Hypertension is common among patients with type 2 diabetes mellitus, increasing their risk of cardiovascular morbidity and mortality. Such patients are also at risk of renal impairment and end-stage renal disease. Long-term, tight blood pressure control (ideally to a target of < 130/85 mmHg) in patients with type 2 diabetes is a highly effective strategy for reducing the risk of cardiovascular complications and is now embodied in the many guidelines of hypertension and diabetes management. More recent studies indicate that the choice of antihypertensive agent is also important. Drugs that block the renin-angiotensin-aldosterone system, such as the angiotensin-II receptor blockers (ARBs), may prevent the onset of diabetes and confer greater cardiovascular benefit among patients who already have this disease compared with some older antihypertensive agents. For example, in type 2 diabetic patients with renal dysfunction, ARBs exert a renal protective effect that extends beyond blood pressure reduction and may retard diabetic nephropathy. Antihypertensive therapy, together with lifestyle modification to address obesity and physical inactivity, can significantly reduce the risk of cardiovascular complications in patients with type 2 diabetes. The challenge is to achieve beneficial, hygienic measures in populations with diverse backgrounds and improve compliance with proven treatments that inevitably involve multiple drugs. Combination therapies comprising agents that offer good tolerability and do not exacerbate existing metabolic disturbances, as well as demonstrating benefit in preventing events in diabetic patients beyond blood pressure reduction itself, seem a likely way forward.

Angiotensin-II receptor blockers (ARBs) have been shown to provide stroke, cardiac and renal protection in high-risk hypertensive patients. Telmisartan is a powerful and selective ARB that provides sustained blood pressure reduction for a full 24 h after a single dose and continues to protect against circadian blood pressure surges in the critical early morning hours. The objective of the Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) is to measure the end-organ protective effects of telmisartan in patients at high risk of renal, cardiac and vascular damage. An extensive series of clinical trials is being conducted to compare telmisartan with valsartan, losartan, amlodipine and ramipril in patients at increased risk of end-organ damage. Nine clinical studies will examine the effects of telmisartan in about 5000 hypertensive patients with isolated systolic hypertension, type 2 diabetes, obesity, left ventricular hypertrophy or renal disease. All of the studies will be conducted using state-of-the-art technology, including such techniques as ambulatory blood pressure monitoring and magnetic resonance imaging. This programme will also investigate the effects of an ARB on key surrogate markers of organ tissue damage. This series of trials will characterize the end-organ protective effects of telmisartan in hypertensive patient populations at high risk of clinical events.

Hypertension in the elderly is characterized principally by increased systolic blood pressure (SBP). Consequently, isolated systolic hypertension (ISH) is the most common subtype in this population. The major haemodynamic determinant underlying ISH is increased large-artery stiffness. This is expressed as an increase in SBP and decrease in diastolic blood pressure (DBP), leading to widening pulse pressure. Epidemiological studies show that ISH and increased pulse pressure in the elderly constitute independent cardiovascular risk factors and may be more robust in predicting the adverse cardiovascular sequelae of hypertension than elevated DBP alone. Reducing high blood pressure (> 140/90 mmHg), including ISH (SBP > 140 mmHg, DBP < 90 mmHg), with conventional and newer antihypertensive agents significantly reduces the risk of major coronary events, stroke, coronary heart disease and all-cause mortality. Among the elderly population, there appears to be no age threshold beyond which treatment of hypertension, including ISH, should not be considered beneficial. Clinical management has to take into account some specific aspects related to its pathophysiology and the patient characteristics of this population. Although the therapeutic goal is < 140/90 mmHg, a decrease of 20-30 mmHg in SBP, even if the overall goal is not achieved, is associated with improved prognosis.

To review the safety and efficacy of the very-low-dose combination of perindopril 2 mg and indapamide 0.625 mg (Per2/Ind0.625) in essential hypertension, in relation to blood pressure control and target-organ damage. We included in this review several double-blind, randomized studies in hypertensive patients, including five main studies from the European registration file and two clinical trials on regression of target-organ damage [large artery stiffness: the Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind Study (REASON); microalbuminuria in patients with type 2 diabetes: the Preterax in Albuminuria Regression (PREMIER) study]. Systolic (SBP) and diastolic (DBP) blood pressures measured at trough with a mercury sphygmomanometer, an automatic device (OMRON), and 24-h ambulatory blood pressure measurements (ABPM). Arterial stiffness, assessed from pulse wave velocity measurement and augmentation index (REASON study). Microalbuminuria (PREMIER study). The Per2/Ind0.625 combination was selected from the dose-finding studies. Twelve weeks after the participants were assigned to study groups, the reductions in SBP, measured with an OMRON device, were 12.3 +/- 15.0 mmHg with Per2/Ind0.625, 8.0 +/- 16.5 mmHg with perindopril 2 mg (P = 0.001), 9.4 +/- 14.3 mmHg with indapamide 0.625 mg (P = 0.023) and 2.1 +/- 16.8 mmHg with placebo (P < 0.001) (mean +/- SD; all P values are for comparisons with Per2/Ind0.625). The reductions in DBP were 6.8 +/- 9.2 mmHg, 5.0 +/- 9.5 mmHg (P = 0.02), 4.7 +/- 8.2 mmHg (P = 0.004) and 2.4 +/- 9.6 mmHg (P < 0.001) in the Per2/Ind0.625, perindopril 2 mg, indapamide 0.625 mg and placebo groups, respectively. During the long-term study, among 235 patients who achieved initial blood pressure normalization with the fixed combination, 79.8% sustained their normalized status over 1 year, with no significant difference regarding safety criteria. During the REASON study, Per/Ind reduced pulse wave velocity to a similar extent as atenolol, and augmentation index to a greater extent. During the PREMIER study, Per/Ind reduced microalbuminuria to a greater extent than did enalapril. The proven efficacy on blood pressure and regression of target-organ damage with a good safety profile confirm that the new fixed-low-dose combination Per2/Ind0.625 is a valuable option in the first-line treatment of hypertension.

