Antihypertensive effect of diltiazem in a slow-release formulation for mild to moderate essential hypertension

The antihypertensive efficacy and frequency of adverse reactions following administration of diltiazem in a new slow-release formulation were compared with placebo in 34 patients with mild to moderate essential hypertension in a randomized, double-blind, crossover study. After 6 weeks of treatment with diltiazem (240 or 360 mg/day), average supine blood pressure (BP) decreased from 165 +/- 21/101 +/- 5 mm Hg at baseline to 152 +/- 16/93 +/- 4 mm Hg compared with 160 +/- 19/100 +/- 7 mm Hg with placebo (p less than 0.01/p less than 0.001). Standing BP decreased from 162 +/- 20/107 +/- 6 mm Hg at baseline to 150 +/- 14/101 +/- 5 mm Hg compared to 159 +/- 18/107 +/- 8 mm Hg with placebo (p less than 0.01/p less than 0.001). The supine heart rate after diltiazem was 65 +/- 7 beats/min and after placebo 69 +/- 9 beats/min (p less than 0.01). There were no hematologic side effects. Only minor differences between diltiazem and placebo were observed in some of the biochemical laboratory values. Four patients were withdrawn due to side effects during treatment with diltiazem and 2 with placebo. Diltiazem in a slow-release formulation given twice a day lowered blood pressure significantly as monotherapy in patients with mild to moderate hypertension and was well tolerated.     

Hydrochlorothiazide with or without amiloride for hypertension in the elderly. A dose-titration study

The blood pressure response to increasing doses of hydrochlorothiazide with or without amiloride was examined in 130 elderly hypertensive patients. After four weeks of placebo, patients were randomly allocated to increasing doses of hydrochlorothiazide or hydrochlorothiazide with amiloride for 12 weeks using a parallel, double-blind study design. Both hydrochlorothiazide and hydrochlorothiazide with amiloride significantly reduced mean (+/- SEM) baseline supine and standing blood pressure (171 +/- 2/102 +/- 1 and 167 +/- 2/102 +/- 1 mm Hg) to 148 +/- 2/84 +/- 1 and 146 +/- 3/85 +/- 1 mm Hg, respectively, at week 16. Amiloride did not exert any additional antihypertensive effect. Only eight patients required hydrochlorothiazide at 100 mg/d, with the remainder responding to 25 to 50 mg/d. Hydrochlorothiazide decreased mean serum potassium level from 4.3 +/- 0.1 mEq/L (4.3 +/- 0.1 mmol/L) during placebo to 4.0 +/- 0.1 mEq/L (4.0 +/- 0.1 mmol/L) at week 16. Ten patients receiving hydrochlorothiazide developed hypokalemia compared with only two receiving hydrochlorothiazide with amiloride. Relatively low doses of hydrochlorothiazide (25 to 50 mg/d) effectively reduce blood pressure in elderly hypertensive patients. Hypokalemia may occur with hydrochlorothiazide alone but is much less common when hydrochlorothiazide is combined with amiloride.     

Diuretics versus calcium-channel blockers in systemic hypertension: a preliminary multicenter experience with hydrochlorothiazide and sustained-release diltiazem

