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You are here: Hot Topics in Cardiology - Editors-in-chief: Sergio Dalla Volta, Christopher P. Cannon
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HOT TOPICS IN CARDIOLOGY: Issue 5, 2007
Angiotensin AT1 receptor antagonists in patients at high risk for cardiovascular events: the state of the art

Angiotensin AT1 receptor antagonists in patients at high risk for cardiovascular events: the state of the art

Thomas Unger, Jan H. Schefe
Correspondence to:
Thomas Unger - M.D.
Professor of Pharmacology
Center for Cardiovascular Research (CCR)/ Institute of Pharmacology
Charité - Universitätsmedizin Berlin
Campus Charité-Mitte
Berlin, Germany
E-mail: thomas.unger@charite.de

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The use of angiotensin AT1 receptor antagonists, or blockers (ARBs), is the most recent step toward innovating antihypertensive drugs in the past 50 years. The first compound of this new drug class, losartan, was launched in 1995 for treatment of hypertension. In the following years, new ARBs-valsartan, irbesartan, eprosartan, candesartan, telmisartan, and olmesartan-were introduced and became important drugs widely used in clinical practice.
Since there are several alternatives to ARBs on the market (eg, beta-blockers, diuretics, calcium channel blockers, and angiotensin-converting enzyme inhibitors [ACEIs]), one may ask whether they constitute a needed new drug class. What is so special about them? Are the ARBs superior to other antihypertensives, especially compared to the well-known ACEIs? Are there any properties that render ARBs more than just antihypertensives?
From a pharmacological point of view, ARBs inhibit-as do the already very successfully used ACEIs-one of the most important cardiovascular regulatory systems: the renin-angiotensin system (RAS). The ACEIs reduce the production of angiotensin II, the effector peptide of the RAS. In contrast, ARBs act more specifically by selectively blocking the angiotensin AT1 receptor (AT1R) without affecting the angiotensin AT2 receptor (AT2R).The question of the "good" versus "bad" guy under the angiotensin receptors has always been a matter of dispute; nevertheless, it is widely acknowledged that most of the negative effects of RAS activation, such as vasoconstriction, sodium retention, and endothelial dysfunction, are widely conducted by the AT1R, whereas the AT2R often functionally offsets the effects of AT1R. This shift could be a major improvement and advantage of the ARBs-but, as always, clinical trials will have to offer the "proof of concept."
From a clinical point of view, ARBs are comparably effective in lowering blood pressure as other antihypertensive drug classes; they also have proved to protect organs in a similar way to that of the ACEIs and, in some cases, offer even superior protection compared to that of other drug classes. This protection of cardiac, renal, vascular, and metabolic function cannot be explained by their blood­pressure-lowering effects alone. Moreover, it also has been shown that ARBs significantly lower hypertension­associated mortality.
Taken together, it is justified to classify ARBs as first­line medication for hypertensive patients. Consequently, ARBs have been integrated into the treatment guidelines of all leading international organizations, especially since this drug class offers very few adverse effects. This lack of adverse effects should contribute to a better and longer­lasting compliance by patients and should ensure a high safety of treatment.
This text is intended to offer state-of-the-art knowledge concerning the ARBs and, especially, their application to patients at high risk for cardiovascular events. The reader will be introduced into the broad field of the RAS-its compounds and its significance under physiological and pathophysiological conditions. After introducing the different ARBs, the focus will shift to the rationale of their application under different pathophysiological conditions, such as hypertension, chronic heart failure, coronary artery disease, stroke, and diabetes. All of these diseases will be addressed by a brief introduction into pathophysiological aspects, the effects of RAS and, especially, AT1R blockade and the state of evidence deduced from clinical trials.

THE RENIN-ANGIOTENSIN SYSTEM: GENERAL ASPECTS

The RAS is an endocrine system whose main effector peptide angiotensin II (Ang II) can be found as a circulating hormone within the plasma, as well as locally produced, and acting in several tissues (as so-called tissue-RAS).The enzyme at the top of the RAS cascade, renin, was discovered in 1898 by Tigerstedt and Bergmann when they observed an increase in blood pressure after injection of kidney extracts into rabbits.
The substrate of renin has been identified as the plasma protein angiotensinogen several years later. Together with the discovery of angiotensin I (Ang I), a decapeptide derived from angiotensinogen, the idea of an RAS was born. Up to the 1950s, scientists assumed that Ang I mediated the vasoconstrictive effects of RAS activation. This model changed when ACE and its enzymatic cleavage of Ang I to the octapeptide Ang II was found in endothelial cells of the lung. In 1958, Gross was able to show aldosterone liberation from adrenal glands after renin-angiotensin activation, thereby adding the last piece of evidence for an RAS as it is basically known today.
Studies in the last decades found more and more evidence not only for a circulating "plasma-RAS" but also a "tissue-RAS," where all components of the RAS (ie, angiotensinogen, renin, ACE, angiotensin peptides, and the angiotensin receptors) are synthesized locally and also seem to be independently and differently regulated from the global, circulating RAS. Known examples for this tissue-RAS are the vessel wall, kidney, adrenal glands, and brain.

Biochemistry of the renin-angiotensin system

The synthesis of Ang II, the effector peptide of the RAS, begins with enzymatic cleavage of angiotensinogen by renin, resulting in the production of Ang I. Ang I is further processed by ACE to Ang II. The action of Ang II is mainly mediated by two receptors, the AT1R and AT2R (Figure 1).

HTC - 5 : Cardio 24-8 fig. 1_th.jpg  Figure 1. Biochemistry of the renin-angiotensin system.

Angiotensinogen

Angiotensinogen is a glycosylated α2-plasma globulin with a molecular weight of approximately 56 kDa, and the only known substrate for renin. The synthesis of angiotensinogen is mainly located in the liver, where it is constitutively liberated into the plasma. As already mentioned, this synthesis may also be found in several tissues, such as in the brain, heart, kidney, adrenal glands, ovaries, and testes. Stimulation of synthesis and liberation within the liver can be induced by glucocorticoids, estrogens, and thyroxine, but also Ang II itself, thereby inducing a positive feedback loop.

Renin

Renin is a member of the aspartyl protease family, which exhibits - in contrast to the other family members - the highest activity at neutral pH values. Its synthesis occurs predominantly in the juxtaglomerular apparatus (JGA) of the kidney from which its release into the plasma is mainly stimulated by a decreased stretch in the afferent arteriole of the JGA, decreased delivery of sodium chloride to the macula densa, or increased adrenergic stimulation via β1-adrenoceptors.
Since the plasma activity of renin may be acknowledged as the rate-limiting step of the RAS cascade, the negative regulation of Ang II on renin liberation via the AT1R logically establishes the most important regulation loop of the RAS homeostasis.
The renin gene transcribes and translates for 340 amino acids of preprorenin, which is processed to prorenin with a molecular weight of 57 kDa within the cell. Under normal conditions, prorenin is enzymatically inactive. Only a part of the prorenin is further cleaved to renin with a molecular weight of 40 kDa. Therefore, the proportion of secreted prorenin to renin is approximately 10 to 1 under physiological conditions. Renin's only classically known "molecular duty" is the enzymatic production of the decapeptide Ang I.

Angiotensin-converting enzyme

ACE is a dipep­tidylcarboxypeptidase with a molecular weight of over 150 kDa, which is mainly localized ubiquitously in the vascular endothelium, most abundantly in the lung. It catalyzes the processing of Ang I into the octapeptide Ang II. In contrast to renin, ACE is not highly specific to only one substrate and also plays a role in the metabolism of bradykinin, enkephalins, substance P, and insulin. The inhibited cleavage of bradykinin to inactive metabolites, especially in the context of ACE inhibition, thereby preserves high bradykinin activity, which results in increased levels of nitric oxide and prostaglandins. This is often discussed as an important mechanism producing the beneficial effects of ACEIs concerning the vascular or cardiac function, but also resulting in the adverse effects of coughing and angioneurotic edema.
As much as ACE may cleave various substrates, there are also various enzymes that may process Ang I to Ang II. Trypsin, chymase, and cathepsin G have been identified as Ang-II-processing enzymes, but their physiological and pathophysiological significance is still a matter of debate. However, they may become important generators of Ang II under the condition of ACE inhibition.

