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In a double-blind randomized study, we evaluated the effects of 25 mg vs 50 mg of hydrochlorothiazide in 51 elderly patients (aged 68.9 +/- 7.0 years) with isolated systolic hypertension (blood pressure, 160 to 239 mm Hg systolic and less than 90 mm Hg diastolic). Dose levels could be increased to twice daily to control blood pressure. The reductions in blood pressure (25.4/6.8 mm Hg and 28.9/7.4 mm Hg) and proportion of patients in whom blood pressure was controlled (78% and 89%) were similar in the lower- and higher-dose groups during the titration phase. However, serum potassium level was reduced more in the higher-dosage (0.57 mmol/L) than the lower-dosage (0.17 mmol/L) group. There were no significant changes in blood pressure during a 24-week maintenance phase. No patient required withdrawal from the study because of adverse effects, and cognitive-behavioral function was well preserved. We conclude that hydrochlorothiazide is effective and well tolerated in older patients with isolated systolic hypertension, many of whom may be effectively treated with 25 mg of hydrochlorothiazide once daily.

Our recent Veterans Administration Cooperative Study--involving 683 hypertensive male patients--showed that a diuretic was more effective than a beta blocker in controlling hypertension in most respects. In addition, in this study we failed to find evidence that thiazide-induced hypokalemia was associated with increased evidence of cardiac arrhythmias in patients without overt heart disease. We are concerned that the current desire to avoid hypokalemia at all costs may result in the prescription of ineffective dosages of diuretics for the treatment of hypertension.

In a double-blind crossover study, 13 patients with pretreatment diastolic blood pressure between 95 and 109 mm Hg received nadolol, 80 mg/day, plus placebo of hydrochlorothiazide and nadolol, plus three different doses of active hydrochlorothiazide. Patients remained on each active regimen for 3 weeks, with an intervening placebo period of 2 to 4 weeks. With 12.5 mg of hydrochlorothiazide daily plus nadolol, there was no greater reduction of blood pressure than with nadolol alone. A dose of 25 mg of hydrochlorothiazide was associated with a significantly greater decrease in systolic but not diastolic pressure, as compared with nadolol alone. A significantly greater reduction in both systolic and diastolic blood pressure was obtained only with the 50 mg/day dose of hydrochlorothiazide. Extension to 6 weeks of treatment with 12.5 mg/day failed to lower the blood pressure more than the level seen at 3 weeks. These results suggest that in combination with nadolol, 12.5 mg of hydrochlorothiazide per day has no significant antihypertensive effect. There was no evidence of a flat dose-response curve in the daily dose range of 12.5 to 50 mg. For most patients, a dose of 50 mg of hydrochlorothiazide was required to lower both systolic and diastolic blood pressure significantly below the level obtained with nadolol alone.

In a double-blind study, 20 hypertensive patients were randomly assigned to a six-week regimen of either ticrynafen or hydrochlorothiazide. Blood pressure was significantly reduced with both medications, although most patients required an increase in dosage from 250 to 500 mg ticrynafen daily. Whereas the serum uric acid level rose moderately in the hydrochlorothiazide-treated patients, it fell strikingly to less than half of the pretreatment level in patients treated with ticryafen. Body weight decreased slightly in both groups, as did serum potassium levels. Blood urea nitrogen and serum creatinine levels rose slightly in both groups. The magnitude of these changes was not significantly different between the two groups. Use of ticryafen was well tolerated. Ticryafen appears to be a useful new antihypertensive agent because of its unique combination of diuretic, antihypertensive, and hypouricemic effects.

Among 447 hypertensive patients, most with a history of diuretic-induced hypokalemia, 252 developed diuretic-induced hypokalemia while receiving hydrochlorothiazide, 50 mg/d. In a randomized study we evaluated the efficacy of three drug regimens in restoring potassium levels while maintaining blood pressure control: hydrochlorothiazide (50 mg/d) plus potassium supplement (20 mmol/d); hydrochlorothiazide (50 mg/d) plus potassium supplement (40 mmol/d); or hydrochlorothiazide (50 mg/d) with triamterene (75 mg/d) in one combination tablet. In all groups, mean serum levels of potassium rose within 1 week and showed no further change thereafter. However, the hydrochlorothiazide/triamterene and hydrochlorothiazide plus 40 mmol of potassium regimens were significantly more effective in restoring serum potassium levels than was the hydrochlorothiazide plus 20 mmol of potassium regimen. A significant increase in magnesium levels was observed only in the group treated with the hydrochlorothiazide/triamterene combination. Each regimen provided continued control of mild to moderate hypertension.

