Adding nebivolol to ongoing antihypertensive therapy improves blood pressure and response rates in patients with uncontrolled stage I-II hypertension.

This study assessed blood pressure (BP) reductions and response rates following addition of nebivolol to ongoing antihypertensive therapy in patients with uncontrolled stage I-II hypertension despite antihypertensive treatment. Patients with an average sitting diastolic BP (SiDBP) > or =90 and < or =109 mm Hg while taking an antihypertensive regimen were included in this double-blind, placebo-controlled, parallel-group study. The primary efficacy end point was reduction from baseline to week 12 in mean trough SiDBP. In total, 669 patients were randomized to once-daily nebivolol 5, 10 or 20 mg or placebo. Addition of nebivolol 5, 10 and 20 mg significantly reduced BP; placebo-subtracted least squares mean reductions in trough SiDBP were -3.3, -3.5 and -4.6 mm Hg, respectively (P<0.001) and -5.7, -3.7 and -6.2 mm Hg in trough sitting systolic BP (SiSBP), respectively (P< or =0.015). Adding nebivolol 5-20 mg resulted in significantly more responders (SiDBP <90 or > or =10 mm Hg reduction; range: 53.0-65.1 vs 41.3% with placebo; P< or =0.028) and significantly better control rates (SiSBP/SiDBP <140/90 mm Hg; range: 41.3-52.7 vs 29.3% with placebo; P< or =0.029). Nebivolol was well tolerated; the incidence of adverse events with nebivolol was similar to that with placebo (40.2 vs 38.9%, respectively; P=0.763). Addition of once-daily nebivolol to ongoing antihypertensive therapy provided significant additional BP reductions and better response rates in patients with uncontrolled hypertension and was well tolerated.

Choosing among renin-angiotensin system blockers for the management of hypertension: from pharmacology to clinical efficacy.

BACKGROUND: Hypertension is an important healthcare challenge, yet despite initiatives to improve detection and advances in therapy, the majority of patients do not achieve recommended blood pressure targets and remain at high cardiovascular risk. Physicians are confronted with an array of antihypertensive agents, accompanied by increasingly complex and often conflicting evidence regarding their efficacy and tolerability. SCOPE: An extensive PubMed and Cochrane database search was conducted to identify clinical literature (published 1990-2009) on the blood pressure lowering efficacy, tolerability and target organ protection of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). While not a systematic review, this article reviews the best available evidence in an attempt to clarify current uncertainty within medical practice regarding treatment options in patients with hypertension. FINDINGS: ACEIs have been at the forefront of hypertension therapy for several years, especially in hypertensive at-risk patients. However, their use is restricted by burdensome side-effects and their limited ability to reach target blood pressure. Newer ARBs, such as telmisartan, have more sustained blood pressure control throughout the 24-h dosing period compared with ACEIs and other ARBs. For uncomplicated hypertension, ARBs are preferred to ACEIs because of their superior tolerability and adherence. In specific patient populations, namely heart failure patients, ARBs have previously shown equal cardiovascular protection to ACEIs. ONTARGET showed that an ARB, in this case telmisartan, was as effective as ramipril in reducing cardiovascular events in a wide cross-section of at-risk cardiovascular patients, but was better tolerated even though patients were screened for ACEI tolerance. CONCLUSION: Telmisartan is currently the only ARB to have demonstrated equivalence to ramipril in reducing cardiovascular events in a broad patient population. In practical terms, telmisartan is superior to the reference standard ramipril because of more powerful blood pressure lowering and superior tolerability. However, in many countries, guidance to physicians prioritizes ACEIs. In these countries, telmisartan should be the first choice ARB for hypertensive at-risk patients who do not achieve adequate blood pressure control with an ACEI, or for whom tolerability is a concern.

Antihypertensive efficacy of telmisartan vs ramipril over the 24-h dosing period, including the critical early morning hours: a pooled analysis of the PRISMA I and II randomized trials.

