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Angiotensin II type 1 (AT1) receptor blockers, such as candesartan, are attractive alternatives to ACE inhibitors in the treatment of hypertension and cardiovascular disease. Although angiotensin-converting enzyme (ACE) inhibitors are able to suppress the renin-angiotensin system (RAS), their mechanism of action may limit their clinical utility in the treatment of hypertension. For example, they act as competitive inhibitors of ACE. This means that their effects can be overcome by high levels of angiotensin I, which occur after ACE inhibition due to removal of the negative feedback effect of angiotensin II on renal renin release. ACE inhibitors are also unable to block the production of angiotensin II by non-ACE-mediated pathways. Furthermore, ACE is not a specific enzyme. Its inhibition therefore has effects on other substances, such as bradykinin, leading to the class-specific side effects associated with ACE inhibitors. Candesartan, on the other hand, binds insurmountably to the AT1-receptor, thereby providing more complete blockade of the negative cardiovascular effects of angiotensin II than is possible with ACE inhibitors. The specificity of AT1-receptor blockade also ensures that efficacy is achieved without inducing the side effect of cough that results from the non-specific consequences of ACE inhibition. Preclinical and early clinical studies demonstrate that AT1-receptor blockers produce at least the same degree of target-organ protection as has been demonstrated for ACE inhibitors. Additional benefits of AT1-receptor blockers may arise from the fact that, unlike ACE inhibitors, they do not prevent the activity of angiotensin II on AT2-receptors in the heart, which is thought to reduce cardiac remodelling. From a mechanistic perspective, therefore, AT1-receptor blockers appear to have advantages over ACE inhibitors, in terms of a more complete blockade of angiotensin II effects, while also avoiding the specific side effects associated with ACE inhibition.

Patients with hypertension do not comprise a homogeneous group, and the majority present with a variety of concomitant and associated conditions. Antihypertensive therapies should therefore be effective and well tolerated in a wide range of patients and should, ideally, ameliorate the negative target-organ effects of hypertension, such as atherosclerosis, cardiovascular remodelling and renal impairment. Evidence is accumulating that the new angiotensin II type 1 receptor blocker, candesartan cilexetil, lowers blood pressure effectively and is well tolerated in a variety of patient groups, including women and the elderly. In patients with severe hypertension, a treatment schedule based on candesartan cilexetil, with the addition of diuretic and calcium antagonist therapy as needed, has been found to control blood pressure successfully. Candesartan cilexetil does not affect glucose tolerance or lipid profiles in patients with diabetes mellitus, and it is not associated with any of the side effects of other antihypertensive agents that would make it unsuitable for use in patients with pulmonary disease. Initial clinical studies have indicated that candesartan cilexetil is well tolerated and effective in patients with heart failure. Furthermore, the available evidence shows that treatment with candesartan cilexetil can reverse the negative effects of hypertension on left ventricular hypertrophy and microalbuminuria. It therefore appears that the pronounced efficacy and placebo-like tolerability of candesartan cilexetil, as demonstrated in large clinical trials of patients with mild to moderate hypertension, can be extended to a wide range of specific patient groups.

There is strong evidence that ambulatory blood pressure measurements show only limited agreement with blood pressures measured in the clinic ("office" blood pressures), and are more relevant to the prognosis of hypertension. Several markers of end-organ damage, for example, have been shown to correlate more strongly with 24-h blood pressure than with office blood pressure. In addition, end-organ damage has been shown to be correlated with 24-h blood pressure variability. Ambulatory blood pressure monitoring (ABPM) has revealed a number of differences between the blood pressure profiles of elderly and younger patients. Since 24-h blood pressure control is now widely accepted as an important goal of antihypertensive therapy, ABPM has a potentially useful role in monitoring treatment in clinical trials in elderly patients.

