Efficacy and tolerability of tasosartan, a novel angiotensin II receptor blocker: results from a 10-week, double-blind, placebo-controlled, dose-titration study. Tasosartan Investigators Group.

BACKGROUND: Angiotensin II receptor antagonists are selective blockers of the renin-angiotensin system and represent an alternative to angiotensin-converting enzyme inhibitors in the treatment of hypertension. Tasosartan is a newly developed nonpeptide AT1 receptor blocker. METHODS AND RESULTS: In this double-blind, randomized, dose-titration, multicenter trial, tasosartan and placebo were compared in patients with stage I and stage II hypertension. A prequalification washout period (antihypertensive medications withdrawn) and a 2-week qualification period (patients received single-blind placebo) preceded a 10-week, double-blind treatment period. The patients received either 50 mg tasosartan (n = 132) or placebo (n = 130) once per day and were evaluated once per week. The dose of tasosartan was increased at 3-week intervals to 100 mg and then to 200 mg if the mean sitting diastolic blood pressure (SiDBP) exceeded 90 mm Hg. Compared with placebo, tasosartan produced significantly (P <.05) greater reductions in both SiDBP (-9.4 +/- 0.7 vs -2.0 +/- 0.7 mm Hg) and sitting systolic blood pressure (SBP) (-12.2 +/- 1.2 vs +0.4 +/- 1.2 mm Hg). The rate of response (SiDBP /=10 mm Hg) was significantly (P <.05) greater in the tasosartan group than in the placebo group (55% vs 19%). The mean 24-hour blood pressure reduction with tasosartan was -12.6 +/- 0. 9/-8.1 +/- 0.6, significantly greater (P <.05) than the reduction with placebo (+0.6 +/- 0.9/+0.5 +/- 0.6 mm Hg). The trough-to-peak ratio (determined from the ambulatory data) was 0.66 for DBP and 0. 72 for SBP for the tasosartan treatment group, demonstrating 24-hour efficacy with once-a-day administration. The safety profile of tasosartan was similar to placebo. CONCLUSIONS: These results demonstrate that tasosartan at 50 to 200 mg given once a day over a titration period of 10 weeks was effective and safe in the treatment of essential hypertension.

First-line therapy option with low-dose bisoprolol fumarate and low-dose hydrochlorothiazide in patients with stage I and stage II systemic hypertension.

This 30-center, randomized, double-blind, placebo-controlled, parallel-group study was designed to (1) establish that 6.25 mg of hydrochlorothiazide (HCTZ) given once daily with 5 mg of bisoprolol fumarate can contribute to antihypertensive effectiveness in patients with stage I and stage II (mild to moderate) systemic hypertension; and (2) assess whether this formulation was more effective or possessed a safety advantage over standard monotherapy with bisoprolol or 25 mg of HCTZ. Results showed that HCTZ 6.25 mg contributed significantly to the antihypertensive effectiveness of bisoprolol 5 mg. Bisoprolol 5 mg/HCTZ 6.25 mg (B5/H6.25) produced significantly greater mean reductions from baseline in sitting systolic and diastolic blood pressure (-15.8 mm Hg/-12.6 mm Hg) than bisoprolol 5 mg alone (-10.0 mm Hg/-10.5 mm Hg) and HCTZ 25 mg alone (-10.2 mm Hg/-8.5 mm Hg). A 73% response rate was achieved with the low-dose formulation compared with 61% for the bisoprolol 5 mg (B5) group and 47% for the HCTZ 25 mg (H25) group. B5/H6.25 was found to be significantly more effective than B5 or H25 in all subgroups of patients, regardless of gender, race, age, or smoking history. Antihypertensive effects were maintained during the 24-hour dosing interval. The incremental effectiveness of B5/H6.25 was not accompanied by an increase in the frequency or severity of adverse experiences; the incidence of adverse experiences in the B5/H6.25 group was comparable to that in the placebo group. B5/H6.25 was shown to provide safety advantages over H25, as shown by less hypokalemia (< 1% with B5/H6.25 versus 6.5% with H25).(ABSTRACT TRUNCATED AT 250 WORDS)

A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide.

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.

Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension.

