Controlling high blood pressure: a simple and effective approach.

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.

Studies in hemodynamics and hypertension.

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.

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.

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.

Current status of diuretics, beta-blockers, alpha-blockers, and alpha-beta-blockers in the treatment of hypertension.

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.

Comparison of plasma lipid and lipoprotein profiles in hypertensive black versus white men. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

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.

Current drug treatment and treatment patterns with antihypertensive drugs.

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.

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.

The efficacy and safety of diuretics in treating hypertension.

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.

Prognosis in elderly hypertensive patients.

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.

Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

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.

The role of salt in hypertension.

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.

Adverse effects 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.

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.

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.