The safety and efficacy of sustained-release diltiazem 120 to 180 mg, 2 times a day, were compared with hydrochlorothiazide 25 to 50 mg, 2 times a day, and the combination of diltiazem and hydrochlorothiazide in 56 patients with mild to moderate hypertension (supine diastolic blood pressure between 95 and 114 mm Hg) using a placebo-controlled, parallel-design protocol. Data from an additional 21 patients were evaluated for safety only. The data reported herein represent the preliminary experience from a larger 200-patient multicenter study. All patients received placebo for 4 weeks, followed by either hydrochlorothiazide or diltiazem titrated to achieve a diastolic blood pressure reduction of greater than or equal to 10 mm Hg to reach a goal supine diastolic blood pressure of less than 90 mm Hg. Patients not achieving the treatment goal received hydrochlorothiazide plus diltiazem. At week 14, on maintenance monotherapy, diltiazem and hydrochlorothiazide produced comparable reductions in blood pressure from placebo baseline (160.3 +/- 24.3/101.7 +/- 5.5 to 145.2 +/- 24.1/89.8 +/- 7.4 mm Hg with diltiazem, 156.0 +/- 15.6/103.7 +/- 4.7 to 134.1 +/- 12.5/89.2 +/- 9.5 mm Hg with hydrochlorothiazide, p less than 0.001 for both). Diltiazem and hydrochlorothiazide achieved goal blood pressure in 42% and 45% of patients, respectively. The effects in responders were sustained for 6 months. In patients who did not achieve the treatment goal, 63% responded to diltiazem plus hydrochlorothiazide.No clinically significant postural hypotension was observed on any regimen. Heart rate was slightly lower with diltiazem than with hydrochlorothiazide. Adverse effects were minimal with diltiazem, hydrochlorothiazide and diltiazem plus hydrochlorothiazide but more hypokalemia occurred with hydrochlorothiazide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension

In a randomized, double-blind, placebo-controlled crossover trial, diltiazem and nifedipine were compared in 10 patients with stable angina pectoris and mild to moderate hypertension (supine diastolic blood pressure greater than or equal to 90 mm Hg). Patients received placebo for 2 weeks, then increasing doses of diltiazem (90 to 360 mg/day) or nifedipine (30 to 120 mg/day) in 3 daily divided doses over 2 weeks, followed by 1 week of therapy at the maximal dose, a 1-week placebo "washout," then crossover to the other drug. Heart rate and blood pressure at rest and during exercise, anginal frequency, nitroglycerin consumption and treadmill exercise tolerance were assessed. Compared with placebo, anginal frequency and nitroglycerin consumption were reduced with both diltiazem and nifedipine (p less than 0.01) and exercise tolerance was increased with both drugs (p less than 0.01). Standing blood pressure at rest was reduced by diltiazem and nifedipine (146.6 +/- 11.4/97.7 +/- 5.3 mm Hg at placebo, baseline reduced to 129.6 +/- 15.2/79.5 +/- 13.7 mm Hg with diltiazem, and to 122.2 +/- 9.9/82.0 +/- 7.1 with nifedipine, p less than 0.01 for both). Compared with placebo, diltiazem and nifedipine also reduced exercise diastolic blood pressure (p less than 0.01), but not systolic blood pressure. Diltiazem lowered the heart rate at rest from 88.5 +/- 14.4 beats/min at placebo baseline to 79.7 +/- 17.9 beats/min (p less than 0.01); the heart rate with diltiazem was 11 beats/min lower than that with nifedipine (p less than 0.05). Both diltiazem and nifedipine had similar effects on the heart rate-blood pressure product at rest and during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of hydrochlorothiazide and sustained-release diltiazem for mild-to-moderate systemic hypertension

The safety and efficacy of sustained-release diltiazem, 120 to 180 mg twice daily, was compared with those of hydrochlorothiazide, 25 to 50 mg twice daily, in 207 patients with mild-to-moderate hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg) using a baseline, placebo, parallel-design study protocol. All patients received placebo for 2 to 4 weeks, followed by either study drug during the double-blind phase, titrated over 8 weeks to achieve a goal of supine diastolic BP reduction of at least 10 mm Hg and/or a diastolic BP of less than 90 mm Hg. Patients not achieving the treatment goal with either drug alone received the other drug in combination. Both drugs produced significant decreases in supine and upright BP throughout the 26-week study. The magnitude of decrease in mean supine diastolic BP was similar for both drugs as monotherapy at week 14 (-11.4 and -12.1 mm Hg, respectively). Hydrochlorothiazide produced significantly greater reductions at week 14 in mean supine systolic BP than sustained-release diltiazem (-19.5 and -12.7 mm Hg, respectively). The difference in mean supine diastolic BP reduction with the 2 drugs diminished when hydrochlorothiazide (50 mg/day) was compared with sustained-release diltiazem. The BP effects were sustained for 6 months with both drugs. The 2 drugs appeared to lower BP more in patients older than 60 years and more in black than in white patients. The combination of the 2 drugs decreased supine diastolic BP to goal levels in about 56% of the patients not achieving goal with either drug alone. Adverse effects were minimal with either drug alone and in combination, except for hypokalemia, which increased with thiazide alone and in combination.     