In the final analysis of this study at Week 26, 26% of the patients randomized to receive amlodipine attained blood pressure control with amlodipine alone compared with 33% of the patients allocated to hydrochlorothiazide (HCTZ). Neither amlodipine nor HCTZ produced clinically significant changes in pulse rate or in the electrocardiogram. Amlodipine treatment did not appear to produce clinically significant changes in blood lipids; HCTZ, however, produced an increase in total plasma cholesterol (delta 22.9 +/- 8.6 mg/dl). The incidence of side effects and the rate of patient withdrawal in the amlodipine and HCTZ groups were comparable. As expected, HCTZ therapy caused well-recognized biochemical alterations in cholesterol and potassium levels, whereas amlodipine was metabolically neutral.

The effect of amlodipine on ambulatory blood pressure in hypertensive patients.

Certain high-risk populations, such as diabetics and blacks, have sustained elevation in blood pressure and heart rate throughout the day and night, with blunting of the usual diurnal variability pattern. This may contribute to their higher incidence of left ventricular hypertrophy (blacks) and cardiovascular complications (diabetics). Hypertensives who maintain a diurnal pattern of blood pressure variation still exhibit higher daytime and nocturnal blood pressure levels than normotensives. Thus, to achieve maximum effectiveness in treating hypertension, 24-hour control of blood pressure is necessary. Antihypertensive agents should effectively reduce blood pressure consistently throughout a 24-hour period. The objective of this study was to assess the effects of amlodipine, 5 mg once daily, on blood pressure measured by 24-hour ambulatory monitoring in a randomized, double-blind, placebo-controlled single-site study. Patients with mild-to-moderate essential hypertension were randomized to receive amlodipine (n = 11) or placebo (n = 5) in a 2:1 ratio. A 4-week single-blind placebo run-in period was followed by a 4-week double-blind phase. Ambulatory monitoring of blood pressure was carried out for 24 hours at the end of each 4-week phase. Patients receiving amlodipine had significantly lower blood pressure compared with placebo 24 hours after the last dose (supine blood pressure -25.1/-10.1 mm Hg; standing blood pressure -21.2/-9.7 mm Hg) after 4 weeks of treatment. This effect was clearly demonstrated by the 24-hour postdose measurement and the mean blood pressure over the 24-hour interval as measured by ambulatory recordings.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of ramipril and enalapril in patients with essential hypertension.

STUDY OBJECTIVE: To compare the clinical safety and efficacy of ramipril, a new long-acting nonsulfhydryl inhibitor of angiotensin-converting enzyme (ACE), with enalapril. DESIGN: A randomized, double-blind trial. SETTING: Multicenter trial involving 4 large teaching hospitals and 12 community medical centers. PATIENTS: One hundred fifty-nine patients with mild to moderate essential hypertension were enrolled. Two patients were excluded from the efficacy analysis because they failed to return for follow-up. INTERVENTIONS: Patients were randomized to receive ramipril 2.5, 5, or 10 mg, or enalapril 5, 10, or 20 mg once/day for 3 or 4 weeks. MEASUREMENTS AND MAIN RESULTS: At baseline, supine diastolic blood pressures ranged from 98-116 mm Hg. Supine and standing systolic blood pressures were reduced by 11.8 and 10.2 mm Hg with ramipril 10 mg (p < or = 0.001) and 9.3 and 10.7 mm Hg with enalapril 20 mg (p < or = 0.001). At the end of the 4-week trial, patients in all six dosage groups had clinically and statistically significant reductions in supine diastolic blood pressure compared with baseline values. The agents did not differ significantly with respect to their blood pressure-lowering effects. Both lowered plasma ACE activity; after 4 weeks, changes from baseline were highly significant for all dosage groups (p < or = 0.001). CONCLUSION: Ramipril was as effective in reducing blood pressure and was as well tolerated as enalapril. A larger average decrease in plasma ACE activity was achieved with ramipril over all dosages (71%) compared with that for enalapril (48%), suggesting that ramipril has greater ACE inhibition in the circulation.

Pentoxifylline in the treatment of vascular impotence--case reports.

Vascular impotence is a common medical problem for which available therapies are limited. Three impotent patients observed in the authors' practice who were receiving pentoxifylline for treatment of claudication of the lower extremities spontaneously reported improved sexual function. A controlled trial of pentoxifylline for vascular impotence may be warranted.

Dose-finding study of cilazapril (Inhibace) in patients with uncomplicated essential hypertension.

