Left atrial size in hypertensive men: influence of obesity, race and age. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

OBJECTIVES: We sought to determine the relations of left atrial (LA) size to blood pressure, obesity, race, age and left ventricular (LV) mass in hypertension. BACKGROUND: Although obesity, race and age may influence LV mass, their effects on LA size have not been defined in hypertension. METHODS: Left atrial size was measured in 690 men (58% African-Americans) with mild to moderate hypertension (mean [+/-SD] blood pressure 152 +/- 15/98 +/- 6 mm Hg) and a high prevalence of LV hypertrophy. Effects of LV mass, adiposity, race, age, physical activity, height, weight, sodium excretion, plasma renin activity and heart rate were examined. RESULTS: Left atrial size was greater (p < or = 0.0001) in obese (44.2 +/- 5.7 mm) than in overweight (41.6 +/- 5.9 mm) or normal weight (38.9 +/- 6.2 mm) patients. Left atrial enlargement (> or = 43 mm) was present in 56% of obese patients compared with 42% of overweight and 25% of normal weight hypertensive men. As age increased, white patients had a greater LA size than African-American patients. Although there was no relation between LV mass and LA size in normal weight patients, there was a significant positive relation in obese patients. On multiple regression analysis, obesity was the strongest independent predictor of increased LA size. CONCLUSIONS: Obesity is the strongest predictor of LA size in patients with hypertension and amplifies the relation between LA size and LV mass. Race influences effects of age and hypertension on LA size. Because increased LA size and LV mass (also influenced by obesity) are associated with an adverse outcome, these findings underscore the importance of obesity, race and age with regard to the cardiac effects of hypertension.

Importance of obesity, race and age to the cardiac structural and functional effects of hypertension. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

OBJECTIVES: The purpose of this study was to determine the effects of obesity and its interaction with age, race and the magnitude of blood pressure elevation in a large cohort of patients with mild to moderate hypertension and a high prevalence of left ventricular hypertrophy. BACKGROUND: Obesity, race and age each have important effects on the incidence and severity of hypertension and may contribute to the effects of blood pressure elevation on the cardiac manifestations of hypertension. METHODS: Left ventricular structure and function were assessed with two-dimensional targeted M-mode echocardiography in 692 men with mild to moderate hypertension (average blood pressure 153/100 mm Hg), and the data were compared in relation to obesity (determined from body mass index), age, race, blood pressure, physical activity, plasma renin activity, urinary sodium excretion, hematocrit, heart rate and serum lipids. RESULTS: Left ventricular hypertrophy was common (63% with increased left ventricular mass, 22% with left ventricular hypertrophy on the electrocardiogram [ECG]). On multivariable regression analysis, body mass index was the strongest predictor of left ventricular mass and magnified the slope relation of blood pressure to left ventricular mass. Despite a greater prevalence of ECG left ventricular hypertrophy in blacks (31%) than in whites (10%), left ventricular mass and echocardiographic prevalence of left ventricular hypertrophy did not differ by race. However, septal, posterior left ventricular and relative wall thickness were greater in black than in white men. CONCLUSIONS: Obesity is the strongest clinical predictor of left ventricular mass and left ventricular hypertrophy in men, even in those with mild to moderate hypertension of sufficient severity to be associated with a high prevalence of left ventricular hypertrophy. Moreover, independent effects of systolic blood pressure on left ventricular mass are amplified by obesity. Although race does not affect left ventricular mass or the prevalence of left ventricular hypertrophy, black race is associated with greater relative wall thickness, itself a predictor of unfavorable cardiovascular outcome.

Angiotensin-converting enzyme inhibitors in hypertension. A dozen years of experience.

Introduction of the first angiotensin-converting enzyme (ACE) inhibitor, captopril, in 1981 marked a major advance in the treatment of essential hypertension. This article reviews the 12 years of clinical experience during which it and other ACE inhibitors have become recognized as first-line agents for treating hypertension. The benefits of ACE inhibition in diabetic patients are being defined. In recent years, beneficial effects on glucose handling, left-ventricular mass, quality of life, renal function, and myocardial protection have become recognized. For these reasons, and because of their excellent safety profile, ACE inhibitors are now widely used for the treatment of hypertensive patients.