Potency and efficacy, duration of action, organ-specific effects and tolerability are the main considerations when choosing among antihypertensive therapies. Candesartan has been shown in in vitro animal models to bind insurmountably to the angiotensin II type 1 (AT1) receptor, thus providing effective blockade of all the major negative cardiovascular effects of angiotensin II. Its binding characteristics differentiate candesartan from other AT1-receptor blockers. Candesartan cilexetil has been found to produce a predictable and pronounced dose-dependent decrease in blood pressure, with placebo-like tolerability even at the highest doses studied. In comparison with the standard 50-mg dose of losartan, candesartan cilexetil, 16 mg, was significantly more effective in suppressing the renin-angiotensin system and in reducing trough diastolic blood pressure. Pooled results from placebo-controlled trials also indicate that candesartan cilexetil has equivalent efficacy to irbesartan. In addition, the extent of blood pressure lowering by candesartan cilexetil has been shown to be similar to that of agents in the other major classes of antihypertensive drugs, and to be effective in combination therapy with diuretics and calcium channel blockers. Candesartan cilexetil combines 24-h blood pressure lowering with placebo-like tolerability and is therefore an important advance in antihypertensive therapy.

Heart failure remains a major and increasing cause of mortality and morbidity, even when the best available treatments are used. One of its key causes is neuroendocrine activation via the sympathetic nervous system and the renin-angiotensin system (RAS). Neuroendocrine blockers of the sympathetic nervous system (beta-blockers) and of the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin II type 1 [AT1] receptor blockers) therefore have an important potential therapeutic role in heart failure. The promising results from clinical trials with beta-blockers suggest that these drugs will become an established part of the future management of patients with mild to moderate symptomatic heart failure. Blockade of the RAS with ACE inhibitors has also been shown to be effective in reducing the risk of morbidity and mortality in patients with heart failure. Blockade of the AT1-receptor, with agents such as candesartan, produces more specific and, theoretically, more complete blockade of the major negative cardiovascular effects of angiotensin II than is possible using ACE inhibitors, whilst maintaining placebo-like tolerability. Furthermore, AT1-receptor blockade leads to increased stimulation of the angiotensin II type 2 (AT2) receptor, which, according to experimental data, may have favourable cardiovascular effects. Following encouraging results from two pilot studies, a major new international study programme - CHARM (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) - has been initiated to define the clinical benefits of candesartan cilexetil in a wide variety of patients with symptomatic heart failure. CHARM is the first study to accept all relevant heart failure patients who may benefit from RAS blockade, irrespective of their left ventricular function or tolerance of ACE inhibitors. The 6500 patients to be recruited will be divided among three integrated outcome studies. Two of these studies will examine the effect of candesartan cilexetil versus placebo in patients with an ejection fraction of 40% or less who are tolerant or intolerant of ACE inhibitors. The third study arm will examine the benefits of candesartan cilexetil in a previously seldom studied group: those with symptomatic heart failure, but with preserved left-ventricular systolic function. Recruitment of patients into the study has started.

The second Swedish Trial in Old patients with Hypertension (STOP-Hypertension-2) was conducted to compare the effects of "newer" antihypertensive therapies (angiotensin converting enzyme [ACE] inhibitors and calcium antagonists) and established therapies (beta-blockers and diuretics) on cardiovascular mortality and morbidity in elderly hypertensive patients. A total of 6614 patients were randomized to receive conventional treatment, ACE inhibitors or calcium antagonists, and followed for a mean of 5 years. The primary endpoint was a combination of fatal stroke, fatal myocardial infarction and other fatal cardiovascular disease; secondary endpoints were a combination of fatal or non-fatal stroke or myocardial infarction, and other cardiovascular mortality. The three treatments produced similar reductions in supine systolic blood pressure. There were no significant differences in the risk of cardiovascular events between patients receiving conventional therapy and those receiving newer therapies. All three treatments were well tolerated. The STOP-Hypertension-2 results thus add to the extensive literature showing the benefits of blood pressure reduction in elderly hypertensive patients. Moreover, they are consistent with current management guidelines which emphasise the importance of the achieved blood pressure reduction in the prevention of cardiovascular events.