Angiotensin receptors

The AT1R is a 7-transmembrane domain receptor, coupled to a guanosine triphosphate-binding protein (G-protein), with a signaling pathway that involves phospholipases A, C, and D; inositol phosphates; calcium channels; and a variety of serine/threonine and tyrosine kinases. It is expressed in somatic and brain tissues, predominantly in organs and tissues involved in fluid and electrolyte balance, as well as blood pressure regulation (ie, adrenal glands, vascular smooth muscle cells, kidney, and heart).
The AT2R is also a 7-transmembrane glycoprotein and has approximately 34% amino acid sequence homology to the AT1R. Less is known about the AT2R signaling pathways, but evidence suggests that serine and tyrosine phosphatases, phospholipase A2, nitric oxide, and cyclic guanosine monophosphate (cGMP) are involved. Direct protein interaction partners of the AT2R (eg, promyelocytic leukemia zinc finger [PLZF] and AT2R binding/interacting protein [ATBP/ATIP]) have been identified.
AT2Rs are present at a high density in many tissues during fetal development, but they are much less abundant in adult tissues, being expressed at high concentrations only in the adrenal medulla, uterus, ovary, vascular endothelium, and specific areas of the brain. However, following ischemic or traumatic injury, AT2R expression can be dramatically increased in the respective tissues. 

Renin receptor

As already described, renin and prorenin are classically thought of as enzymes or proenzymes, but evidence suggests that they can also act as cellular effector hormones because of their ability to bind cellular targets. A human renin receptor (RER), which can specifically bind prorenin and renin, has been cloned [1].This receptor is highly expressed in the brain, heart, and placenta, with highest levels in the brain. It appears that the RER exerts a dual function: First, binding of renin to this receptor increases the catalytic activity of renin approximately four- to fivefold. Furthermore, prorenin, which normally does not catalyse angiotensinogen to generate Ang I, has been reported to gain enzymatic activity comparable to renin by binding to the RER. This suggests that the receptor would be able to unmask the catalytic activity of prorenin. Second, the RER can induce a signal transduction cascade upon ligand binding.
Thus, binding of renin and also prorenin may cause a phosphorylation of the receptor and, subsequently, an activation of the MAP (mitogen-activated protein) kinases ERK1 and ERK2, whereas intracellular calcium or cyclic adenosine monophosphate (cAMP) levels are not altered. Furthermore, and probably more relevant, signaling pathways have been described leading to proliferative, as well as antiapoptotic, responses [2].
For further information on this topic, please see references [3-9].

PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTS OF THE RENIN-ANGIOTENSIN SYSTEM

Angiotensin-mediated effects

RAS activation can be divided into rapid or short- and long­term effects. Whereas rapid actions mainly focus on the prevention of acute hypovolemia and hypotension, the slower effects ensure the sodium homeostasis of the body.The long­term effects are more focused on structural modifications such as vascular growth and cardiac hypertrophy.

Vasoconstriction and blood pressure

Hypovolemia and hypotension are both stimuli for an activation of the RAS and result in an immediate vasoconstrictive response mainly in the arterioles, increasing the peripheral vascular resistance and thereby restoring blood pressure. In the case of minor stimuli for RAS activation and lower doses of Ang II without a direct strong vasopressor effect, the mechanisms of action increasing the blood pressure take more than just a few seconds. In this process, a gradual decrement of vascular (arteriolar) compliance, activation of the sympathetic nervous system, and increased release of aldosterone last a few days.

Sodium retention

The regulation of electrolyte and, especially, sodium balance is one of the most important tasks of a physiologically acting RAS. There are basically two ways by which Ang II mediates sodium retention. First, AT1Rs in the proximal tubuli of the kidney directly respond to high Ang II levels and increase sodium retention. Second, Ang II, also via the AT1R, activates the release of aldosterone from the adrenal glands thereby indirectly increasing sodium retention in the kidney.

Proliferation and apoptosis

In the case of long-term activation of the RAS, different effects prevail. All mechanisms induced by RAS activation described so far tend to adapt and habituate. Therefore, they are not able to ensure the cardiovascular "stability" for a long period. Consequently, the long-term effects of RAS activation induce structural changes, mainly, in the kidney, vessel wall, and heart. Here, Ang II may act as a growth factor on vascular smooth muscle cells (VSMCs) and cardiac myocytes, but also contribute to vascular, cardiac, and renal fibrosis. All these effects are mediated by the AT1R. The alteration of VSMCs increases both the strength of vascular contraction and the sensitivity of the pressor response. The increase of cardiac muscle mass logically improves cardiac strength and-under physiological conditions-ventricular ejection fraction. Taken together, however, both effects can contribute to the long-term maintenance of high blood pressure, cardiac hypertrophy, and heart failure. 

Angiotensin II effects in different organs

Heart  

All components of the RAS have been located in the heart [10]. Although renin and angiotensinogen messenger ribonucleic acids (mRNAs) have been detected in atrial and ventricular cardiomyocytes, it is generally believed that renin enters the heart from the circulation to act within the cardiac RAS [11]. Lowering of plasma sodium levels seems to be an important stimulus for local renin expression and activity, whereas angiotensinogen expression is stimulated-partially comparable to its synthesis in the liver-by glucocorticoids, estrogens, and thyroxine. ACE is also located in the heart, especially in the endothelial cells of the cardiac vasculature and valves. Angiotensin receptors have been mainly localized to cardiac myocytes and sympathetic nerve fibers. The physiological effects of Ang II on heart function are rather complex and modulated by direct and indirect mechanisms. In general, RAS activation causes an increase in heart rate and cardiac strength - first, through direct activation of the AT1R, second, by modulation of the sympathetic nervous system activity. In addition, arrhythmogenic effects have also been ascribed to cardiac AT1R activation (Figure 2).

 
HTC - 5 : Cardio 24-8 fig. 2_th.jpg		 Figure 2. Angiotensin II and cardiovascular disease.

Brain

All RAS components have been located in the brain. The AT1R is located in various brain areas but predominantly in periventricular regions. Injection of Ang II into the ventricles induces various responses that include an activation of the hypothalamus and pituitary gland and a modulation of central sympathetic and vagal tone.
Central AT1R stimulation induces thirst, natriuresis, and water retention by release of increased vasopressin into the circulation, as well as release of thyrotropin, follicle­stimulating, luteinizing, growth, and corticotropin hormones from the pituitary gland. Some of these AT1R-mediated central nervous system Ang II actions can be antagonized by stimulation of AT2R in the brain [12,13].

Kidney

The kidney is probably the most "classical" organ of the RAS-several regulatory processes as well as functional effects of the RAS are located there. Despite the predominant synthesis and release of renin in the JGA, small amounts of renin were detected in the proximal and distal tubules. Angiotensinogen and ACE can be found in high amounts in the proximal tubules, thus causing Ang II concentrations in this area to be 1000 times higher than the average plasma levels. This indicates that the kidney possesses a highly active local tissue-RAS. Activation of the RAS strongly influences glomerular hemodynamics and tubular reabsorption. Ang II induces vasoconstrictive effects on the afferent but, predominantly, efferent arteriole of the glomerulus and increases sodium and water reabsorption in the proximal tubule. Additionally, RAS activation alters the tubular-glomerular feedback leading to a decrease of renal perfusion. Taken together, the main effect of Ang II in the kidney is the retention of water and sodium.
Under evolutionary considerations, the RAS maintains the blood pressure under conditions of poor sodium and water intake. Nowadays, these important mechanisms have to be considered as pathophysiological factors in the development and maintenance of hypertension, renal fibrosis, glomerular sclerosis, and renal failure.

Vascular wall

The vessel wall with its multiple compounds (endothelial cells, VSMCs, fibroblasts, etc) is a highly complex system whose homeostasis concerning tonus, radius, and coagulation is maintained by numerous factors. Vasodilatation is caused by prostacyclins (such as PGI2) or nitric oxide, for example. Main contributors to vasoconstriction are noradrenaline, Ang II, and endothelin. An imbalance between these opposing factors is thought to be a major aspect in the pathogenesis of hypertension, as well as atherosclerosis.
As observed in other tissues, the vessel wall, which contains renin and angiotensinogen, also expresses its own local RAS. ACE is mainly located in endothelial cells.Additionally, there are other enzymes located in the vessel wall (eg, the chymase-like enzyme, chymostatin-sensitive Ang II-generating enzyme [CAGE] and others) bypassing the enzymatic step mediated by ACE. Besides the classical vasoconstrictor response to Ang II, there is also evidence for the induction of vascular hypertrophy and, especially, inflammatory vascular processes by an activated RAS. These effects with crucial significance under condition of (pre)atherosclerosis have all been attributed to the AT1R, while stimulation of AT2R has been shown to exert anti­inflammatory actions.

