Gordon T McInnes
MD FRCP FFPM FB PharmacolS
Professor of Clinical Pharmacology and Honorary Consultant Physician
Division of Cardiovascular and Medical Sciences
University of Glasgow
Over the past 20 years, the clinical importance of treating hypertension with agents that block the renin–angiotensin system has become increasingly clear. Many physicians use angiotensin-converting enzyme (ACE) inhibitors or, more recently, angiotensin-receptor blockers (ARBs) as first-line therapy because they are highly effective and well-tolerated treatments for lowering blood pressure (BP). Of the two classes, ARBs are better tolerated, lacking some of the adverse effects (such as cough and angio-oedema) associated with ACE inhibitors.(1) Valsartan, which is approved for the treatment of hypertension, postmyocardial infarction (MI) patients and heart failure in many countries, is globally the most widely prescribed ARB.(2)
Mechanism of action
Valsartan acts primarily by blocking the effects of angiotensin II (Ang II) through selective antagonism of the Ang II type 1 (AT(1)) receptor subtype in many tissues, including vascular smooth muscle. By selectively blocking the AT(1) receptor, ARBs such as valsartan permit circulating Ang II to stimulate the AT(2) receptor, which has been reported to have a cardioprotective effect.(3)
These agents may have beneficial effects beyond BP lowering. These properties include improvement in endothelial function, contributing to the prevention of atherosclerosis(4) and improved insulin sensitivity in hypertensive patients with or without type 2 diabetes.(5,6)
Potent BP-lowering and cardiorenal protection
Results from the valsartan clinical trial programme, involving approximately 100,000 patients, have demonstrated its benefit across the cardiovascular (CV) continuum.
In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, 15,245 hypertensive patients aged ≥50 years and at high CV risk participated in a randomised, double- blind, parallel-group comparison of amlodipine- and valsartan-based therapy.(7) Although amlodopine-based treatment resulted in a greater BP reduction in the early stages of the trial, the primary endpoint (a composite of cardiac mortality and morbidity) was not significantly different between the treatment groups at 66-month follow-up. The incidence of new-onset diabetes was lower in the valsartan- than in the amlodipine-treated group (13.1% vs 16.4%; p<0.0001). This is the first time that an ARB has shown diabetes prevention compared with a “metabolically neutral” agent. Furthermore, a subsequent analysis that adjusted for the differences in BP reduction between valsartan and amlodipine showed that hospitalisations for heart failure were lower at six months in the valsartan group (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.66–0.99; p=0.040); there was similar risk of stroke in the two groups (HR: 1.02; 95% CI: 0.81–1.28; p=nonsignificant) .(8) The findings from this study emphasise the need for physicians to monitor the patient’s BP response closely and titrate rigorously to rapidly achieve BP target.
The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial was a multicentre, double-blind, randomised, parallel-group study that compared the effect of valsartan, the ACE inhibitor captopril and their combination on mortality in 14,703 patients with MI complicated by left ventricular systolic dysfunction, heart failure or both.(9) A report from the VALIANT Registry showed that patients with MI who develop these complications are four times more likely to die in hospital than patients who do not develop these complications (p<0.001).(10) In contrast to a trial comparing losartan with captopril,(11) VALIANT demonstrated statistical equivalence for valsartan compared with captopril in reducing the risk of all-cause mortality in these high-risk patients. The combined rate of the secondary endpoint of death from CV causes, recurrent MI or hospitalisation for heart failure was similar in the three treatment groups.(9)
The Valsartan Heart Failure Trial (Val-HeFT) was a randomised, double-blind study that compared the effects of valsartan with placebo in 5,010 patients with heart failure (New York Heart Association [NYHA] class II, III or IV) already treated with standard therapy, usually including an ACE inhibitor.(12) The primary endpoints were all-cause mortality and the combined endpoint of all-cause mortality and morbidity. While there were no significant differences in all-cause mortality between the two cohorts, valsartan significantly reduced combined all-cause mortality and morbidity by 13.2% compared with placebo (p=0.009), predominantly because of a 27.5% reduction in the rate of hospitalisation for heart failure (p<0.001). In patients not treated with ACE inhibitors, all-cause mortality and morbidity were significantly reduced in the valsartan treatment group.(13) Treatment with valsartan also resulted in significant improvements in NYHA class, ejection fraction, signs and symptoms of heart failure and quality of life compared with placebo (p<0.01).
A BP-independent, renal-protective effect of valsartan was demonstrated in a multicentre, double-blind, randomised, parallel-group study (Microalbuminuria Reduction with Valsartan [MARVAL]), supporting its benefit in diabetic patients.(14) For the same level of attained BP and the same degree of BP reduction, valsartan lowered elevated urinary albumin excretion more effectively than amlodipine (92% vs 56% reduction from baseline at 24 weeks; p<0.001) in patients with type 2 diabetes and microalbuminuria, including a normotensive subgroup.
Management of global cardiovascular risk
Physicians are increasingly aware of the need to prevent and/or treat all risk factors to lessen the patient’s global CV risk. This concept is being investigated in the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. This placebo-controlled, phase IV trial will compare the ability of valsartan and the oral antidiabetic nateglinide to reduce or delay the development of type 2 diabetes and CV disease in people who already have impaired glucose tolerance (a known risk factor for CV disease) and other predictors of CV risk.
Available data show that the AT(1)-receptor blocker valsartan has benefits across the CV continuum and has the potential to lessen global CV risk. Further data will be generated from ongoing studies, including NAVIGATOR.
The author would like to acknowledge medical writing support and scientific services provided by Thomson ACUMED(®). Funding for this support was provided via an educational grant from Novartis Pharma AG
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- Weber MA, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE trial. Lancet 2004;363:2049-51.
- Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906; erratum 2004;350:203.
- Velazquez EJ, et al. An international perspective on heart failure and left ventricular systolic dysfunction complicating myocardial infarction: the VALIANT registry. Eur Heart J 2004;25:1911-9.
- Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360:752-60.
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