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.

Persistence of normal BP after withdrawal of drug treatment in mild hypertension.

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.

Effectiveness of potassium chloride or triamterene in thiazide hypokalemia.

Potassium chloride was compared with triamterene in a crossover trial involving 16 hypertensive patients with overt diuretic-induced hypokalemia. Potassium chloride, 24 to 96 mEq/day, normalized the plasma potassium (PK) level at 3.5 mEq/L or more in only eight of the patients. The average increase in PK level was 0.58 mEq/L. Triamterene, 50 to 200 mg daily, normalized PK level in ten of the patients. The average increase in PK level was 0.72 mEq/L, which was not significantly different than that with potassium therapy. Some patients who responded to potassium did not respond to triamterene, and vice versa. Most of the administered potassium was excreted in the urine even with persisting hypokalemia. Addition of triamterene to diuretic therapy resulted in a small but statistically significant increase in plasma creatinine level.

Thiazide therapy is not a cause of arrhythmia in patients with systemic hypertension.

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.

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.

Potassium restoration in hypertensive patients made hypokalemic by hydrochlorothiazide.

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.

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.

Treatment of hypertension in 1981.

Antihypertensive drugs reduce cardiovascular morbidity and mortality. This was demonstrated by controlled clinical trials. While most complications are dramatically reduced it is not certain whether the incidence of myocardial infarction is decreased by treatment or whether the severity of the infarct is reduced. The prognosis in patients with borderline and mild hypertension varies widely depending on the number of other risk factors present. Patients with mild hypertension and low risk profiles may not obtain enough benefit from treatment to justify the side effects, inconvenience, and expense of such therapy. Such patients should be individually evaluated as to the need and desirability of treatment. Patients who are not treated with drugs should be seen for an annual follow-up to detect progression. Low sodium diets are effective but they are not practical because it is difficult to adhere to the required degree of sodium restriction. Weight-reducing diets also reduce blood pressure but compliance again is difficult, although it is worth advocating for the few patients who will maintain the diet more or less indefinitely. Between 1973 and 1977 in the United States there has been an 8% decline in deaths due to heart disease, a 17% decrease in deaths due to stroke, and an increase in average life expectancy from 71.3 to 72.8 years. Could this be the result of more widespread treatment?

Serial measurements of systolic time intervals: effects of propranolol alone and combined with other agents in hypertensive patients.

Systolic time intervals (STI) were recorded serially before and during 1 year of treatment in 367 hypertensive men. The patients were randomly assigned, double-blind, to one of the following regimens: propranolol alone (P), propranolol plus hydrochlorothiazide (P + T), propranolol plus hydralazine (P + H), propranolol plus hydrochlorothiazide plus hydralazine (P + T + H), or reserpine plus hydrochlorothiazide (R + T). Systolic time intervals were calculated by a computer pattern-recognition and measurement program. Diastolic blood pressure and heart rate (HR) decreased with each treatment regimen. The preejection period (PEP) was prolonged following P alone. The left ventricular ejection time (LVET), after correction for HR, was shortened with P + T and R + T and prolonged after P + H. The PEP/LVET was reduced with P + H. The prolongation of PEP during long-term administration of P is comparable with previous studies of its acute effects and suggests a moderate decrease in left ventricular performance. Calculation of STI also appears to be a useful method for showing the effects of adding other antihypertensive agents.

Is low-dose hydrochlorothiazide effective?

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.

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.

Department of Veterans Affairs hypertension meeting : a proposal for improved care.

A major invitational hypertension meeting was hosted by the Department of Veterans Affairs (VA) in Washington, DC, on May 26 to 28, 1999. It followed a report that only 25% of hypertensive veterans had adequate levels of treated blood pressure and focused on how control of hypertension could be improved both immediately and in the future. After the presentation of brief outlines of 5 unresolved basic science questions, 2 general topics were considered: (1) 30 years of change in hypertension and its treatment and (2) current healthcare delivery mechanisms and how to improve them. Since 1970, the severity of hypertension has decreased, malignant hypertension has disappeared, and the prognostic roles of systolic and diastolic blood pressure have been reversed as hypertension became milder. Five VA Cooperative Studies have provided important data: the 1970 Freis Trial report demonstrated the value of treatment, 2 trials showed that some controlled patients can decrease or even discontinue pharmacological treatment without recrudescent hypertension, a blinded trial was performed on the efficacy of different antihypertensive drugs, and an unblinded trial showed that diuretics and beta-blockers are the most effective agents when caregivers choose the agent and dose. Two healthcare models were considered: (1) the patient-friendly VA Hypertension Screening and Treatment Program that was introduced in 1972, which controls 80% of patients at the goal of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure with diuretics and keeps patients in the program an average of 7.5 years, and (2) the newer primary care health maintenance organization-like model in the VA and throughout the United States. Choosing a regimen and monitoring control of blood pressure and compliance with therapy were discussed. The meeting was closed with 6 general recommendations for improving the care of hypertensive patients.

Acute and short-term effects of new calcium antagonist in hypertension.