Physiological and pathophysiological aspects of the angiotensin receptors

Virtually all of the known regulatory actions of Ang II on blood pressure and osmoregulation discussed earlier (ie, vasoconstriction, aldosterone and vasopressin release, renal sodium retention, and decreased renal blood flow) have been attributed to the AT1R. These effects on blood pressure and electrolyte homeostasis play an essential and physiological role at an earlier point in animal and human evolution to maintain adequate organ perfusion at times of acute volume loss; nowadays, they seem to be largely redundant in our modern civilizations. More important for "modern" human beings are the pathophysiological consequences caused by AT1R activation.
In this regard, AT1R stimulation has been shown to mediate inflammatory reactions, cell growth, and proliferation of, among others, vascular, cardiac, and renal cells. Accordingly, the AT1R has been implicated in various cardiovascular, renal, and cerebral pathologies, such as left ventricular hypertrophy, vascular media hypertrophy, cardiac arrhythmias, atherosclerosis, glomerulosclerosis, cerebral stroke, and vascular dementia (see Figure 2). Inhibition of the effects of Ang II by selective AT1R blockade is, therefore, expected to offer therapeutic benefit in numerous cardiovascular conditions, for instance, in hypertension to inhibit vasoconstriction and prevent vascular and cardiac hypertrophy and also atherosclerosis.
In contrast, the expression of the AT2R, normally expressed at low levels in the adult, is upregulated under certain conditions, such as in heart failure and postinfarct repair, as well as tissular lesions (eg, in the skin and nervous system).The AT2R thus appears to be involved in the control of cell proliferation, cell differentiation and development, angiogenesis, wound healing, tissue regeneration, and even apoptosis-that is, the biological processes that often counteract the trophic responses mediated by the AT1R. There is experimental evidence that, in a milieu of selective AT1R blockade, circulating Ang II would act at unopposed AT2R, thereby unmasking a vasodilatory component of the arterial blood pressure response to Ang II. By the same inference, AT1R blockade would be expected to preserve or even augment the favorable effects of Ang II on cell growth and proliferation mediated through the AT2R.
For further information on this topic, please see references [3-9].

PHARMACOLOGY OF ANGIOTENSIN AT1 RECEPTOR ANTAGONISTS

General pharmacological aspects

AT1R blockers, so-called ARBs or sartans, are the latest drug class introduced for the treatment of hypertension and were first launched in 1995 (Figure 3). They specifically and selectively block the activation of AT1R by Ang II via direct competition with Ang II at the receptor [14]. As previously mentioned, AT1R and AT2R both reveal similar affinities for Ang II, but clearly distinguish themselves in their molecular structure, their signal transduction, and their intracellular effects. The affinity of ARBs for AT1R is about 10,000 times higher compared to their affinity to AT2R.

HTC - 5 : Cardio 24-8 fig. 3_th.jpg

Figure 3. Development of antihypertensives.


Therefore, AT2R functions are not inhibited by therapeutic doses of ARBs [15].
This contrasts with the ACEIs that reduce the synthesis of Ang II by inhibiting ACE, thereby attenuating the action of Ang II at both angiotensin receptors. As there are alternative pathways to generate Ang II, via ACE-bypassing enzymes such as cathepsin G or chymase, remarkable amounts of Ang II may be still generated. This has been shown, for instance, in cardiac and renal failure [16]. Under these conditions, only ARBs-and not ACEIs-would be able to inhibit AT1R-mediated cellular effects of Ang II completely.
Under blockade of AT1Rs, there is also a lack of negative feedback on the production of renin-the rate­limiting step of the RAS cascade-by Ang II. In patients receiving treatment with ARBs, high plasma levels of Ang II may be detected and should logically increase the stimulation of the AT2R [15]. This could be an additive advantage of ARBs in comparison to the pharmacological concept of ACEIs.
Nevertheless, mechanistic differences between ACEIs and ARBs discussed earlier do not seem to engender any differences in their potential to lower blood pressure. Advantages of one of the drug classes compared to the other concerning end-organ damage or metabolic effects, for example, in long-term use are still under debate and await the results of large clinical trials, such as the ONTARGET/TRANSCEND trial comparing the ARB telmisartan with the ACEI ramipril in patients at high cardiovascular risk. The results will be available in 2008 (see later).

Adverse effects and contraindications

It has been shown in a large amount of clinical trials that the drug class of ARBs is extremely well tolerated. There are nearly no characteristic adverse effects when these drugs are used correctly. Indeed, the observed adverse effects in the ARB-treated groups have not been significantly different from those in the placebo-treated group. Cough, a common adverse effect of ACEIs, has not been observed in ARB-treated patients at an incidence above placebo, and angioneurotic edema has been reported only in a few exceptional cases [17].
The rare case of hypersensitivity against ARBs is obviously a contraindication. During pregnancy and lactation, ARB medication such as ACEI treatment is contraindicated. In all pathologies where an activated RAS substantially contributes to cardiovascular stabilization, all RAS inhibitors, including ARBs, are also contraindicated. These include severe cases of hypovolemia, hypotension, and renal artery stenosis, as well as hemodynamically relevant stenosis of the aortic or mitral valve and primary hyperaldosteronism. An insufficiency of hepatic and renal function is normally no contraindication for ARB medication, but may lead to necessary modifications of the prescribed daily doses.