Cilazapril, an angiotensin converting enzyme (ACE) inhibitor with a long half-life, effectively reduced sitting diastolic blood pressure in patients with uncomplicated essential hypertension at dosages of 2.5, 5.0, and 10.0 mg/day, evaluated in a double-blind, placebo-controlled study. After a four-week placebo run-in period, 235 patients received either cilazapril or placebo for four weeks. At the end of the treatment period, significant decreases from baseline in sitting diastolic blood pressure were seen in all four groups (mean decreases of 3.3 mm Hg with placebo and 6.4, 9.2 and 8.3 mm Hg with 2.5, 5.0 and 10.0 mg cilazapril, respectively). The cilazapril groups had significantly greater blood pressure reductions than did the placebo group (p less than or equal to 0.02). The 5.0 mg cilazapril dose was significantly more effective than the 2.5 mg dose (p less than 0.03). The response rate was notably greater in the cilazapril treatment groups than in the placebo group (placebo, 27.5%; 2.5 mg cilazapril, 42.9%; 5.0 mg cilazapril 62.5%; 10.0 mg cilazapril, 50.0%). Cilazapril was well tolerated at all three dosages.

A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure.

The effects of amlodipine on ambulatory blood pressure were investigated in patients with mild-to-moderate hypertension. Ambulatory recordings showed that amlodipine maintained diastolic and systolic blood pressure below baseline levels for a full 24-h period without altering the normal circadian rhythm. No reflex tachycardia occurred and side effects were rare.

Effect of amlodipine on 24-hour ambulatory blood pressure in hypertensive patients.

Sixteen hypertensive patients (diastolic blood pressure of 95-114 mm Hg) were randomized to receive 5 mg of amlodipine daily or placebo, double blind, for 4 weeks. Antihypertensive efficacy was assessed using ambulatory blood pressure monitoring at baseline and following double-blind therapy in conjunction with sphygmomanometric measurement at 2-week intervals. Laboratory tests, ECG, and adverse effects were recorded to assess tolerability. Amlodipine treatment significantly reduced ambulatory blood pressure without altering the normal circadian variation throughout the monitoring period. Supine and standing blood pressure were significantly reduced by amlodipine 24 h postdose. Amlodipine was well tolerated and was not associated with reflex tachycardia.

Efficacy and safety of a new angiotensin-converting enzyme inhibitor, ramipril, vs. enalapril in essential hypertension: a multicenter trial.

The antihypertensive effect of ramipril, a new angiotensin-converting enzyme (ACE) inhibitor, was evaluated and compared to enalapril in a double-blind, randomized, controlled trial. Subjects received either 2.5, 5, or 10 mg of ramipril given once daily or 5, 10, or 20 mg of enalapril once daily for 4 weeks. Significant decreases from baseline in supine and standing diastolic blood pressures were seen in all dosage groups at end point. There were significant decreases at end point for supine and standing systolic blood pressures at the higher doses. Side effects were minimal and were similar for all treatment groups.

Safety and tolerability of metoprolol OROS in hypertension treatment.

One hundred twenty-six patients with mild to moderate hypertension responsive to beta-adrenergic blocking agents--alone or in combination with other antihypertensive drugs--entered this open-label, multicenter study designed to evaluate the safety and tolerability of metoprolol OROS (metoprolol fumarate). Metoprolol OROS was given once daily for 14 weeks in doses ranging from 100 to 600 mg. Satisfactory blood pressure control was achieved by 85% of the patients at doses between 100 and 400 mg. Mean diastolic blood pressure was maintained at or below 90 mm Hg. Adverse reactions were experienced by 29% of the patients; most of these reactions were mild or moderate, and none was unexpected for treatment with a beta-blocker. Only three patients withdrew because of adverse reactions. The results of this study indicate that metoprolol OROS given once daily is safe and well tolerated.

Comparison of the antihypertensive effects of betaxolol and chlorthalidone as monotherapy and in combination.

