ACEIs are widely prescribed to manage hypertension, and are recommended in recent guidelines (level of recommendation IA) as the basis of antihypertensive strategies, given their ability to reduce BP and CV events in randomized clinical trials . The potency of ACE inhibition is influenced by the affinity of the drug to the zinc (Zn++) ligand of ACE. There are three distinct chemical classes of ACEIs (Table 1): (1) sulfhydryl containing ACEIs (i.e., captopril, zofenopril) which strongly bind the Zn++ ligand, but disulfide formation limits their half-life; (2) drugs containing a carboxyl group (i.e., enalapril, lisinopril, ramipril) that binds to side chains of the enzyme within the active moiety for improved potency and duration of action; and (3) drugs composed of phosphorus-containing ACEIs (i.e., fosinopril) [11, 12]. Although direct ACEIs comparisons among available agents are rare, a Cochrane review has demonstrated that there are no clinically meaningful differences in BP-lowering efficacy between different ACEIs .
ACEIs are the mainstay not only for hypertension management but also for other CVD, including HF, LVD, and acute myocardial infarction (AMI) (Table 2). In HF, ACEIs decrease total peripheral resistance, pulmonary vascular resistance, pulmonary capillary wedge pressure, and mean arterial and right atrial pressures, thus resulting in reduced mortality, regardless of HF severity [7, 8]. In these patients, the use of ACEIs has been shown to increase cardiac index, cardiac output, stroke volume, and exercise tolerance . Many pieces of evidence indicate that BP control delays the onset of HF and, in some cases, contributes to prolonging life, and this also applies to hypertensive patients treated with ACEIs with or without a history of myocardial infarction, especially in older people . As per current guidelines, an ACEI is recommended in addition to a beta-blocker for symptomatic patients with HF with reduced left ventricular ejection fraction (LVEF) to reduce the risk of HF hospitalization and death (recommendation 1A) . A meta-analysis of three randomized trials (SAVE, Survival and Ventricular Enlargement; AIRE, Acute Infarction Ramipril Efficacy; and TRACE, trandolapril in patients with reduced LVD after acute myocardial infarction), including 5966 patients with LVD or HF, have indicated that administration of ACEIs after AMI provides clear benefit and lead to substantial reductions in mortality and morbidity in high-risk patients . Indeed, the proportion of patients readmitted for HF resulted was reduced by 27% with ACEIs [11.9% in the ACEI group vs. 15.5% of the control group; hazard ratio (HR) 0.73 95% CI 0.63–0.85, p < 0.0001], while the combination of death or hospital admission for HF occurred in 30.5% of the ACEI group and 37.0% of the control group . ACEIs are also indicated in patients with asymptomatic LV systolic dysfunction in order to minimize the risk of development of HF, and consequent hospitalization, and death .
In patients affected by coronary artery disease (CAD) with preserved systolic ventricular function, the evidence for routine administration has been conflicting. A metanalysis by Al-Mallah et al. reported a modest benefit of ACEIs on the prognosis of patients with CAD associated with preserved LV systolic function . Data from more than 33,000 patients indicated that ACEIs therapy, when added to conventional therapy (aspirin, beta-blockers, and statins), was associated with a decrease in the rate of CV mortality (risk reduction or RR 0.83, 95% CI 0.72–0.96, p = 0.01), nonfatal MI (RR 0.84, 95% CI 0.75–0.94, p = 0.003), all-cause mortality (RR 0.87, 95% CI 0.81–0.94, p = 0.0003), and coronary revascularization (RR 0.93, 95% CI 0.87–1.00, p = 0.04) . Not all trials, however, described an effective advantage in the use of ACEIs in this setting; hence, current guidelines generally do not recommend ACEIs in chronic coronary syndrome patients without HF or high CV risk, unless with coexisting hypertension, LVEF ≤ 40%, diabetes, or chronic kidney disease. In these latter cases, ACEIs should be considered (level of recommendation IIA) .
Therapy with ACEIs is also common after AMI. Numerous trials have indicated that mortality and morbidity were reduced when ACEIs were administered in a relatively unselected population of patients in the acute phase of MI (“early”) or in patients with evidence of LVD in the subacute phase after MI (“late”) . In their metanalysis, Franzosi et al. collected data from large randomized trials which evaluated the efficacy and safety of treatments with ACEIs given in the acute phase of MI (0–36 h from the onset of symptoms) and continued for a short period of follow-up (generally 4–6 weeks) . These trials were CONSENSUS-II, GISSI-3, ISIS-3, and CCS-1, and included a total of 98,496 patients. The main conclusions of the analysis were: (1) ACEI treatment can be started immediately during the acute phase of MI, in association with other routinely recommended treatments (such as thrombolytics, aspirin, and beta-blockers); (2) the benefit occurs during the first few days after MI, suggesting a positive role of tissue remodeling; (3) the benefit is proportionally larger in higher-risk subgroups (those with an anterior site MI or high heart rate); and (4) early benefits would be complementary to that observed later in trials of prolonged ACEI therapy initiated several days or weeks after MI in patients with evidence of HF or LVD . Due to the lack of clinical trials that directly compared the efficacy of different ACEIs treatment after AMI, these drugs are generally assumed to be equally effective . Analyzing the association between the choice of an ACEI after MI with the risk for mortality and reinfarction, a class effect was described rather than a superiority of some agents, when drugs were used in comparable dosages, thus suggesting that it would be more important initiating treatment and continuing treatment at the recommended dosage than choosing a particular agent to achieve long-term benefits . Current guidelines recommend ACEIs after AMI with ST-elevation, starting within the first 24 h of ST-elevation myocardial infarction (STEMI) in patients with evidence of heart failure, LV systolic dysfunction, diabetes, or an anterior infarct (level of recommendation IA). They should be considered in all patients with AMI unless specifically contraindicated (level of recommendation IIa) .
ACEIs are commonly used in patients with diabetes and/or with renal disease. In a systematic review including 36,917 participants (including 2400 deceased, 766 patients who required dialysis, and 1099 patients in which serum creatinine levels doubled), ACEIs showed higher probabilities of reducing all-cause mortality, use of dialysis, or doubling of serum creatinine levels, and demonstrated renoprotective effects . These observations were confirmed even in chronic renal disease progression when ACEIs decreased BP, and urinary protein excretion slowed the increase in serum creatinine and reduced the risk for end-stage renal disease (ESRD), or for the combined outcome of doubling of the baseline serum creatinine concentration or ESRD by approximately 30% .