Differences between angiotensin AT1 receptor antagonists

All ARBs have an acceptable bioavailability, which is unaffected by parallel food intake (except for valsartan: reduction of resorption is approximately 50%).The duration of action is about 24 h for all substances, with that of losartan, valsartan, and eprosartan being somewhat shorter. Therefore, 1 dose per day is usually sufficient, especially for the newer members of the sartan family such as irbesartan, candesartan, telmisartan, and olmesartan, and for all of them when given in combination with a diuretic or calcium channel blocker. In general, most ARBs are eliminated unchanged by the kidney and via feces.
Losartan [18] was the first developed ARB. Losartan is pharmacologically a prodrug that is converted via CYP2C9 and 3A4 into the active metabolite EXP3174 with a 10 to 40 times higher potency. The daily dose is 50 to 100 mg. In contrast to other ARBs (administered in 1 dose daily), losartan should be administered in 2 daily doses, since the plasma half-life of losartan is only 2 h and that of EXP3174 6 to 9 h. Losartan shows uricosuric activity, which is not a class-specific effect, but may be potentially beneficial when combined with thiazide diuretics.
Losartan was studied in a number of large clinical trials. The ELITE-I study comprising only a small number of patients demonstrated losartan's superiority compared to captopril in patients with chronic heart failure, whereas the ELITE-II study, with appropriate statistical power, showed equal potency of both drugs. In the LIFE study in hypertensive patients with left ventricular hypertrophy, when losartan was compared with atenolol it showed a reduction of the primary end point, stroke incidence, and incidence of new-onset diabetes under conditions of equal blood pressure reduction.
Irbesartan [19] is an ARB with a plasma half-life of 12 to 15 h and is administered at daily doses of 75 to 300 mg. Irbesartan has demonstrated impressive, beneficial actions in hypertensive patients with microalbuminuria and diabetic kidney disease (IRMA-2 and IDNT trial).
Candesartan cilexetil [20] is an inactive prodrug that, after oral administration, is converted into candesartan in the small intestine. The daily dose is 4 to 16 mg (in some countries 32 mg). The CHARM studies established candesartan cilexetil in the treatment of chronic heart failure.
Eprosartan [21] has a plasma half-life of 5 to 7 h comparable to losartan. The daily dose of 300 to 600 mg is administered once or twice a day. Eprosartan reduced cardiovascular events in poststroke patients significantly better than did the calcium channel blocker nitrendipine despite identical blood pressure reductions (MOSES study).
Olmesartan medoxomil [22,23] is the newest member of the ARB family. After oral ingestion, this inactive prodrug is converted into the active metabolite olmesartan. The plasma half-life is 10 to 15 h, allowing for a once-daily administration of 10 to 40 mg. Currently, large-scale intervention studies such as ROADMAP are ongoing. Telmisartan [24] features the longest plasma half-life of all the ARBs. It is administered once daily at doses between 40 and 80 mg. Telmisartan, like some but not all ARBs, has displayed insulin-sensitizing actions through modulation of the nuclear factor peroxisomal proliferator-activated receptor­gamma (PPARγ). So far, telmisartan is the first ARB known to have these effects at plasma concentrations that can be reached by conventional therapeutic doses [25]. The value of this dual mode of action is, among other things, currently the subject of the ONTARGET and TRANSCEND studies.
Valsartan [26] with a plasma half-life of 9 to 12 h can be administered once daily at 80 to 160 mg. Like candesartan, valsartan (320 mg per day) has proved to be effective in the treatment of chronic heart failure (Valsartan Heart Failure Trial [Val-HeFT study]). Like the other ARBs in their particular trials, valsartan also has proved to reduce new-onset diabetes in the VALUE study.
Undoubtedly, the ARBs have enriched the therapeutic options for antihypertensive treatment. All ARBs are characterized by a good antihypertensive effect, acceptable pharmacokinetic profile, and excellent tolerability. Especially the absence of dry cough, a common adverse effect of ACE inhibition, represents a clinical advantage over the ACEIs and greatly helps toward establishing a long-lasting compliance of chronically treated hypertensive patients. Long-term randomized clinical trials (LIFE, VALUE, SCOPE) have not only proved the antihypertensive efficacy of the ARBs but, furthermore, have demonstrated their high potential for protection against the well-known com­plications of hypertensive disease such as myocardial infarction (MI), cerebral stroke, and chronic heart failure.
In their interaction with the AT1R, candesartan, olmesartan, and telmisartan display so-called insur­mountability due to tight receptor-binding of long duration. Valsartan, irbesartan, and the active metabolite of losartan, EXP3174, are intermediates, while losartan itself and eprosartan are surmountable receptor blockers. The feature of insurmountability contributes to the duration of action (together with the plasma half-life) and helps to explain why some of the ARBs can lower blood pressure over more extended periods than can others [27].
Some of the ARBs feature an additional so-called pleiotropic mode of action, such as the activation of PPARγ in the case of telmisartan. The value of such "add-ons" will have to be evaluated in defined clinical studies and in daily practice. However, it is possible that in the future, new ARBs will be developed that maintain their AT1R-blocking ability but have an even higher propensity to activate or modulate PPARs, and by doing so exert even stronger metabolic actions than the presently available ARBs.

ANGIOTENSIN AT1 RECEPTOR ANTAGONISTS AND HYPERTENSION

Hypertension is one of the most significant diseases in modern civilization. According to the World Health Organization's (WHO's) MONICA project (prevalence study with 4000 subjects in Germany), 1 out of 3 persons between the ages of 55 and 64 years suffers from hypertension. The prevalence in the group of people aged over 65 years has been determined as more than 50% [28].
Primary hypertension has to be seen as a multifactorially influenced pathophysiological continuum [29]. Hypertension­associated or hypertension-induced end-organ damage determines mortality.
First, hypertension is a major factor in the development of atherosclerosis and vascular hypertrophy. It further induces an increase in cardiac afterload, thereby increasing intraventricular pressure and ventricular wall tension leading to a hypertrophy of cardiac myocytes and a decrease in cardiac perfusion. Beyond the borders of physiological compensation, the ventricles will dilate, the ejection fraction will decrease, and the myocardial metabolism and perfusion will decompensate with the clinical result of chronic heart failure.
Moreover, hypertension is one of the most important risk factors for nonhemorrhaghic and hemorrhagic cerebral stroke. The risk for apoplexia is 2 to 3 times higher in patients with hypertension than it is in healthy people; probably more than 40% of cerebral strokes could be prevented with adequate lowering of blood pressure [30]. Predominant organs damaged by hypertension are also the kidney and the eyes (hypertensive retinopathy).
For all of these reasons, the best antihypertensive therapy should not only lower blood pressure, but-above all-decrease the risk and progression of hypertension­associated complications. In addition, drugs initially developed to lower blood pressure may also turn out to exert beneficial actions in patients at increased car­diovascular risk with and without hypertension, as already demonstrated in the HOPE trial [31].

Clinical trials

Since the introduction of ARBs for therapy of hypertension, clinical trials have examined whether these drugs provide an equal or even greater reduction in the risk of cardiovascular end points in comparison to classical therapeutic approaches with diuretics, beta-blockers, and calcium channel blockers in hypertensive patients.

LIFE

The Losartan Intervention For Endpoint Reduction in hypertension study [32,33] was a randomized, double-blind study with 9193 patients suffering from hypertension (diastolic blood pressure, 95 to 115 mmHg, and/or systolic, 160 to 200 mmHg, after 2 weeks of placebo treatment) and left ventricular hypertrophy. Patients were treated for no less than 4 years (average of 4.8 years) with losartan or atenolol 50 mg daily, each. If blood pressure was not lowered to the target of 140/90 mmHg after 2 months, 12.5 mg of hydrochlorothiazide (HCT) was added to the medication. If target blood pressure was still not achieved after an additional 2 months, the losartan or atenolol dose was doubled. After another 2 months, those patients with levels still above the target blood pressure point received additional HCT or other open-label medication as diuretics or calcium channel blockers (but no ARBs, ACEIs, or beta-blockers). The primary end point was composite cardiovascular morbidity and mortality defined as MI, cerebral stroke, or cardiovascular death.
At randomization, the mean blood pressure was 174/98 mmHg in a patient population with an average age of 66.9 years and a body mass index of 28.9 kg/mm2. Blood pressure was lowered in the losartan group by 30.2±18.5 (systolic) and 16.1±10.1 mmHg (diastolic) and in the atenolol group by 29.1±19.2 (systolic) and 16.8±10.1 mmHg (diastolic). Mean arterial pressure was nearly identical with 102.2 and 102.4 mmHg in the losartan and atenolol group, respectively. The average doses were 82 mg of losartan and 79 mg of atenolol.
The LIFE study found that only 11% of the patients in the losartan group experienced a primary end point compared to 13% in the atenolol group (adjusted risk reduction [RR; according to Framingham risk score] of 13%, p = .021). The most significant contributor to the composite end point was stroke (10.8/1000 patients treated with losartan vs 14.5/1000 patients treated with atenolol; RR 25%; number needed to treat [NNT] = 270). There was no significant difference in the end points in MI and cardiovascular death. Remarkably, new onset of diabetes showed a relative RR of 25% in the losartan-treated group (13/1000 patients treated with losartan vs 17.5/1000 patients treated with atenolol, NNT = 222; p = .001) [34].
After the initial publication of the results of the LIFE study, several substudies and subanalyses have been published.
Lindholm et al examined statistically a subgroup of patients with diabetes (n = 1195) within the LIFE study with hypertension and left ventricular hypertrophy who were subjected to losartan or atenolol treatment, respectively [34]. The primary composite end point was relatively reduced by 24% in the losartan-treated group (p = .031); cardiovascular and overall mortality showed a RR of 37% (p = .28) and 39% (p = .002), respectively.
Another substudy focused on patients with left ventricular hypertrophy and without any clinical evidence for vascular disease (n = 6866), that is, patients at lower cardiovascular risk. There was a relative RR for the primary composite end point of 19% with losartan in comparison to atenolol.The risk for fatal and nonfatal stroke was reduced by 34% (p <.001), for new onset of diabetes 31% (p <.001) [35].
Additionally, the LIFE study had recruited 1970 patients taking aspirin at baseline. In these patients, the risk for MI and left ventricular hypertrophy was reduced by 32% (p = .001) with losartan when compared to atenolol-treated patients under conditions of equally lowered blood pressure in both groups [36].
Taken together, in the LIFE study, at similar blood pressure reductions, losartan proved to be superior to atenolol with respect to the primary outcome in high-risk hypertensive patients. This was mainly due to a decreased incidence of cerebral stroke. In addition, there was a marked reduction of new-onset diabetes in the losartan­treated group as compared to the atenolol-treated group.

