Influence of beta 2 agonism and beta 1 and beta 2 antagonism on adverse effects and plasma lipoproteins: results of a multicenter comparison of dilevalol and metoprolol.

Dilevalol combines vasodilation due to selective beta 2 agonism and nonselective beta antagonism. We studied 311 patients randomized to dilevalol and 138 to metoprolol in a multicenter trial. After a 4-week placebo washout, dilevalol was titrated from 200 to 1,600 mg once daily and metoprolol from 100 to 400 mg to a goal supine diastolic blood pressure less than 90 and greater than or equal to 10 mm Hg decrease from baseline. Responders were followed for 1 year. The average age of patients was 51 years; 72% were men and 54% were white. Both drugs reduced blood pressure effectively to a similar level. Fewer patients discontinued dilevalol than did those taking metoprolol (9 vs 16%; p less than 0.03). More metoprolol-treated patients withdrew because of depression (6 vs less than 1%; p = 0.03) and impotence (5 vs less than 1%; p = 0.03). Lipoprotein levels before and after treatment were measured in 99 patients treated for 53.5 weeks with dilevalol (mean dose 438 mg). Dilevalol increased high-density lipoprotein (HDL) cholesterol by 2.5 mg/dl to 47.2 (p = 0.05), reduced low-density lipoprotein (LDL) cholesterol by 2.5 mg/dl, increased HDL/LDL by 0.03, and decreased total cholesterol/HDL cholesterol by 0.18. Triglycerides increased by 21 mg/dl (p = 0.06). In patients with an initial HDL cholesterol less than 35 mg/dl, dilevalol increased it by 9 mg/dl. In patients treated with metoprolol, the only significant change (p = 0.02) was a 41.9-mg/dl increase in triglyceride levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolated systolic hypertension in the elderly. A placebo-controlled, dose-response evaluation of chlorthalidone.

One hundred seventy-one patients, 60 years of age or older with isolated systolic hypertension, were randomly assigned to receive chlorthalidone 12.5, 25.0, or 50.0 mg or placebo once daily for 12 weeks. The majority of the patients receiving chlorthalidone 12.5 mg achieved therapeutic success with no clinically significant biochemical changes or side effects. The 50.0-mg dose level enhanced efficacy only minimally over the 25.0-mg dose level. Drug-related side effects were significantly more prevalent in the chlorthalidone 50.0-mg group than in the placebo group. The data suggest that most elderly patients with isolated systolic hypertension, regardless of the severity, could be treated effectively and safely with chlorthalidone 12.5 mg per day.

Comparison of hydrochlorothiazide and hydrochlorothiazide plus bevantolol in hypertension.

The added hypotensive effect of bevantolol, a new cardioselective beta-blocker, was studied in 244 patients with mild to moderate essential hypertension following prior treatment with hydrochlorothiazide or placebo. After four weeks of monotherapy with 50 mg/day or 100 mg/day of hydrochlorothiazide or placebo, the mean diastolic blood pressure of the patients in these groups decreased from baseline by 8.6, 8.8, and 4.3 mmHg, respectively. During the subsequent four weeks of dual therapy with 400 mg/day of bevantolol added to the regimen, additional and uniform mean decreases of 7.5, 7.3, and 7.5 mmHg occurred, providing total mean diastolic pressure decreases from baseline of 16.1, 16.1, and 11.8 mmHg in the three groups, respectively. These diastolic pressures were significantly lower during dual therapy than during monotherapy and lower in both diuretic groups than in the placebo group during monotherapy and dual therapy (P less than 0.001). Fewer adverse reactions occurred during dual therapy than during monotherapy. The addition of bevantolol to a thiazide diuretic regimen provided safe and significantly better control of mild to moderate hypertension than did the diuretic alone.

Propranolol-hydralazine combination in essential hypertension.

