The panel consisted of 36 experts (authors of this article), who were mainly consultant cardiologists and were affiliated with academic institutions in Egypt. A non-probability convenient selection process was used to recruit the experts from 10 major academic institutions in the four main regions in Egypt (Greater Cairo, Northern Egypt, Upper Egypt, and Delta region), in collaboration with experts from the Cardiovascular, Research, Education, and Prevention (CVREP) Foundation. All experts participated in three rounds of a modified Delphi process to gain consensus on the use of ACEis and ARBs for the primary and secondary prevention of cardiovascular outcomes and stroke.

The panel was divided into 13 working groups, which summarized current literature focused on the following topics: pathophysiology key differences, qualitative and quantitative BP reduction, effects on cardiovascular events [myocardial infarction (MI), HF, stroke, mortality], special populations (diabetes, renal disease, post-MI, HF), and safety and tolerability.

All panel members were required to sign a disclosure statement before consensus recommendation development.

Consensus Process

Consensus was based on the three-step modified Delphi method, which is a widely accepted strategy for developing consensus recommendations on the basis of objective expert opinion and is intended to provide guidance in areas where limited evidence-based literature is available [7]. It uses a series of voting rounds plus meetings of the expert panel to reach agreement on statements that did not achieve consensus during voting.

The initial survey allowed three possible responses to each statement (agree/neutral/disagree), and experts could abstain from voting on each statement. Consensus was defined as ≥ 80% agreement. After the first round of voting, an expert panel meeting was held to present the voting results and gather experts’ insights on statements that did not reach the consensus level. Where there was a lack of consensus, the statement was discussed and revised until there was ≥ 80% agreement. If the subsequent discussions and revisions could not produce a statement with ≥ 80% agreement, the statement was abandoned. Next, there was a second round of voting, and revised statements were sent out to the experts. The final consensus statements and manuscript were reviewed and approved by all panel members.

Literature Review and Statement Development

The CVREP Foundation recruited a survey development committee for the expert panel to develop the initial statements for the first round of voting. The pre-voting statements were developed on the basis of a PubMed literature search using the following search terms: “angiotensin converting enzyme inhibitors,” “angiotensin receptor antagonists,” “angiotensin receptor blockers,” “hypertension,” “heart failure,” “coronary artery disease,” and “mortality.” Search filters included: published date (January 2000 to September 2022), humans, meta-analysis, review, systematic review, and English language. In addition, the Cochrane database was searched using the following terms: “renin angiotensin inhibitors,” “angiotensin converting enzyme inhibitors,” “angiotensin receptor antagonists,” “coronary artery disease,” “hypertension,” and “heart failure.” Search filters included: published date (since 2004), systematic review, meta-analysis, and English language.

Overall, the searches identified 1493 relevant published papers (Fig. 1). An initial screening for titles and abstracts was performed, and non-relevant papers were excluded, leaving 107 full publications to be reviewed. Another 74 papers were excluded after screening of the full texts, leaving 46 publications for inclusion (31 meta-analyses, 7 systematic reviews, 6 editorials, 1 observational study, and 1 cohort study). Meta-analyses were further categorized as follows: hypertension (12 publications dating back to 2005), HF and high-risk populations (10 meta-analyses and one observational study dating back to 2000), coronary artery disease (CAD; 2 meta-analyses and one cohort study dating back to 2006), and renal/diabetes (7 meta-analyses dating back to 2005).

Fig. 1.

Literature search results and filtering

Compliance with Ethics Guidelines

As this study was classified as a consensus development technique and did not involve research on patients or patients’ data, obtaining approval from an ethics committee or internal review board was not necessary. All the clinicians who participated in this study are authors, who willingly served as panelists, agreed with the objectives of the modified Delphi panel study, and actively contributed to manuscript development. Doctors who filled in the Delphi questionnaire received an explanation about the project; they were informed about the intention to publish the results and were asked to complete the Delphi questionnaire if they agreed.

Results

All the voting results summarized in this manuscript are the results of the first round of voting (as all statements received agreement above the 80% threshold). However, a second round of voting was conducted, which resulted in 100% consensus on all statements.

I. Pathophysiology

Consensus statement: Different clinical outcomes during treatment with an ACEi versus an ARB might be predicted by well-established pharmacological data:

• ACEis and ARBs have different actions on the RAAS.

• ARBs, but not ACEis, induce an increase in plasma angiotensin II.

• ACEis and ARBs have different effects on bradykinin, which are more favorable with ACEis.

• ACEis and ARBs have different effects on endothelial function.

• ACEis have more favorable effects on the fibrinolytic system than ARBs.

Consensus success percentage: 100.0%

The RAAS is a major physiological regulator of body fluid volume, electrolyte balance, and BP. Figure 2 shows how the vascular effects of the RAAS are mediated through conversion of angiotensinogen to angiotensin I, the formation of angiotensin II through the actions of ACE, and the interaction of angiotensin II with the angiotensin II receptors [8]. The angiotensin II type 1 (AT₁) receptor is a key component of the RAAS. The AT₁ receptor promotes several intracellular signaling pathways that contribute to the development of hypertension, endothelial dysfunction, vascular remodeling, and end-organ damage. The angiotensin II type 2 (AT₂) receptor appears to play a counterregulatory protective role in the regulation of BP and sodium excretion, opposing the AT₁ receptor.

Fig. 2.

The renin–angiotensin–aldosterone system at a glance. Reproduced from Clarke and Turner (2012 [8]; https://doi.org/10.1155/2012/307315) under a CC-BY 3.0 license (https://creativecommons.org/licenses/by/3.0/). ACE(2) angiotensin-converting enzyme (2), Ang angiotensin, AT1R angiotensin II receptor type 1, AT2R angiotensin II receptor type 2, MMP matrix metalloproteinase, NADPH nicotinamide adenine dinucleotide phosphate, NEP neprilysin

Available data indicate that ACEis and ARBs have different actions on the RAAS [8]. ACEis tend to reduce plasma levels of angiotensin II, whereas angiotensin II levels tend to increase during ARB treatment [9–12]. In comparative clinical studies, plasma angiotensin-II concentrations increased in the ARB group and remained significantly higher in patients receiving ARBs than in those receiving ACEis [11, 13]. In addition, ACEis (but not ARBs) block the degradation of bradykinin, and could mediate activity of subtype 2 bradykinin receptors [14]. PERTINENT (Perindopril–Thrombosis, Inflammation, Endothelial Dysfunction and Neurohormonal Activation Trial) demonstrated that patients with CAD treated with an ACEi had significantly higher bradykinin levels at 1-year follow-up than those treated with placebo [15].

On the basis of the differential impact of ACEis and ARBs on levels of angiotensin-II and bradykinin, it could be postulated that they have a different impact on endothelial function [16]. Some studies have used flow-mediated endothelium-dependent dilation of conduit arteries (a direct marker of endothelial health) to test this hypothesis [17]. For example, in a prospective, randomized, parallel-group study, endothelial function was evaluated in 168 individuals with hypertension before and after 6 months’ treatment with antihypertensive drugs [18]. Treatment with an ACEi was associated with significantly greater improvement in flow-mediated endothelium-dependent dilation of conduit arteries compared with other classes of antihypertensives (beta-blockers, CCBs, and some ARBs) [18]. The ACEi perindopril has been also found to be a significantly better modulation of endothelial apoptosis and renewal in vitro compared with the ARB valsartan [19].

