Roland Asmar

The use of mercury in the field of blood pressure measurement will decrease and even disappear by the xxist century. Concurrently, automatic devices outspread will significantly limit the observers' bias. In order to better define hypertension, not only does one have to use several measurement methods but also to consider blood pressure reference values for each of these methods. Moreover, analyzing the various peripheral pressures: systolic, diastolic and pulse pressures have to be completed with further specific parameters such as measurement of central BP and arterial stiffness, major determinants of blood pressure levels. This should lead to improve therapeutical approaches of cardiovascular diseases and consequently, to a better management of hypertensive patients.

Angiotensin receptor blockers (ARBs) have become established as a major class of antihypertensive on the basis of their powerful effects on blood pressure (BP), excellent tolerability and pleiotropic end-organ-protective effects. However, individual ARBs vary in antihypertensive efficacy, which may be important to clinical outcome. Several strategies are available to ensure that BP reductions with ARBs are at least as great as that which can be achieved with other antihypertensive classes. Firstly, several newer ARBs, including irbesartan, candesartan, telmisartan and olmesartan, have been reported to provide equivalent antihypertensive efficacy to amlodipine and greater efficacy than either losartan, valsartan or both. Secondly, increases in dose may improve the antihypertensive efficacy of agents such as valsartan, although clinical studies are necessary to provide characterisation of new, higher-dose monotherapies. Thirdly, fixed dose combinations with hydrochlorothiazide (HCTZ) increase the antihypertensive effect of all ARBs. It is likely that differences in efficacy between newer and older ARBs will in some cases be sustained in combination therapy, such that the most potent ARBs and HCTZ will provide another tier of control. The future use of ARBs is likely to involve a growing emphasis on compound-specific data, with regard to the antihypertensive efficacy and pleiotropic protective actions of agents.

The objective of this prospective, randomized, open-label, blinded-endpoint study was to compare the antihypertensive efficacy of valsartan 80 mg v irbesartan 150 mg when combined with hydrochlorothiazide (HCTZ) 12.5 mg. Untreated or uncontrolled hypertensive adults (n = 800) were enrolled by primary care physicians. After a 5-week open-label lead-in phase in which all patients received 12.5 mg HCTZ once daily, subjects whose blood pressure (BP) remained uncontrolled were randomized (n = 464) to valsartan/HCTZ (80/12.5 mg) or irbesartan/HCTZ (150/12.5 mg) for 8 weeks. Home BP monitoring (HBPM) was performed in the morning and in the evening for 5 days, at baseline, and after 8 weeks. Office BP measurements were obtained at baseline and after 8 weeks. Irbesartan/HCTZ produced greater reductions in average systolic BP (SBP) and diastolic BP (DBP) measured by HBPM than valsartan/HCTZ (SBP: -13.0 v -10.6 mm Hg, P = .0094; DBP: -9.5 v -7.4 mm Hg, P = .0007). These differences were more pronounced in the morning (trough) than in the evening. Office BP measurements also showed greater reductions in trough seated SBP and DBP with irbesartan/HCTZ compared with valsartan/HCTZ. Normalization rates observed with HBPM (SBP <135 mm Hg and DBP <85 mm Hg) were significantly greater with irbesartan/HCTZ than with valsartan/HCTZ (50.2 v 33.2%; P = .0003). The overall safety was similar in the two groups. The superior BP-lowering potency of the fixed combination irbesartan/HCTZ (150/12.5 mg) over valsartan/HCTZ (80/12.5 mg), evidenced independently from the investigators by HBPM, supports the use of this technique in trials with prospective, randomized, open-label, blinded-endpoint designs.

Meta-analyses of clinical trials of antihypertensive medications which have measured regression of left ventricular hypertrophy reveal differences between classes of agent, with ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium antagonists being more effective than beta-blockers. The PICXEL study showed that a strategy based on a low-dose combination of the ACE inhibitor perindopril and the diuretic indapamide was significantly more effective than the ACE inhibitor enalapril alone in reducing left ventricular mass. The cardioprotective effect of the combination appears to be independent of its blood pressure lowering effect. A pilot study in patients has shown that perindopril/indapamide improves coronary perfusion which is reduced in hypertension, especially in patients with left ventricular hypertrophy. In a separate study perindopril/indapamide has shown a trend towards reducing cardiovascular events. Animal studies suggest that the combination reverses the changes in arteriolar and capillary densities associated with hypertension. Clinical and experimental studies of the cardioprotective actions of antihypertensive agents are providing a better understanding of how cardiovascular complications in hypertension can be reduced by careful choice of antihypertensive medication.

