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 [9,10,11,12]. 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 ControlQuantitative 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 [22,23,24]. 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 [26,27,28,29]. 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% [27,28,29,30,31,32,33].

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) [44,45,46].

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