Renal and electrolyte complications of congestive heart failure and effects of therapy with angiotensin-converting enzyme inhibitors.

Blood pressure declines in virtually all patients with severe congestive heart failure given an angiotensin-converting enzyme (ACE) inhibitor, but hypotension is of concern only if symptomatic. Acute renal insufficiency induced by an ACE inhibitor is due to reduced renal perfusion pressure together with blockade of angiotensin II-induced constriction of the efferent arteriole. Risk factors (or markers) for renal failure include hyponatremia, hypotension, volume contraction. Hyponatremia is an index of increased hemodynamic impairment, marked activation of the renin-angiotensin-aldosterone axis, and poor prognosis. Preventive measures for both ACE inhibitor-associated hypotension and renal insufficiency include withholding diuretics for a few days, initiating therapy with very small doses of ACE inhibitors, and cautious dose titration. Therapy for both hypotension and renal insufficiency involves increasing dietary sodium intake and reducing the dosage of, or temporarily discontinuing, the diuretic. The ACE inhibitor may have to be given at reduced dosage or discontinued for a time. If discontinuation is deemed necessary, administration of these survival-prolonging medications should be reinitiated after a brief respite whenever possible.

Cigarette smoking interferes with treatment of hypertension.

We retrospectively analyzed two studies to determine whether smoking affected the treatment of hypertension. In a study of the effects of propranolol hydrochloride (a hepatically metabolized beta-blocker) vs hydrochlorothiazide, 108 smokers and 232 nonsmokers were randomized to the propranolol treatment group. The propranolol-treated smokers tended to be younger, taller, thinner, and wre more likely to be black. This group also had an initial blood pressure reduction (+/- SD) of -7.9 +/- 12.9/-8.7 +/- 8.4 mm Hg compared with -10.7 +/- 13.0/-10.9 +/- 7.1 mm Hg for the nonsmokers. Blood pressure increased less during the one-year maintenance period for the nonsmokers. However, when analyzed by race, this effect was seen in blacks, but not in whites. Diastolic blood pressure tended to be reduced more in nonsmokers (vs smokers) receiving hydrochlorothiazide (-12.1 +/- 6.7 vs -10.7 +/- 6.7 mm Hg, respectively). The second study compared the effects of nadolol (a renally excreted beta-blocker) with bendroflumethiazide. There were no significant effects on blood pressure for either of these drugs. In both studies, there was a greater tendency for smokers to be terminated from the study irrespective of drug group. We conclude that cigarette smoking does interfere with the treatment of hypertension in general, and especially with reduction of blood pressure by propranolol in black patients.

Placebo-associated blood pressure response and adverse effects in the treatment of hypertension: observations from a Department of Veterans Affairs Cooperative Study.

BACKGROUND: The use of placebo in clinical trials has been vigorously debated. Placebo control may be useful in disease states, such as stage 1 and stage 2 hypertension as defined by the Sixth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VI), in which response rates for placebo are high or close to response rates for effective therapies, or when established interventions have significant adverse effects. OBJECTIVE: To compare rates for the control of blood pressure and adverse effects of placebo vs active treatment in patients with stage 1 and stage 2 hypertension. METHODS: This study is a randomized controlled trial evaluating the blood pressure response and adverse effects of placebo vs 6 active treatments administered in 15 Veterans Affairs hypertension centers. The 1292 subjects of the Veterans Affairs Cooperative Study receiving single-drug therapy for hypertension were randomly allocated to receive treatment with 1 of 6 active drugs (n= 1105) or placebo (n=187). Treatment success was defined as maintaining a diastolic blood pressure of less than 95 mm Hg for at least 1 year. We compared treatment success rates for the control of blood pressure and adverse effects of placebo vs active treatment. Using the Kaplan-Meier method, we also compared rates of discontinuation from placebo vs active drug treatment over time as a result of adverse drug effects and blood pressure exceeding safety limits. RESULTS: At the end of the titration phase, 58 patients who were treated with placebo (31%) achieved a goal diastolic blood pressure lower than 90 mm Hg and 57 (30%) achieved success at 1 year. Older white patients who received placebo had a success rate of 38% vs 23% to 27% for the other age-race subgroups. The rates of discontinuation as a result of adverse drug effects were 13% for patients receiving placebo vs 12% for patients receiving active treatment (P=.40). The rates of discontinuation for blood pressure being too high were 14% for patients receiving placebo vs 7% for patients receiving active treatment (P=.01). CONCLUSIONS: Placebo control provides an important benchmark for both efficacy and adverse effects. It continues to have an appropriate place in certain therapeutic trials, particularly those involving the treatment of stage 1 and stage 2 hypertension.

Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: Stroke incidence and mortality rates are higher in the southeastern region of the United States, which is called the "Stroke Belt." We compared the response to antihypertensive medication use in patients from different US regions. METHODS: The short-term and 1-year efficacy of the antihypertensive medications hydrochlorothiazide, atenolol, diltiazem hydrochloride (sustained release), captopril, prazosin hydrochloride, and clonidine was compared by US region in a randomized controlled trial of 1,105 men with hypertension from 15 US Veterans Affairs medical centers. RESULTS: Compared with patients outside the Stroke Belt, patients inside the Stroke Belt achieved significantly lower treatment success rates of diastolic blood pressure control at 1 year with hydrochlorothiazide (63% vs 41%), atenolol (62% vs 46%), captopril (60% vs 30%), and clonidine (69% vs 43%); there were no differences in treatment success rates with diltiazem (70% vs 71%) or prazosin (54% vs 53%). When controlling for race, patients inside the Stroke Belt had significantly lower treatment success rates with hydrochlorothiazide (P = .003) and clonidine (P = .003), and the lower success rate with atenolol approached significance (P = .15). Regardless of region, blacks were less likely than whites to achieve treatment success with atenolol (P = .02) or prazosin (P = .03) and more likely with diltiazem (P = .05). There was a trend for blacks residing inside the Stroke Belt to have a lower treatment success rate than other race-region groups when treated with captopril (P = .07). Many regional and racial differences in diet, lifestyle, and other characteristics were observed. After adjustment for these characteristics by regression analysis, the effect of residing inside the Stroke Belt remained for captopril (P = .01) and clonidine (P = .01) and approached significance for hydrochlorothiazide (P = .10). CONCLUSIONS: Hypertension in patients residing inside the Stroke Belt responded less to the use of several antihypertensive medications and important differences were shown in a number of characteristics that may affect the control of blood pressure, compared with patients residing outside the Stroke Belt.

Diuretics and beta-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: Concern based on the reported short-term adverse effects of antihypertensive agents on plasma lipid and lipoprotein profiles (PLPPs) has complicated the therapy for hypertension. OBJECTIVE: To compare the long-term (1-year) effects of 6 different antihypertensive drugs and placebo on PLPPs in a multicenter, randomized, double-blind, parallel-group clinical trial in 15 US Veterans Affairs medical centers. PATIENTS AND METHODS: A total of 1292 ambulatory men, 21 years or older, with diastolic blood pressures (DBPs) ranging from 95 to 109 mm Hg taking placebo were randomized to receive placebo or 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, or prazosin. After drug titration, patients with a DBP of less than 90 mm Hg were followed up for 1 year. Plasma lipids and lipoprotein profiles were determined at baseline, after initial titration, and at 1 year. RESULTS: After 8 weeks on a regimen of hydrochlorothiazide, increases of 3.3 mg/dL (0.09 mmol/L) in total cholesterol and 2.7 mg/dL in apolipoprotein B were significantly different (P< or =.05) from decreases of 9.3 mg/dL in total cholesterol and 5.4 mg/dL in ApoB levels while receiving prazosin but not from placebo. Patients achieving positive DBP control using hydrochlorothiazide (responders) showed no adverse changes in PLPPs, whereas nonresponders exhibited increases in triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. Plasma lipids and lipoprotein profiles did not change significantly among treatment groups after 1 year except for minor decreases in high-density lipoprotein 2 levels using hydrochlorothiazide, clonidine, and atenolol. CONCLUSIONS: None of these 6 antihypertensive drugs has any long-term adverse effects on PLPPs and, therefore, may be safely prescribed. Previously reported short-term adverse effects from using hydrochlorothiazide are limited to nonresponders.

Treatment of hypertension in the elderly. III. Response of isolated systolic hypertension to various doses of hydrochlorothiazide: results of a Department of Veterans Affairs cooperative study. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

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.