Patients with hypertension usually have reduced levels of tissue plasminogen activator (tPA) and elevated levels of plasminogen activator inhibitor-1 (PAI-1), resulting in reduced capability for endogenous fibrinolysis, which is an important natural defense against thrombosis and vessel occlusion; this puts patients with hypertension at higher future risk for incident cardiovascular events [20]. ACEis have different effects on tPA and PAI-1 compared with ARBs. Brown and colleagues provided the first evidence for this, showing that treatment with the ACEi quinapril, but not losartan (an ARB), was associated with a decrease in both PAI-1 antigen (p = 0.03) and activity (p = 0.018) [21]. In contrast, plasma tPA antigen concentrations decreased during treatment with losartan (p = 0.03), but not quinapril.

II. BP Reduction (Quantitative and Qualitative)

Consensus statement: The benefit of effective treatment for hypertension is derived from achieving the target reduction in arterial BP (in mmHg), in achieving consistent control of BP throughout the 24-h dosing interval, and controlling BP variability and central aortic BP. When treating hypertension, the agent(s) chosen should guarantee achievement of all these goals.

Consensus success percentage: 100.0%

Efficacy of ACEis Versus ARBs for BP Control

Quantitative BP Reduction

ACEis and ARBs efficiently lower BP via inhibition of the RAAS and are equivalently recommended as first-line antihypertensive medications. No clinical differences in antihypertensive efficacy have been shown between ACEis and ARBs [22–24]. In Egyptian patients with uncontrolled hypertension despite treatment with ≥ 2 antihypertensives, fixed-dose combination (FDC) perindopril/amlodipine, with or without a diuretic, significantly decreased systolic BP (SBP) and diastolic BP (DBP) after 3 months, and the majority of patients achieved BP control [25]. However, there are limited published head-to-head comparisons of ACEis and ARBs. To compare the real-world effectiveness of ACEis versus ARBs in the first-line treatment of hypertension, all patients with hypertension starting monotherapy with an ACEi or ARB between 1996 and 2018 across eight databases were studied [22]. This large-scale study included over 3 million patients worldwide and found no statistically significant differences in rates of SBP and DBP control with ACEis versus ARBs at the drug class level [4].

Qualitative BP Reduction

BP variability (BPV) is a complex phenomenon with several patterns including very short- (beat to beat), short- (hour to hour), medium- (day to day), and long-term (visit to visit) variability. BPV is associated with adverse cardiovascular outcome, irrespective of average BP [26–29]. Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) showed that an amlodipine-based regimen (amlodipine ± perindopril) decreased BPV compared with an atenolol-based regimen (atenolol ± thiazide) [29]. Apart from long acting CCBs, other first-line antihypertensive agents have a modest effect on BPV.

Increased central blood pressure (CBP) is another parameter that is associated with hypertensive-mediated target organ damage. Preterax in Regression of Arterial Stiffness in a Controlled Double-blind study (REASON) showed that the perindopril–indapamide combination was associated with twice the reduction of CBP compared with atenolol [30]. Anglo-Scandinavian Cardiac Outcomes Trial—Conduit Artery Function Evaluation (ASCOT-I) showed that amlodipine (± perindopril) was associated with a larger reduction of CBP (4.3 mmHg) than atenolol (± thiazide) [31]. The valsartan–amlodipine combination showed similar reduction in CBP as compared with the atenolol–amlodipine combination [32]. Finally, the ideal RAAS blocker should have consistent effect over the entire 24-h period as assessed by trough-peak ratio (TPR). Perindopril shows the highest TPR (75–100%) followed by telmisartan (50–90%). The rest of the ACEis and ARBs have TPRs averaging 50% [27–33].

III. Effects of ACEis and ARBs on Myocardial Infarction (Primary Prevention)

Consensus statement: Physicians need to be aware of the unique characteristics of ACEis and ARBs with respect to MI risk. ACEis have consistently been shown to reduce the occurrence of MI, while ARBs have not been shown to reduce MI in any RCT. Evidence would therefore dictate reaching for an ACEi instead of an ARB to prevent more MIs, and as such, ACEis should be the first choice across the spectrum of cardiometabolic risk reduction.

Consensus success percentage: 97.3%

Data from RCTs show a clear difference between the effect of ACEis and ARBs for the primary prevention of MI (Fig. 3). The results of 9 of the 11 key studies of an ARB have reported an excess of MI events in the treatment group, which achieved statistical significance against the comparator group in two studies [Valsartan Antihypertensive Long-term Use Evaluation (VALUE) and Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Alternative (CHARM-alt)] [34]. In the VALUE study (n = 15,245), there was a 19% relative increase in MI events in the valsartan versus amlodipine group [35]. In CHARM-alt (the only study not to require/permit background ACEi treatment), participants in the candesartan group had a 52% higher rate of total MI compared with the placebo group (p < 0.025), despite a greater reduction in SBP/DBP with candesartan versus placebo (by 4.4/3.9 mmHg) [36]. In the Study on Cognition and Prognosis in the Elderly (SCOPE) study, the candesartan group showed a 10% statistically nonsignificant higher rate of fatal or nonfatal MI compared with the placebo group, even though mean SBP/DBP was 3.2/1.6 mmHg lower in the candesartan versus placebo group [37]. Two studies with telmisartan [Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) and Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS)] found no difference in the incidence of MI between patients receiving the ARB and those receiving placebo [38, 39].

Fig. 3.

Clinical studies showing the differing effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of acute myocardial infarction. Reproduced with permission from Dézsi and Szentes (2016) [34], under a CC-BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/). AMI acute myocardial infarction, CCB calcium channel blocker, CHARM-alt Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Alternative study, CI confidence interval, EUROPA European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease study, HOPE Heart Outcomes Prevention study, HR hazard ratio, IDNT Irbesartan Diabetic Nephropathy Trial, NS non-significant, I-PRESERVE Irbesartan in Heart Failure with Preserved Ejection Fraction study, LIFE Losartan Intervention for Endpoint Reduction study, ONTARGET Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, SCOPE Study on Cognition and Prognosis in the Elderly, VALUE Valsartan Antihypertensive Long-term Use Evaluation study

In contrast, ACEis have shown a consistently positive effect on the rate of MI. In the Heart Outcomes Prevention (HOPE) study, treatment with ramipril reduced the rate of MI by 20% versus placebo (p < 0.001) [40]. Similarly, treatment with an ACEi in the European trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease (EUROPA) was associated with a 22% reduction in the rate of MI compared with placebo (p < 0.001) [41]. Perindopril Protection against Recurrent Stroke Study (PROGRESS) also evaluated ACEi- versus placebo-based treatment and found that there was a 38% reduction in the rate of MI in individuals with or without hypertension who had a history of cerebrovascular disease [42]. Results from ASCOT-BPLA are consistent with the other studies, with a 13% reduction in the rate of MI in the amlodipine + perindopril versus amlodipine + thiazide diuretic group [43].

Several meta-analyses have also highlighted the different effects of ACEis and ARBs on rates of MI, with odds ratio (OR) or hazard ratio (HR) values for the risk of MI with ACEis versus control ranging from 0.81 to 0.96 (all p < 0.05), and for ARBs versus control ranging from 0.90 or 0.93 (both p > 0.05) to 1.1 (p = 0.03) [44–46].