As part of the Veterans Administration cooperative studies on antihypertensive agents, systolic time intervals (STIs) were recorded before and after 2 or 4 weeks of treatment with hydrochlorothiazide (HCTZ) alone in 320 asymptomatic patients with mild to moderate hypertension. After treatment with HCTZ, left ventricular ejection time corrected for heart rate (delta LVET) was significantly reduced. This decrease is consistent with other hemodynamic observations indicating a reduced preload and stroke volume after administration of thiazides. Electromechanical systole corrected for heart rate (delta QS2) decreased, while the ratio of preejection period to LVET (PEP/LVET) increased, reflecting reduced left ventricular function. PEP did not change. Four step 2 drugs--hydralazine, prazosin, oxprenolol and propranolol--were then added randomly to HCTZ and further recordings of STIs were taken at 1 and 6 months after administration of these drugs. The delta LVET and delta QS2 increased and PEP/LVET decreased, suggesting improved left ventricular function after administration of all 4 agents. These changes may have been due to the added agents or to the recovery of cardiac output that occurs independently during long-term treatment with thiazide diuretic drugs alone. PEP decreased slightly after hydralazine and prazosin and increased slightly after treatment with the beta-blocking drugs, although none of these changes were significant except those during hydralazine treatment. Processing of the STIs was greatly facilitated by the automated system for recording and analyzing the measurements.

Two groups of patients with uncomplicated systemic hypertension were studied. Group 1 included 11 patients who had overt hypokalemia with diuretic drug treatment, and group 2 included 11 patients who remained normokalemic. After baseline studies without treatment were performed, both groups received hydrochlorothiazide, 50 mg twice daily. Plasma potassium (PK) was significantly reduced within the first day of treatment and stabilized by day 7 in both groups. The average decrease in PK was 1.0 +/- 0.1 mEq/liter (p less than 0.01) in the first group and 0.6 +/- 0.2 mEq/liter (p less than 0.01) in the second group. Cumulative losses of K were approximately 200 mEq in the hypokalemic group and were minimal in the normokalemic group as assessed by 24-hour urinary collections. Patients in the hypokalemic group also had a greater reduction in body weight and blood pressure. Supplementation with KCl, 96 mEq/day, or triamterene, 200 mg/day, in 9 hypokalemic patients resulted in an increase of PK to approximately 3.5 mEq/liter leveling off by day 7, and a cumulative K retention of approximately 200 mEq. Thus, overt thiazide-induced hypokalemia was associated with small and biologically unimportant losses of K from body stores. With replacement therapy the estimated amount of retained K was also small.

In a double-blind crossover study, the effectiveness of furosemide, 40 mg twice daily, was compared with hydrochlorothiazide, 50 mg twice daily, in hypertensive patients. Both hydrochlorothiazide and furosemide significantly reduced blood pressure (BP) during three months of therapy. However, the fall in BP was consistently greater with hydrochlorothiazide than with furosemide, although the difference was significant only with respect to systolic BP. The somewhat greater antihypertensive effectiveness of hydrochlorothiazide may be related to its longer action permitting a more continuous diuretic effect and, hence, maintenance of reduced extracellular fluid volume throughout the 24-hour period.

Forty-four patients with uncomplicated systemic hypertension underwent 48-hour electrocardiographic monitoring before and after four weeks of treatment with hydrochlorothiazide, 100 mg daily. Plasma potassium concentration decreased from 4.07 +/- 0.26 mmol/L (4.07 +/- 0.26 mEq/L) to 3.36 +/- 0.44 mmol/L (3.36 +/- 0.44 mEq/L). The average number of premature ventricular contractions, couplets, or ventricular tachycardia episodes did not change significantly. Twenty patients had more than minimal ventricular ectopy (class 2 to 5) before and 17 after diuretic therapy. Further analysis revealed that following diuretic therapy, neither patients with plasma potassium levels of 3.4 mmol/L or less (less than or equal to 3.4 mEq/L) nor patients with left ventricular hypertrophy had increased ectopy as compared with baseline. At baseline, patients with left ventricular hypertrophy had more arrhythmias than patients without. We conclude that the results of this study provide no evidence that diuretic therapy or diuretic-induced hypokalemia results in increased ventricular ectopy, and that patients with left ventricular hypertrophy may have more ventricular ectopy than patients without, but these arrhythmias are not adversely effected by diuretic therapy.