Efficacy of diltiazem in elderly patients with stable effort angina

The antianginal effects of 360 mg/day of diltiazem were evaluated, using intrapatient comparisons, in a double/blind, randomized, placebo/controlled trial in 24 young patients (50 +/- 7 years) and in 16 elderly patients (67 +/- 3 years) with stable effort angina. All patients had angiographic documentation of significant coronary artery disease. An open-labelled, randomized, crossover design was employed. For 1 week prior to beginning the study, the patient was on no medication except sublingual nitrates. The study consisted of an initial 2-week single-blind placebo run-in period followed by a 4-week randomized double-blind crossover between diltiazem, 120 mg t.i.d., and placebo. A diary of chest pain and nitroglycerin usage was kept during this period and run-in. Exercise tests were carried out during the run-in period (2 tests) and at the end of the 4-week treatment. After diltiazem 12 of the 24 young patients stopped the exercise test because of angina. A similar number (9/16) of elderly patients stopped the exercise test because of angina. During diltiazem treatment, weekly angina frequency was significantly reduced in the young patients (1.25 +/- 0.67 vs 3.87 +/- 1.19-run-in, 4.08 +/- 1.24-placebo; p less than 0.01) and in the elderly patients (0.87 +/- 0.71 vs 4.06 +/- 1.48-run-in, 4.12 +/- 1.5-placebo; p less than 0.01). Weekly TNT consumption significantly decreased in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of differences in the hemodynamic response to passive postural stress in healthy subjects greater than 70 years and less than 30 years of age

To test the hypothesis that age-related increases in arterial pressure alter the cardiovascular response to physiologic stress, 9 healthy elderly volunteers (74 +/- 2 years) and 7 young subjects (27 +/- 3 years) were subjected to a standard 60 degrees upright tilt. Cardiac volumes were measured with patients in the supine position and 5 minutes after they assumed an upright posture using radionuclide ventriculography, while heart rate, blood pressure and forearm cutaneous flow were recorded continuously and simultaneously. Only the expected age-related increase in mean arterial pressure (young subjects, 79 +/- 1 mm Hg; elderly subjects, 99 +/- 3 mm Hg; p less than 0.001) distinguished the 2 groups at baseline. However, during upright tilt, elderly subjects had significant decreases in stroke volume (supine [108 +/- 9 ml] vs upright [78 +/- 9 ml]; p less than 0.01) and cardiac index (supine [3.4 +/- 0.2 liters/min/m2] vs upright [2.8 +/- 0.2 liters/min/m2]; p less than 0.05) because of an inability to reduce end-systolic volume (supine, 44 +/- 6 ml; upright, 51 +/- 7 ml); however, mean arterial pressure was maintained through an increase in peripheral resistance. In contrast, the young relied solely on cardiac adaptations to postural stress by decreasing end-systolic volume (supine, 62 +/- 5 ml; upright, 39 +/- 5 ml; p less than 0.01) and increasing heart rate (57 +/- 2 min-1 to 71 +/- 3 min-1, p less than 0.01), whereby cardiac output and mean arterial pressure were maintained during tilt.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension

Diltiazem concentrations and blood pressure, heart rate, PR interval and forearm vascular resistance responses to intravenous (25 and 50 mg) and oral (120 mg) diltiazem were compared in 13 elderly persons (mean age 68 +/- 4 years) and 10 young persons (mean 30 +/- 5 years) with essential hypertension. Diltiazem elimination was slower in the elderly. After a dose of 25 mg, clearance was 13 +/- 4 ml/min/kg in the elderly and 23 +/- 7 in the young (p less than 0.05); after 50 mg, 16 +/- 6 and 21 +/- 12 ml/min/kg (p less than 0.05); and after oral administration, 22 +/- 9 and 35 +/- 14 ml/kg/min (p less than 0.02). No age-related differences in volume of distribution (by model or area methods) were seen. Elimination half-lives were 4.5 +/- 2.2 hours in the elderly and 3.8 +/- 0.7 hour in the young persons (p less than 0.01); 4.5 +/- 1.6 and 3.3 +/- 0.7 hours (p = 0.10); and 4.7 +/- 1.5 and 3.3 +/- 1.8 hours (p = 0.08) after 50, 25 and 120 mg. Maximal decreases in mean blood pressure were from 113 +/- 14 to 91 +/- 12 mm Hg (19%) in the elderly patients and from 108 +/- 8 to 99 +/- 9 mm Hg in the younger patients (8%) after 50 mg; from 106 +/- 13 to 93 +/- 14 mm Hg and from 109 +/- 11 to 99 +/- 13 mm Hg, respectively, after 25 mg; and from 113 +/- 10 to 97 +/- 10 mm Hg and from 109 +/- 11 to 97 +/- 8 after 120 mg orally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of diltiazem and atenolol in young, physically active men with essential hypertension

The antihypertensive efficacy and effect on maximal exercise performance of diltiazem was evaluated and compared with atenolol in patients specifically selected on the basis of their being young and physically active. Diltiazem (sustained-release preparation, 90 mg twice daily) was administered to 14 patients (aged 33 +/- 2 years) and atenolol (50 mg once daily) to 13 patients (aged 30 +/- 2 years) with essential hypertension in a 16-week randomized, double-blind, parallel study. The 2 drugs had comparable antihypertensive effects at rest, with mean decreases of 18 and 17 mm Hg (p less than 0.001) for supine and standing diastolic blood pressure (BP), respectively, during diltiazem treatment, and mean decreases of 21 and 18 mm Hg (p less than 0.001) during atenolol treatment. During maximal graded exercise testing, systolic BP, diastolic BP, heart rate and heart rate-BP product were significantly reduced by both drugs. However, the reductions in systolic BP, heart rate and heart rate-BP product during exercise were considerably greater (p less than 0.001) with atenolol than with diltiazem. Maximal exercise performance was essentially unchanged with diltiazem and slightly (3%, p less than 0.05) reduced with atenolol. Thus, diltiazem is effective and well-tolerated single therapy for young patients with mild to moderate essential hypertension who lead a physically active life style and compares favorably with atenolol.     

Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension

Pharmacodynamics and pharmacokinetics of labetalol, a combined alpha- and beta-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 +/- 8 vs 25 +/- 13 mm Hg, p less than 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 +/- 10 mm Hg) and young (17 +/- 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 +/- 16 vs 16 +/- 14 mm Hg, p less than 0.001) and similar decreases in standing diastolic BP (21 +/- 7 vs 17 +/- 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 +/- 16 vs 17 +/- 7 mm Hg systolic and 24 +/- 6 vs 12 +/- 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 +/- 1.05 vs 0.326 +/- 0.490 ng/ml X mm Hg-1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 +/- 0.063 vs 0.406 +/- 0.303 ng/ml X beats/min-1 (p less than 0.05), with 2 elderly patients showing no decrease in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of sustained-release diltiazem as replacement therapy for beta blockers and diuretics for stable angina pectoris and coexisting essential hypertension: a multicenter trial

