Physical health, behavioral and emotional functioning in children of gulf war veterans.

OBJECTIVE: We examined whether the prevalence of medical and behavioral conditions is higher in children of deployed veterans (DVs) versus non-deployed veterans (NDVs) after the 1991 Gulf War. METHODS: We examined 1387 children of 737 veterans. Children ages 2-18 had physical exams and parental reports of physical history and behavior. RESULTS: Physical health was analyzed using GEE models. Behavioral health [total, internalizing, and externalizing behavior problems (TBP, IBP, EBP)] was analyzed with mixed-effects regression models. Analyses were conducted by age group (2-3, 4-11, 12-18), and gender (ages 4-11, 12-18). Children of DVs ages 2-3 had significantly worse dentition (13.9% vs. 4.8%, P = 0.03) and more EBP {least square means (lsmeans) 54.31 vs. 47.59, P = 0.02}. Children of DVs ages 4-11 had significantly more obesity (18.8% vs. 12.7%, P = 0.02). Among children 4-11, male children of DVs had significantly more TBP (lsmeans 70.68 vs. 57.34, P = 0.003), IBP (lsmeans 63.59 vs. 56.16, P = 0.002) and EBP (lsmeans 61.60 vs. 52.93, P = 0.03), but female children did not. For children ages 12-18, male children of DVs had more EBP (lsmeans 63.73 vs. 43.51, P = 0.008), while female children of DVs had fewer EBP (lsmeans 45.50 vs. 50.48, P = 0.02). Veteran military characteristics and mental health, and children's social status and health, including obesity, predicted children's TBP for one or more age groups. CONCLUSIONS: Children of DVs experienced worse dentition, greater obesity, and more behavioral problems compared to NDV children, suggesting adverse health effects associated with parental deployment in need of further exploration.

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.

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.

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.

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.

Ventricular and myocardial function following treatment of hypertension.

This study assesses and evaluates left ventricular (LV) contractile function after treatment of hypertension, with an emphasis on LV midwall mechanics. Although prior studies have assessed cardiac function after hypertension treatment, none has performed an analysis of LV midwall mechanics. The Veterans Affairs Study of monotherapy in hypertension was a study large enough to permit analysis of midwall mechanics across a wide spectrum of mass changes accompanying hypertension treatment. LV chamber function was assessed by computing fractional shortening at the endocardial surface; LV midwall shortening was used to define myocardial function. Both shortening indexes were related to end-systolic circumferential stress in the entire population by partitioning values of mass and relative wall thickness changes. Two hundred sixty-eight patients were studied at baseline and again after a 1- or 2-year period. In the entire group, there was no significant change in circumferential shortening either at the endocardium (38 +/- 8% at baseline vs 37 +/- 7% at follow up, p = 0.29) or in shortening at the midwall (20 +/- 3% vs 20 +/- 3%, p = 0.53). However, 83 patients had a reduction in relative wall thickness and an increase in midwall shortening. The change in midwall shortening was significantly related to changes in relative wall thickness (r = -0.53, p = 0.0001). Thus, reductions in LV mass associated with antihypertensive therapy are generally not accompanied by a decrement in LV chamber or myocardial function. Improvement in midwall shortening is more closely related to normalization of LV geometry than to reduction in LV mass.

Lessons from combination therapy in Veterans Affairs Studies. Department of Veterans Affairs Cooperative Study Group on antihypertensive agents.

A subset of 102 patients of an original cohort of 1292 with stage 1 to 2 hypertension was characterized by having failed to achieve goal blood pressure (< 90 mm Hg diastolic) after treatment with two single antihypertensive drugs. These patients were given a combination of the two drugs on which they had failed to achieve blood pressure goal when they were administered as single-drug therapy. The drugs were hydrochlorothiazide, atenolol, captopril, diltiazem-SR, clonidine, and prazosin. We examined the responses in each of the drug combination categories by the order that the drugs were administered, by estimated total response rates for the combinations, and by age and race. The order of drug administration did have an effect for some of the drug pairs. This was of two types: 1) different results for each member of the pair, but the same combination result; and 2) different end result of the combination. An example of the first type is that prazosin had only a 6% response rate in patients who had failed on diltiazem, while diltiazem had a 22% response rate in patients who had failed on prazosin. Nevertheless, the combinations yielded the same total responses (86% and 84%) regardless of order. An example of the second type is that captopril-diltiazem was less effective in total response than diltiazem-captopril (88% v 97%). Differences were seen in the response to combinations in the race and age groups. There were ordering differences of type similar to those described above. We conclude that combination drug therapy is highly effective even when the individual components have failed and that some differences in response by order of drug administration may occur.

