Hypertension management: rationale for triple therapy based on mechanisms of action.

An estimated 25% of patients will require 3 antihypertensive agents to achieve blood pressure (BP) control; combination therapy is thus an important strategy in hypertension treatment. This review discusses the triple-therapy combination of an angiotensin receptor blocker (ARB) or direct renin antagonist (DRI) with a calcium channel blocker (CCB) and a diuretic, with a focus on mechanisms of action. Multiple physiologic pathways contribute to hypertension. Combining antihypertensive agents not only better targets the underlying pathways, but also helps blunt compensatory responses that may be triggered by single-agent therapy. DRIs and ARBs target the renin-angiotensin-aldosterone system (RAAS) at the initial and final steps, respectively, and both classes lower BP by reducing the effects of angiotensin-2; however, ARBs may trigger a compensatory increase in renin activity. Dihydropyridine CCBs target L-type calcium channels and lower BP through potent vasodilation, but can trigger compensatory activation of the sympathetic nervous system (SNS) and RAAS. Thiazide diuretics lower BP initially through sodium depletion and plasma volume reduction, followed by total peripheral resistance reduction, but can also trigger compensatory activation of the SNS and RAAS. The combination of an agent targeting the RAAS with a CCB and diuretic is rational, and triple combinations of valsartan/amlodipine/hydrochlorothiazide, olmesartan/amlodipine/hydrochlorothiazide, and aliskiren/amlodipine/hydrochlorothiazide have demonstrated greater effectiveness compared with their respective dual-component combinations. In addition, single-pill, fixed-dose combinations can address barriers to BP control including clinical inertia and poor adherence. Fixed-dose antihypertensive combination products capitalize on complementary mechanisms of action and have been shown to result in improved BP control.

Coadministered amlodipine and atorvastatin produces early improvements in arterial wall compliance in hypertensive patients with dyslipidemia.

BACKGROUND: Combining statins with antihypertensive therapy has been demonstrated to provide an early reduction in cardiovascular events. This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance, to evaluate the vascular benefits of coadministered therapy. METHODS: During an initial 8-week, double-blind phase, patients with concomitant hypertension and dyslipidemia were randomized into four treatment groups (placebo, amlodipine 5 mg, atorvastatin 10 mg, or coadministered amlodipine 5 mg and atorvastatin 10 mg). The sustained effect of combined therapy was evaluated during subsequent 8-week, single-blind, and 12-week, open-label periods. In the single-blind phase, all patients were coadministered amlodipine 5 mg and atorvastatin 10 mg, which were then titrated to optimize blood pressure and low-density lipoprotein cholesterol control during the open-label phase. Arterial compliance was assessed every 4 weeks using the HDI/Pulsewave CR-2000. RESULTS: Overall, 668 patients (61% male, mean age 55 years) were randomized to treatment. A 19% improvement in small artery compliance (C2) was observed with coadministered amlodipine and atorvastatin from baseline to week 8, which was significantly greater than with either treatment alone or with placebo (P = 0.03 to 0.0001). After 28 weeks, C2 was increased from baseline in all groups, but the overall improvement was greatest in the group receiving coadministered drugs for the entire study period (P < 0.05). CONCLUSIONS: Early and sustained improvement in small artery compliance was observed following coadministration of amlodipine and atorvastatin, thus demonstrating a vascular benefit with simultaneous treatment of hypertension and dyslipidemia.

Comparison of angiotensin II type 1 receptor antagonists in the treatment of essential hypertension.