SCOPE

The Study on Cognition and Prognosis in the Elderly [37] followed 4937 patients with a mean age of 76 years for a duration of 3.7 years. Patients had to have systolic blood pressure of 160 to 179 mmHg and/or diastolic pressure of 90 to 99 mmHg, as well as a Mini-­Mental-Score of ≥24. Initially, treatment was administered with candesartan as compared to placebo. This scheme was altered during the course of the trial so that, in the end, two active treatment groups were compared. The primary end point was defined as similar to the LIFE study. An identical reduction in blood pressure was not achieved (-21.7/10.8 mmHg in the candesartan group, -18.5/9.2 mmHg in the control group). There was no significant difference between both treatment groups concerning overall stroke incidence, MI, and cardiovascular death. However, regarding nonfatal stroke, candesartan showed a relative RR of 27.8% (p = .04).

VALUE

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) study [38,39] was a randomized, double-blinded, and prospective trial with 15,245 patients older than 50 years with an untreated blood pressure of 160 to 200/≤110 mmHg and high cardiovascular risk. The patients were either treated with a valsartan-based or amlodipine-based therapy. The mean duration of follow-up was 3.6 years, and the prescribed mean daily doses were 151.7 mg valsartan or 8.5 mg amlodipine. The initial blood pressure reduction was significantly greater in the amlodipine group (with -4.0/2.1 mmHg in the amlodipine group vs the valsartan group after 1 month).This difference was reduced by higher doses of valsartan (-1.5/1.3 mmHg in the amlodipine group vs the valsartan group after 1 year), but never disappeared completely throughout the study. There was no significant difference in primary end points and cardiovascular mortality in both study arms, but fatal and nonfatal MI showed a relative RR of 19% (p = .02) in the amlodipine group. However, when comparisons were made on the basis of equal blood pressure reduction, these differences disappeared, and valsartan even proved superior to reduce congestive heart failure.
Similar to the LIFE trial, the valsartan group showed a relative RR of 23% (NNT = 98.3, p <.0001) in new-onset diabetes compared to a metabolically "neutral" calcium channel blocker.

Ongoing clinical trials

The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) [40] is divided into three study arms: telmisartan alone, ramipril alone, and a combination of both. The study compares the composite cardiovascular end point of MI, cerebral stroke, hospitalization for chronic heart failure, and death for 23,400 patients aged 55 years or older at high risk for adverse events, but not necessarily with hypertension. The patients' profile is similar to the one in the HOPE trial. The ONTARGET trial is a 5.5 year study, with data available in early 2008.
Patients intolerant of ACEIs have been randomized to a parallel study called, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) [41]. The 5000 recruited patients in this study are subjected to treatment with telmisartan or placebo. Data will be available in 2008.
The Randomized Olmesartan and Diabetes Micro­albuminuria Prevention (ROADMAP) study [41] compares olmesartan with placebo in the development of micro­albuminuria in 4400 patients for a duration of 5 years at high cardiovascular risk (hypertension and type 2 diabetes with normoalbuminuria).

Conclusion

The clinical studies performed so far have shown that ARBs are potent drugs for lowering blood pressure with an excellent profile concerning adverse effects.Taken together in these trials, thousands of patients have been in­vestigated in a randomized, prospective fashion. Con­sistently, there appear to be advantages of ARBs concerning protection against stroke and new-onset diabetes [42].
An important issue in this context is obviously the drug dose. Because of the high tolerability of ARB medication even at high doses, many experts favor the use of ARBs at these high doses to further increase protection against end-organ complications of hypertension. Support for this assumption comes not only from hypertension trials such as LIFE but also from clinical trials in patients with heart failure and those with diabetes (discussed later).

ANGIOTENSIN AT1 RECEPTOR ANTAGONISTS IN CHRONIC HEART FAILURE

The management of patients with chronic heart failure calls for an efficient, safe, and tolerable long-term pharma­ceutical treatment. Therapy has to ensure a reduction of symptoms, disability, and morbidity, as well as a maximal prolongation of remaining lifetime. A substantial number of large clinical trials have been performed on the ability of ARBs to fit those criteria.
As discussed in this text, the different ways by which ARBs and ACEIs interfere with the RAS has been made responsible for putative advantages of ARBs over ACEIs. For instance, while it is well known that inhibition of ACE may reduce Ang II generation to nondetectable levels after acute administration, under long-term treatment Ang II plasma levels are often restored indicating effects of ACE-replacing enzymes such as chymase [43,44]. Such an angiotensin "escape" has been observed in patients with chronic heart failure under ACEI therapy but does not occur with ARBs, which block the system at the effector site- the AT1R-independently of how angiotensin was generated and its quantity. In addition, while it was thought previously that only ACEIs increase kinins and, in turn, nitric oxide and prostacyclin generation, more recently, it was demonstrated that ARBs can also increase nitric oxide generation by mechanisms that may or may not include kinins.Thus, on theoretical grounds, ARBs should be at least as effective as ACEIs in a disease such as chronic heart failure. Obviously, there is also the opportunity to combine both drugs. This has been done in a number of clinical trials. However, since these studies were always designed to apply an ARB on top of an ACEI and not also the reverse, observed benefits of combination therapy do not allow for conclusions about the value of the combination per se. They can only be interpreted to mean that adding an ARB improves the effects of an ACEI, but it does not mean that an ACEI helps an ARB.

Clinical trials

CHARM-alternative

The Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity- alternative study [45,46] recruited 2028 patients with symptomatic heart failure and intolerance of ACEI medication. The mean age of the patients was 67 years.
The patients received add-on medication with can­desartan, starting with 4 mg daily, up-titrated to a maximum of 32 mg per day, or placebo. The primary end point was defined as cardiovascular death or admission to hospital because of decompensated heart failure. Patients were followed for a mean duration of 33.7 months.
The relative RR for the primary end points in the candesartan group was 23% (p = .004) compared to placebo treatment, with the biggest effect on heart failure hospitalizations (relative RR of 39%). All-cause mortality was significantly reduced after adjustment of covariates (absolute RR 3.1%, relative RR 17%, p = .033). Generally, candesartan treatment was well tolerated and a substantial improvement of clinical symptoms was observable in 7% of the patients with chronic heart failure.

CHARM-preserved

The CHARM-preserved study [46,47] is the very first study to assess the putative effects of pharmacological treatment in patients with clinical symptoms of chronic heart failure without a detectable left ventricular systolic dysfunction or hemodynamically rele­vant valve disease. This group of 3205 patients was pathophysiologically heterogeneous and probably included misdiagnosed patients as well as patients with isolated diastolic heart failure and others.
The patients were randomized and followed for a mean of 36.6 months. Patients received add-on medication with candesartan or placebo at dosages equivalent to the CHARM-alternative study. Primary end point definition was also identical to the CHARM-alternative trial.
There was no significant difference in the event rate for primary end points, but there was a significant reduction in heart failure hospitalizations after statistical adjustments (adjusted relative RR of 16%, p = .047).

CHARM-added

The CHARM-added trial [46,48] enrolled 2548 patients with symptomatic heart failure (New York Heart Association [NYHA] class II-IV) and left ventricular systolic dysfunction. All patients were randomized to candesartan (dosage according to the other CHARM trials) or placebo added to their basal medication, which had to include substantial doses of ACEIs (eg, a mean of 17 mg per day enalapril).
After a mean follow-up duration of 41 months, the primary end point (defined identically to the other CHARM trials) was relatively reduced by 15% (RR; p = .011) in the candesartan group. There was a trend of all-cause mortality reduction in the candesartan group. An improvement of clinical symptoms was observed in 8% of patients treated with ARBs.