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

Pulse pressure (PP) corresponds to the difference between arterial systolic blood pressure and diastolic blood pressure. Central PP seems to be a stronger coronary risk marker than brachial PP. Central PP can be estimated by aortic PP measured non invasively by aplanation tonometry of the carotid artery. The aim of this study was to compare 2 methods of estimation of aortic PP: estimation from Pulse Wave Velocities (PWV) and by aplanation tonometry of the carotid artery. Estimation from PWV is based on the non uniform transmission of the PP i.e. the amplification of PP from the aorta to brachial artery, through arteries of increasing impedance. One hundred and fifty one subjects were included, 111 hemodialysis patients and 40 subjects free of cardiovascular treatment or cardiovascular organ damage, recruited in a preventive medicine setting. Central PP was measured by aplanation tonometry of the carotid artery. The following formula was used for the relationship between PP and PWV in the two arterial segments considered for pulse wave travel (waterhammer formula): [formula: see text] Where measurement of brachial PP (PPBr) and PWV at aortic (PWVAo) and brachial (PWVBr) gives an estimation of aortic PP (PPAo estimated). Carotid-femoral PWV was used for PWVAo and carotid-radial PWV was used for PWVBr. The two methods were compared by t-test and according to Bland and Altman's method. In the hemodialysis group (73 males, 44 +/- 12 years old), brachial PP was 56 +/- 15 mm Hg and central PP as measured at the carotid level was 47 +/- 15 mmHg. In the healthy group (29 males, 46 +/- 11 years old), these values were 46 +/- 10 mmHg and 35 +/- 10 mmHg respectively. Compared to carotid artery aplanation tonometry, PPAo estimated was larger than central PP by 2.9 +/- 6.3 mmHg in hemodialysis patients and by 5.4 +/- 6.6 mmHg in the healthy group. The difference was significantly larger in healthy subjects than in hemodialysis patients (p = 0.031). The PWV estimated PP is larger than the central PP measured at the carotid level by aplanation tonometry. The difference is larger in cardiovascular event free subjects than in patients on hemodialysis.

In hypertension, consideration of systolic blood pressure (SBP) and pulse pressure (PP) is now well recognized from epidemiological and therapeutical points of view, after numerous years of interest in only diastolic blood pressure. SBP, and also PP, are tightly linked to mechanical properties of large arteries. It is now possible to investigate precisely, with very good repeatability, these mechanic properties. The REASON study is an international multicenter randomised, controlled, parallel-groups study in essential hypertensives. The very low dose perindopril/indapamide combination (Per/Ind: 2 mg/0.625 mg) was compared with atenolol (50 mg) for a 12-month active treatment period in terms of blood pressure reduction efficiency and change in large artery hemodynamics to attempt to relate changes in pressure and changes in arterial mechanics. 471 patients suffering from hypertension were included, 406 benefitted from the treatment for one year (per-protocol analysis) and 96 benefitted from arterial investigations (pulse wave velocity and aortic wave reflection with applanation tonometry). Changes in brachial and central SBP and PP were higher with Per/ind than with atenolol. The reduction in pulse wave velocity was similar with both drugs, but aortic wave reflections were more reduced with Per/Ind than with atenolol. The very low dose perindopril/indapamide decreases SBP and PP to a larger extent than does a betablocker after a 12-month treatment. Changes in arterial mechanics, non invasively measured, were the same (pulse wave velocity) or in favour of Per/Ind vs atenolol (higher reduction in aortic wave reflection, with higher reductions in central systolic and pulse pressures).

Arterial wall stiffness, an important independent risk factor for cardiovascular disease in patients with hypertension, is worsened by the coexistence of diabetes mellitus. This randomised, prospective, double-blind, crossover trial assessed the effects of telmisartan on arterial stiffness in patients with Type 2 diabetes with essential hypertension. After a two-week placebo wash out period, 28 ambulatory patients received telmisartan (40 mg) or placebo for three weeks. Following a second two-week placebo wash out period, patients received the alternate treatment for a further three weeks. Augmentation index and central blood pressure (BP) were determined using the SphygmoCor™ device and pulse wave velocity (PWV) was measured using an automatic device, the Complior™, at the beginning and the end of each period. Telmisartan significantly reduced the carotid—femoral PWV compared with placebo (mean adjusted treatment difference —0.95 m/s; 95% CI: —1.67, —0.23 m/s; p=0.013). Peripheral and central diastolic, systolic and pulse pressures were also significantly reduced with telmisartan compared with placebo. In conclusion, telmisartan reduces arterial stiffness and peripheral and central BPs as assessed by PWV and pulse contour analysis in hypertensive patients with Type 2 diabetes. These properties of telmisartan suggest that it may improve cardiovascular outcome in this patient population.

THE PLACEBO EFFECT: In controlled clinical trials, use of a placebo has demonstrated that the lowering of blood pressure in hypertensive patients under medication is associated with a reduction in cardiovascular morbidity and mortality. Although a placebo clearly lowers levels of systolic and diastolic blood pressure (to varying degrees depending on the measurement used), it does not appear to have any effect on the pulse pressure, representing the difference between the systolic and diastolic pressures. CENTRAL MECHANISMS: The absence of placebo effect on the pulse pressure, demonstrated by controlled studies, suggests the activity of central mechanisms (notably bulbar), common to the placebo effect and to the control of neurogenic coupling between the heart and the large caliber arteries. Since the pulse pressure after the age of 60 is a major factor for predicting myocardial infarction, these results suggest that modifications in pulse pressure should be more closely studied during controlled cardiovascular clinical trials in elderly patients.