Cardiovascular risk is subject to circadian variation, with peak morning incidence of myocardial infarction and stroke correlating with the early morning blood pressure (BP) surge (EMBPS). Ideally, antihypertensive therapy should maintain control of BP throughout the 24-h dosing cycle. In two sister studies, Prospective, Randomized Investigation of the Safety and efficacy of Micardis vs Ramipril Using ABPM (ambulatory BP monitoring) (PRISMA) I and II, BP control was compared in patients with essential hypertension (24-h mean baseline ambulatory BP approximately 148/93 mm Hg) randomized to the angiotensin receptor blocker, telmisartan (80 mg; n=802), or the angiotensin-converting enzyme inhibitor, ramipril (5 or 10 mg; n=811), both dosed in the morning. The primary end point was the change from baseline in mean ambulatory systolic BP (SBP) and diastolic BP (DBP) during the final 6 h of the 24-h dosing cycle. The adjusted mean treatment differences in the last 6-h mean ambulatory SBP/DBP were -5.8/-4.2 mm Hg after 8 weeks and -4.1/-3.0 mm Hg after 14 weeks, in favour of telmisartan (P<0.0001 for all four comparisons). Secondary end point results, including the mean 24-h ambulatory BP monitoring, day- and night-time BP and 24-h BP load, also significantly favoured telmisartan (P<0.0001). Both treatments were well tolerated; adverse events, including cough, were less common with telmisartan. These findings suggest that telmisartan is more effective than ramipril throughout the 24-h period and during the EMBPS; this may be attributable to telmisartan's long duration of effect, which is sustained throughout the 24-h dosing period.

Initial combination therapy for rapid and effective control of moderate and severe hypertension.

Moderate (grade 2) and severe (grade 3) hypertension are important public health problems associated with high cardiovascular risk. Blood pressure (BP) control becomes more difficult to achieve as hypertension progresses. Therefore, early and effective treatment is essential to prevent hypertensive urgencies and emergencies and reduce cardiovascular risk. Currently, less than 50% of patients being treated for moderate or severe hypertension in the United States achieve their BP goal as recommended by treatment guidelines. This review examines the cardiovascular risk and physician inertia associated with moderate and severe hypertension, and concludes that increased use of initial combination therapy can overcome many of the barriers to effective BP control. Furthermore, initial combination therapy with a renin-angiotensin system (RAS) inhibitor and diuretic has the potential to rapidly and effectively reduce BP across a range of baseline BPs, with a comparable adverse event profile to monotherapy.

Magnitude of the early morning blood pressure surge in untreated hypertensive patients: a pooled analysis.

OBJECTIVES: A post hoc analysis was performed to assess the magnitude of the early morning blood pressure surge (EMBPS), which is associated with peak cardiovascular risk, in untreated hypertensive patients enrolled in two sister studies (Prospective, Randomised Investigation of the Safety and efficacy of MICARDIS vs. ramipril using ambulatory blood pressure monitoring I and II) with identical design. METHODS: In adults with a mild-to-moderate primary hypertension and no significant comorbidities, 24-h ambulatory blood pressure monitoring was conducted after a 2- to 4-week placebo run-in period and before treatment initiation. Individual blood pressure measurements at 20-min intervals were analysed. RESULTS: In 1419 hypertensive patients with normal sleeping times, blood pressure displayed a typical circadian rhythm, with a mean EMBPS of 29/24 mmHg. An EMBPS of >or= 25 mmHg was observed in around 60% of patients. The surge was significantly increased with smoking, alcohol consumption, longer sleep, later waking times, and increased blood pressure variability during waking and sleeping. The magnitude of the EMBPS was significantly reduced in Black vs. White patients. The surge was not affected by gender, body mass index or duration of hypertension. Further analysis showed that ethnicity, alcohol consumption and smoking were all found to have a significant impact on surge around waking and age, sleep duration and sleep blood pressure variability were all found to have an effect on the prewake surge. CONCLUSIONS: In untreated hypertensive patients, the magnitude of the EMBPS is significant when compared with the 24-h mean and is affected by individual patient characteristics. In light of these findings, physicians should understand the importance of 24-h blood pressure control and the modification of certain lifestyle factors as ways of reducing the EMBPS.

A comparison of the efficacy and safety of irbesartan/HCTZ combination therapy with irbesartan and HCTZ monotherapy in the treatment of moderate hypertension.