Hypertension is a major health problem worldwide, yet remains under-diagnosed and under-treated. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) are highly effective at reducing blood pressure (BP), exhibit renoprotective properties and have placebo-like tolerability. However, it is unclear whether there are clinical differences in efficacy and tolerability between the available ARBs. A review of published, randomized, comparative clinical trials suggests that differences in BP-lowering efficacy and 24-hour BP control may exist between ARBs, although it appears that there is no evidence for important differences in tolerability between ARBs. Few studies have assessed attainment rates for important combined systolic BP (SBP)/diastolic BP (DBP) goals recommended in treatment guidelines. Likewise, few studies have directly compared more than two agents or ARB/hydrochlorothiazide fixed-dose combinations, and most ARBs have not been compared across their full recommended dosage ranges. Overall, there is insufficient weight of evidence to allow definitive conclusions to be drawn regarding the comparative efficacy of the available ARBs. However, newer ARBs (e.g. olmesartan medoxomil and telmisartan) appear to be more effective than older ARBs (e.g. losartan and valsartan) in reducing DBP and/or SBP in some trials. In addition, olmesartan medoxomil treatment regimens resulted in high BP control rates in several trials, but head-to-head trials with other ARBs are required to put these control rates into perspective, especially for SBP control with various agents. The purpose of this review is to present published data from ARB efficacy trials for a comparison of various efficacy parameters among the agents within this drug class.

Fixed-dose combination antihypertensives and reduction in target organ damage: are they all the same?

Hypertension is a multifactorial disorder leading to pathophysiologic changes in target organs over time through diverse mechanisms. In addition, hypertension frequently resists control with monotherapy, necessitating combination therapy with two or more antihypertensive agents. Many currently available fixed-dose antihypertensive combinations combine drugs with different, but complementary, mechanisms of action to improve overall efficacy and tolerability. In addition, it is possible to select drug combinations whereby one drug offsets the negative effects of the other drug. Fixed-dose antihypertensive combinations may provide significant advantages over high-dose monotherapy, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to BP control. Combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients, such as those with stage 2 hypertension. The combination of a renin-angiotensin-aldosterone system-targeting agent, such as an ACE inhibitor or angiotensin II receptor antagonist (ARB), and a diuretic or calcium channel antagonist appears to provide synergy with regard to BP lowering. In addition, ACE inhibitors and ARBs have demonstrated beneficial effects beyond BP reduction, reducing cardiovascular morbidity and mortality, inhibiting development and progression of type 2 diabetes mellitus and the progression of renal disease. Preliminary studies of fixed-dose combinations have shown reductions in left ventricular hypertrophy and improvements in markers of renal function. Additional studies currently underway will compare the effects of available fixed-dose combinations on cardiovascular morbidity and mortality, and markers of renal dysfunction.

Dose-response characteristics of olmesartan medoxomil and other angiotensin receptor antagonists.

Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are an effective initial antihypertensive monotherapy in many patients. However, when initial ARB monotherapy fails to achieve the recommended BP goal, there is some controversy as to whether dose uptitration or the addition of a diuretic is more appropriate. This article addresses this issue by reviewing the dose-response characteristics of olmesartan medoxomil and other ARBs, as well as the relationship between ARB uptitration and BP goal attainment. Two types of trial designs are used to assess dose response: dose-ranging studies (usually a parallel design using different doses across different patient groups), which are used to establish the optimal dose for US FDA registration purposes, and dose-titration studies (increased dosing within the same patients and treating to goal BP). Since dose titration is within the same patient, it may be considered more appropriate for demonstrating dose-response characteristics and demonstration of BP goal attainment. While results from dose-ranging studies suggest that the dose-response curve for some ARBs may be flat, dose-titration studies indicate that significant improvements in BP control and BP goal attainment can be achieved with ARB uptitration. In an integrated analysis of seven US and European randomized, placebo-controlled, dose-ranging trials involving 3055 patients with stage 2 hypertension treated with olmesartan medoxomil 2.5-80 mg/day or placebo for 8 weeks, all olmesartan medoxomil doses were significantly more effective than placebo in lowering the mean DBP and mean SBP (p

Efficacy of combination therapy with amlodipine besylate/benazepril hydrochloride for lowering systolic blood pressure in stage 2 hypertension.

The Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study compared daily treatment with combination amlodipine besylate/benazepril hydrochloride 5/20 mg, amlodipine besylate 5 mg, and benazepril hydrochloride 20 mg in 505 patients aged 55 years of age or older with stage 2 hypertension (systolic blood pressure [BP] > or =160 and < or =200 mm Hg and diastolic BP > or =60 and < or =100 mm Hg). BP and pulse pressure were assessed by conventional office BP measurements and 24-hour ambulatory BP monitoring. In this analysis, combination therapy was associated with significantly greater reductions in mean 24-hour BP, pulse pressure, and mean ambulatory BP during various time intervals compared with either monotherapy in the intent-to-treat population, in those with isolated and predominantly systolic hypertension, and in dippers and nondippers. Adverse event rates were low and similar in all treatment groups. This study demonstrated that combination therapy is superior to monotherapy in older patients with stage 2 systolic hypertension and is well tolerated.

Experimental and theoretical 17O NMR study of the influence of hydrogen-bonding on C=O and O-H oxygens in carboxylic solids.

A systematic solid-state 17O NMR study of a series of carboxylic compounds, maleic acid, chloromaleic acid, KH maleate, KH chloromaleate, K2 chloromaleate, and LiH phthalate.MeOH, is reported. Magic-angle spinning (MAS), triple-quantum (3Q) MAS, and double angle rotation (DOR) 17O NMR spectra were recorded at high magnetic fields (14.1 and 18.8 T). 17O MAS NMR for metal-free carboxylic acids and metal-containing carboxylic salts show featured spectra and demonstrate that this combined, where necessary, with DOR and 3QMAS, can yield site-specific information for samples containing multiple oxygen sites. In addition to 17O NMR spectroscopy, extensive quantum mechanical calculations were carried out to explore the influence of hydrogen bonding at these oxygen sites. B3LYP/6-311G++(d,p) calculations of 17O NMR parameters yielded good agreement with the experimental values. Linear correlations are observed between the calculated 17O NMR parameters and the hydrogen bond strengths, suggesting the possibility of estimating H-bonding information from 17O NMR data. The calculations also revealed intermolecular H-bond effects on the 17O NMR shielding tensors. It is found that the delta11 and delta22 components of the chemical shift tensor at O-H and C=O, respectively, are aligned nearly parallel with the strong H-bond and shift away from this direction as the H-bond interaction weakens.

Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study.

Systolic hypertension is predominant among patients over 50 years of age, is a more important cardiovascular risk factor than diastolic blood pressure, and is more difficult to control than diastolic blood pressure. Consequently, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends combination therapy as first-line treatment for patients with stage 2 hypertension. In the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study, 24-hour ambulatory blood pressure monitoring was used to identify patients with systolic hypertension and to determine the impact of 8 weeks of treatment with either amlodipine besylate/benazepril HCl 5/20 mg combination therapy (n=149), amlodipine besylate 5 mg (n=146), or benazepril HCl 20 mg (n=148). Combination therapy was significantly more effective in reducing systolic blood pressure and pulse pressure than either monotherapy (p<0.0001). Significantly greater percentages of patients in the combination group compared with either monotherapy achieved blood pressure control (p<0.0001). Adverse events were low in all three treatment arms, with less peripheral edema in the combination group than in the amlodipine-treated group. The combination of amlodipine besylate/benazepril HCl given to patients with stage 2 systolic hypertension resulted in significantly greater reductions in blood pressure and pulse pressure than those seen with monotherapy and was at least as well tolerated as the separate components. This data supports the recommendation of the JNC 7 for the use of combination therapy in patients with stage 2 hypertension.

Use of 24-hour ambulatory blood pressure monitoring to assess antihypertensive efficacy: a comparison of olmesartan medoxomil, losartan potassium, valsartan, and irbesartan.