Our recommendation is consistent with the 2023 European Society of Hypertension (ESH) guidelines, which also recommend an ACEi in preference to an ARB to prevent CAD in patients with hypertension [3]. However, guidelines from ISH (published in 2020), the European Society of Cardiology (ESC; 2018), and the American Heart Association (AHA; 2018) make no specific recommendations about the use of ACEis or ARBs for the prevention of MI [5, 47, 48].

Pathophysiological Rationale

One potential mechanism underling the increased risk of MI during treatment with an ARB is related to blockade of the AT₂ receptor, whereby ARBs may stimulate plaque vulnerability and propensity to rupture [49].

The biology of the angiotensin II type 4 (AT₄) receptor is less definite but has been related to the release of PAI-1 [34]. PAI-1 is a major inhibitor of fibrinolysis and a powerful independent predictor of death after transmural MI [50]. For the same decrease in BP, ACEis offer a greater PAI-1 reduction than ARBs in insulin-resistant hypertensive subjects (Fig. 4) [51]. Whether angiotensin II-mediated AT₄ stimulation, observed during chronic ARB therapy, is responsible for the assessed paradoxical increase in PAI-1 remains to be determined. Irrespective of the mechanism, from a biological standpoint, the observation that ARBs increase PAI-1 to a greater extent relative to ACEis may point to a different effect of these agents on plaque vulnerability.

Fig. 4.

Presumed differences in mechanisms of action of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers with respect to myocardial infarction events. Elevated levels of plasminogen activator inhibitor-1 and decreased tissue plasminogen activator activity affect the coronary circulation causing coronary heart disease. Evidence suggests that bradykinin (which is increased by angiotensin-converting enzyme inhibitors only) stimulates tissue plasminogen activator and angiotensin-4 receptors (which are also only inhibited by angiotensin-converting enzyme inhibitors), which results in increased plasminogen activator inhibitor-1 secretion in endothelial cells. Reproduced with permission from Dézsi and Szentes (2016) [34], under a CC-BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/). ACE(I) angiotensin-converting enzyme (inhibitor), ARBs angiotensin receptor blockers, AT angiotensin; NO nitric oxide; PAI-1 plasminogen activator inhibitor-1, PGI₂ prostaglandin I₂, t-PA tissue plasminogen activator

IV. Effects of ACEis and ARBs on Heart Failure (Primary Prevention)

Consensus statement: For patients with hypertension who are at high risk of developing HF, there is consistent evidence that treatment with an ACEi reduces new-onset HF and HF-related hospitalizations. Therefore, an ACEi is the first choice of treatment for the primary prevention of HF; use of ARBs in this setting should be reserved for individuals who cannot tolerate an ACEi.

Consensus success percentage: 97.3%

Evidence for antihypertensive therapy in the primary prevention of HF has so far only been seen with a subset of available drug classes [52]. Based on data from 12 RCTs of ACEi in patients with hypertension, a reduction in SBP/DBP 4/2 mmHg with ACEi therapy versus placebo was associated with significant reduction in the risk of HF [−21%; 95% confidence interval [CI] −7%, −34%], CAD (−13%; 95% CI −3%, −21%), and major cardiovascular events (composite of stroke, CAD, and HF; −17%; 95% CI −8%, −25%) [52]. In high-risk patients without HF (n = 108,212), meta-analysis data showed a significant reduction in the risk of new-onset HF during treatment with ACEis (OR 0.789; 95% CI 0.686, 0.908; p = 0.001; Fig. 5) [45]. For the use of ARBs in patients with hypertension, data from 13 RCTs showed that a SBP/DBP reduction of 3.7/2.0 mmHg versus placebo was associated with a significant reduction in the risk of HF (−10%; 95% CI −3%, −17%) and major cardiovascular events (composite of stroke, CAD, HF; −9%; 95% CI −5%, −14%), but not the risk of CAD (−6%; 95% CI 4%, −14%) [52].

Fig. 5.

Effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of all-cause and cardiovascular death, myocardial infarction, stroke, new-onset heart failure, and new-onset diabetes mellitus [45]. Reprinted from Savarese G et al. (2013) with permission from Elsevier. ACE-Is angiotensin-converting enzyme inhibitors, ARBs angiotensin receptor blockers, OR odds ratio

RCT evidence for the primary prevention of HF came from several landmark studies. In the HOPE study, treatment with ramipril reduced the rate of HF by 23% [relative risk (RR) 0.77; p < 0.001] in 9297 high-risk patients without previous documentation of a low ejection fraction or HF [40]. Similarly, in EUROPA (12,218 patients with stable CAD and no significant HF), hospital admission for HF was reduced by 39% (p = 0.002) in the ACEi (perindopril) versus placebo group [53]. In the Losartan Intervention for Endpoint Reduction (LIFE) study in high-risk patients with hypertension, losartan reduced the rate of hospitalization for HF by 3% versus amlodipine, but this was not statistically significant (HR 0.97; 95% CI 0.78, 1.21; p = 0.765) [54]. The difference in the rate of HF-related hospitalization with valsartan versus amlodipine in the VALUE study also did not reach statistical significance (HR 0.89; 95% CI 0.77, 1.03; p = 0.12) [35].

In the only head-to-head study comparing an ACEi and an ARB that assessed cardiovascular outcomes, including hospitalizations for HF, in individuals at high cardiovascular risk [Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)] [49], the rate of HF-related hospitalizations in the telmisartan group was numerically higher than that in the ramipril group (by 12%; RR 1.12; 95% CI 0.97, 1.29), despite significantly better 24-h BP control in the telmisartan group [55].

Our recommendation for the use of ACEis to prevent HF development is consistent with US guidelines for patients with pre-HF [left ventricular ejection fraction (LVEF) ≤ 40%] [56]. The US guidelines note that ACEis prevent symptomatic HF and reduce mortality in this patient group [56]. While ESH guidelines recommend ACEis and ARBs among other antihypertensives to prevent HF development, they do not specify one class of RAAS inhibitor over another [3].

V. Effects of ACEis and ARBs on Stroke

Consensus statement: A reduction in BP during treatment with an ACEi or ARB is associated with a significant beneficial effect for the primary prevention of stroke events in patients with hypertension. In contrast, only treatment with an ACEi is effective for the secondary prevention of stroke; thus, available evidence favors the use of an ACEi rather than an ARB for patients with previous stroke.

Consensus success percentage: 100%

Hypertension is the most common risk factor for stroke, and has been reported in about 77% of stroke survivors [57]. A meta-analysis of data from 147 RCTs stated that a SBP reduction of 10 mmHg and a DBP reduction of 5 mmHg was associated with a 41% (95% CI 33%, 48%) decrease in stroke overall, a 46% (95% CI 35%, 55%) decrease in stroke in primary prevention studies, and a 44% (95% CI 21%, 44%) decrease in stoke in secondary prevention studies [58].

Overall, the RAAS, with angiotensin II as its major effector, is involved in the regulation of BP and blood volume homeostasis. In the brain, the local RAAS is involved in the regulation of many functions, including memory, central control of BP, and other metabolic processes [59]. In addition to its involvement in the pathophysiology of hypertension, angiotensin II is also involved in the development of stroke [60]. Angiotensin II exerts its effects through AT₁, AT₂, and AT₄ receptors. The deleterious effects of angiotensin II, via AT₁ receptors, include cerebral vasoconstriction, impaired autoregulation of brain blood flow, increased secretion of reactive oxygen species, and pro-inflammatory effects [61]. Therefore, using antihypertensive drugs such as ACEi or ARBs has a beneficial effect on the risk of stroke independently of their BP-lowering effects.