This prospective, double-blind, parallel-group study randomized patients with moderate hypertension (seated systolic blood pressure (SeSBP) 160-179 mm Hg when seated diastolic blood pressure (SeDBP) <110 mm Hg; or SeDBP 100-109 mm Hg when SeSBP <180 mm Hg) 3:1:1 to treatment with irbesartan 300 mg/hydrochlorothiazide (HCTZ) 25 mg combination therapy (n=328), irbesartan 300 mg monotherapy (n=106) or HCTZ monotherapy 25 mg (n=104). Treatment was initiated at half dose, with forced titration to full dose after two weeks followed by ten further weeks' treatment. The primary efficacy variable was the mean reduction in SeSBP from baseline to week 8. Baseline characteristics were similar between groups, with mean baseline blood pressure approximately 162/98 mm Hg; the mean age was 55 years. At week 8 there was a reduction in SeSBP of 27.1 mm Hg with irbesartan/HCTZ, compared with 22.1 mm Hg with irbesartan monotherapy (P=0.0016) and 15.7 mm Hg with HCTZ (P<0.0001). Both the rate of decline and the total degree of decline achieved were greatest with irbesartan/HCTZ and least with HCTZ. A significantly greater percentage of patients reached a treatment goal of SeSBP <140 mm Hg and SeDBP <90 mm Hg by week 8 with irbesartan/HCTZ (53.4%), compared with irbesartan (40.6%; P=0.0254) and HCTZ (20.2%; P<0.0001) alone. Treatment was well tolerated in all three-treatment groups with a slight increase in adverse events in the combination therapy group. In conclusion, irbesartan/HCTZ (300/25 mg) is well tolerated and achieves rapid and sustained reductions in both systolic blood pressure and diastolic blood pressure in patients with moderate hypertension.

Effects of a structured treatment algorithm on blood pressure goal rates in both stage 1 and stage 2 hypertension.

This study analysed the efficacy of an angiotensin receptor blocker-based treatment algorithm for achieving goal blood pressure (BP) in patients with stage 1 (systolic BP (SBP) 140-159 mmHg or diastolic BP (DBP) 90-99 mmHg) or stage 2 (SBP > or = 160 mmHg or DBP > or = 100 mmHg) hypertension. In this 24-week, open-label, multicentre study, patients followed a six-step algorithm until goal BP (< or = 130/85 mmHg) was attained. Initially, olmesartan medoxomil 20 mg/day was administered for 4 weeks. The regimen was modified every 4 weeks until goal BP was attained: increase olmesartan medoxomil to 40 mg/day; add hydrochlorothiazide (HCTZ) 12.5 mg/day; increase HCTZ to 25 mg/day; add amlodipine besylate 5 mg/day; increase amlodipine besylate to 10 mg/day. In patients with stage 1 hypertension, 80% (63/79) and 56% (44/79) achieved BP goals of < or = 140/90 mmHg and < or = 130/85 mmHg, respectively, with olmesartan medoxomil monotherapy (94% (74/79) and 89% (70/79) with olmesartan medoxomil/HCTZ double therapy, and 96% (76/79) and 98% (77/79) with addition of amlodipine besylate (triple therapy)). Mean SBP/DBP reductions were 16.7/11.6, 24.8/15.8, and 26.4/16.5 mmHg for mono-, double-, and triple-therapy, respectively. In patients with stage 2 hypertension, 42% (42/100) and 19% (19/100) achieved BP goals of < or = 140/90 mmHg and < or = 130/85 mmHg, respectively, with monotherapy (75% (75/100) and 54% (54/100) with double therapy, and 90% (90/100) and 81% (81/100) with triple-therapy). Mean SBP/DBP reductions in stage 2 patients were 18.4/10.0, 32.7/16.3, and 39.1/19.4 mmHg for mono-, double, and triple therapy, respectively. Overall, most patients with stage 1 or stage 2 hypertension achieved goal BP.

Ambulatory blood pressure comparison of the anti-hypertensive efficacy of fixed combinations of irbesartan/hydrochlorothiazide and losartan/hydrochlorothiazide in patients with mild-to-moderate hypertension.