In this multicenter, double-blind, parallel study, the antihypertensive effects of betaxolol (20 mg once daily) and/or chlorthalidone (25 mg once daily) were analyzed in 186 patients with essential hypertension. Following a 2- to 4-week placebo baseline period, patients were randomized to one of two treatment groups (betaxolol or chlorthalidone) and studied for 6 weeks while receiving single therapy and an additional 6 weeks with a combination of the two agents. Significant decreases from baseline supine diastolic blood pressure (SDBP) were observed in both groups at the end of the single-therapy phase (11 mm Hg in SDBP for betaxolol and 12 mm Hg in SDBP for chlorthalidone); a further significant decrease (7 mm Hg for betaxolol and 8 mm Hg for chlorthalidone in SDBP) was observed from the end of the single-therapy phase to the end of the combination-therapy phase. Changes in supine systolic blood pressure (SSBP) from baseline to the end of the single-therapy phase were 10 mm Hg for the betaxolol and 16 mm Hg for the chlorthalidone group. In all cases, within-group changes were statistically significant. From the end of single therapy to end of combination therapy there was an additional 14-mm Hg and 13-mm Hg reduction in SSBP in the betaxolol and chlorthalidone groups, respectively. Overall, 89% of the randomized patients completed the single-treatment phase (phase I), and 89% of those patients completed the combined therapy phase (phase II). There was no significant difference between treatment groups in the clinical response rate (SDBP at or below 90 mm Hg or a decrease from baseline of at least 10 mm Hg). A substantial percentage of patients completing phase I responded to either single agent (58% for betaxolol and 65% for chlorthalidone). Among patients completing phase II therapy, the combination of the two agents produced a greater response rate (83% for the betaxolol-first group and 85% for the chlorthalidone-first group). In conclusion, both agents were effective and well tolerated. The most frequent adverse events in the single-therapy phase were headache, arthralgia, and dizziness, while bradycardia, rhinitis, arthralgia, and dizziness were most frequent in the combination-therapy phase. The combination of betaxolol (20 mg) and chlorthalidone (25 mg) once daily produced an additive antihypertensive effect regardless of which drug was administered first.

Remission of mild to moderate hypertension after treatment with carteolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity.

Previous studies have indicated that some hypertensive patients, following a period of effective treatment with certain antihypertensive drugs, may experience prolonged normotension after drug withdrawal. We have studied the ability of carteolol, a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity, to produce such remissions of hypertension. Thirty-four patients whose diastolic blood pressure was controlled at 90 mm Hg or less with carteolol monotherapy (2.5 to 5.0 mg/d for an average of 328 days) were randomized to a nine-month, double-blind, placebo-controlled drug-withdrawal trial. Those patients randomized to continue carteolol therapy had initially responded to carteolol treatment with reduction in blood pressure from 151 +/- 4/99 +/- 2 to 132 +/- 4/80 +/- 2 mm Hg. Those randomized to treatment with placebo had initially responded with blood pressure reductions from 154 +/- 4/97 +/- 2 to 137 +/- 4/81 +/- 2 mm Hg. Changes in mean systolic and diastolic blood pressure (mm Hg +/- SEM) from baseline during carteolol therapy to the final visit at nine months were not different for patients receiving placebo (13 +/- 5/6 +/- 4 mm Hg, recumbent; 11 +/- 6/4 mm Hg, standing) or carteolol (11 +/- 5/7 +/- 3 mm Hg, recumbent; 12 +/- 6/7 +/- 3 mm Hg, standing). The final mean recumbent diastolic blood pressure (86.9 mm Hg) was the same in both groups. Prolonged normotension may follow a period of carteolol treatment, again suggesting the potential importance of periodic withdrawal of antihypertensive medication.

Comparison of the antihypertensive effects of betaxolol to atenolol.

A randomized double-blind multicenter study compared a new oral beta 1-adrenergic antagonist, betaxolol 10 to 40 mg (n = 71), with atenolol 25 to 100 mg (n = 75). Each drug was administered once daily for 24 weeks in patients with mild to moderate hypertension. Blood pressure (BP) measurements were taken 24 hours after dosing. Each drug produced significant (p less than 0.01) reductions in mean supine diastolic BP. The mean decrease in supine diastolic BP with betaxolol was significantly greater at weeks 4, 6, 10 and 12 (p less than 0.05). Throughout the remainder of the trial (weeks 14 to 24), no significant differences in BP reduction were noted between treatment groups. Normotension (supine diastolic BP less than or equal to 90 mm Hg) was achieved in 72% of those given betaxolol compared with 52% of those given atenolol (p less than 0.05). The most common side effects noted were bradycardia, fatigue and headache. The incidence of these and of central nervous system side effects was similar between the betaxolol and atenolol groups. Both agents were well tolerated. At recommended doses, betaxolol once daily may be more effective than atenolol once daily in patients with mild to moderate hypertension.