INTRODUCTION: Goal rates, the percentage of patients with hypertension achieving recommended SBP/DBP, are a clinically important assessment of an antihypertensive agent's efficacy. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) allows accurate assessment of a patient's hypertension and risk for cardiovascular events, and provides the most accurate measure of an antihypertensive agent's efficacy throughout a 24-hour dosing interval. METHODS: A 12-week (4-week single-blind placebo run-in phase followed by an 8-week double-blind active treatment phase) randomized, parallel-group study reported that the recommended starting dose of the angiotensin II receptor antagonist (angiotensin receptor blocker; ARB) olmesartan medoxomil (Benicar(trade mark)) 20 mg/day was more effective than starting doses of losartan potassium (Cozaar) 50 mg/day, valsartan (Diovan) 80 mg/day, or irbesartan (Avapro) 150 mg/day in reducing cuff DBP in patients with essential hypertension. The present report includes analyses of secondary efficacy variables from this 12-week trial. RESULTS: The mean reduction in blood pressure from baseline to week 8 (end of treatment) was significantly greater with olmesartan medoxomil than with valsartan for all ABPM times analyzed (24 hours, daytime, night-time, and last 2 and 4 hours of monitoring). Statistical significance was reached for comparisons of olmesartan medoxomil with losartan potassium for a majority of times analyzed and with irbesartan for SBP in the last 4 hours of monitoring. Goal rates for accepted critical ambulatory blood pressure (ABP) values of <130/80 mm Hg for mean 24-hour ABP, <135/85 mm Hg for mean daytime ABP, and <120/75 mm Hg for mean night-time ABP were significantly greater for patients receiving olmesartan medoxomil than for those receiving losartan potassium or valsartan. Goal rates were numerically superior, but not statistically significant, to those achieved with irbesartan. Compared with losartan potassium or valsartan recipients, a significantly higher percentage of patients treated with olmesartan medoxomil achieved the 24-hour ABP goal of <130/85 mm Hg. The last 2 and 4 hours of ABPM indicated that olmesartan medoxomil maintained larger mean decreases in blood pressure through the morning surge. DISCUSSION/CONCLUSION: ABP goal rates are a meaningful measure of antihypertensive efficacy. The effects on mean change from baseline in ABP and ABP goal rates after 8 weeks of treatment were numerically better, but not statistically significant, for olmesartan medoxomil than for irbesartan. However, olmesartan medoxomil was significantly more effective than losartan potassium or valsartan.

Use of an olmesartan medoxomil-based treatment algorithm for hypertension control.

Hypertension guidelines recommend a stepped-care approach that starts with titration of the initial agent followed by the addition of other agents, as necessary, to achieve goal blood pressure. This study assessed the effectiveness of an antihypertensive treatment algorithm with olmesartan medoxomil as the initial agent. This was a 24-week, open-label trial in patients (N=201) with mean seated diastolic blood pressure of 90-109 mm Hg. Following placebo run-in, all patients received olmesartan medoxomil 20 mg/d for 4 weeks. At subsequent 4-week intervals, the regimen was modified in patients with blood pressure >130/85 mm Hg: up-titration of olmesartan medoxomil to 40 mg/d; addition of hydrochlorothiazide 12.5 mg/d; up-titration of hydrochlorothiazide to 25 mg/d; addition of amlodipine besylate 5 mg/d; and up-titration of amlodipine besylate to 10 mg/d. Patients who achieved blood pressure < or =130/85 mm Hg at any point exited the study with no further follow-up. At Week 24, reductions in blood pressure from baseline were 33.7/18.2 mm Hg. Altogether, 87.7% of patients reached the goal blood pressure of < or =130/85 mm Hg and 93.3% achieved a blood pressure of < or =140/90 mm Hg. Thus, an antihypertensive algorithm with olmesartan medoxomil as the initial agent controlled blood pressure in the majority of patients, but with >60% of patients also requiring the use of a thiazide diuretic or a thiazide and a calcium channel blocker.

Cn microspheres as surrogate membranes in glycosidase-catalysed hydrolysis of glycolipids.

Glycosidase catalysed hydrolysis of glycolipids non-covalently attached to C(n) microspheres proceeds to completion for appropriate glycolipid-microsphere combinations in contrast with hydrolysis of covalently immobilised analogues which in all cases studied stops significantly short of complete hydrolysis.