Primary Prevention

Some clinical studies have examined the effectiveness of ACEis or ARBs for the primary prevention of stroke. In the HOPE study of individuals at high cardiovascular risk, with or without hypertension [40], the ACEi ramipril reduced the number of strokes by 32% compared with the placebo group [62]. In the Hypertension in the Very Elderly Trial (HYVET), investigators randomized 3845 patients ≥ 80 years of age with SBP ≥ 160 mmHg to placebo or indapamide, with perindopril or placebo added as needed to achieve a target a BP < 150/80 mmHg [63]. After 2 years of treatment, mean seated SBP had decreased by 15 mmHg in the perindopril versus placebo group; in addition, there was a 30% reduction in stroke events (p = 0.06), a 39% reduction in fatal stroke (p = 0.046), and a 21% reduction in overall mortality (p = 0.02) with perindopril versus placebo treatment [63]. The TRANSCEND study of telmisartan compared with placebo added to usual therapies found that telmisartan had no significant effect on the composite primary outcome (cardiovascular death, MI, stroke, or hospitalizations for HF; HR 0.92; 95% CI 0.81, 1.05; p = 0.216) [38]. For the secondary outcome of stroke, the rate was 3.8% in the telmisartan group versus 4.6% in the placebo group (HR 0.83; 95% CI 0.64, 1.06; p = 0.136) [38]. Despite a similar reduction in BP in the losartan and atenolol groups in the randomized LIFE study, the losartan group showed a greater reduction in the primary composite endpoint (death, MI, or stroke) than the atenolol group, largely due to a reduction in the number of fatal and non-fatal strokes, which was consistent in all clinical subgroups except for those defined by age and ethnicity [54, 64]. In the ONTARGET study, the primary composite outcome of cardiovascular death, MI, stroke, or hospitalization for HF occurred in 16.7% of patients in the telmisartan group, 16.5% in the ramipril group, and 16.3% in the telmisartan + ramipril group [49]. The corresponding rates of stroke were 4.3%, 4.7%, and 4.4%, respectively. Although the stroke rate was not significantly different between groups in ONTARGET, it was lower in the groups receiving telmisartan, which may reflect a better 24-h BP control profile with a long-acting ARB compared with a short-acting ACEi. Rates of angioedema were lower in the telmisartan versus ramipril group [49]. A network meta-analysis of 27 RCTs, including a total population of 125,330 patients, assessed the effects of ACEis and ARBs on the composite endpoint of cardiovascular death, MI, and stroke [65]. The findings showed that both drug classes reduced the risk of the composite endpoint to a similar extent. Compared with placebo, both ACEis (RR 0.80; 95% CI 0.69, 0.9) and ARBs (RR 0.83; 95% CI 0.70, 0.98) significantly reduced the risk of stroke [65].

Secondary Prevention

The equivalent therapeutic effects of ACEis and ARBs for primary prevention of stroke are not mirrored by findings in the secondary prevention setting. Data from the PROGRESS (perindopril) and HOPE (ramipril) studies showed that long-term lowering of BP after stroke, reduced the risk of recurrent stroke events [40, 62, 66]. The reduction in risk was seen irrespective of baseline BP, which suggests that ACEi might exert beneficial effects on recurrent stroke beyond BP control. The absolute risk reduction during treatment with these ACEis was greater in participants who had greater baseline risk and with more intensive reductions in BP [40, 62, 66]. In contrast, the PROFESS study of telmisartan failed to find a significant effect of therapy with this ARB on the rate of recurrent stroke, major cardiovascular events, or diabetes [39]. One potential explanation for this difference is that ARBs may cause unopposed prolonged upregulation of angiotensin II, thereby augmenting matrix metalloproteinase (MMP) that may be involved in degradation of the thin fibrous cap over an atheroma, resulting in rupture of vulnerable plaques [34].

US guidelines for secondary stroke prevention also recommend RAAS inhibitors, but differ from our recommendations in that they make no distinction between ACEis and ARBs in this setting [47, 67].

VI. Effects of ACEis and ARBs on Mortality

Consensus statement: ACEis consistently reduce the risk of total and cardiovascular mortality. No RCTs have shown a significant mortality benefit of treatment with an ARB.

Consensus success percentage: 100.0%

Hypertension is a significant contributor to poor health outcomes worldwide, including cardiovascular and all-cause mortality, especially in the presence of other co-morbidities such as diabetes and chronic kidney disease (CKD). In the primary prevention setting, ACEis and ARBs are prescribed, alone or in combination with other antihypertensives, as first-line treatment options for patients with hypertension, with or without diabetes mellitus.

Decreasing BP is Beneficial

An individual participant-level data meta-analysis performed by the Blood Pressure Lowering Treatment Trialists’ Collaboration concluded that each 5 mmHg reduction in SBP was associated with an approximately 10% reduction in the risk of major cardiovascular events, irrespective of cardiovascular disease history, even at normal or high–normal BP values not currently considered to need treatment, and in both the primary and secondary prevention settings [68].

RAAS Blockers Versus Others

Overall, meta-analysis data show that RAAS inhibition compared with control (placebo or active treatment) is associated with a significant 5% reduction in all-cause mortality (HR 0.95; 95% CI 0.91, 1.00; p = 0.032) and a 7% reduction in cardiovascular mortality (HR 0.93; 95% CI 0.88, 0.99; p = 0.018) in patients with hypertension [69]. These benefits are one of the reasons that RAAS inhibitors are recommended as first-line therapy for hypertension in European guidelines [48]. However, this is largely due to the beneficial effects of ACEis rather than ARBs, as detailed below.

ACEis Versus ARBs

ACEis have been shown to reduce mortality and morbidity in randomized, placebo-controlled studies, but this is not the case for ARBs (Fig. 6). In the meta-analysis highlighted above, the overall treatment effect of RAAS inhibitors was entirely due to the benefits of ACEis, which were associated with a 10% reduction in all-cause mortality (HR 0.90; 95% CI 0.84, 0.97; p = 0.004); in contrast, no significant mortality reduction was associated with ARB treatment in patients with hypertension (HR 0.99; 95% CI 0.94, 1.04; p = 0.683) [69].

Fig. 6.