Department of veterans Affairs single-drug therapy of hypertension study. Revised figures and new data. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

The antihypertensive efficacy of six drugs and placebo was compared in 1292 men with untreated diastolic blood pressure of 95 to 109 mm Hg. The primary end point "success" was defined as the patient having achieved a diastolic blood pressure of < 90 mm Hg at the end of the drug titration period and having maintained a diastolic blood pressure of < 95 mm Hg for 1 year without drug intolerance. The original published success rate data (N Engl J Med 1993;328:914-921) were discovered to be in error due to a computer programming code omission (N Engl J Med 1994;330:1689). This paper presents corrected graphic figures. The corrected success rates were generally higher than originally published. Overall, diltiazem (72%) was significantly higher than hydrochlorothiazide (55%), prazosin (54%), captopril (50%), and placebo (31%); clonidine (62%) and atenolol (60%) were intermediate. There were some changes in the hierarchy of drug response, but important differences in success rates according to age by race subgroups remained. Whites responded well to all drug classes, except for lower efficacy of hydrochlorothiazide in younger whites. Blacks responded better to diltiazem than other agents. In addition, we have analyzed the data using a definition of success based on < 90 mm Hg for 1 year. Use of the <90 mm Hg criterion reduced the rate of success, but had only a minor effect on the drug success rate hierarchy. We conclude that single-drug antihypertensive therapy is effective in a majority of stage 1 to 2 diastolic hypertensive patients, although there are important age-by-race differences in success rates among various drug classes.

Effects of antihypertensive single-drug therapy on heart rate. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

Heart rate increasingly is being recognized either as an independent risk factor for a wide variety of cardiovascular disorders or as a surrogate marker for them. We analyzed the changes in heart rate associated with antihypertensive therapy with six drugs and placebo from the VA Cooperative Study on Single-Drug Therapy. These results were published previously (American Journal of Hypertension 1998;11:597-601). This paper provides a summary of the earlier publication with the addition of three figures not previously published. Atenolol had the greatest effect on heart rate reduction, followed by clonidine and diltiazem-SR. Hydrochlorothiazide and captopril were associated with small reductions in heart rate over time, whereas prazosin increased heart rate. Patients whose blood pressure was controlled by placebo had a 3.1 beats/min reduction of heart rate at 2 years. When the baseline heart rate was 65 beats/min or less, all drugs increased the heart rate except for atenolol, which further reduced it. Although it is clear that each of the six drugs used in our study had a different effect on heart rate, we cannot state that drug-induced reduction in heart rate per se confers a decrease in cardiovascular risk.

Comparison of effects of antihypertensive drugs on heart rate: changes from baseline by baseline group and over time. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

Baseline heart rate is becoming recognized as a predictor of cardiovascular risk. Various antihypertensive drugs have differing effects on heart rate. A randomized controlled clinical trial of 1292 ambulatory men with stage 1 or 2 hypertension was conducted in 15 Veterans Affairs medical centers. Patients were treated with hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo for up to 2 years. Heart rates were measured at baseline, the end of titration, 1 year, and 2 years. Data were also stratified by baseline heart rate. A subset of patients had heart rate also determined by electrocardiogram. All drugs except prazosin reduced heart rate from baseline; additional small decreases were obtained over time with hydrochlorothiazide and placebo. The decrease initially achieved with clonidine was attenuated over time. The overall reduction in heart rate was greatest for atenolol (-12.2 beats/min) and least for prazosin (+3.8 beats/min). Only atenolol effected a further reduction of heart rate for patients whose baseline rate was < or =65 beats/min. All drugs reduced heart rate when the baseline was > or =85 beats/min. Data derived by electrocardiogram yielded similar results. The drugs used in this study differ in their ability to reduce heart rate, sustain that reduction over time, and to change heart rate in groups with high or low rates at baseline. The importance of these comparative changes as independent cardiac risk factor variables remains to be determined.

Penile carcinoma: a twenty-five-year experience.