Nitrendipine (Bay e 5009) is a new calcium antagonist antihypertensive agent similar in structure and function to nifedipine. Nitrendipine was tested in a range of single and repeated doses in 10 adult males with uncomplicated mild to moderate hypertension. The treatment goal was reduction of diastolic blood pressure to 90 mm Hg or less. The dose that achieved goal blood pressure ranged between 10 and 30 mg. Systolic and diastolic blood pressure began to fall within 15 minutes following ingestion of single oral doses of nitrendipine. The maximum effect of the drug was achieved in 60 to 90 minutes and remained at approximately this level for 6 to 8 hours. The average reduction in supine diastolic was more than twice as great as the fall in systolic blood prere began to fall within 15 minutes following ingestion of single oral doses of nitrendipine. The maximum effect of the drug was acheived in 60 to 90 minutes and remained at approximately this level for 6 to 8 hours. The average reduction in supine diastolic was more than twice as great as the fall in systolic blood pressure. With continuous doses given three times daily, all patients' blood pressures were as low or lower than the maximal effect observed after single doses. The reduction in blood pressure was sustained for the full 3 weeks of treatment. There was a sustained small increase in pulse rate averaging 6 beats/min. The drug was generally well tolerated by most patients. Mild to moderate headache that resolved with continued treatment was the most frequent side effect. This preliminary trial indicates that nitrendipine is an effective antihypertensive agent that merits further study.

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.

Normal cardiac output during beta blockade with timolol in hypertensive patients.

Data published by this laboratory indicated that the beta adrenergic blocking drugs timolol and propranolol exerted equivalent beta blocking and antihypertensive actions in patients with mild essential hypertension, but that whereas cardiac output fell acutely with both drugs, it returned to normal after 5 wk of treatment with timolol, but remained depressed after propranolol. This preliminary observation needed further confirmation in a larger series of patients. In this study, 11 patients with initial diastolic blood pressures between 90 and 125 mm Hg were given timolol for 5 wk. Hemodynamic measurements were made before and at the end of treatment. Mean heart rate fell from 76.8 to 64.3 bpm (p less than 0.001), and blood pressure was reduced from 179.4/99 mm Hg to 167.4/93.3 mm Hg (less than 0.02). Cardiac output averaged 6.29 L/min before timolol, and fell to 5.95 L/min (NS) after treatment. Stroke volume increased significantly, while total peripheral resistance was unchanged. These results confirm our earlier observations that timolol is an effective beta adrenergic blocking drug with antihypertensive action that does not reduce cardiac output significantly when given chronically. This drug merits further evaluation in other cardiovascular disorders since it may have advantages over other beta adrenergic blocking drugs.

Informed consent: how much does the patient understand?

Comprehension and recall of the information contained in the informed consent statement was tested in clinically hypertensive patients entering a controlled trial comparing hydrochlorothiazide and propranolol. The consent statement was the primary vehicle for conveying the information to the patient. The average of correct answers to a multiple-choice quiz was 71.6% at 2 hr and 61.2% at 3 mo after the consent procedure. The effectiveness of recall did not correlate with level of education. Patients exhibited greater comprehension of the action of the drugs than of their side effects. Nearly all patients indicated their belief that they would receive the best possible care. While 95% wanted to be informed about the trial, 75% stated they would have given their consent even without this information.

Treatment of severe hypertension with intravenous labetalol.

The effectiveness of repeated intravenous injections of labetalol in reducing blood pressure (BP) was evaluated in patients with severe hypertension. The subjects were 10 patients who were 29 to 61 yr old and who had diastolic blood pressure (DBP) of 125 mm Hg or higher. Repeated injections titrated from 20 to 80 mg were given at 15-min intervals until there was a reduction in DBP of 30 mm Hg or until 300 mg had been administered. The average reduction of BP ranged from 201 +/- 5/132 +/- 1 to 157 +/- 6/108 +/- 4 mm Hg (mean +/- SEM). Four patients responded with a reduction in DBP of 30 mm Hg or more with total doses of 60 to 220 mg. Of the remaining six who received the full dose, in four there was a 20 to 29 mm Hg reduction in DBP, in one there was a 10 mm Hg fall, and in one there was no reduction. There was a positive correlation between age and response to intravenous labetalol. No severe side effects were encountered. Intravenous labetalol is useful and well tolerated in patients with severe hypertension.

Veterans Administration Cooperative Study Group on Hypertensive Agents: effects of age on treatment results.

In three double-blind studies of 1,396 hypertensive patients, the age-related effects of hydrochlorothiazide or bendroflumethazide were compared with those of propranolol, nadolol, or captopril, given singly or in combination with a thiazide. Patients in each treatment group were divided into those aged 55 to 69 years and those aged under 55. Whereas no age-related differences were apparent with propranolol, nadolol alone, or captopril alone, in all three studies the blood pressure-reducing effect was found to be greater in the older group of thiazide-treated patients than in the younger thiazide-treated group. The antihypertensive drugs studied are at least as effective in older as in younger hypertensive patients and the antihypertensive response with diuretics is greater in older patients than in younger patients.