Effect of antihypertensive monotherapy and combination therapy on arterial distensibility and left ventricular mass.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) increase arterial compliance and decrease left ventricular mass in hypertensive patients. This study examined whether combined therapy has greater arterial and cardiac effects than doubled doses of the individual drugs. METHODS: This prospective, randomized, open-label study enrolled 106 patients aged >/=18 years with mild-to-moderate hypertension. Patients were randomized to 5 mg of amlodipine or 20 mg of benazepril for 2 weeks; then, depending on randomization assignment, they were force-titrated to 10 mg of amlodipine or 40 mg of benazepril monotherapy, or to combination amlodipine (5 mg) and benazepril (20 mg) treatment for 22 weeks. Arterial distensibility was assessed using the DynaPulse ambulatory system, and left ventricular mass was assessed by echocardiography. RESULTS: Combination therapy (0.71% +/- 0.51% mL/mm Hg) increased arterial distensibility more than amlodipine (0.28% +/- 0.69% mL/mm Hg; P =.008) or benazepril (0.39% +/- 0.62% mL/mm Hg; P =.03) monotherapies. Left ventricular mass decreased more with combination treatment (65 +/- 56 g) than with amlodipine (28 +/- 4 g; P <.02); the difference from benazepril (42 +/- 50 g) was not significant. CONCLUSIONS: Combined ACE inhibitor and CCB treatment was more efficacious than high doses of the individual agents in increasing arterial compliance and reducing left ventricular mass. These findings indicate that appropriately selected combinations of antihypertensive drugs might have enhanced cardioprotective effects.

Comparison of telmisartan versus losartan: meta-analysis of titration-to-response studies.

OBJECTIVES: To compare the ability of telmisartan and losartan to reduce mean diastolic blood pressure (DBP) during the last 6 h of the 24-h dosing interval in a prospectively planned meta-analysis of ambulatory blood pressure monitoring (ABPM) data from two independent studies. METHODS: Data were from two independent randomized, double-blind, double-dummy, titration-to-response studies conducted in patients with mild-to-moderate hypertension (seated cuff DBP 95-109 mmHg, 24-h mean ambulatory DBP >or=85 mmHg). After a 4-week placebo run-in period, patients received once-daily telmisartan 40 mg or losartan 50 mg, with up-titration after 4 weeks to telmisartan 80 mg or losartan 100 mg, respectively, if seated trough cuff DBP >or=90 mmHg. Blood pressures were recorded using ABPM immediately before randomization and after 8 weeks of active treatment. In addition, seated trough cuff blood pressures were measured at baseline and after 4 and 8 weeks of active treatment. RESULTS: Titration to the higher dose was required in 60.1% of telmisartan patients and 69.5% of losartan patients (P=0.01). Reductions from baseline in the last 6 h mean ambulatory DBP with telmisartan and losartan were 6.6+/-0.4 and 5.1+/-0.4 mmHg, respectively (P<0.01, adjusted for baseline and study); the effects were homogeneous across the two studies. During the last 6 h of the 24-h dosing interval, telmisartan produced greater reductions in each of the observed hourly mean ambulatory DBP values. Telmisartan-induced reductions were also greater for the majority of the observed hourly mean ambulatory DBP values over the entire 24-h dosing interval. Reductions from baseline in the last 6 h adjusted mean ambulatory systolic blood pressure (SBP) for telmisartan and losartan were 9.9+/-0.6 and 7.8+/-0.6 mmHg, respectively (P=0.01). The 24-h profiles of ambulatory SBP hourly mean reductions were similar to those for DBP. Both telmisartan and losartan were found to be safe and well tolerated. CONCLUSIONS: Telmisartan 40/80 mg is superior to losartan 50/100 mg in controlling DBP and SBP during the last 6 h of the 24-h dosing interval.

Purification, crystallization and preliminary X-ray crystallographic studies on acetolactate decarboxylase.

Acetolactate decarboxylase has the unique ability to decarboxylate both enantiomers of acetolactate to give a single enantiomer of the decarboxylation product, (R)-acetoin. A gene coding for alpha-acetolactate decarboxylase from Bacillus brevis (ATCC 11031) was cloned and overexpressed in B. subtilis. The enzyme was purified in two steps to homogeneity prior to crystallization. Three different diffraction-quality crystal forms were obtained by the hanging-drop vapour-diffusion method using a number of screening conditions. The best crystal form is suitable for structural studies and was grown from solutions containing 20% PEG 2000 MME, 10 mM cadmium chloride and 0.1 M Tris-HCl pH 7.0. They grew to a maximum dimension of approximately 0.4 mm and belong to the trigonal space group P3(1,2)21, with unit-cell parameters a = 47.0, c = 198.9 A. A complete data set was collected to 2 A from a single native crystal using synchrotron radiation.