RESOLVD

The Randomized Evaluation of Strategies for Left Ventricular Dysfunction trial [49] randomized a total of 768 patients with symptomatic heart failure and left ventricular ejection fraction <40% to an add-on medication of enalapril (10 mg twice a day), candesartan (4, 8, or 16 mg 3 times a day), or a combination of both. The primary end points included exercise distance, cardiac function, neuroendocrine parameters, clinical symptoms, and quality of life.
Patients were followed for only 43 weeks, because the trial stopped prematurely due to a higher incidence of death in the candesartan-only group (6.1%) and the combination treatment group (8.7%) than there was in the enalapril-only group (3.7%).
The combination therapy did not improve exercise distance, cardiac function, clinical symptoms, quality of life, norepinephrine plasma level, or endothelin plasma level compared to enalapril or candesartan alone. There was a trend to reduce brain natriuretic peptide and aldosterone plasma levels under combination therapy. Combination therapy also induced a further reduction in blood pressure by 5 mmHg. Due to the short period of follow-up, long-term consequences of these effects were not monitored.

Val-HeFT

The Valsartan Heart Failure Trial [50,51] compared valsartan and placebo as add-on medication in 5010 patients with already-treated symptomatic heart failure. Of these patients, 93% took recommended doses of ACEIs. Valsartan medication started at 40 mg twice daily and was up-titrated to a target dose of 160 mg twice daily. The primary end point was defined as a composite of decompensation of heart failure (with hospitalization and/or intravenous drug administration) and cardiovascular death. The patients were followed for a mean of 23 months.
There was a 13% relative RR in the valsartan group with respect to the primary end point. Furthermore, addition of valsartan in the overall study reduced decompensation of heart failure with a relative RR of 24% (p = .001) and improved the NYHA designation by one full class in 5% of the patients.
A much more dramatic benefit of the two primary end points (decompensation of heart failure: 17.3 vs 27.1%, p = .017; cardiovascular death: 24.9 vs 42.5%, p <.001; each valsartan vs placebo) was observed in a substudy on patients who had not received an ACEI, although the number of patients was relatively small (n = 366) [52].  

ELITE and ELITE-II

The Evaluation of Losartan in the Elderly Study [53] randomized 722 patients who had heart failure (age ≥65 years) and left ventricular systolic dysfunction ( ≤40%), without renal dysfunction (serum creatinine ≤2.5 mg/dL), to captopril (50 mg 3 times daily) or losartan (50 mg once daily) treatment and followed them for 48 weeks. The primary end point was defined as an increase of serum creatinine of more than 0.3 mg/dL. The secondary end point was defined as all-cause death or hospitalization due to decompensated chronic heart failure.
The primary end point occurred in 10.5% of the patients in both groups, but there was a relative RR of 46% (p = .038) on overall mortality in the losartan group, mainly due to a reduction of sudden death and MI. The absolute number of events (especially death) was low, indicating a relatively mild form of chronic heart failure in these patients. The tolerabilty of losartan was better compared to captopril: Discontinuation rate of drug intake was 18.2% for losartan and 28.6% for captopril (p = .001).
The ELITE-II study [54] was designed according to the ELITE study, but with a substantial increase in the number of enrolled patients to provide additional statistical power for end point evaluation. ELITE-II compared losartan with captopril at the same doses as in the ELITE study in 3152 patients (age ≥60 years) with symptomatic heart failure and left ventricular systolic dysfunction ≤40%. The primary end point was all-cause mortality.
There was a tendency to a higher mortality in the losartan-treated group without statistical significance. Furthermore, there was also no significant difference in the rate of hospitalization because of decompensated heart failure or other reasons between both groups. Since this study was designed as a superiority trial, the results are difficult to interpret. Most experts hold that the dose of losartan used in ELITE II (50 mg once daily) was not sufficiently high enough to observe potentially beneficial effects of this compound in comparison with the solid dose of the comparator, captopril (50 mg 3 times daily).

Conclusion

The new drug class of ARBs has been intensively studied in chronic heart failure. The trials presented here were able to prove the superiority of ARBs against placebo in improving symptoms, morbidity, and even mortality. Moreover, in general, ARBs were not inferior to ACEIs in treatment of chronic heart failure. The combination of ARBs and ACEIs yielded results still difficult to interpret. So far, there is no clear evidence for a reduced mortality when using combination therapy as compared to the use of ARBs alone.

ANGIOTENSIN AT1 RECEPTOR ANTAGONISTS IN ACUTE AND POST-ACUTE MYOCARDIAL INFARCTION

MI is still one of the leading causes of death in modern civilizations. In addition to the immediate mortality after MI, the reduction of systolic ventricular function or the development of chronic heart failure after nonfatal MI are severe complications in those patients demanding an appropriate and highly effective long-term cardiovascular medication. The Survival and Ventricular Enlargement (SAVE) study [55], Acute Infarction Ramipril Efficacy (AIRE) study [56], and TRAndolapril Cardiac Evaluation (TRACE) study [57] were able to demonstrate clearly the efficacy of ACEIs in the treatment of post-MI heart failure. According to these studies, ACEIs reduced the overall mortality by 5.7% (23.4% in the ACEI group vs 29.1% in the placebo group after 4.2 years of follow-up).Together, these results indicate that inhibition of RAS has become a crucial part in the medication of patients suffering from acute MI or chronic heart failure post-MI.
Two large clinical trials, the Effects of Losartan and Captopril on Mortality and Morbidity in High Risk Patients after Acute Myocardial Infarction study (OPTIMAAL) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT), were designed to compare the effects of ARBs with those of the ACEIs or with the combination of both in post-MI patients.

Clinical trials

OPTIMAAL

The OPTIMAAL study [58] recruited 5477 patients with a mean time of 84.9 h after MI and clinical evidence of heart failure and/or a left ventricular ejection fraction less than 35%. The patients were randomized and subjected to losartan (50 mg once daily) or captopril (50 mg 3 times daily) treatment. The mean follow-up was 2.7 years.
At the end of the trial there was no significant difference in all-cause mortality and in all other defined secondary end points with tendencies of captopril to perform better on most of the examined items (eg, overall mortality: 16.4% captopril vs 18.2% losartan). In comparison, tolerability was significantly better under losartan treatment with a rate of permanent discontinuation of drug intake of 17% in the losartan group and 23% in the captopril group.
While the results of this trial were discussed controversially, most experts agree that, similar to ELITE II, the dose chosen for losartan (50 mg per day) was too small to unfold the potential of angiotensin receptor antagonism versus ACE inhibition. Indeed, whenever the dose of losartan had been increased to 100 mg daily as in the LIFE (see earlier) and RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) studies, the beneficial effects of losartan on primary and secondary end points became apparent.

VALIANT

The study [59] enrolled 14,500 patients between 12 h and 10 days following MI with evidence for heart failure or a left ventricular ejection fraction of less than 40%. Patients were randomly assigned to treatment with valsartan, captopril, or a combination of both. Valsartan medication started at a dose of 40 mg (twice daily; target dose was 160 mg twice daily alone, and 80 mg twice daily in combination with captopril), and captopril medication started at a dose of 25 mg (3 times daily; target dose was 50 mg 3 times daily alone and in combination therapy with valsar­tan). Up-titration was performed in 4 steps within 90 days.
The average follow-up period was 2.0 years. Mortality was nearly identical in all 3 treatment groups (19.9 % in the valsartan group, 19.5% in the captopril group, and 19.3%, in the valsartan/captopril combination group). In addition, secondary composite end points (cardiovascular death, new MI, and severe heart failure) did not show any significant differences. As in the OPTIMAAL study, the ARB was better tolerated than the ACEI (permanent dis­continuation of drug intake of 5.8%), whereas the com­bination therapy had the highest rate (9.0%).

Conclusion

In the OPTIMAAL and VALIANT studies, ARBs were able to prove their noninferiority compared to ACEIs, but they did not prove to be superior to them. As already mentioned, at least in the OPTIMAAL study, the low dosage of the ARB was a major issue. It seems, however, that in the case of post-MI treatment, ACEIs and ARBs can be used likewise with no superiority on either side.
Furthermore, the VALIANT study tested the com­bination therapy of ACEIs and ARBs and examined possible synergistic or additive effects. In fact, the combina­tion therapy of ARB and ACEI did not perform better in patients after MI but engendered more adverse effects.