This study examined whether the greater anti-hypertensive efficacy of irbesartan monotherapy over losartan monotherapy extends to the respective fixed-dose combinations with hydrochlorothiazide (HCTZ) in patients with mild-to-moderate hypertension. Patients were treated with either irbesartan 150 mg/HCTZ 12.5 mg or losartan 50 mg/HCTZ 12.5 mg over a 4-week period. Twenty-four hour daytime and night-time mean blood pressure (BP), BP load and duration of action were assessed using ambulatory BP monitoring. Both treatment regimens significantly reduced BP from baseline for all efficacy variables assessed. A significant difference was noted in adjusted mean changes from baseline in 24-h ambulatory diastolic BP with irbesartan/HCTZ versus losartan/HCTZ. Reduction in diastolic load was significantly greater with irbesartan/HCTZ than with losartan/HCTZ as was mean ambulatory systolic BP during the last 4 h of the dosing interval. Both regimens were well tolerated, with no significant differences in terms of adverse event profile observed. Irbesartan 150 mg/HCTZ 12.5 mg resulted in greater reductions in ambulatory BP than losartan 50 mg/HCTZ 12.5 mg.

Effect of the renin--angiotensin system on the vessel wall: using ACE inhibition to improve endothelial function.

Plasma renin activity and cardiovascular disease (CVD) incidence correlate closely in people with hypertension. The effects of angiotensin II (Ang II) on blood pressure (BP) are important in hypertensive patients; accumulating data suggest that the growth effects of Ang II in the cardiovascular system play a critical role in the development of atherosclerosis. Atherosclerosis development in hypertensive patients requires fundamental changes in endothelial structure and function. Key among the factors that may affect the endothelium is the renin--angiotensin--bradykinin system. Ang II, independent of other environmental and neurohormonal factors, mediates the vessel wall changes critical for the development of atherosclerotic disease. A strong correlation appears to exist between Ang II and CVD. Blockade of the renin-angiotensin system has a major impact on arterial structure and function independent of BP. Certain angiotensin-converting enzyme (ACE) inhibitors produce significant improvements in arterial compliance, which may yield a reduction in cardiovascular events. Blockade of the neurohormonal system may be a critical first-line approach to management of hypertension in an effort to prevent or reverse endothelial dysfunction. Moreover, the effects of ACE inhibition, in addition to its effect on BP, suggest that this therapeutic approach may be appropriate for managing patients at risk of CVD who do not yet have hypertension. The ideal antihypertensive agent should yield smooth, consistent BP control over the entire 24-hour period, both to avoid BP variability that places patients at increased risk of cardiovascular events and to offer protection during the vulnerable early morning hours when patients are well known to be at high risk.

Telmisartan vs losartan plus hydrochlorothiazide in the treatment of mild-to-moderate essential hypertension--a randomised ABPM study.

The objective of this prospective, randomised, open-label, blinded-end point parallel-group, multicentre study was to show that telmisartan 80 mg is not inferior to a fixed-dose combination of losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg in patients with mild-to-moderate hypertension. The criterion for noninferiority was a treatment difference of < or =3.0 mmHg in the reduction of 24-h mean ambulatory diastolic blood pressure (DBP) from the end of the 4-week placebo washout period to the end of the 6-week active treatment period. In the intent-to-treat analysis, the mean reduction in 24-h DBP was 8.3+/-6.7 mmHg among telmisartan-treated patients (n=332) and 10.3+/-6.3 mmHg among losartan/HCTZ-treated patients (n=350). The mean adjusted difference in 24-h DBP between the two treatment groups was 1.9 mmHg, allowing rejection of the a priori null hypothesis of a treatment difference of >3 mmHg. The reduction in mean 24-h systolic blood pressure was 13.2+/-10.2 mmHg with telmisartan and 17.1+/-10.3 mmHg with losartan/HCTZ. Both drugs provided effective control over the 24-h dosing interval. Analyses of morning (0600-1159) ambulatory blood pressure monitoring DBP means and trough cuff DBP confirmed the noninferiority hypothesis of the protocol for telmisartan 80 mg vs losartan 50 mg/HCTZ 12.5 mg. The reductions in office blood pressures measured at trough in patients treated with telmisartan were -16.3/-9.6 and -18.5/-11.1 mmHg in the patients treated with losartan/HCTZ (difference -2.4/-1.2 mmHg). There were no differences between the side-effect profiles of the two treatments.

