The evolution of ACE inhibition – A turning point in cardiovascular medicine

Inhibition of the angiotensin‐converting enzyme (ACE) system, introduced in the clinic some 25 years ago, stands out as a major therapeutic strategy in cardiovascular medicine. The discovery of the renin–angiotensin system by Robert Tigerstedt was made back more than a century ago [1,2] and the actual discovery of ACE by Leonard T. Skeggs followed some 50 years later. Initially, the clinical importance to come of this enzyme in blood pressure (BP) regulation and cardiovascular therapy was largely unrecognized. However, when the pharmacologist Sérgio Henrique Ferreira in 1970 discovered that the venom of the pit viper (Bothrops jararaca) was able to potentiate the action of bradykinin, this became the starting point for the development of the nonapeptide called teprotide (SQ 20,881). This agent potently inhibited ACE and caused hypotensive effects in vivo[1,2]. Further research during the early 1970s expanded the knowledge on the structure–activity relationship of the novel class of ACE inhibitors (ACEIs), which eventually led to the development of captopril in 1975, the first orally active ACEI. Captopril was initially launched for clinical use in the USA in 1981 followed by the non‐sulphhydryl‐containing ACEI enalapril 2 years later. Today several third‐ and fourth‐generation ACEIs are available for clinical use.

The clinical utility of the ACEIs in the management of cardiovascular disease has increased dramatically in the last 25 years. After the initial launch of captopril for the treatment of hypertension, subsequent clinical research and intervention studies have documented the efficacy of a wide range of ACEIs in the prevention and treatment of several other cardiovascular disorders, including congestive heart failure (CHF), remodelling after acute myocardial infarction (MI), and diabetic nephropathy [3–5].

Zofenopril is a highly lipophilic third‐generation ACEI characterized by a high degree of tissue penetration and long‐term cardiac ACE inhibition [3]. Further, zofenopril and its active moiety zofenoprilat possess in vitro and in vivo antioxidant activity, which may contribute to the anti‐ischaemic and antiatherogenic effects observed in experimental models [3]. Thus, based on preclinical and experimental clinical findings, zofenopril has the profile of an ACEI with high potency, significant tissue selectivity with a rapid onset and a long duration of action [6,7].

The efficacy and tolerability of zofenopril in the treatment of essential hypertension have been evaluated in monotherapy as well as combination therapy [3],[6]. In monotherapy, dosages of zofenopril 7.5–60 mg/day are significantly more effective than placebo in reducing 24‐h ambulatory BP. In the four comparative studies published in this supplement [8–11], zofenopril 30–60 mg/day once daily was at least as effective as atenolol 50–100 mg/day, amlodipine 5–10 mg/day, enalapril 20–40 mg/day or losartan 50–100 mg/day when assessed by reductions in diastolic BP. Moreover, adverse effects reported for zofenopril are generally class‐specific and transient, and the incidence is similar or compares favourably with other first‐line or major classes of antihypertensive drugs.

In combination therapy, clinical trials comparing zofenopril/HCTZ with each agent administered as monotherapy have demonstrated that combination therapy was more effective in normalizing BP [6,7]. This effect was particularly evident in one trial in which patients who were non‐responsive to zofenopril monotherapy were studied. In addition, in clinical trials to date, combination therapy provided sustained and consistent BP control over the entire 24‐h dose interval. Despite the greater efficacy of the zofenopril/HCTZ combination, there were no significant differences in the nature, severity or incidence of treatment‐related adverse events when directly compared with each agent administered as monotherapy. Therefore, zofenopril/HCTZ, in a dose of 30/12.5 mg/day, provides the possibility of managing patients not controlled with monotherapy alone by providing a more optimal BP control in a larger group of patients.

Two major controlled trials have evaluated the cardiovascular outcome of zofenopril treatment. The Survival of Myocardial Infarction Long‐term Evaluation (SMILE) trial [12–15] assessed 6 weeks of zofenopril treatment in 1556 patients with anterior acute (<24 h from symptoms) MI not receiving thrombolytic therapy. Zofenopril significantly reduced the relative risk for of death or severe CHF at 6 weeks by 32.7% (95% CI 6.8–51.4%) compared with placebo. Mortality at 12 months was also significantly reduced in zofenopril versus placebo recipients, indicating that the benefits of zofenopril therapy extended beyond the treatment end. The second outcome trial, SMILE‐2 [15], compared the safety and efficacy of zofenopril to lisinopril after thrombolysis in patients with acute MI. The study evaluated both treatments in terms of the incidence of severe hypotension (systolic BP <90 mmHg), as well as additional safety and efficacy parameters. The SMILE‐2 study showed that the two ACEIs zofenopril and lisinopril were safe when administered to thrombolysed patients with acute MI.

The results of the SMILE trials demonstrate that the early administration of zofenopril to patients with acute MI is safe and associated with a significant reduction in the 6‐week occurrence of major CV events (death and CHF) in high‐risk patients with anterior non‐thrombolysed MI. Furthermore, the beneficial effect of zofenopril was enhanced in some higher‐risk subgroups of patients, notably as those with a history of diabetes or arterial hypertension.