Treatment effects on all-cause mortality in studies of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on mortality (versus control). Used with permission of Oxford University Press. From Van Vark et al. [69]. Permission conveyed through Copyright Clearance Center, Inc. ACE angiotensin-converting enzyme, ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicrom MR Controlled Evaluation, ALLHAT Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack, ANBP-2 Australian National Blood Pressure 2 study, ARB angiotensin receptor blockers, ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm, CASE-J Candesartan Antihypertensive Survival Evaluation in Japan, CI confidence interval, HIJ-CREATE Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease, HR hazard ratio, HYVET Hypertension in the Very Elderly Trial, IDNT Irbesartan Diabetic Nephropathy Trial, JMIC-B Japan Multicenter Investigation for Cardiovascular diseases-B, LIFE Losartan Intervention for Endpoint Reduction study, MOSES Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention study, PROFESS Prevention Regimen for Effectively Avoiding Second Strokes study, RENAAL Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study, SCOPE Study on Cognition and Prognosis in the Elderly, TRANSCEND, Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease, VALUE Valsartan Antihypertensive Long-term Use Evaluation study

Similar findings have been reported in another meta-analysis of data from patients with hypertension and diabetes (n = 56,444 from 36 studies) [70]. ACEi treatment was associated with a 13% reduction in all-cause mortality (p = 0.02) and a 17% reduction in cardiovascular mortality (p = 0.04) compared with control (placebo/active treatment). Treatment with an ACEi also reduced the rate of major cardiovascular events versus control by 14% (p = 0.003), including MI by 21% (p = 0.01) and HF by 19% (p = 0.002). Treatment with an ARB only significantly reduced the risk of HF (by 30% versus control; p = 0.01), but had no effect on rates of all-cause death, cardiovascular death, major cardiovascular events, or MI [70]. Another, earlier meta-analysis of data from 108,212 high-risk patients without HF also showed that ACEis substantially reduced all-cause mortality compared with placebo, whereas ARBs did not seem to reduce the rate of all-cause death (Fig. 5) [45].

Overall, these findings support the use of ACEis as first-line therapy in patients with hypertension and other risk factors (such as diabetes). Differences in the mortality benefit associated with ACEi and ARB treatment could be due to several factors, including different sites and mechanisms of action (e.g., effect on bradykinin), differences in BP-lowering effects, and differences in BP-independent effects (e.g., reduced oxidative stress and endothelial dysfunction, and inhibition and stabilization of atherosclerotic plaques), as described above.

Comparison between Different ACEis

Although head-to-head clinical studies of different ACEis in patients with hypertension are unavailable, differences may still exist between members of the same drug class. Agents in the ACEi class differ in chemical structure, ACE ligand potency, and pharmacokinetics (including absorption, elimination, and duration of action); the latter pharmacokinetic differences are influenced by the degree of lipophilicity of the compound [71].

The superiority of ACEis with respect to all-cause mortality benefit versus control in the 2012 meta-analysis by Van Vark et al. was primarily driven by perindopril-based studies ASCOT-BPLA, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), and HYVET; pooled HR 0.87; 95% CI 0.81, 0.93; p < 0.001], and to a lesser extent by data for lisinopril and enalapril in the HYVET-Pilot and Australian National Blood Pressure 2 (ANBP2) studies, respectively [69]. Another landmark study, the HOPE study, in which nearly half of the recruited patients had hypertension, showed significant reductions in both cardiovascular morbidity and mortality with ramipril treatment versus placebo in patients with high cardiovascular disease risk [40]. However, this study was underpowered for the assessment of both all-cause and cardiovascular death in individuals with hypertension.

Evidence for local RAAS in various organs, including those involved in cardiovascular regulation (i.e., heart, vascular wall, kidney, adrenal gland and brain) has raised the possibility that the ability to inhibit tissue ACE might differ between ACEis. It has been postulated that tissue penetration of ACEis could be a crucial determinant of the ability of these drugs to reach their target enzyme (i.e., ACE) within tissues. Tissue penetration mainly depends on molecular size and lipophilicity, along with the presence of blood-tissue barriers, such as the blood–brain barrier [72].

VII. Effects of ACEis and ARBs on Diabetes Mellitus

Consensus statement: ACEis reduce all-cause mortality, cardiovascular mortality, and the rate of major cardiovascular events in patients with diabetes, whereas ARBs have no significant beneficial effects on these outcomes. Therefore, ACEis appear preferable to ARBs for patients with hypertension and type 2 diabetes mellitus.

Consensus success percentage: 100.0%

Hypertension commonly coexists with chronic metabolic conditions, including overweight/obesity, insulin resistance and diabetes [73]. Globally, the incidence and prevalence of type 2 diabetes mellitus is increasing. It is estimated that the number of people with diabetes will rise from 171 million in 2000 to 366 million by the year 2030 [74]. The number of adults with hypertension worldwide is estimated to increase from 972 million in the year 2000 to 1.56 billion by 2025 [75].

The rate of diabetes in individuals with hypertension has been estimated to be twice as high as that in those without diabetes [76]. Of people with diabetes, 80% die from cardiovascular disease, especially hypertension and stroke [77]. The coexistence of hypertension and diabetes mellitus has been estimated to be associated with a 7.2-fold increase in mortality compared with diabetes alone [78]. In the Framingham Offspring Study, the presence of diabetes mellitus at baseline was a significant predictor of incident hypertension (OR 3.14) regardless of age, sex, family history of diabetes mellitus, and body mass index (BMI) [73].

Effective BP control in patients with diabetes has a beneficial effect on cardiovascular disease outcomes as the relationship between hypertension and the risk of cardiovascular events is continuous and consistent. The United Kingdom Prospective Diabetes Study (UKPDS) showed that each 10 mmHg decrease in mean SBP was associated with a 12% reduction in the risk of diabetes-related complications and 15% reduction in diabetes-related deaths [77].

Hyperglycemia, insulin resistance, and dyslipidemia are all characteristics of diabetes. All of these contribute to the development and progression of atherosclerosis by promoting inflammation, coagulation, endothelial dysfunction, and defragmentation of platelets; in turn, these lead to narrowing of the blood vessels and increased peripheral vascular resistance, contributing to the development of hypertension [79]. Recognizing risk factors for hypertension in people with diabetes is essential to determine the appropriate strategies for successfully managing hypertension and its life-threatening complications.

Hypertension is particularly common in obese individuals with type 2 diabetes [80, 81], and the associated risk is closely related to central fat distribution [82, 83]. Taken together, the coexistence of obesity, hypertension, type 2 diabetes, and dyslipidemia is referred to as metabolic syndrome. Insulin resistance with hyperinsulinemia is characteristic of metabolic syndrome, which has been related to increased risk for macrovascular and microvascular complications, morbidity, and mortality [84].

Effective control of BP should be a high priority in people with type 2 diabetes. UKPDS data showed that targeting a BP of < 150/85 mmHg versus < 180/105 mmHg decreased the rate of composite microvascular and macrovascular diabetes complications by 24% and diabetes-related death by 32% [85]. Meta-analysis data show that treatment with antihypertensives in populations with diabetes and a baseline BP ≥ 140/90 mmHg reduces the risks of atherosclerotic cardiovascular disease (ASCVD), HF, and mortality [86].

Individuals with hypertension and diabetes are considered to be at moderate-to-high cardiovascular risk and should be treated with a RAAS plus a CCB or diuretic [3]. The results of the placebo-controlled ADVANCE study, conducted in patients with type 2 diabetes, highlighted the benefit of treatment with a perindopril/indapamide FDC for reducing the rate of macro- and microvascular events versus placebo [87]. The relative risk of all-cause death was also significantly reduced in the perindopril/indapamide versus placebo group in this study [87]. Treatment with an ACEi has also been shown to decrease all-cause mortality, cardiovascular mortality, and major cardiovascular events with clear reno-protective effects in patients with diabetes mellitus, and these effects appear to be maintained over longer-term follow-up [70, 87, 88]. In contrast, in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, the ARB olmesartan showed a benefit in reducing the risk of renal outcomes but was associated with a significant increase in the risk of cardiovascular death in patients with pre-existing coronary artery disease (2.0% versus 0.2% with placebo; p = 0.02) [89]. Overall, there is no evidence that ARBs are any better than ACEis in this setting; thus, ACEis should be considered as first-line therapy to limit excess mortality and morbidity in individuals with diabetes [70].