1. The results of the Veterans Administration Co-operative Study have been extended by the subsequent clinical trials, which included patients of both sexes and with less vascular disease. The later studies confirm the effectiveness of treatment in preventing most complications except myocardial infarction and sudden death. Furthermore, the lower diastolic blood pressure in which treatment has been shown to have a significant beneficial effect has been lowered from 105 mmHg as indicated by the Veterans Study to 100 mmHg as shown by the much larger Australian trial. The possibility of reducing the incidence of sudden death and fatal myocardial infarction has been suggested by other recent control trials using beta-adrenoreceptor-blocking drugs, an approach that needs further exploration. 2. A number of interesting and useful new drugs have appeared which include tienilic acid, minoxidil, saralasin and captopril, and in addition recent controlled trials have re-emphasized the effectiveness of the old drug, reserpine, when combined with a diuretic. The art of treatment of hypertension therefore appears to be in a healthy state and we should expect more advances in the future.

Three double-blind Veterans Administration Cooperative Studies are reviewed to determine age-related changes in response to antihypertensive agents. In the first study 312 patients received hydrochlorothiazide titrated from 25 to 100 mg twice daily to lower diastolic blood pressure (BP) to less than 90 mm Hg. Of 121 patients aged 55 to 65 the decrease in BP averaged -21.8/-12.9 mm Hg, while in the 191 patients younger than 55 the reduction averaged -15.7/-11.5 mm Hg (p less than 0.001; p = 0.048, respectively). Both systolic and diastolic BP reductions averaged significantly more in older whites; in older blacks it was systolic BP only. An additional 298 patients received titrated doses of propranolol alone. In this group there were no significant differences in BP response between younger patients and patients aged 55 to 65 except in the subgroup of white patients older than 60, in whom the systolic reduction was significantly less than in the younger patients. In a second study of bendroflumethiazide alone and with nadolol, systolic BP decreased more in older than in younger patients but there was no age-related reduction with nadolol alone. In the third trial captopril was first given alone and later with hydrochlorothiazide. There were no age-related differences with captopril alone, but after the addition of hydrochlorothiazide there was a trend toward a greater antihypertensive response in the patients aged 55 to 69. Thus, responsiveness of older patients varies with the type of antihypertensive drug. Age appears to increase the antihypertensive response to thiazide diuretics but not to beta-adrenergic blocking drugs or to captopril.

The effect of aerobic exercise on cardiac arrhythmias, plasma catecholamines, potassium and magnesium in patients with systemic hypertension was assessed. Twenty patients (age 54 +/- 8 years) with uncomplicated hypertension underwent exercise treadmill testing twice while receiving placebo and twice while receiving hydrochlorothiazide 100 mg daily. Blood samples for electrolytes and catecholamines were obtained at rest, at peak exercise and 10 minutes after exercise. There were no substantial differences comparing the first to the second placebo phase or the first to the second treatment period. As expected, hydrochlorothiazide treatment caused a significant decrease in serum potassium (4.00 +/- 0.44 to 3.32 +/- 0.49 mEq/liter, p less than 0.001). Serum magnesium did not change with treatment. Serum potassium, serum magnesium and plasma catecholamines increased significantly with exercise. No rebound hypokalemia occurred during recovery. Occasional ventricular premature contractions were noted at rest during all phases of the study, with only a slight increase in frequency during exercise. Couplets were noted only rarely. No difference in the frequency or complexity of arrhythmias was noted between placebo and treatment periods. Diuretic therapy or diuretic-induced hypokalemia has no profound effect on cardiac arrhythmias during or after exercise in patients with uncomplicated systemic hypertension.

