Search

Fixed-dose combination tablets, such as diuretic plus beta-adrenergic blocking drug or ACE inhibitor are more effective than is any monotherapy. Other advantages include simple titration, low toxicity and reduced expense which encourage better compliance required for optimal blood pressure control.

This review covers a representative sampling of investigations in hemodynamics and hypertension performed by the author during the period from approximately 1945 to 1980. The hemodynamic studies included a description of changes associated with congestive heart failure and with acute myocardial infarction. These studies emphasized for the first time the importance of left ventricular afterload and of the mobilizable venous reservoir. Other hemodynamic studies included diverse subjects such as the first and only recordings of pulse waves in arteries as small as 200 gammam in diameter, velocity differences between red blood cells and plasma, turbulent blood flow in the ascending aorta, increase in velocity of blood flow of leg veins under compression, rates of transcapillary flow of solutes in humans, and the first use of external arterial pulse wave recordings to assess vascular compliance. Pioneer studies in hypertension included the first use of an antihypertensive drug to treat malignant hypertension and the first report of the treatment of hypertension with a thiazide diuretic.

The article describes the current status of four main antihypertensives. Diuretics are making a bit of a comeback after seeing their popularity wane during the 1980s. beta-blockers also saw a bit of a popularity decrease in the 1980s due to some adverse side effects which the author feels were somewhat exaggerated. alpha-blockers have yet to be particularly successful in the treatment of hypertension, due to adverse side effects. alpha-beta-blockers appear to hold significant promise in the further treatment of hypertension.

An abnormal plasma lipid and lipoprotein profile is an independent and strong predictor of mortality and morbidity from coronary artery disease (CAD). We report on plasma lipid and lipoprotein profiles with respect to race, age, obesity, blood pressure (BP), smoking, and drinking history in 1,292 male veterans with a diastolic BP of 95 to 109 mm Hg while off antihypertensive medications. Blacks had 24% (p <0.001) lower triglycerides than whites. In contrast, the following parameters were higher in blacks than in whites by the indicated percentages: high-density lipoprotein (HDL) cholesterol, 16% (p <0.001); HDL2 cholesterol, 36% (p <0.001); apolipoprotein (Apo) A1, 8% (p <0.001); HDL/low-density lipoprotein (LDL), 18% (p = 0.018); HDL2/LDL, 36% (p = 0.031); HDL2/HDL3, 21% (p <0.001); and Apo A1/Apo B, 15% (p <0.001). Triglycerides were unchanged up to age 60, but were lower by 24% (p <0.001) in those aged > or = 70. Apo A1 levels were higher (p <0.001), whereas LDL cholesterol was lower (p <0.008) in moderate alcohol consumers versus abstainers. Triglycerides were higher (p <0.001), whereas HDL, HDL2 cholesterol, and Apo A1 were lower (p <0.001) with increasing obesity. Moderate alcohol consumption had a strong favorable effect on HDL, HDL2, and HDL3 cholesterol among subjects of normal weight, but this effect was diminished in obese subjects. Total and LDL cholesterol were higher by 6.4% (p = 0.001) and 9.4% (p <0.003), respectively, whereas HDL cholesterol remained unchanged in those with diastolic BP of 105 to 109 mm Hg versus those with diastolic BP of 95 to 99 mm Hg. We conclude that hypertensive black men have lipid and lipoprotein profiles indicative of less CAD risk than white men. Chronic moderate alcohol consumption correlates with a favorable plasma lipid and lipoprotein profile in normal, but not obese, men. Obesity is associated with an adverse plasma lipid and lipoprotein profile. Thus, race, alcohol intake, and obesity may be important modifiers of CAD in untreated hypertensive men.

The 4 major classes of antihypertensive drugs are diuretics, beta-blockers, ACE inhibitors and calcium antagonists. The diuretics have recently regained prominence, largely due to the results of recent controlled trials. These trials in elderly patients demonstrated that low-dose diuretics were effective not only in preventing stroke but also in greatly reducing coronary-related events. Diuretics also decrease left ventricular mass more than the other major drug classes. In addition, they are the most effective drugs for use in combination therapy. By contrast, the safety of calcium antagonists has recently been questioned because of report of increased coronary morbidity and mortality. However, these adverse events may be restricted to the short-acting preparations, especially nifedipine, which causes cardiac stimulation. ACE inhibitors, like beta-blockers, are not only effective in reducing blood pressure, particularly when combined with a diuretic, but also improve angina and decrease postinfarction mortality. They also benefit congestive heart failure, stabilise or improve renal function in hypertensive and diabetic nephropathy and reduce albuminuria. Beta-Blockers are especially effective in reducing sudden cardiac death in patients with coronary heart disease, particularly in postinfarction patients. Final proof of the relative effectiveness of these drugs in preventing morbidity and mortality must await the outcome of large comparative trials currently under way. A recent national survey in the US found that more than 75% of hypertensive patients did not have their hypertension completely controlled. Possible reasons for this disturbing statistic are discussed along with suggestions for improvement.