Arterial compliance abnormalities in isolated systolic hypertension.

Arterial compliance measurements using intraarterial pulse contour analysis and a modified Windkessel model were carried out in 19 patients with isolated systolic hypertension (> or = 160/< or = 90 mm Hg) and compared to measurements in 29 patients with essential hypertension (diastolic blood pressure [BP] > or = 95 mm Hg) and 47 normotensive control subjects. Arterial capacitive compliance was significantly lower in isolated systolic hypertension than in essential hypertension (P < .0002) and significantly lower in essential hypertension than in normotensive control subjects (P < .0001). Although the isolated systolic hypertension group was older than the essential hypertension group, the reduction of capacitive compliance in isolated systolic hypertension persisted even when comparison was made with a more nearly age-matched group of essential hypertension. In contrast, oscillatory compliance was reduced similarly in isolated systolic hypertension and essential hypertension compared to normotensive control subjects (P < .0001). Although pulse pressure was greater in isolated systolic hypertension than in essential hypertension, only a weak correlation (r = -0.34) existed between pulse pressure and capacitive compliance. These data indicate that both essential hypertension and isolated systolic hypertension patients exhibit comparably abnormal structure or tone of the small vessels that are the site of oscillations or reflections in the arterial vasculature. In isolated systolic hypertension there is a profound reduction in large artery or capacitive compliance that accounts for the increase in systolic BP and decrease in diastolic BP. This abnormality cannot be accurately assessed by pulse pressure alone.

Beyond the sphygmomanometric numbers: hypertension as a syndrome.

Blood pressure is a critical element of hypertension, but evidence shows that many other interrelated risk factors--such as hypercholesterolemia, left ventricular hypertrophy, insulin resistance, and vascular dysfunction--contribute to form a complex syndrome of hypertension. Studies have demonstrated that these other risk factors often precede the onset of elevated blood pressure (BP). Significantly, this has been shown in the normotensive offspring of hypertensive parents. One factor that the elements of the hypertension syndrome have in common is endothelial dysfunction. An upset in the normal balance of angiotensin II and nitric oxide in the endothelial cell is associated with manifestation of the hypertension syndrome-associated risk factors. Recognition of this fact can and should be constructively incorporated into clinical practice in three ways: earlier identification of patients with the hypertension syndrome, earlier treatment to prevent disease onset/progression, and the use of angiotensin converting enzyme inhibitors to correct the critical imbalance in the endothelial cell.

Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake.

Previous clinical trials have demonstrated the important influence of ethnicity and dietary salt on the antihypertensive efficacy of drugs that block the renin angiotensin system. Angiotensin II receptor blockers are a new therapeutic entity that have not been widely studied in African American hypertensives, either alone, or in combination with other therapies such as diuretics or angiotensin converting enzyme inhibitors. We performed a pilot, prospective, open label, randomized design clinical trial to evaluate the effects of the angiotensin II receptor blocker valsartan (160 mg once a day) on systolic and diastolic blood pressure in hypertensive African Americans (n = 88) on a low salt (100 mEq Na+/day) for 2 weeks and the same diet supplemented by 100 mEq Na+ for 4 weeks. After this evaluation, while continuing the Na+ supplementation, patients were randomized to valsartan 320 mg/day (n = 28), or the addition of hydrochlorothiazide (HCTZ) 12.5 mg/day (n = 30), or benazepril 20 mg/day to the valsartan 160 mg/day for an additional 6 weeks. Valsartan (160 mg/day) lowered blood pressure significantly in African American patients on both low salt (-6.4/-4.8 mm Hg: P < .001) and a high salt diet (-4.9/-3.8 mm Hg: P = .01). The high salt diet attenuated the antihypertensive effect slightly (1.6/1.3 mm Hg, P = not significant). When comparing the efficacy of the three randomized therapeutic regimens while on the Na+ supplement, the valsartan 160 mg/HCTZ 12.5 mg was the most effective therapy with an incremental reduction in blood pressure of -10.5/-6.9 mm Hg (P < .01), compared to valsartan 160 mg/day alone. Doubling the dose of valsartan to 320 mg incrementally lowered blood pressure by -3.8/-3.3 mm Hg (P = not significant). The least effective approach was adding benazepril 20 mg/day to valsartan 160 mg/day with no incremental reduction in systolic blood pressure and diastolic blood pressure reduction of only 1.7 mm Hg (P = not significant). We conclude that in our open label pilot study, the antihypertensive activity of valsartan is not significantly attenuated by supplemented salt diet in hypertensive African Americans. Moreover, adding a low dose of HCTZ appears to be the most effective strategy in enhancing the antihypertensive activity of this angiotensin II receptor blocker in contrast to either doubling the dose or adding an angiotensin converting enzyme inhibitor.

Efficacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy: a clinical experience trial. ACTION Study Investigators.

A large-scale, 8-week, open-label, clinical experience trial evaluated the efficacy of the angiotensin II receptor (AT1 subtype) blocker candesartan cilexetil (16 to 32 mg once daily) either alone or as add-on therapy in 6465 hypertensive patients. The study population was 52% female and 16% African American with a mean age of 58 years. It included 5,446 patients who had essential hypertension (HBP) and 1,014 patients who had isolated systolic hypertension (ISH). These patients had either untreated or uncontrolled hypertension (systolic blood pressure [SBP] 140 to 179 mm Hg or diastolic blood pressure [DBP] 90 to 109 mm Hg inclusive at baseline) despite a variety of antihypertensive medications including diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and alpha- or beta-blockers, either singly or in combination. The mean baseline blood pressure for the HBP group was 156/97 mm Hg. Candesartan cilexetil as monotherapy (in 51% of HBP patients) reduced mean SBP/DBP by 18.7/ 13.1 mm Hg. As add-on therapy (in 49% of HBP patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.8/11.3 mm Hg), calcium antagonists (16.6/11.2 mm Hg), beta-blockers (16.5/ 10.4 mm Hg), ACE inhibitors (15.3/10.0 mm Hg), alpha-blockers (16.4/10.4 mm Hg). The mean baseline blood pressure for the ISH group was 158/81 mm Hg. Candesartan cilexetil, as monotherapy (in 34% of ISH patients), reduced SBP/DBP by 17.0/4.4 mm Hg. As add-on therapy (in 66% of ISH patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.4/5.1 mm Hg), calcium antagonists (15.6/3.6 mm Hg), beta-blockers (14.0/4.8 mm Hg), ACE inhibitors (13.4/4.3 mm Hg), and alpha-blockers (11.6/4.5 mm Hg). The further blood pressure lowering effects of candesartan cilexetil as add-on therapy were seen regardless of age, sex, and race. Overall, 6.8% of the 6465 patients withdrew because of adverse events, most commonly headache (6.3%) and dizziness (5.0%). Orthostatic hypotension was infrequent; 0.2% with candesartan cilexetil alone, and 0.8% with candesartan cilexetil as add-on therapy. Thus, candesartan cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice settings.

Ambulatory blood pressure monitoring to assess the comparative efficacy and duration of action of a novel new angiotensin II receptor blocker--telmisartan.

Although a wide range of antihypertensive agents is available, adequate blood pressure control is achieved in only about 25% of hypertensive patients. Poor control rates are often due to inadequate patient compliance and unacceptable side-effects. The importance of once-daily dosing is now fully acknowledged, but it is crucial that therapy when given once a day must be effective at the end of the dosing interval to order to minimize the likelihood of sudden cardiac death, myocardial infarction and stroke. Ambulatory blood pressure monitoring (ABPM) provides a thorough assessment of the blood pressure-lowering characteristics of an antihypertensive agent throughout the dosing interval and can more accurately evaluate differences in the duration of the antihypertensive effect of different agents. Telmisartan, a new angiotensin II receptor antagonist, has been extensively studied in clinical trials using ABPM. When compared with dihydropyridine calcium antagonists, beta-adrenergic blockers, angiotensin-converting enzyme inhibitors and other angiotensin II receptor antagonists, telmisartan has proved superior in diminishing ambulatory blood pressure throughout the 24-h period between doses. Telmisartan also has excellent tolerability and in clinical trials demonstrates no increase, irrespective of dose level, over placebo in the incidence of adverse events. Thus, telmisartan given once daily provides high efficacy and tolerability, and will hopefully assist in improving both blood pressure control rates and cardiovascular outcomes in the future.