Epidemiological studies have highlighted the increasing prevalence of hypertension with age, and the associated increase in the risk of cardiovascular disease. A number of randomized controlled trials have shown that antihypertensive treatment significantly reduces cardiovascular mortality and morbidity in elderly patients, and there is evidence that the benefit achieved is related to the extent to which blood pressure is lowered. Furthermore, a recent analysis of data from the Hypertension Optimal Treatment (HOT) Study shows that intensive therapy produces significantly greater reductions in blood pressure in elderly patients than in younger patients, without increasing the risk of adverse events. As a result, the latest management guidelines recommend that the goal of antihypertensive therapy in elderly patients should be to achieve at least high normal blood pressures (below 140/90 mmHg). Angiotensin II type 1 receptor antagonists offer a new option for antihypertensive therapy in elderly patients, and trials such as the Study on Cognition and Prognosis in the Elderly (SCOPE) are currently investigating the effect of these agents on cardiovascular mortality and morbidity in elderly hypertensive patients.

Suppression of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors is an established method for controlling blood pressure and reducing the risk of cardiovascular disease. In addition to reducing blood pressure, suppression of the RAS is able to protect against the target-organ damage that results from hypertension. Unfortunately, despite the use of ACE inhibitors and agents from the other classes of conventional antihypertensives, effective control of blood pressure remains poor. A major contribution to this failure to control blood pressure appears to be lack of compliance with the prescribed medication, arising from the presence of unacceptable side effects. Angiotensin II type 1 (AT1) receptor blockers, such as candesartan, are the latest class of antihypertensive agent to be developed. They target the AT1-receptor - the final common pathway for all the known negative cardiovascular effects of angiotensin II - and provide pronounced antihypertensive efficacy without the side effects of cough and angioneurotic oedema that are associated with the use of ACE inhibitors.

Candesartan cilexetil is highly effective at lowering blood pressure, whilst maintaining placebo-like tolerability, in a wide range of patient groups. Although the benefit of lowering blood pressure in elderly patients with moderate hypertension has been demonstrated in several large-scale clinical trials, elderly patients with mild hypertension have rarely been studied. The high incidence of cardiovascular and cerebrovascular mortality and morbidity, including dementia, in the elderly means that control of blood pressure is particularly important in this patient group. A major new international clinical trial - SCOPE (Study on COgnition and Prognosis in the Elderly) - has therefore been initiated. This is a prospective, randomized, double-blind, parallel comparison of the effects of candesartan cilexetil, 8 or 16 mg once daily, and placebo in about 5000 patients who will be followed for a mean of 2.5 years. SCOPE is the first study designed to assess the effect of antihypertensive therapy in elderly patients (70-89 years of age) with mild hypertension (sitting systolic blood pressure of 160-179 mmHg and/or sitting diastolic blood pressure of 90-99 mmHg). The primary objective of the study is to determine the effect of candesartan cilexetil on major cardiovascular events (cardiovascular death, non-fatal stroke and myocardial infarction, and silent myocardial infarction), while an important secondary objective is to determine the effect of such treatment on the prevention of cognitive impairment. SCOPE should provide definitive evidence of the cardiovascular and cerebrovascular benefits of treating mildly hypertensive elderly patients with angiotensin II type 1 receptor blockers, which not only reduce blood pressure, but may also provide significant protection from the negative effects of angiotensin II on target organs.

Several angiotensin II type 1 (AT1) receptor blockers are now available for the treatment of hypertension. Although the agents in this class all act by blocking the AT1-receptor, they differ in their pharmacokinetics and binding characteristics. One of the newest AT1-receptor blockers, candesartan cilexetil, is administered in an inactive form and is rapidly and completely converted to the active drug, candesartan, during gastrointestinal absorption. In vitro studies have shown that candesartan has the highest receptor affinity of all the available AT1-receptor blockers and is not displaced from the receptor by high concentrations of angiotensin II. The tight and long-lasting binding of candesartan to the AT1-receptor provides effective blockade of the negative cardiovascular effects of angiotensin II.