The efficacy of a propranolol-hydralazine combination tablet was compared with that of each of its two components in the twice-daily treatment of mild to moderate essential hypertension (diastolic blood pressure: 100 to 125 mmHg). After a three-week, single-blind, placebo period, a 9- to 18-week, single-blind, dose-finding phase with the combination was performed. The daily doses of propranolol/hydralazine were 40 mg/25 mg, 80 mg/25 mg, 80 mg/50 mg, 120 mg/50 mg, 160 mg/50 mg, and 160 mg/100 mg. Of 83 patients, 73 (88%) had decreases in diastolic blood pressure equal to or greater than 10 mmHg. Thirty-eight (46%) patients had a diastolic blood pressure equal to or less than 90 mmHg while taking 80 mg propranolol/50 mg hydralazine or less given BID. Mean systolic and diastolic pressures were reduced by 16.8 mmHg (10.9%) and 17.6 mmHg (16.7%), respectively (P less than 0.001). A ten-week, double-blind, parallel-treatment phase followed in which patients were randomly assigned to the combination tablet or to propranolol or hydralazine. There were significantly larger increases in mean systolic (P less than 0.01) and mean diastolic (P less than 0.03) blood pressure when the components were taken alone than with the combination from the mean of the last three weekly dose-finding visits to the mean of the last four biweekly parallel-treatment visits. The changes in systolic/diastolic blood pressures were: hydralazine (n = 30), 14.43/8.62 mmHg; propranolol (n = 24), 9.87/6.09 mmHg; and the combination (n = 27), 1.47/1.53 mmHg. During the parallel-treatment phase, the proportions of patients with new complaints were: hydralazine, 16/31 (52%); propranolol, 10/25 (40%); and the combination, 11/27 (41%). In the hydralazine group, three patients had cardiovascular events (severe tachycardia, mild palpitations, and skipped heart beats) and two patients had mild anxiety; no such occurrences were noted in the propranolol or combination group. The mean change (increase) in heart rate from the end of dose-finding to the end of the double-blind period was significantly larger for patients taking hydralazine than for patients taking propranolol or the combination. Mean changes for these groups were: hydralazine, 12.4 beats/min; propranolol, 2.9 beats/min; and the combination, 1.8 beats/min (P = 0.0001). This study found the combination of propranolol plus hydralazine to be safe and more effective than either component.

Clinical efficacy and safety of indapamide in essential hypertension.

Indapamide, a new methylindoline diuretic that appears to act on the distal renal tubules, is also reported to reduce vascular smooth muscle vasopressor reactivity and possibly to have a calcium-antagonist effect. Since 1973, sixteen studies by a number of European investigators who treated 301 patients with indapamide have revealed satisfactory control in 53% of patients with mild hypertension (standing diastolic pressures less than 90 mm Hg) and in 43% of patients with moderate hypertension when the drug was used without other agents. Multiple American clinical trials of indapamide in hypertension have been conducted, including double-blind, placebo-controlled protocols and trials comparing indapamide with traditional diuretic agents. A cooperative, double-blind, 40-week study compared antihypertensive response to indapamide, 2.5 mg and 5 mg daily, with response to hydrochlorothiazide, 50 mg daily, in the treatment of mild to moderate hypertension. Pretreatment diastolic blood pressures averaged 101 mm Hg. At 40 weeks of treatment, indapamide, 2.5 mg daily, had produced a fall in diastolic pressure of 15 mm Hg; indapamide, 5 mg daily, a reduction of 16 mm Hg; and hydrochlorothiazide, 50 mg daily, a fall of 15 mm Hg. Seventy-five percent of patients taking 2.5 mg of indapamide daily and 88% of those taking 5 mg achieved satisfactory blood pressure reduction. Hypokalemia may occur with indapamide but is a minor problem and seldom necessitates potassium supplementation. Serum uric acid increases were observed in only a few subjects, and clinical side effects are infrequent and mild. Indapamide is a useful antihypertensive agent with good patient tolerance in mild or moderate hypertension and may offer advantages over traditional diuretics in view of its possible vasodilator and calcium-antagonist properties, once-a-day dosage, and good therapeutic effect with prolonged usage.