The most important issues facing clinicians is the transfer of evidence from clinical trials into practice. Physician, patient and community acceptance of the evidence are key components of this process. Although barriers to this exist, in the case of transfer of evidence from the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) into clinical practice, these are minimal. Hence, transfer of this information into clinical practice should put blood pressure lowering in place as the fourth major secondary prevention strategy for stroke.

Essential hypertension is a very heterogeneous disease and different pressor mechanisms might interact to increase blood pressure. It is therefore not surprising that antihypertensive drugs given as monotherapies normalize blood pressure in only a proportion of hypertensive patients. This is, for instance, the case for diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor antagonists administered as single agents. The rationale for combining antihypertensive agents relates in part to the concept that the blood pressure-decreasing effect may be enhanced when two classes are coadministered. Also, combination treatment serves to counteract the counter-regulatory mechanisms that are triggered whenever pharmacologic intervention is initiated and act to limit the efficacy of the antihypertensive medication. For example, the compensatory increase in renin secretion induced by sodium depletion may become the predominant factor sustaining high blood pressure. Simultaneous blockade of the renin-angiotensin system, with either an ACE inhibitor or an AT1 receptor blocker, makes this compensatory hyper-reninaemia ineffective and allows maximum benefit from sodium depletion. The increased effectiveness obtained by combining a blocker of the renin-angiotensin system with a low dose of a diuretic is not obtained at the expense of reduced tolerability compared with the individual components administered alone. Fixed very-low-dose combinations containing an ACE inhibitor or an AT1 receptor blocker and a diuretic are therefore likely to become increasingly used, not only as second-line therapy, but also as first-line treatment. This is the case, for instance, for the fixed very-low-dose combination of the ACE inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), as this preparation is very effective in decreasing blood pressure while maintaining a tolerability that is similar to that of placebo.

Stroke is a leading cause of death and disability in the world, and the worldwide burden from stroke will increase further during the 21st century. Major advances in the treatment and prevention of stroke have occurred but additional measures are needed. Much of the modern care of stroke mimics the modern treatment of heart disease, in part because of the success of thrombolytic therapy in improving outcomes. Nevertheless, the impact of thrombolytic therapy is limited because of the short therapeutic window. Additional measures are needed to limit the neurological consequences of stroke. Prevention remains a critical component of the management of patients with cerebrovascular disease. Although surgical therapies and antithrombotic medications (antiplatelet agents and anticoagulants) are effective in lessening the likelihood of stroke or recurrent stroke, new strategies are needed to lower the risk further. Measures aimed at stabilizing the vascular endothelium or preventing fracture of atherosclerotic plaques show great promise. Medications including cholesterol-lowering agents and antihypertensive medications, such as the angiotensin-converting enzyme inhibitors, appear effective in stroke prevention. These agents could be combined with antithrombotic agents and surgical interventions to lessen the risk of stroke.

To determine the effects of a perindopril-based blood pressure lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack (TIA). 6105 subjects from 172 centres in Asia, Australasia, and Europe were randomised to receive active treatment (n = 3051) or placebo (n = 3054). Active treatment consisted of a flexible regimen based on the angiotensin-converting enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide, at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat. Active treatment reduced blood pressure by 9/4 mmHg over 4 years of follow-up. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo [relative risk reduction 28% (95% confidence interval 17-38), P < 0.0001]. Active treatment also reduced the risks of total major vascular events [26% (16-34)] including non-fatal myocardial infarction [38% (14-55)], severe cognitive decline [19% (4-32)], stroke-related dementia [34% (3-55)] and disability [18% (8-28)]. There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (P < 0.01). Combination therapy with perindopril plus indapamide lowered blood pressure by 12/5 mmHg and stroke risk by 43%. Single-drug therapy lowered blood pressure by 5/3 mmHg and produced no significant fall in the risk of stroke. The blood-pressure lowering regimen used in Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) reduced the risks of stroke and other serious events in hypertensive and non-hypertensive subjects with a history of stroke (whatever the subtype) or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger stroke reductions than monotherapy with perindopril alone. Treatment with these two agents should be considered routinely for all patients with a history of previous stroke or TIA, whether hypertensive or normotensive.

Several classes of drugs are used to treat hypertension but how they affect cardiovascular morbidity and mortality in high-risk patients is still under investigation. Recent outcome trials have examined the benefits associated with different levels of blood pressure control or have compared several of the 'newer' classes of antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers, with 'older' drug classes, such as diuretics and beta-blockers. Other trials have compared antihypertensive drugs with placebo. We performed a meta-regression analysis of 30 clinical trials that included a total of 149,407 patients. We based our analysis on summary statistics reported in the literature, and showed that blood pressure gradients accounted for most, if not all, of the differences in outcome in patients with hypertension or at high cardiovascular risk. We also conducted a study in older patients with isolated systolic hypertension and showed that antihypertensive drug treatment starting with the dihydropyridine calcium channel blocker, nitrendipine, reduced the risk of stroke and all cardiovascular complications. In addition, nitrendipine-based blood pressure-lowering therapy decreased the incidence of dementia. In diabetic patients, nitrendipine reduced the risk of proteinuria, decreased total mortality, and markedly improved cardiovascular prognosis. Taken together, these findings emphasize the desirability of tight blood pressure control.