Our recommendation for first-line use of RAAS inhibitors for hypertension management in patients with diabetes is consistent with current recommendations from the ESC [48, 90], AHA [47], International Diabetes Federation (IDF) [91], and ISH [5], but those guidelines make no distinction between ACEis and ARBs. However, as we have, the 2024 guidelines by the American Diabetes Association (ADA) recommend ACEis in preference to ARBs for patients with diabetes to reduce cardiovascular risk and prevent the development of diabetic kidney disease [92].

VIII. Effects of ACEis and ARBs on Renal Disease

Consensus statement: Benefits of ACEis are consistent: ACEis should be the first-choice intervention for the primary prevention of diabetic kidney disease because, as well as reducing the risk of kidney failure, they are more likely than ARBs to reduce the risk of cardiovascular events and death in people with CKD.

Consensus success percentage: 94.3%

Management of cardiovascular disease is challenging in patients with renal disease, and renal outcomes are important determinants of morbidity and mortality in patients with hypertension [93]. Available data from estimates of death in 188 countries from 1990 to 2013 suggest that 4% of deaths (n = 2.2 million) could be attributed to a reduced glomerular filtration rate (GFR; i.e., renal dysfunction) [94–98]. More than half of these deaths were due to cardiovascular causes [94–98].

A meta-analysis of data from 17 RCTs that included a total of 17,951 patients showed that treatment with an ACEi or ARB reduced urinary protein levels and improved BP; agents from both classes were similarly effective in reducing urinary protein excretion [96]. A Cochrane systematic review found that treatment with an ACEi effectively prevented new-onset diabetic kidney disease and death compared with placebo or a CCB in normoalbuminuric people with diabetes, whereas treatment with an ARB had no significant effect on the development of end-stage renal disease or death [97]. Data from other large meta-analyses also showed that ACEis were superior to ARBs for the prevention of kidney events, cardiovascular morbidity and mortality, and all-cause mortality in patients with stage 3–5 CKD [99, 100]. The only study to show primary and secondary prevention of CKD in addition to cardiovascular and all-cause mortality was the ADVANCE study that used an ACEi in a FDC with the thiazide-like diuretic indapamide (Table 1) [87].

Table 1.

Summary of results of large, randomized controlled trials with renal endpoints including patients with diabetes mellitus

RCT	Treatment	BP at baseline, mmHg	SBP difference versus control, mmHg	Reduction in renal outcomes	Reduction in mortality
					Cardiovascular	Total
IDNT (N = 1148) [138]	Irbesartan versus placebo	159/87	−3.3	−20% (p = 0.02) Secondary prevention	No	No
RENAAL (N = 1513) [139]	Losartan versus placebo	153/82	−2	−16% (p = 0.02) Secondary prevention	–	No
DIRECT-Renal (N = 5231) [140]	Candesartan versus placebo	118/73	−3.3	−5.5% (p = 0.024) Secondary prevention	–	No
ROADMAP (N = 4447) [89]	Olmesartan versus placebo	136/81	−3	Yes Primary prevention	No	No
TRANSCEND (N = 5927) [38]	Telmisartan versus placebo	141/82	−4	No	No	No
ONTARGET (N = 17,118) [49]	Telmisartan versus ramipril	142/82	−2.4	No	No	No
ADVANCE (N = 11,140) [87]	Perindopril/indapamide versus placebo	145/81	−5.6	−21% (p < 0.0001) Primary and secondary prevention	−18% (p = 0.025)	−14% (p = 0.027)
ACCOMPLISH (N = 11,506) [141]	Benazepril/amlodipine versus benazepril/HCTZ	145/80	−1.1	−48% (p < 0.0001) Secondary prevention	No	No
ACCORD (N = 4733) [142]	Intensive versus standard	139/76	−14.2	Yes Secondary prevention	No	No

ACCOMPLISH Avoiding Cardiovascular events through Combination Therapy in Patients Living with Systolic Hypertension, ACCORD Action to Control Cardiovascular Risk in Diabetes, ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation study, BP blood pressure, DIRECT-Renal Diabetic Retinopathy Candesartan Trials – Renal Analysis, HCTZ hydrochlorothiazide, IDNT Irbesartan Diabetic Nephropathy Trial, ONTARGET Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, RENAAL Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study, ROADMAP Randomized Olmesartan and Diabetes Microalbuminuria Prevention, SBP systolic blood pressure, TRANSCEND Telmisartan Randomized Assessment Study in ACE-intolerant Subjects with Cardiovascular Disease

Our recommendation for ACEis as the preferred RAAS inhibitor for patients with renal disease is consistent with ISH [5], ESH [3], and AHA guidelines on hypertension [47], and with the international Kidney Disease Improving Global Outcomes (KDIGO) guidelines [101, 102].

IX. Effects of ACEis and ARBs after Myocardial Infarction

Consensus statement: Consistent with the Class I recommendation from the European Society of Cardiology [103], start treatment with an ACEi within the first 24 h after an ST-elevation MI in patients with evidence of HF, left ventricular systolic dysfunction, and/or diabetes, and continue long term. Treatment with an ACEi should also be considered in all patients who do not have any contraindications to therapy (Class IIa). An ARB, preferably valsartan, is an alternative to an ACEi in patients who have HF and/or left ventricular systolic dysfunction who are intolerant of ACEis.

Consensus success percentage: 100.0%

In post-MI patients, RAAS inhibition attenuates left ventricular remodeling, reduces infarct expansion, induces peripheral vasodilatation, decreases the plasma concentration of PAI-1, and enhances the release of tPA [104–106]. Treatment with an RAAS inhibitor after MI also has an antiarrhythmic effect, reducing the occurrence of atrial and ventricular arrhythmias, including atrial fibrillation. This occurs via a decrease of sympathetic tone, improvement of baroreceptor sensitivity, and interference with ion currents [107–109]. A meta-analysis of studies that investigated treatment with an ACEi after MI found that this reduced rates of total and cardiovascular death, and sudden cardiac death compared with placebo [110]. A significant reduction in mortality at 1 month after ST-elevation acute MI was also seen during ACEi therapy in another meta-analysis [111]. Furthermore, a meta-analysis of three large trials [Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE), and Trandolapril Cardiac Evaluation (TRACE)] documented a long-term mortality benefit plus reductions in recurrent MI and HF-related readmissions [112]. In addition, several RCTs showed improved left ventricular ejection fraction from 1 month to 1 year after ST-elevation MI in individuals treated with an ACEi [109, 113].

Two large studies have compared an ACEi to an ARB in patients with acute MI. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) demonstrated a non-significant difference in total mortality that favored captopril over losartan after a mean 2.7-year follow-up in high-risk patients treated after an acute MI [114]. This between-group difference in mortality appeared to be mainly driven by a significant excess of cardiovascular deaths in the losartan group. In contrast, the Valsartan in Acute Myocardial Infarction (VALIANT) study found that there was no difference in the risk of all-cause death between the captopril and valsartan groups in post-MI patients with HF and/or left ventricular dysfunction [115].