Defining the antihypertensive properties of the angiotensin receptor blocker telmisartan by a practice-based clinical trial.

Traditional randomized controlled clinical trials are designed to define the specific properties of individual antihypertensive drugs but do not provide full information about their use in clinical practice. To carry out a large-scale practice-based open-label trial to evaluate the safety and efficacy of an angiotensin receptor blocker (ARB) in controlling blood pressure (BP) in the community setting, 703 practitioners recruited 2705 hypertensive patients. There were three groups: untreated at the time of study entry with uncontrolled BP (>/=140/90 mm Hg) (N = 1957); treated but uncontrolled on current monotherapy (N = 685); and treated and controlled, but with unacceptable side effects (N = 63). After stopping any previous treatment, patients received telmisartan (40 mg daily) for 2 weeks; the dose was increased to 80 mg if BP remained >/=130/85 mm Hg. Participants were then followed for a further 4 weeks. Blood pressure decreased by 18.9/12.3 mm Hg in the untreated group, by 13.1/7.9 mm Hg in the previously treated but uncontrolled group, and increased slightly by 3.5/1.3 mm Hg in the previously controlled group. Patients not responding adequately to the 40-mg telmisartan dose had an initial BP reduction of 7.3/4.5 mm Hg; titration to 80 mg gave an additional 7.5/5.0 mm Hg reduction and controlled BP (<140/90 mm Hg) in 44% of these titrated patients. Overall, control occurred in 56% of white patients; 52% of black patients (who responded well to dose titration); 60% of patients <65 years; and 46% of patients >/=65 years. Thus, in contrast with the relatively flat dose response effects in controlled parallel group trials, this practice-based trial has demonstrated the value of titrating telmisartan to its maximum dose in patients with inadequate BP responses to the initial dose, and has shown its efficacy across major demographic groups.

Improving patient compliance: a major goal in the management of hypertension.

The primary goal in the treatment of hypertension is to reduce the incidence of cardiovascular events in hypertensive patients. Studies performed to assess the impact of treating hypertension have revealed very disappointing reductions in the incidence of coronary heart disease. There are several reasons for these poor reductions in the incidence of cardiovascular disease; however, the most important is related to the fact that worldwide less than one quarter of hypertensive patients are adequately controlled for hypertension. Again, there are multiple reasons for these poor blood pressure (BP) control rates; however, most physicians would agree that patient compliance with their antihypertensive treatment is a major contributing factor. This is an area that we need to refocus on in our management of hypertensive patients. Issues such as safety, convenience, polypharmacy, cost, and education in the selection of antihypertensive agents are all critically important issues in the treatment of hypertensive patients. In addition, the level of patient involvement in their treatment seems to be essential in obtaining goal BP. Newer approaches to the management of hypertension such as earlier control of BP and the more aggressive use of low-dose combination therapy as first-line treatment of hypertension also need to be considered in our effort to improve BP control rates. Achieving goal BP in hypertensive patients is one of the most important clinical dilemmas facing physicians. There is little doubt that an improvement in control rates will result in substantial reductions in cardiovascular disease.

Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database.

Angiotensin II receptor blockers are well tolerated and improve compliance in hypertensive patients. The need for 24-hour blood pressure control has focused attention on whether all agents in this class maintain smooth antihypertensive effects over a 24-hour period. Insight into this issue emerged from a meta-analysis of five large, multicenter trials in which ambulatory blood pressure monitoring was used to compare the antihypertensive effects of three angiotensin II receptor blockers: telmisartan, losartan, and valsartan. These trials used either a double-blind, placebo-controlled or a prospective, randomized, open-label, blinded-end point design. Initial analysis established the validity of combining ambulatory blood pressure monitoring data from the double-blind, placebo-controlled and prospective, randomized, open-label, blinded-end point designs. Subsequent analyses revealed that telmisartan 80 mg was significantly more effective than losartan 50 mg and valsartan 80 mg for reducing 24-hour mean blood pressure. Furthermore, telmisartan 80 mg was comparable to amlodipine 5 mg for controlling the early morning surge in blood pressure.

