In the 1970s, a series of observations demonstrated that angiotensin II has deleterious effects on the heart and kidney and that patients with high levels of plasma renin activity are at a higher risk of developing stroke or myocardial infarction than those with low plasma renin activity.1 2 Thereafter, the development of pharmacological probes that block the renin-angiotensin system helped define the contribution of this system to blood pressure control and to the pathogenesis of diseases such as hypertension, congestive heart failure, and chronic renal failure. Thus, the concept of treating hypertension and congestive heart failure by a specific blockade of the renin-angiotensin system was first established with the use of saralasin, a nonselective peptidic antagonist of angiotensin II receptors.3 4 5 6 7 8 9 With saralasin, it became possible to demonstrate that angiotensin II receptor blockade, alone or in combination with salt depletion, lowers blood pressure in hypertensive patients and improves systemic hemodynamics in patients with congestive heart failure.3 4 5 6 7 8 9 10 However, saralasin had many drawbacks. Because it is a peptide, it had to be administered intravenously. This characteristic limited its use to hours or a few days at maximum. In addition, at higher doses, saralasin had some partial agonist, angiotensin II–like effects.

The next major breakthrough in the understanding of the renin-angiotensin system was triggered by the development of orally active angiotensin-converting enzyme (ACE) inhibitors.10 11 12 13 14 15 Studies performed with these agents rapidly confirmed and reinforced the seminal clinical observations made with saralasin. ACE inhibitors are now recognized as an important therapeutic step to control blood pressure in hypertensive patients and to reduce morbidity and mortality in patients with congestive heart failure.16 In addition, because of their ability to lower proteinuria, ACE inhibitors have …

Angiotensin II type 1 receptor blockers.

Objectives To investigate the screening performance of measuring blood pressure and other variables in identifying those who will develop, or die from, ischaemic heart disease and stroke. To quantify by how much drugs that lower blood pressure will reduce the risk of ischaemic heart disease and stroke in those designated 'screen positive'. Data sources MEDLINE, Cochrane collaboration and Web of Science databases; Stroke registries; Health Survey for England; Office of National Statistics; BUPA (British United Provident Association) study. Review methods Relevant cohort studies and randomised trials were identified and analysed. Statistical analysis was used to determine drug efficacy and adverse effects. Results Lowering blood pressure by 5 mmHg diastolic reduces the risk of stroke by an estimated 34% and ischaemic heart disease by 21% from any pre-treatment level; there is no threshold. These estimates, from cohort studies, have been corroborated by the results of randomised trials in persons with high, average and below average levels of blood pressure. In spite of its importance in causing cardiovascular disease blood pressure is a poor predictor of cardiovascular events. Its poor screening performance is illustrated by the findings that in the largest cohort study, persons in the top 10% of the distribution of systolic blood pressure experienced only 21% of all ischaemic heart disease events and 28% of all strokes at a given age. Combining several reversible risk factors adds little to the screening performance of blood pressure alone; for example the 25% of men aged 5564 at highest computed risk (> or =1%) experience only 46% of all ischaemic heart disease events. The main methods of screening should be to identify all persons with a history of cardiovascular disease events (for example identifying patients at the time of hospital discharge following a first myocardial infarction detects 50% of all heart disease deaths in a population at a false positive rate of 12%), and to use a person's age. Identifying everyone with a history of myocardial infarction or stroke in a population and everyone aged 55 or more would include 98% of all deaths from ischaemic heart disease and stroke. The five main categories of blood pressure lowering drugs, thiazides, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists and calcium channel blockers, significantly reduce blood pressure from all pre-treatment levels though the extent of the blood pressure reduction increased with pre-treatment blood pressure. The reductions were similar at standard dose for the five categories; average reduction was 9.1 systolic and 5 diastolic. The effect of combinations of two drugs on blood pressure was additive. No effect of age was apparent, given blood pressure. There were no serious metabolic consequences of using these drugs in standard dose. Conclusions The evidence presented indicates that three drugs in combination may reduce stroke by about two-thirds and ischaemic heart disease by half. The report suggests that the term hypertension should be avoided because it is not a disease and it implies another category (normotensives) who would not benefit from lowering blood pressure. Blood pressure reduction using combinations of safe, well-established drugs is effective in preventing cardiovascular events. It is therefore suggested that such preventive therapy be considered more widely in people who by virtue of existing disease or simply age are at risk of a heart attack or stroke regardless of initial blood pressure.

Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

Valsartan competitively and selectively inhibits the actions of angiotensin II at the AT1 receptor subtype which is responsible for most of the known effects of angiotensin II. In clinical trials in patients with mild to moderate essential hypertension valsartan was as effective as losartan, lisinopril, enalapril, amlodipine and hydrochlorothiazide. Addition of the latter reduced blood pressure in patients who did not respond sufficiently to valsartan monotherapy. Preliminary data also suggest valsartan may be effective in patients with severe essential hypertension. The drug was as effective as lisinopril as treatment for mild to moderate essential hypertension in patients with renal insufficiency and did not worsen renal function. Headache, dizziness and fatigue were the most common adverse events in placebo-controlled studies; the incidence of these adverse events was not significantly different between placebo and valsartan recipients. Compared with ACE inhibitors, valsartan was associated with a significantly lower incidence of dry cough. Thus, valsartan is an effective treatment for mild to moderate essential hypertension and may be particularly useful in patients who experience persistent cough during ACE inhibitor therapy.

Valsartan. A review of its pharmacology and therapeutic use in essential hypertension.

We compared the antihypertensive efficacy of available drugs in the new angiotensin-II-antagonist (AIIA) class. The antihypertensive efficacy of losartan, valsartan, irbesartan, and candesartan was evaluated from randomized controlled trials (RCT) by performing a metaanalysis of 43 published RCT. These trials involved AIIA compared with placebo, other antihypertensive classes, and direct comparisons between AIIA. A weighted-average for diastolic and systolic blood pressure reduction with AIIA monotherapy, dose titration, and with addition of low-dose hydrochlorothiazide (HCTZ) were calculated. Weighted-average responder rates were also determined. The metaanalysis assessed a total of 11,281 patients. The absolute weighted-average reductions in diastolic (8.2 to 8.9 mm Hg) and systolic (10.4 to 11.8 mm Hg) blood pressure reductions (not placebo-corrected) for AIIA monotherapy were comparable for all AIIA. Responder rates for AIIA monotherapy were 48% to 55%. Dose titration resulted in slightly greater blood pressure reduction and an increase in responder rates to 53% to 63%. AIIA/hydrochlorothiazide combinations produced substantially greater reduction in systolic (16.1 to 20.6 mm Hg) and diastolic (9.9 to 13.6 mm Hg) blood pressure reductions than AIIA monotherapy and responder rates for AIIA/HCTZ combinations were 56% to 70%. This comprehensive analysis shows comparable antihypertensive efficacy within the AIIA class, a near-flat AIIA-dose response when titrating from starting to maximum recommended dose, and substantial potentiation of the antihypertensive effect with addition of HCTZ.

Stephen Dyke

Papers

The efficacy and safety of valsartan compared with placebo in the treatment of patients with essential hypertension