Looking at real-world data, the Korea Acute Myocardial Infarction Registry (KAMIR) showed that the use of an ACEi at discharge reduced the rate of major adverse cardiovascular events and was associated with better 1-year survival compared with use of an ARB at discharge [116]. Additional KAMIR data showed that ARB therapy was associated with higher incidence of 2-year major adverse cardiac events, cardiac death, all-cause death, and MI than ACEi therapy (Fig. 7) [117]. Overall, it is likely that the superiority of ACEis over ARBs in the post-MI setting can primarily be attributed to reduced angiotensin II levels and activation of bradykinin with ACEis, whereas ARBs may cause prolonged elevation of angiotensin II levels and the upregulation of angiotensin.

Fig. 7.

Kaplan–Meier curves and adjusted hazard ratios for 2-year A all-cause death, B cardiac death, and C myocardial infarction in propensity score-matched patients with angiotensin receptor blockers versus angiotensin converting enzyme inhibitors. Reproduced from Lee LG et al. (2023 [117]; https://doi.org/10.1371/journal.pone.0281460) under a CC-BY 4.0 license (https://creativecommons.org/licenses/by/4.0/). ACEI angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, CI confidence interval, HR hazard ratio

European guidelines recommend that ACEis be considered for all patients after acute coronary syndrome [103], and AHA guidelines recommend ACEis over ARBs in patients with a recent MI and LVEF ≤ 40% [56].

X. Effects of ACEis and ARBs on Heart Failure with Reduced Ejection Fraction

Consensus statement: In patients with previous or current symptoms of chronic HF with reduced ejection fraction (HFrEF), the use of an ACEi is recommended to reduce morbidity and mortality when the use of an ARNi is not feasible; an ARB is recommended as second-line therapy in cases of ACEi intolerance [56, 118–123].

Consensus success percentage: 100.0%

There is extensive evidence that the modulation of the RAAS is associated with improved survival, reduced risk of HF-related hospitalizations, and improved symptoms in patients with HFrEF. Four drug classes are recommended to modulate the RAAS in these individuals: ACEis, ARBs, ARNis, and mineralocorticoid receptor antagonists (MRAs). Although the use of an ARNi has been reported to be superior to an ACEi in patients with HFrEF, an ACEi remains a suitable option for those in whom an ARNi is not feasible.

Our recommendations are consistent with US guidelines for the management of patients with HFrEF [56], but 2023 ESH hypertension guidelines [3] and ESC HF guidelines do not specifically recommend one class of agent (ARNi, ACEi, or ARB) over another; however, ARBs are only recommended in case of ACEi intolerance [124]. In most countries, ARNis (valsartan/sacubitril) is only approved for the treatment of HF [3].

Why are ACEis Rather Than ARBs Recommended as First-Line Therapy in HFrEF?

Treatment with an ACEi has been shown to reduce all-cause mortality by 20–30% in patients with left ventricular systolic dysfunction (LVEF ≤ 40%), including those with asymptomatic left ventricular dysfunction up to those with moderate or severe HFrEF. No individual study or meta-analysis has reported a positive impact of treatment with an ARB on the incidence of MI, cardiovascular death, or all-cause death.

The superiority of ACEis over ARBs in this setting is thought to be because ACEis, but not ARBs, inhibit the degradation of bradykinin, leading to increased levels of nitric oxide and vasoactive prostaglandins (i.e., more vasodilation). Furthermore, because ARBs selectively block AT₁ receptors, there is a 200–300% increase in angiotensin II levels, which causes unopposed stimulation of upregulated AT₂ receptors. The latter may be harmful due to its mediation of growth stimulation, fibrosis, and hypertrophy, plus proatherogenic and proinflammatory effects.

There do not appear to be any differences between currently available agents in the ACEi class with respect to effects on symptoms or survival. However, agents within the class are heterogeneous, with differences in pharmacologic properties, including half-life, availability, first-dose hypotension, tissue-ACE binding, and lipophilicity [125].

Use of an ARB in patients with HFrEF is only recommended for patients who are unable to tolerate an ACEi due to side effects such as cough or angioedema. However, an ARB should be used with caution in patients with a history of ACEi-induced angioedema because there are case reports of patients who subsequently develop angioedema with ARB therapy [126]. In the CHARM-alt study, treatment with the ARB valsartan reduced the rate of cardiovascular death and HF hospitalizations in patients who were not receiving an ACEi due to previous intolerance [36]. When added to usual therapy in the Valsartan Heart Failure Trial (Val-HeFT), valsartan reduced the rate of HF hospitalizations [127]. However, no ARB has reduced all-cause mortality in any study.

XI. Safety and Tolerability of ACEis and ARBs

Consensus statement: The rate of ACEi-induced dry cough is often overestimated, and its occurrence can be reduced by using a lipophilic ACEi or combining an ACEi with a CCB. If still not tolerated, the alternative is to switch to an ARB.

Consensus success percentage: 100%

A patient-level analysis in which data were tested for completeness, internal consistency of patients' records, and consistency with the published reports reported that more than 96% of 27,492 treatment-naïve patients taking an ACEi did not experience cough, because the overall incidence of cough in patients starting treatment with an ACEi was around 3.9% [128]. A score has been proposed to predict which individuals will develop cough during ACEi therapy, which includes older age (> 65 years), female sex, and concomitant use of lipid-lowering agents (total possible score = 3) [128]. The incidence of ACEi-induced cough is around 2.2% when the score is 0 and increases to 8.5% when the score is 3. The occurrence of ACEi-induced cough is not dose dependent, and the risks are probably multifactorial. The most likely mechanism is that the ACEi prevents the breakdown of bradykinin and substance P, and these substances act as pro-tussive mediators in the respiratory tract. Moreover, increased bronchial tissue bradykinin may stimulate phospholipase A2, which in turn activates the arachidonic acid pathway, leading to increased prostanoid synthesis, which stimulates vagal sensory C fibers and local release of histamine, causing a cough reflex [129, 130]. Increased bradykinin is also believed to contribute to the development of ACEi-induced angioedema [131], an unusual but potentially serious side effect.

A recent review by Borghi and colleagues discussed the pathophysiology of ACEi-induced cough and noted that there is a difference in the likelihood of cough between hydrophilic ACEi (e.g., enalapril, cough incidence of 7%) and lipophilic ACEi (e.g., perindopril or zofenopril, cough incidence 2.2% or 2.4%, respectively) [132]. This is most likely because cough is stimulated initially through increased bronchial tissue bradykinin, while the aqueous bronchial fluid has low affinity for lipophilic drugs [133]. These data support the importance of the tissue-binding selectivity of ACEis compared with their effects mediated in the circulation, even in terms of adverse events.

A meta-analysis of data from 22 RCTs showed that the rate of cough was 13.5% with an ACEi and 8.5% with placebo (p < 0.0001) [134]. However, the analysis found that 63% of all cases of cough in patients taking an ACEi were potentially not caused by the ACEi. The authors concluded that other causes of cough, such as smoking or worsening HF symptoms, should be excluded before treatment with an ACEi is withdrawn. Due to the significant benefits of ACEi therapy, trialing a different agent from this class or rechallenging with the original ACEi after cough recovery should be considered before permanent withdrawal or replacement of an ACEi. Furthermore, the occurrence of ACEi-induced cough can be reduced by co-prescription of a dihydropyridine CCB and/or a diuretic, which reduced the incidence of cough from 7% to 1% in male patients and from 12% to 0% in female patients in one study [135].

