End-organ protection with candesartan

Angiotensin-II blockade can improve quality of life

Angiotensin II is a powerful vasoconstrictor. It is also central to many physiologic and pathologic processes like coagulation, cardiac hypertrophy, endothelial problems, and sympathetic activation. Angiotensin is also thought to have a role in the stimulation of adhesion molecules, inflammatory cytokines such as interleukin, the generation of free radicals, activation of monocytes and macrophages, vascular-smooth-muscle-cell growth and hypertrophy, and an increase in the proclotting elements such as PAI-1, which all contribute to atherosclerosis. Therefore, angiotensin is no longer considered as just a vasoconstrictor. Its role as a hARBinger of multiorgan involvement has been recognized.

    The answer to preventing these complications is to block the renin-angiotensin system (RAS). There are three RAS blockers: angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB), and spironolactone.

    Trials showing that ACE inhibitors can prevent major cardiovascular events are aplenty. But their shortcomings and limitations have also been pointed out. For one, there are various adverse effects associated with ACE inhibitors--hyperkalemia, first-dose hypotension, renal failure, dry cough, and angioedema. Their nonselective action on both AT1 and AT2 receptors is also a factor.

     According to Dr. Jorge Sison, research coordinator of the Philippine Council on Hypertension, AT1 is the so-called bad receptor as it causes all the unwanted effects that need to be modulated--vasoconstriction, aldosterone release, vasopressin release, and cell growth and proliferation. The "good" subtype receptor AT2 is the balancing receptor of AT1.

    Speaking in a symposium on The Emerging Role of ARBs on Interfacing Benefits of End-Organ Protection held in May, Sison pointed out that unlikle ACE inhibitors, which block both receptors, ARBs leave the AT2 receptors alone while blocking the detrimental effects of AT1-receptor activation, giving the extra benefit of vasorelaxation.

    Also, the presence of a non-ACE pathway for the conversion of angiotensin I to angiotensin II may explain the escape phenomenon seen with ACE inhibitors. When ACE inhibitors are started, there is a decrease in angiotensin-II levels. Subsequently, through the activation of the non-ACE pathway, angiotensin-II levels return to baseline. A sustained decrease in the plasma le-vels of angiotensin-converting enzyme is seen; despite that, there is a progressive increase in the level of angiotensin II. This could explain why many patients on chronic ACE-inhibitor therapy retrogress as time goes by.

Benefits of candesartan

    Sison said a surer way to block angiotensin II is with an agent that is selective to the bad receptor--an ARB like candesartan, which has been the focus of many landmark trials. In the recent Study on Cognition and Prognosis in the Elderly (SCOPE), candesartan was shown to reduce the incidence of all stroke by 24 percent and nonfatal stroke by 28 percent. A subgroup analysis of patients with impaired cognition at baseline also showed candesartan benefited patients at high risk of developing these disorders.

    Candesartan significantly reduces left ventricular hypertrophy. Furthermore, the RESOLVD trial showed that the combination of an ARB (candesartan) and an ACE inhibitor (enalapril) has an additive effect of blocking the RAS both upstream and downstream, resulting in significantly reduced brain natriuretic-peptide levels. Is also afforded a reduction in the end diastolic ventricular volume, leading to improved myocardial function.

    Sison also cited the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM), the landmark trial that used candesartan as an add-on treatment to the conventional heart-failure regimen. It involved three arms: candesartan as an alternative drug for patients unable to tolerate ACE inhibitors (CHARM-Alternative); as an add-on treatment to patients with low ejection fraction (<40 percent) despite ACE-inhibitor use (CHARM-Added); and as a treatment on top of the conventional regimen among patients with preserved ejection fractions of >40 percent (CHARM-Preserved).

    All three arms showed a significant decrease in the combined end point of cardiovascular death and CHF hospitalization. CHARM-Alternative therefore showed that candesartan can confidently be substituted for an ACE inhibitor. CHARM-Added proved that candesartan offers a benefit over and above that of an ACE inhibitor among patients with decreased systolic function. CHARM-Preserved showed that candesartan offers significant benefits even among patients with preserved systolic function.

    The rate of sudden cardiac death was also decreased in the Added and Alternative arms. As in most ACE-inhibitor trials that showed prevention of diabetes mellitus, the CHARM Trial also showed a reduction in the incidence of diabetes. Throughout the continuum of cardiovascular and multiorgan derangement--from the interplay of risk factors up to the acceleration of vascular and endothelial function to renal death and end-stage heart disease, ARBs, particularly candesartan, offered the promise of improved quality of life, Sison said.