Response to a second single antihypertensive agent used as monotherapy for hypertension after failure of the initial drug. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: An important issue in clinical practice is how to treat patients whose blood pressure does not respond to the first antihypertensive drug selected. OBJECTIVE: To analyze the antihypertensive response of patients who had failed to achieve their diastolic blood pressure goal (< 90 mm Hg at the end of 8 to 12 weeks of titration) with one of six randomly allocated drugs or placebo to the random allocation of an alternate drug. METHODS: We initially randomized 1292 men with diastolic blood pressure of 95 to 109 mm Hg to treatment with hydrochlorothiazide, atenolol, captopril, clonidine hydrochloride, diltiazem hydrochloride (sustained release), prazosin hydrochloride, or placebo. Of 410 men in whom initial treatment failed, 352 qualified for randomization to the alternate drug. RESULTS: Of the 352 patients, 173 (49.1%) achieved their goal diastolic blood pressure, in 133 (37.8%) the alternate drug failed, and 46 (13.1%) left the study for various reasons. Overall response rates were as follows: diltiazem, 63%; clonidine, 59%; prazosin, 47%; hydrochlorothiazide, 46%; atenolol, 41%; and captopril, 37%. The best response rate for patients in whom hydrochlorothiazide failed was achieved with diltiazem (70%); after atenolol failure, clonidine (86%); after captopril failure, prazosin (54%); after clonidine failure, diltiazem (100%); after diltiazem failure, captopril (67%); and after prazosin failure, clonidine (53%). The combined response rate for patients initially randomized to an active treatment was 76.0%, which is similar to that achieved by the combination of two drugs in previous studies. CONCLUSIONS: We conclude that sequential single-drug therapy is a rational approach for treatment of hypertension in patients in whom initial drug therapy has failed.

Volume (weight) loss and blood pressure response following thiazide diuretics.

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.

Systolic function in hypertensive men with concentric remodeling.

Hypertensive patients with concentric remodeling (relative wall thickness > or = 0.45 and normal left ventricular [LV] mass index) may have poor outcomes. It is unclear whether systolic function abnormalities, shown to be present in some patients with concentric LV hypertrophy (increased LV mass index and relative wall thickness > or = 0.45), are also present in patients with concentric remodeling. To assess LV pump, chamber, and myocardial function in hypertensive men with concentric remodeling, clinical and echocardiographic data of 118 hypertensive men with concentric remodeling were compared with data from 104 hypertensive men with normal relative wall thickness and normal LV mass index. Chamber function was assessed by relating endocardial fractional shortening to end-systolic circumferential stress, myocardial function was assessed by relating midwall fractional shortening to circumferential stress, and pump performance was assessed by stroke volume (Teichholz method). Compared with hypertensive men with normal relative wall thickness, concentric-remodeling patients had lower stroke volume (84 +/- 20 versus 111 +/- 20 mL, P < .001). Endocardial shortening was no different between the two groups (38 +/- 7% versus 40 +/- 7%, P=NS), but midwall shortening was lower in patients with concentric remodeling (20 +/- 3% versus 22 +/- 3%, P < .001), despite lower end-systolic stress (81 +/- 25 versus 117 +/- 37 g/cm2, P < .001). Endocardial and midwall stress-shortening regression plots classified 28% and 42%, respectively, of the concentric remodeling patients below the fifth percentile of hypertensive patients with normal geometry. These data indicate that indexes of chamber and myocardial function are lower than those observed in hypertensive patients with normal geometry. Thus, indices of chamber, myocardial, and pump performance indicate potential abnormalities in systolic function in men with concentric remodeling.

Treatment of hypertension in the elderly: I. Blood pressure and clinical changes. Results of a Department of Veterans Affairs Cooperative Study.