Although there is a Class 1a recommendation for the use of a RAAS blocker in patients with mild CKD [47], these agents have the potential to cause initial increases in serum creatinine and potassium levels by lowering intraglomerular pressure, which in turn reduces the GFR. However, this action reduces hyper-filtration and thus reduces proteinuria. Monitoring serum levels of potassium and creatinine, along with the GFR, is important during ACEi therapy in patients with CKD. Traditional risk factors for hyperkalemia include renal insufficiency, HF, diabetes mellitus, endogenous potassium load (as in hemolysis or gastrointestinal bleeding), exogenous potassium load (dietary consumption or blood products), other medications (e.g., MRAs, non-steroidal anti-inflammatory drugs, and heparin), advanced age, and lower BMI [136]. However, some of these risk factors are also indications for ACEi therapy. Data from a cohort study of 122,363 patients who had started on an ACEi or ARB found that cardio-renal outcomes were worse when serum creatinine increased by ≥ 30% after starting treatment [137].

The following are recommended before starting or changing the dose of ACEi, especially in patients with risk factors for hyperkalemia [136]: review medications and adjust if needed; check baseline blood levels of potassium, creatinine, and proteinuria; give dietary advice; and ensure the patient is volume replete. If the serum creatinine level increases by < 30% from baseline and the GFR falls by < 25%, it is recommended to titrate the ACEi dosage upward slowly every 2 weeks and to reduce the dosage if the maximal dosage is not tolerated. If the serum potassium level is persistently above 5.0 mmol/L, serum creatinine increases by > 30% from baseline, or the GFR falls by > 25%, additional causes for these changes should be investigated (e.g., bilateral renal artery stenosis), and the ACEi dosage should be halved. If there is still no improvement, the ACEi dosage should be reduced further, or treatment stopped completely.

Discussion

There is no doubt that a RAAS blocker is an essential component of therapeutic strategies designed for the primary and secondary prevention of cardiovascular disease, especially in patients with hypertension (where the risk of cardiovascular death is high). Both ACEis and ARBs are potential options for RAAS inhibition, but these agents have different mechanisms of action and therefore differ in their cardioprotective effects (although both have similar BP-lowering activity; Table 2). We recommend ACEis over ARBs after acute MI, in patients with HFrEF, for the secondary prevention of stroke, and in patients with diabetes mellitus. Both classes of agent have beneficial effects on renal outcomes, but an ACEi is preferred over an ARB due to the additional cardiovascular risk reduction. Only ACEis have been shown to significantly reduce both cardiovascular and all-cause death. The risk of ACEi-induced cough is often overestimated, and this can be reduced with the use of a lipophilic ACEi or by adding a CCB.

Table 2.

Summary of key differences between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular outcomes

	ACEi	ARB
Myocardial infarction	• Reduces the incidence of MI • Indicated in STEMI and NSTEMI with LV dysfunction, diabetes mellitus	• RCTs have shown an increase in the incidence of MI • Could be used when the patient is ACEi intolerant
Heart failure	• Reduces the incidence of new-onset HF • ACEi and ARNi are first-line therapies in HFrEF	• Indicated in HFrEF if the patient is ACEi/ARNi intolerant
Stroke	• Effective for primary prevention of stroke • Effective for the secondary prevention of stroke	• Effective for primary prevention of stroke
Diabetes mellitus	• Reduces new-onset diabetes • Reduces all-cause death and MACE	• Reduces new-onset diabetes
Chronic kidney disease	• Reduces albuminuria and progression to ESRD • Decreases all-cause death and MACE	• Reduces albuminuria and progression to ESRD
Total death	• Significant reduction (ramipril, perindopril)	• No significant reduction
Cardiovascular death	• Significant reduction (ramipril, perindopril)	• No significant reduction

ACEi angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, ARNi angiotensin receptor-neprilysin inhibitor, ESRD end-stage renal disease, HF heart failure, HFrEF heart failure with reduced ejection fraction, LV left ventricular, MACE major adverse cardiac events, MI myocardial infarction, NSTEMI non-ST-elevation myocardial infarction, RCT randomized controlled trial, STEMI ST-elevation myocardial infarction

Currently, there are gaps in the literature regarding the comparative efficacy and safety of ACEis and ARBs in some clinical settings. As with other consensus statements, we have made recommendations on the basis of the best available evidence in the literature without any newly generated data. However, by not addressing the gaps in the literature, the extent of these findings may be limited. It seems unlikely that many more major cardiovascular outcomes studies will be undertaken comparing ACEis or ARBs, given the age of these agents and the cost of such clinical trials, but registry studies or real-world observational studies may help to supplement the existing data.

Conclusion

RAAS blockade is an essential component of hypertension therapy. Because the protective effects provided by ACEis are substantially greater than those of ARBs, ACEis are indicated in almost all cases, except when not tolerated.

Author Contributions

Mohamed Sobhy, Adel Eletriby, Hany Ragy, Hossam Kandil, Mohamed Ayman Saleh, Nabil Farag, Ramez Guindy, Ahmed Bendary, Ahmed Mohamed Elmahmoudy Nayel, Ahmed Shawky, Ayman Khairy, Ayman Mortada, Bassem Zarif, Haitham Badran, Hazem Khorshid, Kareem Mahmoud, Karim Said, Khaled Leon, Mahmoud Abdelsabour, Mazen Tawfik, Mohamed Aboel-Kassem F Abdelmegid, Mohamed Koriem, Mohamed Loutfi, Moheb Wadie, Mohamed Elnoamany, Mohamed Sadaka, Mohamed Seleem, Mohamed Zahran, Osama A. Amin, Sameh Elkaffas, Sherif Ayad, Wael El Kilany, Walid Ammar, Waleed Elawady, Walid Elhammady, and Yasser Abdelhady attended the meetings to discuss the statements and voted for their agreement on the statements, contributed to the literature analysis and drafting or reviewing of the manuscript, and approved the final version of the manuscript.

Funding

The consensus was financially supported by Servier without any influence on the process, data collection, data management, and/or the editorial process. The journal’s Rapid Service Fee and medical writing assistance in the preparation of this manuscript, were funded by Servier.

Data Availability

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Mohamed Sobhy, Adel Eletriby, Hany Ragy, Hossam Kandil, Mohamed Ayman Saleh, Nabil Farag, Ramez Guindy, Ahmed Bendary, Ahmed Mohamed Elmahmoudy Nayel, Ahmed Shawky, Ayman Khairy, Ayman Mortada, Bassem Zarif, Haitham Badran, Hazem Khorshid, Kareem Mahmoud, Karim Said, Khaled Leon, Mahmoud Abdelsabour, Mazen Tawfik, Mohamed Aboel-Kassem F Abdelmegid, Mohamed Koriem, Mohamed Loutfi, Moheb Wadie, Mohamed Elnoamany, Mohamed Sadaka, Mohamed Seleem, Mohamed Zahran, Osama A. Amin, Sameh Elkaffas, Sherif Ayad, Wael El Kilany, Walid Ammar, Waleed Elawady, Walid Elhammady, and Yasser Abdelhady have nothing to disclose.

Ethical Approval

As this study was classified as a consensus development technique and did not involve research on patients or patients’ data, obtaining approval from an ethics committee or internal review board was not necessary. All the clinicians who participated in this study are authors, who willingly served as panelists, agreed with the objectives of the modified Delphi panel study, and actively contributed to manuscript development. Doctors who filled in the Delphi questionnaire received an explanation about the project; they were informed about the intention to publish the results and were asked to complete the Delphi questionnaire if they agreed.