The angiotensin converting enzyme (ACE) inhibitors, developed initially for blood pressure control, have become an essential part of the treatment of hypertension, congestive heart failure and the prevention of atherosclerosis complications. The evidence supporting the benefit of ACE inhibitors is extensive and not confined to single clinical trials. A number of ACE inhibitors are currently available that have different pharmacological properties. Consequently, the extrapolation of the results of clinical trials with one ACE inhibitor and the application for use with another ACE inhibitor is not certain. Angiotensin receptor blockers (ARBs) were introduced more recently and shown to have similar blood pressure lowering properties as ACE inhibitors. However, ARBs have not been shown, convincingly, to prevent vascular complications, nor to be either equivalent or better than ACE inhibitors for the management or prevention of heart failure.

Angiotensin II plays a central role in the development of atherosclerosis and the subsequent complications associated with the disease. Angiotensin II increases blood pressure by direct arteriolar vasoconstriction, enhances sympathetic nervous system activity, and promotes salt and fluid retention. Hypertension is a primary risk factor for both stroke and myocardial infarction The endothelial cell lining of the arteries is important for the maintenance of the integrity of the artery. Normally, it prevents and limits thrombosis within the vessel, as well as, entry of inflammatory cells into the arterial wall. The endothelium produces nitric oxide (NO) that is an essential agent for maintaining vessel patency, limiting cell proliferation and inhibiting thrombosis. When endothelial function is impaired, the synthesis of nitric oxide is reduced and there is enhanced synthesis of agents that promote the development of atherosclerosis as well as thrombosis. In the abnormal endothelium, angiotensin II synthesis is increased, leading to increased oxygen free radical formation and resulting in tissue damage as well as the neutralization of nitric oxide. Angiotensin II promotes inflammation by inducing the synthesis of cytokines and adhesion molecules that encourage monocyte adhesion and migration into the vessel wall. Consequently, a vicious cycle is created, as the increased number of inflammatory cells result in more angiotensin II synthesis. Angiotensin II synthesis is central to the development of endothelial dysfunction, which is the initial step in the development of atherosclerosis and its complications.

Angiotensin converting enzyme (ACE) transforms angiotensin I to the active peptide angiotensin II. This enzyme is also responsible for the breakdown of bradykinin to inactive peptides. Inhibition of ACE not only reduces angiotensin II levels, but also increases the availability of bradykinin. Bradykinin is a vasodilator that promotes the synthesis of NO and stimulates the synthesis of vasodilatory prostaglandins. This mechanism appears to be an important component of the ACE-inhibitor induced improvement of endothelial function in coronary circulation. In contrast, while ARBs potentially provide a more complete blockade of the renin-angiotensin system by blocking the action of angiotensin II at the receptor level, they do not enhance nitric oxide synthesis by the bradykinin mediated pathway to the same extent as ACE inhibitors.

Clinical trials of ACE inhibitors for the management of heart failure showed that ACE inhibition reduced heart failure mortality, hospitalization for heart failure, and the development of heart failure in patients with left ventricular dysfunction (LVD). Studies that observed subjects for more than 3 years (SOLVD and SAVE trials) showed a consistent reduction of myocardial infarction (MI) during the period of treatment. Trials with shorter duration of treatment such as AIRE and TRACE showed a non-significant trend to less MI. These trials led to the HOPE trial, which showed that ramipril 10mg daily given for a period of 4 years to patients at high risk of heart attack or stroke (established vascular disease or diabetes) reduces vascular events by 22%. The SOLVD Investigators. N Engl J Med 1992;327:685-91 and N Engl J Med 1991;325:293-302. Rutherford JD, et al (SAVE Investigators). Circulation 1994;90:1731-38 and Pfeffer MA, et al, N Engl J Med 1992;327:669-77. Cleland JG, et al, (AIRE Investigators). Eur Heart J 1997;18:41-51 and Lancet 1993;342:821-28. Kober L, et al (TRACE study group). N Engl J Med 1995;333:1670-6. Yusuf S, et al. (HOPE Investigators). N Engl J Med 2000;342:145-53. 