Twenty patients with uncomplicated systemic hypertension underwent treadmill testing twice during placebo treatment and twice during hydrochlorothiazide treatment. Data were collected at rest, at peak exercise and 10 min after exercise. Serum potassium, magnesium and plasma catecholamines increased significantly with exercise. There was no rebound hypokalaemia during the recovery period. Occasional ventricular premature complexes were recorded in all phases of the study. However, there was no difference in the frequency or complexity of arrhythmias between the placebo and the treatment periods.

Antihypertensive therapy was discontinued in 24 patients with mild hypertension whose BPs had been well controlled with diuretics alone. Eleven patients (46%) maintained normal diastolic BPs (less than or equal to 90 mm Hg) for six months after stopping treatment and five patients (21%) for 12 months. All patients who remained normotensive for six to 12 months had mean diastolic BPs of 82 mm Hg or less during treatment. There was no significant correlation between maintenance of normotension and any of the following: pretreatment BP, presence of target-organ damage, duration of known hypertension, family history of hypertension, heart rate, body weight, weight gain after stopping diuretic therapy, 24-hour urinary sodium and potassium excretion, serum electrolyte values or renin profile. This study demonstrates that hypertension may be favorably modified, sometimes for many months, by effective antihypertensive treatment.

In this study, the relation between renin activity and therapeutic response to hydrochlorothiazide or propranolol was studied. Patients with a diastolic blood pressure of 95 to 114 mm Hg were treated with propranolol (40 to 320 mg twice daily) or hydrochlorothiazide (25 to 100 mg twice daily). The initial renin profiles were: low, 56 percent (n = 300); normal, 33 percent (n = 174); high, 11 percent (n = 60). A greater incidence of low and fewer high renin profiles (p less than 0.001) were observed in blacks. After furosemide administration (40 mg intravenously), 55 percent of patients (n = 291) had a low renin response and 45 percent (n = 240) had a normal renin response. No correlation between renin profile and renin response was observed, although low renin response and low renin profile occurred more frequently in older patients. Hydrochlorothiazide administration resulted in a greater decrement in diastolic blood pressure (p less than 0.05) in the total group. Irrespective of renin activity, both hydrochlorothiazide and propranolol reduced diastolic blood pressure. When renin profile was considered, no significant variation in response to hydrochlorothiazide therapy was observed, and there was a greater reduction in diastolic blood pressure in the patients with a high renin profile receiving propranolol. In comparing therapeutic response, patients with a low renin profile had a better response to hydrochlorothiazide, and propranolol was more effective in patients with a high renin profile. The anticipated effect of therapy on plasma renin activity was observed. Although these results are consistent with a volume-vasoconstrictor analysis of hypertension, the results of therapy could not have been prejudged from renin profile or responsivity. The slight differences observed do not warrant the expense of renin determinations when a simple determination of therapeutic response is sufficient.

Correlations were made between weight change (as an index of volume loss) and blood pressure (BP) reduction before and after hydrochlorothiazide treatment. A total of 343 patients with mild to moderate hypertension (95-114 mm Hg) received hydrochlorothiazide alone. The diuretic was titrated from 50 to 100 to 200 mg daily as needed until the diastolic BP fell below 90 mm Hg (goal BP) or side effects supervened. Of the 305 patients who completed the 10-week titration period, 65% attained goal BP. The effective dose of hydrochlorothiazide in 52% of these responders was 50 mg/day, and this was associated with weight loss averaging 1.58 kg. An additional 29% achieved goal BP with a similar degree of weight loss, but they required double the dose, or 100 mg/day. The remaining 19% of responders required significantly greater weight reductions averaging 3.14 kg to achieve goal BP, which necessitated hydrochlorothiazide, 200 mg/day. More blacks than whites attained goal BP despite similar degrees of weight loss in the two races. Plasma renin activity was initially higher in whites than in blacks and rose significantly more in blacks and whites requiring the greatest volume losses and the highest dose of hydrochlorothiazide to attain goal BP. Nonresponders had less weight loss than responders. Thus, diuretic dose requirements vary in different patients and are related either to different volume losses in response to a given dose or to different degrees of BP reduction in response to the same volume loss.