ANGIOTENSIN AT1 RECEPTOR ANTAGONISTS IN CEREBRAL STROKE

Cerebral ischemia represents one of the leading causes of morbidity, disability, and mortality worldwide [60,61]. According to data from WHO, stroke accounted for 4.3 million lives worldwide. Extrapolated data indicate that this number will increase up to 7.7 million in the year 2020. Notwithstanding the rate of immediate death from stroke, the rate of permanent disability caused by cerebral stroke is still over 30%, thereby creating enormous costs: 3 to 4% of total health care costs in Western countries have to be invested in the permanently disabled [62].
Without any doubt, next to age and atrial fibrillation, elevated blood pressure is the most powerful risk factor for stroke. Starting at about 115 mmHg, the risk for cerebral stroke increases in a linear fashion by doubling for every 20 mmHg increment in systolic blood pressure [63,64]. Hypertension contributes to virtually all subtypes of stroke. It accelerates the formation of atherosclerotic plaques, as well as micro- or macroaneurysms, and promotes development of atrial fibrillation thereby contributing to cardioembolic events [65].
It has been significantly shown that lowering blood pressure decreases incidence of cerebral stroke [66-68]. However, there is no strictly proportional relation between the level of blood pressure reduction and the lowering of stroke incidence [69]. This suggests that various drug classes of antihypertensives might contribute differently to this kind of protection against end-organ damage.
As already discussed, the development of a more selectively acting drug class for blockade of the RAS-the ARBs-has raised hopes for a better performance of these drugs in treatment of several diseases, including stroke prevention and treatment. The influence of RAS activation in the brain and the role of central nervous system angiotensin receptors have been thoroughly studied in the last few years. In addition, experimental evidence has been provided for a beneficial effect of AT2R activation under ischemic conditions, suggesting protective effects of ARBs in cerebral stroke beyond blood pressure reduction [70].

Clinical trials

The Perindopril Protection against Recurrent Stroke Study (PROGRESS) [71] enrolled 6105 patients with a history of stroke within the previous 5 years. Patients were randomized to perindopril (4 mg once daily) or placebo treatment and also received the diuretic indapamide (2.5 mg once daily) for blood pressure control, if there were no contraindications. Perindopril treatment alone led to a significant decrease in blood pressure (-5 mmHg compared to placebo), but did not result in a significant reduction of stroke incidence. The combination therapy of perindopril and indapamide induced a further reduction of blood pressure (-12 mmHg compared to placebo) and a relative RR of 40% (p <.01) for cerebrovascular events.
The Heart Outcomes Prevention Evaluation (HOPE) [72] study recruited 9297 subjects at high cardiovascular risk, treated them with ramipril (10 mg once daily) or placebo, and followed them for 5 years on average.Treatment with ramipril induced a relative RR of 30.6% (p <.001) for cerebral stroke compared to placebo. The investigators of this study attributed this effect to being independent of blood pressure differences. In fact, the ACEI-treated patients had an average systolic blood pressure of 3 mmHg lower than did the placebo-treated group. This, according to some clinicians [73,74], was sufficient to account for the difference in stroke incidence between the ramipril and the control group.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [75,76] enrolled a total of 33,357 patients for treatment with the diuretic chlorthalidone (12.5 to 25 mg once daily), the calcium channel blocker amlodipine (2.5 to 10 mg once daily), or the ACEI lisinopril (10 to 40 mg once daily). In order to participate, patients had to have hypertension and at least one cardiovascular risk factor and were followed for an average of 4.5 years. Chlorthalidone lowered blood pressure significantly more than did lisinopril in these patients. There was no significant difference between chlorthalidone and amlodipine treatment in reduction of cerebrovascular events, but chlorthalidone was apparently superior to lisinopril with a relative RR of 15% (p <.05), a difference entirely attributable to the greater fall in blood pressure with chlorthalidone.
As this study was ridden with serious flaws in design and methodology [77], its results can only be interpreted with utmost caution.
The Second Australian National Blood Pressure Study (ANBP2) [78] recruited 6083 subjects with hypertension and randomized them to open-label medication including ACEIs.There was no evidence for any difference in the rate of cerebrovascular events between both groups.
Meta-analyses of all the previously mentioned trials combined indicate noninferiority but not superiority of ACEIs in prevention from cerebrovascular complications compared to other blood-pressure-lowering drug classes. Thus, the relative RR observed in the PROGRESS and HOPE studies may as well be explained by differences in blood pressure lowering.
In contrast to these results, the LIFE study (see earlier), which compared losartan with atenolol at comparable blood pressure levels in both groups, showed a significant reduction in fatal and nonfatal cerebral strokes (relative RR 25%, p <.001) in the losartan-treated patients. The SCOPE and VALUE studies (see earlier sections) showed no significant difference concerning the overall incidence of cerebrovascular events. In the SCOPE study (candesartan vs placebo or active treatment), there was a trend in RR that just failed to reach statistical significance (relative RR 24%, p = .056) but showed a significant reduction of nonfatal stroke in favor of candesartan. When comparing valsartan and amlodipine in the VALUE study, there was an opposite trend against the ARB (relative RR of amlodipine of 15%, p = .08), which can be explained by the fact that the valsartan group had significantly less blood pressure reduction than did the amlodipine group throughout the study.
The Morbidity and Mortality after Stroke-Eprosartan compared with Nitrendipine for Secondary Prevention (MOSES) study [79] randomized 1405 patients with hypertension and a history of cerebrovascular events (ischemic stroke, transient ischemic attack [TIA] or cerebral hemorrhage) within 2 years before randomization to eprosartan or nitrendipine treatment. Patients were followed for 55.6 months. The primary end point was defined as a composite of cardiovascular events (MI or new-onset heart failure), cerebrovascular events (TIA, prolonged reversible ischemic neurological deficit [PRIND], recurrence of stroke, or cerebral hemorrhage), or death. Blood pressure reduction was absolutely identical in both groups throughout the study. Eprosartan reduced the relative risk for the primary end points by 21% (p <.05) and the risk for fatal and nonfatal stroke by 25% (p = .026) compared to nitrendipine treatment.

Conclusion

Blockade of the RAS is a highly effective way of blood pressure reduction in patients at high risk for cerebrovascular events. While ACE inhibition was not superior to other drug classes in reducing cerebrovascular events, blockade of AT1Rs showed superiority in a number of studies as it has also been described in a meta-analysis [42].

ANGIOTENSIN AT1 RECEPTOR ANTAGONISTS IN DIABETES AND METABOLIC SYNDROME

Several studies indicate that hypertensive patients run a 2­to 2.5-times greater risk of developing diabetes mellitus compared to patients who are normotensive [80]. This might be due to shared risk factors for both diseases. However, there is also evidence for hypertension as an independent factor in the development of diabetes. Studies (such as CHARM, HOPE, VALUE, and ALLHAT) have indicated that drugs inhibiting the RAS, such as ACEIs and ARBs, can prevent or delay new-onset diabetes. It has been estimated that 60 to 70 patients have to be treated with an ARB or ACEI instead of a diuretic or beta-blocker for 4 years to avoid one case of new-onset diabetes [81].
Evidence has also been provided that some members of the ARB family have insulin-sensitizing properties [25]. This so-called pleiotropic effect, comparable to, but not identical with, the mechanism of action of thiazolidinediones might represent a major pharmacological advantage of these drugs.

