Aliskiren - Clinical Benefits in the Management of Hypertension

Aliskiren - Clinical Benefits in the Management of Hypertension

Schmieder Roland E
European Cardiovascular Disease 2007 - Issue II
Published: November 2007
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It is widely acknowledged that effective management of hypertension – even if blood pressure (BP) is reduced by only 2mmHg – can significantly reduce the incidence of stroke, myocardial infarction (MI) and heart failure (HF).1 However, despite the wide range of conventional antihypertensive agents available, approximately 70% of patients fail to achieve adequate BP control.2 Furthermore, although certain antihypertensive agents – such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) – have been shown to provide organ protection beyond BP control, these agents have failed to provide the anticipated great step forwards to improved cardiovascular (CV) morbidity and mortality.3–5 There is still room for improvement in terms of the clinical benefits provided by antihypertensive therapy.

The renin system has a key role in controlling BP.6 Renin, a proteinase enzyme synthesised by the kidney, catalyses the conversion of angiotensinogen to angiotensin I (Ang I). Ang I is then converted by ACE to angiotensin II (Ang II), which regulates BP via its interaction with the AT1 receptor. Binding of Ang II at the AT1 receptor increases BP by stimulating generalised vasoconstriction, promoting re-absorption of sodium and stimulating aldosterone secretion. In hypertension, the renin system can become chronically activated, resulting in a persistently elevated concentration of circulating and/or locally activated renin. Aliskiren is the first orally effective direct renin inhibitor (DRI),7 and has recently been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of hypertension. It inhibits the activity of renin, controlling the renin system at the rate-limiting step. The antihypertensive efficacy of aliskiren as monotherapy has been established, as well that as of aliskiren in combination with other antihypertensive agents.8–12 In addition, the potential organ-protective benefits of aliskiren are being investigated in an extensive, ongoing clinical study programme. The aim of this review is to evaluate the clinical benefits provided by direct renin inhibition, and to explore the wider potential benefits of aliskiren in the management of hypertension.

Control of the Renin System with Direct Renin Inhibition
Hypertension can cause the renin system to become pathologically activated, as indicated by an increase in plasma renin activity (PRA) . a measure of the rate at which Ang I is generated. ACEIs and ARBs lower BP by attenuating the deleterious effects of Ang II. However, neither class of antihypertensive provides complete control of the renin system. By reducing activity at the AT1 receptor, both ACEIs and ARBs stimulate renin release via a negative feedback mechanism, ultimately increasing PRA.5 Aliskiren binds to the active site of renin, inhibiting the enzymatic conversion of angiotensinogen to Ang I and, consequently, reducing the amount of Ang II.13 Aliskiren therapy reduces both Ang I and Ang II. However, in contrast to ACEIs and ARBs aliskiren inhibits the activity of secreted renin, thereby lowering PRA and providing more complete control of the renin system.14,15

Aliskiren. A Novel Monotherapy for the Treatment of Hypertension
A wealth of clinical evidence supports the BP-lowering efficacy of aliskiren monotherapy in patients with mild to moderate hypertension . defined as mean sitting diastolic blood pressure (DBP) .95mmHg and <110mmHg. In dose-response studies, the optimal starting dose of aliskiren was 150mg, with optional titration to 300mg if additional BP-lowering efficacy was required.8,16 Analysis of pooled BP efficacy data from over 3,500 patients showed that aliskiren 150mg once daily lowered systolic blood pressure (SBP) by 12.5mmHg and DBP by 10.1mmHg (both p<0.0001 versus placebo). Increasing the dosage of aliskiren to 300mg/day reduced mean SBP by 15.2mmHg and mean DBP by 11.8mmHg (both p<0.0001 versus placebo)9 (see Figure 1). The BP-lowering effect of aliskiren is observed irrespective of age (. or .65 years), gender or presence of co-morbid diseases (such as obesity and diabetes).9,17,18 Furthermore, no dosage adjustment is necessary in the elderly or in those patients with renal or hepatic impairment.19

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