Treatment of hypertension with an angiotensin II-receptor antagonist compared with an angiotensin-converting enzyme inhibitor: a review of clinical studies of telmisartan and enalapril.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII)-receptor antagonists suppress the effects of ATII and are effective antihypertensive agents. However, the use of ACE inhibitors is sometimes associated with intolerable side effects (eg, cough, angioedema), and patients may develop a compensatory rise in ATII levels. ATII-receptor antagonists have tolerability profiles similar to that of placebo and inhibit the effects of ATII more completely by blocking the AT1 receptor. OBJECTIVE: This review summarizes clinical studies comparing the efficacy and tolerability of the ATII-receptor antagonist telmisartan with the ACE inhibitor enalapril in patients with hypertension. METHODS: Randomized, controlled clinical trials comparing telmisartan with enalapril in patients with primary hypertension were identified through a PubMed search of the English-language literature from 1998 through 2001 and from bibliographic data provided by the manufacturer of telmisartan. RESULTS: In 2 randomized, double-blind, placebo-controlled trials (total number of patients, 647), telmisartan 40 or 80 mg/d was at least as effective as enalapril 20 mg/d for lowering blood pressure (BP) in patients with mild to moderate hypertension. An open-label, titration-to-response study involving 86 patients with severe hypertension found that telmisartan 80 to 160 mg/d was as efficacious as enalapril 20 to 40 mg/d. The antihypertensive effects of telmisartan 20 to 80 mg/d and enalapril 5 to 20 mg/d were comparable in 278 elderly patients (age > or = 65 years) with mild to moderate hypertension enrolled in a 26-week, double-blind, dose-titration study. A double-blind, titration-to-response study in 71 patients with moderate renal impairment and mild to moderate hypertension found equivalent reductions in BP with telmisartan 40 to 80 mg/d and enalapril 10 to 20 mg/d without any clinically relevant decline in renal function. Telmisartan tended to be better tolerated than enalapril in this study, with fewer patients experiencing treatment-related adverse events (8.9% vs 26.9%, respectively). CONCLUSIONS: Based on the literature included in this review, telmisartan and enalapril produced comparable reductions in BP in a broad range of patients with hypertension. Telmisartan appeared to have a better tolerability profile.

Strategies to meet lower blood pressure goals with a new standard in angiotensin II receptor blockade.

The continued poor rates of blood pressure (BP) control to the recommended target BP of <140/90 mm Hg in patients with hypertension indicate a persistent need for improved antihypertensive therapy. Angiotensin II receptor blockers (ARBs) constitute the newest approved class of antihypertensive agents. As with angiotensin converting enzyme inhibitors, ARBs block the renin-angiotensin-aldosterone system, but do so through a more specific mechanism. Angiotensin converting enzyme inhibitors block the conversion of angiotensin I to angiotensin II, but angiotensin II may be produced by several alternate pathways. Angiotensin II receptor blockers, by contrast, inhibit the binding of angiotensin II to the angiotensin II type 1 (AT1) receptor, independent of the pathway of angiotensin II production. Comparative safety and efficacy trials indicate that ARBs are similar to other antihypertensive drugs in terms of BP-lowering effectiveness and have superior tolerability. Olmesartan medoxomil is the newest and one of the most effective of the ARBs. In controlled trials, it has been shown to provide 24-h BP control with antihypertensive efficacy at least as good as that of the calcium channel blockers amlodipine besylate and felodipine and the beta-blocker atenolol. In a comparative study, olmesartan medoxomil demonstrated significantly greater reductions in diastolic BP than did three other leading ARBs-losartan potassium, irbesartan, and valsartan. With the convenience of placebo-like tolerability and once-daily dosing, combined with excellent antihypertensive efficacy, olmesartan medoxomil may be a useful addition to our management of hypertension.