Clinical studies of CS-866, the newest angiotensin II receptor antagonist.

Angiotensin II receptor blockers have shown widespread efficacy as antihypertensive medications. These agents bind selectively to angiotensin II type 1 (AT(1)) receptors, specifically blocking the renin-angiotensin system at the last step in its cascade. CS-866 is the most recently introduced drug in this class. This article presents integrated safety and efficacy data from 7 randomized, double-blind, placebo-controlled, parallel group studies in which once-daily CS-866 monotherapy was used in the treatment of patients with essential hypertension (sitting diastolic blood pressure > or =100 mm Hg and < or =115 mm Hg). Data from a total of 2,145 CS-866-treated patients were included in the efficacy analysis. Safety data were available from 2,540 CS-866-treated patients, with a cumulative exposure of 5,888 patient-months. The antihypertensive efficacy of the drug was assessed using both cuff blood pressure measurements and 24-hour ambulatory blood pressure monitoring. The data show that CS-866 is effective and safe for the treatment of hypertension. Dose-dependent reductions in both diastolic and systolic blood pressures occurred within 1 week of initiating treatment, and the response was almost maximal within 2 weeks. There was no difference in efficacy between younger (<65 years) and older (> or =65 years) groups of patients. Trough-to-peak ratios showed that CS-866 retains the majority of its peak effect 24 hours after treatment, and is therefore suitable for once-daily dosing. Dizziness was the only treatment-emergent adverse event with which CS-866 was associated.

The importance of 24-h blood pressure control.

The primary goal of antihypertensive therapy is to restore blood pressure to normal levels and to prevent the complications associated with hypertension. In order to maximize these goals by improving patient compliance, clinical researchers have focused on developing antihypertensive agents that can be given once daily. These agents provide many advantages over multiple-dose daily therapies, but it should not be assumed that they are all equivalent in providing adequate blood pressure control over the full 24-h dosing interval. Ambulatory blood pressure monitoring has uncovered important differences in commonly used once-daily therapies and has provided additional insights into the cardiovascular risks associated with high blood pressure loads and blood pressure variability. In addition to ambulatory blood pressure monitoring data, the calculated trough:peak ratio provides useful information on an agent's ability to provide smooth and consistent blood pressure control. Using such assessments, it has been found that agents with a trough:peak ratio > or = 0.50 are better able to control blood pressure over the full 24h while maintaining natural circadian patterns. Ambulatory blood pressure monitoring studies assessing a recently introduced class of antihypertensive drugs, the angiotensin receptor blockers, have demonstrated 24-h efficacy with once-daily dosing, particularly with the newer agents.

A new chronotherapeutic oral drug absorption system for verapamil optimizes blood pressure control in the morning.

A novel verapamil chronotherapeutic oral drug absorption system (CODAS-Verapamil) designed for bedtime dosing and with controlled onset and extended-release properties was evaluated in 257 patients with mild-to-moderate essential hypertension in an 8-week, double-blind, placebo-controlled trial. After bedtime dosing (9 PM to 11 PM, this delivery system delays drug release for 4 to 5 h, and provides the highest concentrations of verapamil between 6 AM and noon. The study results showed that CODAS-verapamil produced its greatest antihypertensive effect during this morning period (6 AM to 12 noon) and also provided effective trough diastolic blood pressure reductions at 200, 300, and 400 mg. Significant trough systolic blood pressure reductions were achieved only with the 300- and 400-mg doses. The nighttime dosing regimen was not associated with excessive blood pressure (BP) reductions during the sleeping hours, when the antihypertensive effect was generally slightly less than that of the 24-h mean reduction. The CODAS-verapamil provides enhanced BP reduction during the morning period when compared with other time intervals of the 24-h dosing period.