To determine if a sustained-release form of the calcium entry blocker diltiazem would be a satisfactory substitute for the combination of beta-adrenergic blocking agent and thiazide diuretic in the treatment of systemic hypertension and angina pectoris, 38 patients were studied in a 4-center trial. Blood pressure and heart rate were measured in the supine position, immediately after and 5 minutes after standing. Modified Bruce protocol treadmill tests were performed to determine the time to onset of 1 mm ST-segment depression, time to onset of chest pain and time to termination of exercise. Diltiazem monotherapy resulted in equivalent blood pressure control in 28 of 38 patients (74%). In the remaining patients, blood pressure control was achieved with resumption of the diuretic. Blood pressure with beta blocker plus diuretic compared with diltiazem were, in the supine position 137 +/- 22/82 +/- 7 (+/- 1 standard deviation) versus 139 +/- 22/82 +/- 8 mm Hg, immediately after standing 131 +/- 20/84 +/- 9 versus 133 +/- 21/82 +/- 10 mm Hg and after standing for 5 minutes 134 +/- 19/85 +/- 8 versus 137 +/- 18/85 +/- 9 mm Hg (difference not significant for each). The heart rate with diltiazem was higher supine (67 +/- 11 versus 60 +/- 11 beats/min), standing (73 +/- 13 versus 64 +/- 14 beats/min) and 5 minutes after standing (73 +/- 14 versus 63 +/- 14 beats/min, p less than 0.01 for each).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of enalapril and nifedipine on orthostatic hypotension in older hypertensive patients

OBJECTIVE: To compare the effect of enalapril with long-acting nifedipine on orthostatic hypotension in older patients. DESIGN: A prospective, double blinded, cross-over study. SETTING: The outpatient clinic of a university hospital. PARTICIPANTS: Thirty-nine patients aged 65 years or older with systolic blood pressure (SBP) of 140-190 mm Hg and diastolic blood pressure (DBP) of 90-110 mm Hg. INTERVENTION: Enalapril 5-20 mg od or nifedipine 30-90 mg od for 8 weeks, followed by 4 weeks washout and cross-over for a second 8-week period. MEASUREMENTS: Supine and standing 0-, 1-, and 5-minutes blood pressure was recorded before and at the end of each treatment period. RESULTS: At baseline, SBP was 158.8 +/- 8.7 mm Hg, and DBP was 97.1 +/- 5.9 mm Hg. There was a decline in SBP of 6.1 +/- 2.7 mm Hg and 8.4 +/- 4.1 mm Hg after 1 and 5 minutes of standing, respectively. Both agents caused a significant decline in supine blood pressure. Enalapril: supine SBP 158.8 +/- 8.7 to 143 +/- 7.3 mm Hg; supine DBP 97.1 +/- 5.9 to 85.1 +/- 5.1 mm Hg (P = .0001). The drop in SBP after standing for 5 minutes was only 2.4 +/- 1.6 mm Hg with no change in diastolic values. A > or = 10 mm Hg drop in SBP was observed in only three patients, and no patient experienced a decline of 20 mm Hg or more. Nifedipine: supine SBP: 160.3 +/- 9 to 145.3 +/- 8.1 mm Hg; supine DBP: 96.3 +/- 5.7 to 86.3 +/- 5.8 (P = .0001). Nifedipine induced an orthostatic decline in SBP values; there was an 8.7 +/- 4.8 mm Hg difference between supine and 5 minutes standing values (P = .0005) without change in diastolic values. An orthostatic decline in SBP of > or = 10 mm Hg occurred in 13 patients, and there was a drop of > or = 20 mm Hg in six patients. The cross-over of enalapril and nifedipine reproduced the hypotensive effect and reversed the postural effect. (P = .0002 nifedipine vs enalapril) CONCLUSIONS: Enalapril and nifedipine were equipotent in reducing supine blood pressure levels. Enalapril also reduced the number of orthostatic episodes significantly, whereas nifedipine aggravated this phenomenon.     

Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients. Altered electrocardiographic and hypotensive responses