Nitrendipine in severe hypertension. Satellite symposium on calcium antagonists.

We report the results of a multicenter trial in which nitrendipine, alone or in combination with a diuretic, a beta-blocker, or both, was administered to 114 patients with severe hypertension (greater than or equal to 115 mm Hg). Nitrendipine was titrated in doses of 5 to 30 mg b.i.d. If blood pressure was not controlled with nitrendipine alone, hydrochlorothiazide or propranolol or both were added. After a mean of 29 days in the study, 96 (90%) of 107 patients reached the initial goal of therapy; in 44 (41%) given nitrendipine alone the mean decrease in supine blood pressure was 38/25 mm Hg. After a mean of 91 days, 69 (72%) of 96 patients achieved the final goal of therapy; in 24 (25%) patients given nitrendipine alone the mean supine blood pressure decrease from baseline was 49/33 mm Hg. Falls in blood pressure were comparable in the patients given drug combinations. Seventy-two of 114 patients given study drug(s) had adverse experiences; headache and edema were the most frequent complaints. Only four patients dropped out of the study because of adverse effects. Most abnormal laboratory values occurred when nitrendipine was given with hydrochlorothiazide or propranolol or both. Analysis of severely hypertensive patients followed up in our Virginia center revealed continued control of blood pressure after long-term follow-up (43 +/- 3 [SD] months). Average supine blood pressure was reduced from 180/121 +/- 21/5 to 140/90 +/- 16/9 (SD) mm Hg (p less than 0.001). It was concluded that the calcium antagonist nitrendipine, alone or in combination with a diuretic or beta-blocker or both, is effective in the treatment of severe hypertension.

A double-blind evaluation of the effect of amlodipine on ambulatory blood pressure in hypertensive patients.

Amlodipine is a new long-acting calcium antagonist that has a long half-life and appears to be suitable for once-daily administration. A double-blind, randomized, parallel, placebo-controlled study was conducted to evaluate the effect of amlodipine on ambulatory blood pressures in hypertensive patients. The study consisted of a 4-week single-blind placebo run-in phase, followed by 4 weeks of double-blind therapy. Ambulatory blood pressure was measured for 24 h at the end of the placebo run-in phase and after double-blind therapy. Sixteen patients were randomized to receive either amlodipine 5 mg or placebo in a 2:1 ratio. Amlodipine 5 mg daily significantly reduced supine and standing blood pressure 24 h postdose. Ambulatory blood pressure recordings revealed adequate blood pressure control throughout the 24-h dosing interval. Amlodipine was well tolerated and only two patients reported side effects--neither was withdrawn from therapy. No treatment-related abnormalities were noted. It was concluded that amlodipine 5 mg daily was effective antihypertensive therapy throughout the 24-h dosing period in the patients studied, and it was well tolerated.

Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension.

Amlodipine, a new long-acting dihydropyridine calcium antagonist, was compared with hydrochlorothiazie (HCTZ) in 145 patients with mild to moderate hypertension. After 4 weeks of single-blind placebo runin, patients were randomly allocated to receive amlodipine (2.5-10 mg once daily, n = 97) or HCTZ (25-100 mg once daily, n = 48). At study week 12 response rates for amlodipine and HCTZ were 61.5 and 60.5%, respectively. There were clinically significant reductions in 24-h postdose blood pressures with both amlodipine (-18/-11 mm Hg supine: -14/-10 mm Hg standing) and HCTZ (-18/-10 mm Hg supine, -18/-9 mm Hg standing). After study week 12, atenolol (50-100 mg once daily) was added to the regimen of those patients whose hypertension was not controlled with monotherapy. Neither amlodipine nor HCTZ produced clinically significant changes in pulse rate, electrocardiogram, or chest x-ray film. Although amlodipine increased and HCTZ decreased the high-density lipoprotein (HDL)/total cholesterol ratio and the HDL/(low-density lipoprotein + very-low-density lipoprotein) ratio, the difference between the two treatments was not statistically significant. The incidence of side effects and the rate of patient withdrawal was comparable in the two groups. The incidence of laboratory abnormalities was 56% with HCTZ (mainly hypokalemia and hyperuricemia) and 16% with amlodipine. Amlodipine was an effective, well-tolerated agent for treatment of mild-to-moderate hypertension in this study, as single-daily-dose monotherapy and in combination with atenolol.