Clinical trials

The LIFE (losartan vs atenolol) and VALUE (valsartan vs amlodipine) studies both showed a significant decrease in incidence of new-onset diabetes (25%, p <.001, and 23%, p <.0001, respectively) when comparing losartan or valsartan to another antihypertensive drug (atenolol or amlodipine, respectively). The ALPINE study recruited a relatively small number of patients (n = 392) randomized to candesartan (±felodipine) and HCT (±atenolol) treatment. There were very few cases of new-onset diabetes; yet, there was a significant advantage with ARB treatment (1/195 in the candesartan group vs 8/188 in the HCT group, p = .03) [82].
In the population examined in the CHARM-preserved study (see earlier), there was a significant reduction in new­onset diabetes with 47/1080 cases in the candesartan vs 77/1086 cases in the placebo control group (p = .005). The CHARM-overall study also showed a significant reduction of new-onset diabetes by 22% (p <.05). All other CHARM trials-all were using the ARB candesartan-achieved no significance on this item.
There are a number of important questions remaining for further studies: First, are ARBs only lacking metabolically adverse effects, or do they have antidiabetic effects? Second, are all ARBs identical concerning their metabolic properties? Third, if there is a protective effect, is it clinically relevant in terms of its impact on the development and progress of diabetes mellitus? Will they be able to cause a reduction of morbidity and mortality?
There are several ongoing large-scale clinical trials that intend to answer some of these questions. The data from the ONTARGET, TRANSCEND, and Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trials are impatiently awaited.
Some smaller studies with fewer patient numbers and only short follow-up periods have already been performed. Derosa et al [83] compared 119 patients with hypertension and type 2 diabetes and found a significant reduction of triglyceride concentrations (after 12 months) in a tel­misartan-treated group when compared to eprosartan- or placebo-treated patients. There was no effect on fasting glucose levels and HbA1c. Honjo et al [84] found tel­misartan to modestly reduce HbA1c after 3 months, which was not the case for candesartan-treated patients. Vitale et al [85] observed a significant reduction in fasting glucose, HbA1c, insulin resistance, and insulin levels after 3 months in patients with metabolic syndrome and telmisartan treatment, whereas losartan had no effect.
All these studies cannot be assumed to be sufficient to prove the metabolic superiority of ARBs in comparison to metabolically "neutral" drugs such as the dihydropyridine calcium channel blockers, but they serve us with important tendencies. ARBs seem to have the potential to influence metabolic parameters positively. It also seems that the drug class of ARBs might be heterogeneous concerning this property as shown by the superiority of telmisartan when compared to other ARBs.
Likewise, the "older" ACEIs have been subjected to several studies to examine their metabolic effects. Results of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial have been published. This trial enrolled 5269 patients without cardiovascular disease but with impaired fasting glucose levels or impaired glucose tolerance and randomized them to treatment with ramipril (up to 15 mg once daily), rosiglitazone (up to 8 mg once daily), or placebo. Remarkably, the ACEI was not able to significantly change the incidence of new-onset diabetes or death when compared to placebo. Nevertheless, ramipril did significantly increase regression to normoglycemia by 16% (p = .001) [86].

Mechanisms

The mechanisms that may contribute to the putative antidiabetic effects of ARBs are diverse and can be divided in two general categories: the blockade of Ang II effects on the development of diabetes, and possible pleiotropic effects of particular ARBs. Many in vitro experiments and studies have demonstrated the role of activated RAS and high Ang II levels in the pathophysiology of insulin resistance. Ang II influences the insulin signaling pathways, induces oxidative stress, alters the sympathetic activity, and promotes adipogenesis [87-90].
Since not all ARBs seem to equivalently interfere with the progression of diabetes, other (pleiotropic) mechanisms might also play an important role in this context. In the last few years, it has been shown that increased levels of bradykinin (induced by ACEIs or ARBs) upregulate expression and translocation of GLUT4 glucose transporters mediated by increased concentrations of nitric oxide [91,92]. AT2R activation under AT1R blockade with ARBs may also contribute to these positive effects.
Remarkably, it has been found that the ARB telmisartan and, at high concentrations, irbesartan may activate PPARγ (Figure 4) [25,93]. This has been achieved in in vitro experiments at concentrations that might also beachieved by administration of high standard doses of telmisartan in patients. The amount of maximal activation was up to 25 to 30% compared to the full agonists pioglitazone and rosiglitazone, suggesting a rather potent insulin-sensitizing efficacy of telmisartan.

HTC - 5 : Cardio 24-8 fig. 4_th.jpg  Figure 4. Metabolic effects of angiotensin II receptor blockers (ARBs): Peroxisomal proliferator-activated receptor-gamma (PPARγ) activation. Summary of potential mechenisms whereby ARBs interact with PPARγ, either directly (by crossing the cell membrane and activating the PPARγ-retinoid X receptor [RxR] complex) or indirectly (by allowing activation of the angiotensin II receptor [AT2R] unopposed by angiotensin 1 [AT1R] activation).

Conclusion

Diabetes and metabolic syndrome are diseases with rapidly increasing incidence and prevalence in Western countries. The coincidence of hypertension with obesity, dyslipo­proteinemia, and impaired fasting glucose or diabetes is a fatal combination putting all patients at extremely high risk for nonfatal and fatal cardiovascular events.
This group of patients requires extremely effective and early therapy to protect them from major complications for the longest possible period. An adequate medication has to include satisfactory blood pressure control with minimal adverse effects ensuring maximal long-term compliance of the patients and a high potential for preventing patients at high cardiovascular risk from serious complications.
In many studies, the concept of AT1R blockade has proven to be an adequate and powerful pharmaceutical intervention mechanism to treat patients at high car­diovascular risk with accompanying metabolic diseases or complications. ARBs and ACEIs have been evaluated as metabolically superior drugs when compared to diuretics or beta-blockers. Nevertheless, more trials will be necessary, and already ongoing trials will help to demonstrate clearly the positive influence of these drugs on morbidity and mortality in diabetic patients.
An additional promising aspect is the putative insulin­sensitizing property of some ARBs. This could be a major advantage compared to other antihypertensives or even members of the same drug class. Nevertheless, the clinical significance-concerning morbidity and mortality-of this pleiotropic effect has to be demonstrated in clinical studies.

ANGIOTENSIN AT1 RECEPTOR ANTAGONISTS IN PATIENTS AT HIGH CARDIOVASCULAR RISK

The RAS clearly plays an important role in hemodynamic homeostasis through short-term effects on the vasculature and kidney. However, long-term tissue effects of the RAS are integral to many other (patho)physiological functions and systems that regulate inflammation and cellular growth, such as fibrosis, hypertrophy, and tissue re­modeling processes.
Consequently, chronic RAS activation has been implicated as a major factor contributing to progressive dysfunction of several organs. Identification of this link between Ang II and the pathophysiological changes associated with various cardiovascular diseases prompted the development of pharmaceutical agents capable of blocking the actions of Ang II and reversing the associated pathologies. First, the ACEIs were available and, more recently, so were the selective antagonists of the AT1R. Most of the negative cardiovascular actions of Ang II appear to be mediated through the AT1R, whereas the AT2R has largely beneficial effects under certain pathophysiological conditions. Thus, it is possible that ARBs may drive Ang II (whose plasma levels are increased by treatment with these agents) to activate the unopposed AT2R, thereby providing additional end-organ protection, compared with ACEIs. More complete RAS blockade using a combination of an ACEI and an ARB could provide even greater attenuation of the deleterious Ang-II-induced local tissue effects. In addition, the potentially beneficial properties associated with increased bradykinin and substance P levels resulting from ACE inhibition should be maintained. All these rather theoretical ideas remain to be clarified by large-scale, double-blind, prospective, and randomized trials. All antihypertensive drug classes have proved to lower blood pressure significantly. Therefore, the prevention from end­organ damage, as well as cardiovascular and metabolic complications, is of major importance.
The LIFE and SCOPE trials compared losartan and candesartan to older antihypertensives and demonstrated a risk reduction for cerebral stroke and new-onset diabetes. The MOSES study could show a decreased risk of cardiovascular end points and, especially, stroke in eprosartan-treated patients compared to nitrendipine­treated patients at high cardiovascular risk after cerebral stroke. The VALUE study did not succeed in demonstrating a lowering of cardiovascular complications under valsartan treatment when compared to amlodipine. Nevertheless, there was a significant decrease in new-onset diabetes. Results indicate putative direct insulin-sensitizing actions of some ARBs via activation of PPARγ.

CONCLUSION

Since the introduction of ARBs to the market, more than 10 years of clinical usage and excessive clinical trials recruiting more than 100,000 patients have passed. ARBs have proven to reduce effectively blood pressure and to be extremely well tolerated. This positive profile of adverse effects is probably the most obvious advantage of this new drug class when compared to all other antihypertensives. Several trials have been performed and clearly have indicated the noninferiority of ARBs when compared to other drug classes with respect to blood pressure control, end-organ damage, and cardiovascular complications. Some of these studies have also indicated superiority to other antihypertensives with particular cardiovascular, cerebrovascular, and metabolic complications.
Nevertheless, the results of ongoing large-scale clinical trials (eg, ONTARGET, TRANSCEND, Scandinavian Candesartan Acute Stroke Trial [SCAST], and ROADMAP) are awaited to clarify whether all hypothetical expectations and first indications will translate into real improvements in patient morbidity and mortality when treated with ARBs rather than with other antihypertensives.

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