The efficacy of thiazides and related diuretics in preventing most of the complications of hypertension has been conclusively documented in long-term controlled trials. Among their adverse effects, thiazides may induce a short-term increase in serum cholesterol levels. However, the elevation returns to pretreatment levels during long-term therapy. In addition, long-term treatment with thiazides is not associated with an elevation of blood glucose levels or an increased incidence of diabetes. Because the long-term controlled trials have shown that thiazides provide more protection against stroke than against coronary heart disease events, it is possible that the difference may be caused by adverse effects of the diuretics. In three of four recent trials that used low doses of thiazides plus potassium-sparing diuretics, the number of sudden deaths was reduced more than in other trials that used high doses of diuretics alone. A recent case-control study also found that small doses of diuretics combined with potassium-sparing drugs were associated with a reduced number of sudden deaths compared with high doses used alone. Although these results suggest that small doses reduce the risk for sudden death more than do large doses, they cannot be regarded as conclusive. A randomized double-blind trial comparing low and high doses of thiazide diuretics and potassium-sparing drugs must be done. For now, however, small doses seem prudent for treating hypertension.

Hypertension is much more prevalent in the aged than in younger individuals and the risk of cardiovascular complications increases with age. Treatment of hypertension reduces this risk significantly. The benefits of treatment in improving prognosis are at least as striking in elderly as in young and middle-aged hypertensive patients.

Background: Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents, but this clinically important issue has not been examined in sufficiently large trials, involving all standard treatments, to determine the effect of such factors., Methods: In a randomized, double-blind study at 15 clinics, we assigned 1292 men with diastolic blood pressures of 95 to 109 mm Hg, after a placebo washout period, to receive placebo or one of six drugs: hydrochlorothiazide (12.5 to 50 mg per day), atenolol (25 to 100 mg per day), captopril (25 to 100 mg per day), clonidine (0.2 to 0.6 mg per day), a sustained-release preparation of diltiazem (120 to 360 mg per day), or prazosin (4 to 20 mg per day). The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year., Results: The mean (+/- SD) age of the randomized patients was 59 +/- 10 years, and 48 percent were black. The average blood pressure at base line was 152 +/- 14/99 +/- 3 mm Hg. Diltiazem therapy had the highest rate of success: 59 percent of the treated patients had reached the blood-pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year. Atenolol was successful by this definition in 51 percent of the patients, clonidine in 50 percent, hydrochlorothiazide in 46 percent, captopril in 42 percent, and prazosin in 42 percent; all these agents were superior to placebo (success rate, 25 percent). Diltiazem ranked first for younger blacks (< 60 years) and older blacks (> or = 60 years), among whom the success rate was 64 percent, captopril for younger whites (success rate, 55 percent), and atenolol for older whites (68 percent). Drug intolerance was more frequent with clonidine (14 percent) and prazosin (12 percent) than with the other drugs., Conclusions: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of a drug.

There is considerable evidence that salt is an important cause of hypertension. Primitive societies who ingest little or no salt have no hypertension. Also when diets very low in salt such as the rice and fruit diet are given to hypertensive patients, the blood pressure often falls toward normal. Unfortunately, when diets only moderately low in sodium have been given only minor reductions in blood pressure occur. Salt-induced hypertension has been produced in both man and experimental animals. The basic cause of the hypertension is an inability of the kidney to excrete the increased salt. Hemodynamic changes then occur which raise the blood pressure and so excrete the excess salt by pressure diuresis. The ability to excrete salt at normal levels of blood pressure varies from one individual to another. Those who require a higher than normal blood pressure are said to be "salt-sensitive". Those who can excrete excess salt at normal levels of blood pressure are called "salt resistant". The difference may be due to an inherited defect in the kidney to excrete salt. In any event, salt sensitive hypertension is effectively controlled with the administration of diuretics.