We compared the efficacy and adverse effects of antihypertensive drug regimens in 690 men past age 60 with diastolic blood pressure 90-114 mm Hg and systolic blood pressure less than 240 mm Hg. They received either a low (25-50 mg) or high (50-100 mg) dose of hydrochlorothiazide daily. Of 644 patients who completed the hydrochlorothiazide titration, 375 (58.2%) were responders (diastolic blood pressure less than 90 and less than or equal to 5 mm Hg below baseline) and 92.8% of these completed a 6-month maintenance period. Blood pressure was reduced from 157.6/98.5 mm Hg by 18.3/9.5 mm Hg with low dose hydrochlorothiazide and by 20.4/9.6 mm Hg with high dose hydrochlorothiazide; more patients achieved goal blood pressure with the high dose. Whites and blacks responded equally. Serum potassium less than 3.5 mmol/l occurred in 104 of 321 (32.3%) of the high dose versus 62 of 333 (18.6%) of the low dose hydrochlorothiazide patients. The 269 nonresponders to hydrochlorothiazide were randomly assigned in a double-blind study to receive hydralazine, methyldopa, metoprolol, or reserpine in addition to hydrochlorothiazide; 79.2% responded to the addition of the second drug and 87.3% of these completed a 6-month maintenance phase. Overall, there were no significant efficacy differences among the step 2 regimens. We conclude that the lower dose of hydrochlorothiazide was nearly as effective as the higher dose, and the addition of a second drug was effective and generally well tolerated in elderly patients.

Treatment of hypertension in the elderly: II. Cognitive and behavioral function. Results of a Department of Veterans Affairs Cooperative Study.

This study was designed to determine whether blood pressure reduction, per se, causes adverse effects on cognitive and behavioral function in elderly hypertensive patients. Men with mild-to-moderate diastolic hypertension who had passed their 60th birthday were entered into the trial. After a placebo washout period, they were assigned in a randomized, double-blind manner to one of two groups receiving hydrochlorothiazide (either 25 mg once or twice daily or 50 mg once or twice daily). Responders entered a 1-year maintenance period. Nonresponders were randomly assigned to double-blind treatment with hydralazine, methyldopa, metoprolol, or reserpine added to the diuretic therapy. During the placebo and treatment periods, patients underwent a battery of psychometric tests designed to assess cognitive function, motor skills, memory, and affect. A separate questionnaire assessed the patient's ability to perform activities of daily living. A subset of patients blindly being treated with placebo received the same battery of tests as a control for practice effect. The results showed that there was similar improvement on the psychometric tests between those patients whose blood pressure was successfully reduced and the placebo-treated control group. Therefore, the practice effect did not obscure a true deterioration in function. There were no substantive differences between the lower and higher doses of diuretic or among the four drugs added to the diuretic, although there were qualitative differences in side effects. We conclude that blood pressure reduction, per se, does not adversely affect cognitive and behavioral function in elderly hypertensive patients and that antihypertensive treatment is safe and effective in these patients.

Antihypertensive effects of oxprenolol and propranolol.

The antihypertensive effects of the beta blockers oxprenolol and propranolol were compared in a randomized double-blind study of patients with standing diastolic pressures (SDP) exceeding 99 mm Hg when receiving hydrochlorothiazide alone. After 3 wk of hydrochlorthiazide with placebo, the latter was replaced with oxprenolol (n= 12) or propranolol (n = 14), 20 mg three times daily. Beta blocker was increased subsequently to 40 and 80 mg three times daily if SDP exceeded 89 mm Hg. Nine oxprenolol and 7 propranolol subjects were hospitalized for 24-hr monitoring. With oxprenolol, standing pressure declined from 135 +/- 2 (SE)/104 +/- 1 MM Hg to 128 +/- 3/90 +/- 2. SDP declined to under 91 mm Hg in 7 of 12 subjects, and to from 91 to 95 in 3 subjects. With propranolol, findings were 138 +/- 3/106 +/- 2 to 123 +/- 3/89 +/- 3; in 7 of 12 to less than 91 mm Hg and from 91 to 95 in 4 subjects. Decrements in supine and SDP were slightly (4 mm Hg) greater for propranolol than for oxprenolol. Both drugs gave similar 24-hr blood pressure control. We conclude that oxprenolol and propranolol used to supplement hydrochlorothiazide provide comparable reductions in blood pressure and smooth control over a 24-hr period in most patients with hypertension.

Antihypertensive effectiveness of oxprenolol administered twice daily.