The HOPE (Heart Outcomes Prevention Evaluation) study was carried out at 267 centres in 19 countries over 3 continents, and enrolled 9297 high-risk patients with a history of coronary disease, stroke, peripheral vascular disease, or diabetes, with at least 1 risk factor for vascular disease. The subjects were >55 years old, had no history of heart failure, recent MI or stroke, and when known, a LVEF >40%. Eligible patients were randomized to either ramipril 10 mg daily or placebo. During the 4.5-year follow-up period, ramipril-treated patients had 22% less cardiovascular death, MI, or stroke. Similar benefits were observed in a wide range of patient groups. Those enrolled with or without cardiovascular disease, diabetes, hypertension, prior MI, cerebrovascular disease, or peripheral vascular disease had similar 20% to 25% reductions of vascular events. Each of the components of the primary endpoint (CVD death, stroke, MI) was significantly reduced. In addition, there was a 32% reduction in the incidence of new diabetes. These benefits are summarized by the treatment effect for 1000 patients receiving ramipril 10 mg daily for 4 years; treatment will prevent 20 deaths, 24 MIs, 23 revascularizations, or 150 events in 70 patients. The results of on-going trials such as PEACE, EUROPA, and IMAGINE are awaited to further our knowledge of the use of ACE inhibitors for vascular protection. In the current recommendations of the AHA/ACC, the American Diabetic Association, and the Canadian Hypertensive Society, ACE inhibitors are first-line treatment for patients with a high-risk of vascular disease.

Hypertension Renal dysfunction Clinical trials examining the benefits of ARBs have focused on patients with hypertension, renal dysfunction, and heart failure; few have had sufficient power to show a significant impact on the prevention of myocardial infarction, stroke, or cardiovascular mortality. Hypertension The LIFE trial compared losartan with atenolol in 9193 subjects, 55 to 80 years old, with moderately severe hypertension and ECG evidence of left ventricular hypertrophy (LVH). Over the 5-year treatment period, patients receiving losartan had a 13% reduction of the primary composite endpoint of CV mortality, MI, and stroke; however, the positive composite endpoint was the result of a 25% reduction of stroke, with no significant reduction of MI, or CV mortality. (Dahlof B, et al. Lancet 2002;359:995-1003. Renal dysfunction Studies, such as IRMA, IDNT, and RENAAL, have demonstrated that ARBs retard the progression of diabetic nephropathy over the spectrum of the early stages of microalbuminuria to the more advanced stage of nephropathy with overt proteinuria. However, despite the high incidence of cardiovascular complications, there was no evidence of cardio-protection. (Brenner BM, et al. N Engl J Med 2001;345:870-878.)

Post myocardial infarction Clinical trials examining the benefits of ARBs have focused on patients with hypertension, renal dysfunction, and heart failure; few have had sufficient power to show a significant impact on the prevention of myocardial infarction, stroke, or cardiovascular mortality. Post myocardial infarction The OPTIMAAL trial enrolled 5477 patients with MI and symptomatic heart failure or LVD to randomized treatment with losartan 50 mg daily or captopril 50 mg tid. The primary endpoint of all-cause mortality tended to be lower in the captopril-treated patients and CV mortality was significantly lower. The results do not encourage the use of ARBs as a replacement for ACE inhibitors in patients following MI. (Dickstein K, et al. Lancet 2002;360:752-60). Heart failure A recent meta-analysis concluded that it could not show ARBs were superior to ACE inhibitors in patients with heart failure. Trials which have compared ARBs with placebo indicated that there was a trend to a benefit from ARBs. The Val-HeFT trial, for example, demonstrated a modest reduction of CHF hospitalization, but not total mortality. (Cohn JN, Tognoni G. N Eng J Med 2001;345:166-75). However, there is no conclusive trial to show that ARBs are a replacement for ACE inhibitors .

Cardiovascular disease accounts for more than 70% of the mortality in the diabetic population. The MICRO-HOPE study demonstrated the enhanced benefit of Ramipril in diabetic patients; with a 37% reduction of  cardiovascular mortality, 22% reduction of MI, and 33% reduction of stroke. The LIFE trial enrolled 1195 patients with diabetes. Patients in the losartan arm of the trial had a 24.5% reduction of cardiovascular mortality compared to the atenolol treated group. However, there was no reduction of myocardial infarction or stroke. Furthermore, the application of the results of the LIFE trial is limited to patients with moderately severe hypertension and ECG evidence of LVH. Gerstein HC, et al. (MICRO-HOPE). Diabetes Care 1996;19:1225-28. Lindholm LH, et al. (LIFE) Lancet 2002;359:1004-10.

Angiotensin converting enzyme inhibitors have been shown in multiple clinical trials to limit the progression of cardiovascular disease from asymptomatic phase through to severe heart failure. Consistent benefits are observed with ACE inhibition in a wide range of sub-groups. ARBs in contrast, have made little impact on the progression of cardiovascular disease. The only ARB study (LIFE) with vasculo-protective data shows inconsistent outcomes across subgroups, and the findings are not widely applicable.

ACE inhibitors should be strongly considered for cardiovascular protection in high risk patients, just as we consider lipid lowering today. ARBs are a useful adjunct for enhanced blood pressure control, especially in the diabetic patient with nephropathy. For patients with heart failure who are intolerant of ACE inhibitors, an ARB may be used with some confidence. However, there is no evidence to support the claim that ARBs are a replacement for ACE inhibitors, especially for vascular protection, but more data may be forthcoming.