Analysis of the available evidence indicates that diuretics do not increase coronary heart disease morbidity and mortality. The multiclinic trials supporting the cardiotoxicity hypothesis are few in number and flawed in design. The majority of the trials, including the well designed trials, indicate no excess of coronary heart disease (CHD) events in diuretic-treated patients compared with those given other drugs or placebo. Recent studies indicate no increase in cardiac arrhythmias after diuretic treatment. Also, although depletion of intracellular potassium and magnesium occurs in patients with congestive heart failure even without diuretics, intracellular concentration of these ions is not significantly reduced by diuretics in patients with uncomplicated hypertension. Modest elevations of serum cholesterol may occur during the first 6 to 12 months of treatment with thiazide diuretics. However, after this time these elevations fall to or below the pretreatment level. The fall may be greater in patients receiving other drugs but the differences are small and their clinical significance is questionable. The incidences of hyperglycaemia and diabetes were only minimally increased in long term clinical trials while the importance of hyperinsulinism and insulin resistance in causing CHD remains unproven in patients. Thiazides remain, therefore, a safe and effective treatment for patients with hypertension.

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.

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.

Careful consideration of all relevant scientific evidence and a critical assessment of data quality show that thiazide diuretics are not cardiotoxic. Of 12 reported trials only two recorded more coronary heart disease events in thiazide-treated patients than in controls. One of these two was a subgroup of a larger study (Heart Attack Prevention in Primary Hypertension, HAPPHY) which found no difference between thiazide-treated and beta-blocker-treated patients. The other, the Oslo study, was too small to allow valid conclusions. Results from a subgroup in the Multiple Risk Factor Intervention Trial (MRFIT) that appeared to supply evidence for thiazide-related cardiotoxicity are suspect when examined critically. Further evidence from 24- to 28-h ECG monitoring does not support the hypothesis that thiazide diuretics, either in the presence or absence of hypokalemia, increase the frequency or severity of ventricular arrhythmias. Reports of a thiazide-induced intracellular magnesium deficiency as a cause of ventricular arrhythmias have also not been confirmed; the development of arrhythmias in acute myocardial infarction appears to be due to an increase in catecholamine levels rather than hypokalemia. There appears to be little evidence to support the assumption that long-term use of thiazide diuretics aggravates or accelerates atherosclerosis of the coronary arteries; any fall in serum cholesterol appears to be transient. For the great majority of patients with uncomplicated hypertension, without a previous myocardial infarction, congestive heart failure, diabetes mellitus or gout, thiazide diuretics appear to be both safe and effective antihypertensive agents.

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.

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.

A new automated ECG system using advances in microprocessor technology and computerized electrocardiography is described. This microcomputer-based system is self-contained and mobile. It acquires both the 12-lead and orthogonal lead (Frank) electrocardiograms and analyzes the latter within minutes. Software includes the program developed in the Veterans Administration which uses advanced statistical classification techniques and a large well-documented patient data base. Diagnostic probabilities are computed using a Bayesian approach. Diagnostic performance has been tested using independent clinical criteria and found to be quite accurate. This system enables the clinician to immediately review the computer's identifications, measurements, and diagnostic classifications and quickly use these results in clinical decision making. Serial comparisons are readily made since all previous recordings are stored on floppy diskettes. The use of microprocessors in this system makes it economically feasible for practicing physicians.

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

The authors previously observed increased Na+-K+ pump inhibitory activity in the plasma of low renin essential hypertensive unselected with respect to renin status. The present experiments were done to determine the effect of acute volume expansion on plasma Na+-K+ pump inhibitory activity in normotensive subjects. The data show that acute volume expansion increases vascular Na+-K+ pump inhibitory activity in plasma, suggesting that the increased level of this inhibitory activity in low essential hypertensives is probably volume dependent. The unique feature of this study is the use of vascular tissue for the bioassay.

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?

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

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

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.

Hemodynamic studies were carried out before and during 8 weeks of treatment with hydrochlorothiazide 50 mg. twice daily in 11 hypertensive patients. Forty-eight hours after beginning treatment there was a significant reduction in blood pressure, cardiac output, plasma volume, and extracellular fluid volume (thiocyanate space) while total peripheral resistance increased. After 6 and 8 weeks of treatment, the blood pressure and the plasma and extracellular volumes remained reduced. However, total peripheral resistance fell while cardiac output rose to control levels. These results were consistent with the "reverse autoregulation" theory of the action of the thiazides as proposed by Tobian. The present evidence discussed below makes it appear unlikely that the thiazides have an important direct vasodilator effect.

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.