The treatment of 34 patients with carcinoma of the penis was reviewed during a twenty-five-year period (1958-1983). There were 26 patients with Stage I disease, 7 patients with Stage II, and 1 patient with Stage III disease. Among the Stage I group, 12 patients underwent partial/total penectomy and immediate ilioinguinal lymphadenectomy; 14 patients were treated with partial/total penectomy and observation of clinically nonpalpable nodes. Within the observation period, 10 of the 26 patients died, with a mean survival time of one hundred thirty-three months (standard error = 20.4), and a median of one hundred twenty months. Both the Mantel-Cox and Breslow test statistics showed the survival distribution of these groups of patients not to be significantly different from each other. All 7 patients with Stage II penile cancer died, with a mean survival time of 10.6 months (standard error = 2.1) which is significantly different from the Stage I group and the reported survival of 30-60 percent in the literature. A plan of management for the primary lesion and the role of ilioinguinal lymphadenectomy are presented.

Results of combination anti-hypertensive therapy after failure of each of the components. Department of Veterans Affairs Cooperative Study Group on Anti-hypertensive Agents.

We randomised ambulatory men with diastolic blood pressure (BP) 95-109 mmHg without anti-hypertensive medication to single drug treatment with either hydrochlorothiazide 12.5-50 mg/day, atenolol 25-100 mg/day, captopril 25-100 mg/day, clonidine 0.2-0.6 mg/day, diltiazem-SR 120-360 mg/day, prazosin 4-20 mg/day or placebo in a double-blind prospective trial. The assigned drug was titrated to a goal BP of < 90 mm Hg. Patients not achieving goal BP were rerandomised to an alternative single active drug. Non-responders to the second drug received the first drug in combination with the second. Of the 102 non-responders to both drugs who qualified for the combination, 59 (57.8%) responded. The combination pairs that included a diuretic achieved diastolic goal BP in 69% and < 140 mm Hg systolic in 77% compared with 51% and 46%, respectively, for those combinations without a diuretic (P = 0.067; P = 0.002). Six of the eight terminations due to adverse drug reactions were in combinations containing prazosin; three of these six were hypotensive reactions. We conclude that two single drugs of insufficient efficacy to control BP individually have a high probability of achieving goal BP when combined, especially if the combination contains a diuretic.

Proteinuria in mild to moderate hypertension: results of the VA cooperative study of six antihypertensive agents and placebo. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

The prevalence and natural history of severe proteinuria in mild to moderate hypertension are not completely defined. We screened 1635 men with a history of hypertension and randomized 1292 with untreated diastolic blood pressure (DBP) 95-109 mmHg to single-drug treatment with either hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem-SR, prazosin, or placebo in a double-blind prospective trial. Twenty-seven of 1635 patients (1.7%) satisfying clinical criteria for primary hypertension were found to have developed proteinuria > 1000 mg/24 hours and were removed from the study. Follow-up data were obtained on 19 of these 27 patients. One patient was found to have focal segmental sclerosis and progressed to end-stage renal disease. Three other patients developed severe (serum creatinine > 3.5 mg/dl) chronic renal failure (one with diabetic nephropathy), one progressed from serum creatinine 1.4 to 2.2 mg/dl, but 14 of the 19 remained with stable serum creatinine < 2.0 mg/dl on follow-up for 6-9 years. Data were available for 1076 of 1155 (93%) treated study patients at end titration, 522/600 (87%) at one year and 322/444 (73%) at two years. There were significant associations for proteinuria with obesity and higher systolic blood pressure. There was a trend toward significant difference in mean 24-hour protein excretion rates at baseline between black (127 mg) and white (139 mg) patients (p = 0.07). There were no statistically significant changes in urinary protein excretion/24 hours between or within the different treatment groups (including placebo). Eighteen patients were removed from the study during the active treatment phase for proteinuria > 1000 mg/24 hours: hydrochlorothiazide 4, placebo 3, diltiazem 3, prazosin 3, atenolol 2, clonidine 2, and captopril 1. We conclude: (1) the prevalence of severe (> 1 g/24 hours) proteinuria in the hypertensive population is significant but does not necessarily imply a poor prognosis; (2) mean 24-hour urinary protein excretion rates did not vary in response to the different classes of antihypertensive drugs; and (3) there was no drug-specific increase in proteinuria detected in this study.