We studied verapamil pharmacodynamics and disposition in seven young, ten elderly, and seven very elderly hypertensive males. Maximal decrease in mean (+/- SD) blood pressure tended to be greater in the elderly (-13.5 +/- 5.9 mm Hg) and the very elderly patients (-15.9 +/- 9.6 mm Hg) compared with that in young patients (-7.3 +/- 4.2 mm Hg). Disparate effects on heart rate responses were noted with reflex tachycardia in young patients compared with decreases in heart rate among the elderly and very elderly. Sensitivity to verapamil-induced prolongation in electrocardiographic P-R interval was less in the very elderly, and maximal prolongation in P-R interval induced by verapamil was less in the elderly and very elderly. Verapamil disposition was also age related. Total verapamil clearance was decreased in elderly (10.5 +/- 3.5 mL/min X kg; p less than 0.05) and very elderly (8.0 +/- 4.1 mL/min X kg; p less than 0.01) when compared with that in young patients (15.5 +/- 4.5 mL/min X kg). Elimination half-life was prolonged in the elderly (7.4 +/- 3.3 h; p less than 0.01) and very elderly (8.0 +/- 1.2 h; p less than 0.01) compared with that in young patients (3.8 +/- 1.1 h). Our data indicate age- and hypertension-related physiologic changes result in predictable pharmacokinetic changes. However, the complex alterations in verapamil pharmacodynamic responses indicate an interaction between direct drug effects and age- and disease-related changes in hemodynamic and autonomic nervous system function.     

Effects of hydrochlorothiazide and diltiazem on reflex vasoconstriction in hypertension

The purpose of our study was to determine the effects of treatment with hydrochlorothiazide (n = 10) or diltiazem (n = 8) on reflex humoral, hemodynamic, and vascular responses to graded lower body negative pressure in subjects with mild to moderate hypertension (supine diastolic pressure, 95-114 mm Hg). All subjects received placebo for 2 to 4 weeks followed by either hydrochlorothiazide (25-50 mg b.i.d.) or diltiazem (120-180 mg b.i.d.) to achieve a reduction in supine diastolic pressure of 10 mm Hg or more and a final pressure below 90 mm Hg. Mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and renin responses to graded lower body negative pressure (-10, -20, -40 mm Hg) and head-up tilt were examined before and after 12 weeks of treatment with either drug. Pretreatment basal values of mean arterial pressure (114 +/- 2 vs 117 +/- 2 mm Hg), forearm vascular resistance (29 +/- 3 vs 35 +/- 7 units), and plasma renin activity (0.7 +/- 0.2 vs 0.6 +/- 0.2 ng angiotensin I/ml/hr) were not significantly different between groups. There were no significant differences in basal plasma norepinephrine or in the increases of norepinephrine in response to lower body negative pressure before and after treatment in either group. Forearm vascular resistance responses to lower body negative pressure were virtually abolished in the diltiazem-treated group but not in the hydrochlorothiazide-treated group despite similar levels of mean arterial pressure and basal forearm vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of an oral fixed low-dose perindopril 2 MG/indapamide 0.625 MG combination: a randomized, double-blind, placebo-controlled study in elderly patients with mild to moderate hypertension.

The efficacy and safety of 12 weeks treatment with an oral fixed low-dose perindopril 2 mg + indapamide 0.625 mg (Per/Ind) combination in elderly and very elderly patients (65-85 years) with mild to moderate systolic and diastolic hypertension (SDH) or isolated systolic hypertension (ISH) were investigated vs placebo. This trial was a multinational randomized double-blind study with doubling of active drug dosage in nonresponders. Intention to treat analysis was performed in 383 patients (age 72.4 years; ISH 32%). 58.5% remained on their initial dosage. Per/Ind decreased supine diastolic and systolic blood pressure (sDBP/sSBP) by 13.2+/-8.0 mm Hg and 22.5+/-13.9 mm Hg (P <.0001) versus placebo -7.3+/-9.0 mm Hg and -12.3+/-15.2 mm Hg, respectively. In ISH (n = 123), Per/Ind decreased sSBP by 23.0+/-11.8 mm Hg (P <.0001). Overall response and normotension rates was 81.3% with Per/Ind (P <.0001). Adverse event rates (including hypokalemia) were similarly low in both groups. Analysis in the over-75 year subgroup showed similar safety and efficacy results. Fixed low-dose Per/Ind is a safe and effective treatment of hypertension including isolated systolic hypertension in the elderly.     