Oxprenolol, a beta-blocker, is an effective antihypertensive when administered 3 or 4 times daily. We evaluated the antihypertensive effect of oxprenololgiven twice daily (bid). The subjects were 15 ambulatory men whose standing diastolic blood pressure (BP) was at least 100 mm Hg after 3 wk of treatment with hydrochlorothiazide and oxprenolol placebo. Oxprenolol 40 mg twice daily was then substituted for the placebo. On subsequent weekly vists oxprenolol was titrated to 80 and 160 mg bid if the standing diastolic BP was greater than 90 mm Hg. BLood pressures on the last visit on placebo were compared to those on the last visit on oxprenolol. Standing BP declined from 145 +/- 4/108 +/- 1 to 130 +/- 4/98 +/- 4 on a mean dose of 256 mg of oxprenolol (p less than 0.001 syst.; p less than 0.01 diast.). Recumbent BP fell from 146 +/- 4/107 +/- 1 to 138 +/- 5/93 +/- 2 (p less than 0.06 syst.; p less than 0.01 diast.). During the final week, 13 of the 15 patients were admitted to the hospital for 24-hr monitoring of BP. The 24-hr BP readings showed a mean coefficient of variation of 6.6% recumbent and 7.2% standing. we conclude that bid oxprenolol will maintain 24 hr BP control in most patients.

Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose.

A multicenter study of chlorthalidone was performed to determine the relative antihypertensive efficacy and side effects of doses lower than those usually recommended for therapy. After a 4-wk placebo control period 100 patients with mild hypertension were randomly assigned doubleblind to 12.5-, 25-, 50-, or 75-mg regimens of chlorthalidone or to placebo for 12 wk. The groups of patients taking 25, 50, and 75 mg had declines in blood pressure which were not significantly different from each other. Serum potassium decreased in the 50- and 75-mg groups but not significantly in the 25-mg group. We conclude that chlorthalidone, 25 mg daily, was at least as effective for hypertension as 50 and 75 mg with less perturbation of potassium. Use of smaller initial diuretic doses may provide equal efficacy with fewer side effects for many patients.

Monotherapy of hypertension with angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme (ACE) inhibitors are clearly effective treatment for all stages of hypertension. Since the introduction of captopril in 1981, numerous ACE inhibitors have been synthesized and are under investigation. Their exact antihypertensive mechanism of action remains unclear. Part of their effect may be mediated by vasodilator prostaglandins. Early studies with as much as 1,000 mg a day captopril demonstrated the agent's ability to reduce blood pressure, but only 10 percent of the severely hypertensive patients were controlled with monotherapy. Subsequent studies have demonstrated that patients with mild to moderate hypertension can be controlled with ACE inhibitor alone, although there is a tendency for the very low doses to lose their effect with time. Black patients are less readily controlled with monotherapy. Captopril has now been demonstrated to be effective in the hypertension of scleroderma and has reversed scleroderma renal crisis. ACE inhibitors are also effective for the treatment of severe congestive heart failure.

Comparison of propranolol or hydrochlorothiazide alone for treatment of hypertension. III. Evaluation of the renin-angiotensin system.

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.

Adverse effects of angiotensin-converting enzyme inhibitors in antihypertensive therapy with focus on quinapril.

Angiotensin-converting enzyme (ACE) inhibitors are useful first-line drugs in the therapy of mild and moderate hypertension. Adverse reactions to this drug class are rarely serious. Hypotension, cough, rash, and taste disturbance are uncommon; reduced glomerular filtration and hyperkalemia occur infrequently; angioedema is rare and neutropenia is extremely rare. Quinapril is a new ACE inhibitor that is converted to biologically active quinaprilat in the liver. This ACE inhibitor has a rapid onset of action and inhibits local tissue converting enzyme systems in kidney, heart, and brain, as well as in the circulating renin-angiotensin system. Clinically significant adverse effects of quinapril occur at low rates. In 1,771 patients receiving quinapril, the reported incidence of the first occurrence of orthostatic hypotension was comparable to that seen in patients receiving placebo. In other studies, headache was reported by up to 4.7% of patients receiving quinapril, which is comparable to reported incidences of headache in patients receiving other ACE inhibitors. Other adverse events reported at rates greater than 1% include cough with associated rhinitis and bronchitis, dizziness, and somnolence. Such adverse events have only rarely led to the withdrawal of patients from clinical studies of quinapril.