A randomized controlled trial of the effects of three antihypertensive agents on blood pressure control and quality of life in older women

We conducted a multicenter, randomized, double-blind, parallel group trial to compare the impact of titrated doses of atenolol (50 to 100 mg once a day), enalapril (5 to 20 mg once a day), and diltiazem (sustained release) (60 to 180 mg twice a day) on blood pressure and quality of life in older hypertensive women. Two hundred forty-two patients were randomized. Dose titration was completed by week 4 after randomization, and the maintenance phase was completed at week 16. Diltiazem (sustained release) demonstrated greater diastolic blood pressure lowering at both weeks 8 and 16 by an intent-to-treat analysis. At week 16, diltiazem changed diastolic blood pressure -13.7 +/- 0.7 mm Hg compared with -10.8 +/- 1.1 mm Hg for atenolol, and -10.5 +/- 0.9 mm Hg for enalapril. Diltiazem also demonstrated greater lowering of systolic blood pressure at week 3, but these differences in systolic blood pressure had decreased by week 16. More patients were classified as treatment failures during the 16 weeks of the trial for atenolol (15%) than for diltiazem (2.5%), while the treatment failure rate was intermediate with enalapril (8%). Total rates of adverse events were equivalent across the three treatment arms. There were few significant differences in the impact of the three treatments on mean scores of quality-of-life measures at week 16. There was a trend for atenolol to have somewhat worse quality-of-life scores, but none of these differences were statistically significant. In conclusion, all three treatment regimens were effective in lowering diastolic blood pressure without significant differences in rates of adverse events or deleterious effects on quality of life.     

Diltiazem versus propranolol in essential hypertension: responses of rest and exercise blood pressure and effects on exercise capacity

Both beta-blocking and calcium channel-blocking drugs are being used with increasing frequency as initial therapy for essential hypertension. The present study was designed to compare the antihypertensive effects of a beta-blocking drug, propranolol, with a calcium channel-blocking drug, diltiazem, at rest and during upright bicycle exercise and to determine whether exercise capacity is altered by these therapies. Twenty-one patients with uncomplicated systemic hypertension and a diastolic blood pressure (BP) of 95 to 110 mm Hg without medication were randomly assigned to propranolol or diltiazem therapy in a double-blind manner. The total daily dosages were titrated as needed, from 160 to 480 mg of propranolol (mean 371 mg) and 120 to 360 mg of diltiazem (mean 307 mg) over 12 weeks, and the titrated dose was maintained for 4 additional weeks. Both drugs significantly reduced supine BP (from 149 +/- 14/101 +/- 4 to 136 +/- 17/89 +/- 10 mm Hg with propranolol and from 157 +/- 14/103 +/- 4 to 144 +/- 13/93 +/- 8 with diltiazem. Only diltiazem reduced BP during submaximal exercise, but both agents produced significant responses during maximal exercise. Diltiazem had no effect on maximal heart rate, exercise duration or O2 uptake, whereas propranolol reduced maximal VO2 from 27 +/- 6 to 22 +/- 6 ml/min/kg (p less than 0.01) and also shortened duration of exercise. Propranolol, despite its effects on heart rate, maintained the workload VO2 relation at submaximal loads, suggesting an increased oxygen delivery. However, these adaptive mechanisms appear to be insufficient during maximal effort.     

Chronic dietary tyrosine supplements do not affect mild essential hypertension

The blood pressure and plasma norepinephrine response to oral tyrosine, the precursor of norepinephrine, supplementation (2.5 g t.i.d.) of regular meals was examined in 13 untreated patients with mild essential hypertension. Using a randomized double-blind crossover design, each 2-week treatment was followed by a 2-week supplement-free interval. Supine and standing blood pressure and plasma norepinephrine levels were measured at the beginning and end of each 2-week treatment. Plasma tyrosine levels increased (p less than 0.001) from 71.2 +/- 8.0 nM/ml at baseline to 152.8 +/- 17.4 nM/ml 2 hours after the tyrosine supplement. Blood pressure under control conditions was 144 +/- 3 Hg systolic, 91 +/- 2 mm Hg diastolic (109 +/- 2 mm Hg mean) after 30 minutes in the supine position and 148 +/- 4 mm Hg systolic, 102 +/- 3 mm Hg diastolic (117 +/- 3 mm Hg mean) after 5 minutes of standing. Plasma norepinephrine levels were 191 +/- 18 pg/ml in the supine subjects and 390 +/- 33 pg/ml in the standing subjects. No difference in systolic, diastolic, or mean blood pressure, heart rate, or plasma norepinephrine levels were seen between the beginning and end of each period or between groups. Individual changes in blood pressure showed no correlation with individual changes in norepinephrine levels. These results indicate that the addition of a tyrosine supplement to the usual diet of mild hypertensive subjects has no beneficial effect on blood pressure.     

Diltiazem as monotherapy for systemic hypertension: a multicenter, randomized, placebo-controlled trial

A multicenter, randomized, placebo-controlled, parallel group study of diltiazem in essential hypertension was carried out in 77 patients (40 diltiazem, 37 placebo) with stable supine diastolic blood pressure (BP) between 95 and 110 mm Hg. Patients were withdrawn from previous antihypertensive therapy for at least 4 weeks, titrated to the optimal dose, and followed for a total of 12 weeks during therapy. A diltiazem dose of 360 mg/day was required in 85% of the patients. Average BP in all positions was significantly (p less than 0.0001) reduced by diltiazem compared with placebo. With diltiazem, average supine BP fell from 156/100 mm Hg at baseline to 141/87 at end titration and 145/90 mm Hg at week 12, whereas average standing BP fell from 152/101 mm Hg to 136/90 and 143/91 mm Hg, respectively, at those times. There was no significant change in heart rate at week 12. Diltiazem tended to be more effective in older patients, but caused no increase in orthostatic BP drop. There were no statistically significant changes in BP in the placebo group. Two patients receiving placebo and 1 patient receiving diltiazem discontinued therapy as a result of adverse effects, and overall, side effects were only slightly more common with diltiazem treatment. Thus, diltiazem was effective and well tolerated single therapy for mild to moderate systemic hypertension and appears to compare favorably to most agents being used.     

Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation

We evaluated the efficacy and the safety of medium-(240 mn/day) and high-dose (360 mg/day) diltiazem alone and in combination with digoxin when used for control of heart rate in 12 patients with chronic atrial fibrillation. Medium-dose diltiazem was comparable to therapeutic dose of digoxin at rest (88 +/- 19 vs 86 +/- 12 beats/min) but superior during peak exercise (154 +/- 23 vs 170 +/- 20 beats/min; p less than .05). High-dose diltiazem resulted in better control of heart rate than digoxin both at rest (79 +/- 17 beats/min; p less than .05) and exercise (136 +/- 25 beats/min; p less than .05) but was associated with side effects in 75% of the patients. Combined therapy of digoxin and diltiazem enhanced the effect of digoxin alone and resulted in significantly better control of heart rate at rest (67 +/- beats/min with medium-dose and 65 +/- beats/min with high-dose diltiazem) and during peak exercise (132 +/- 32 and 121 +/- 24 beats/min, respectively). However, the difference in heart rate between these two doses was not significant. Reduction of heart rate combined with concomitant effect on blood pressure resulted in a significant fall in pressure-rate product at rest from 10,077 +/- 1708 mm Hg/min on digoxin alone to 7877 +/- 1818 mm Hg/min after the addition of medium-dose diltiazem (p less than .05) and during exercise form 25,670 +/- 3606 to 18,439 +/- 4115 mm Hg/min (p less than .05). Continued therapy with digoxin combined with diltiazem 240 mg/day for 21 +/- 8 days in nine patients showed persistent effect on heart rate and blood pressure without any toxic manifestations or change in serum digoxin (1.5 +/- 0.4 vs 1.3 +/- 0.4 ng/ml) or plasma diltiazem concentrations (204 +/- 72 vs 232 +/- 129 ng/ml). In conclusion, medium-dose diltiazem when combined with digoxin is an effective and safe regimen for the treatment of patients with chronic atrial fibrillation and enhances digoxin-mediated control of heart rate both at rest and during exercise.